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A bstract Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with ‘isoglycaemic’ i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA 1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss. Graphical Abstract

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.

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.

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.

The South Atlantic rift basin evolved as a branch of a large Jurassic–Cretaceous intraplate rift zone between the African and South American plates during the final break-up of western Gondwana. While the relative motions between South America and Africa for post-break-up times are well resolved, many issues pertaining to the fit reconstruction and particularly the relation between kinematics and lithosphere dynamics during pre-break-up remain unclear in currently published plate models. We have compiled and assimilated data from these intraplated rifts and constructed a revised plate kinematic model for the pre-break-up evolution of the South Atlantic. Based on structural restoration of the conjugate South Atlantic margins and intracontinental rift basins in Africa and South America, we achieve a tight-fit reconstruction which eliminates the need for previously inferred large intracontinental shear zones, in particular in Patagonian South America. By quantitatively accounting for crustal deformation in the Central and West African Rift Zones, we have been able to indirectly construct the kinematic history of the pre-break-up evolution of the conjugate west African–Brazilian margins. Our model suggests a causal link between changes in extension direction and velocity during continental extension and the generation of marginal structures such as the enigmatic pre-salt sag basin and the São Paulo High. We model an initial E–W-directed extension between South America and Africa (fixed in present-day position) at very low extensional velocities from 140 Ma until late Hauterivian times (≈126 Ma) when rift activity along in the equatorial Atlantic domain started to increase significantly. During this initial ≈14 Myr-long stretching episode the pre-salt basin width on the conjugate Brazilian and west African margins is generated. An intermediate stage between ≈126 Ma and base Aptian is characterised by strain localisation, rapid lithospheric weakening in the equatorial Atlantic domain, resulting in both progressively increasing extensional velocities as well as a significant rotation of the extension direction to NE–SW. From base Aptian onwards diachronous lithospheric break-up occurred along the central South Atlantic rift, first in the Sergipe–Alagoas/Rio Muni margin segment in the northernmost South Atlantic. Final break-up between South America and Africa occurred in the conjugate Santos–Benguela margin segment at around 113 Ma and in the equatorial Atlantic domain between the Ghanaian Ridge and the Piauí-Ceará margin at 103 Ma. We conclude that such a multi-velocity, multi-directional rift history exerts primary control on the evolution of these conjugate passive-margin systems and can explain the first-order tectonic structures along the South Atlantic and possibly other passive margins.

BackgroundRecent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants’ privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups.MethodsFFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer’s Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests.ResultsAutomated analysis methods failed in 0–19% of cases in FFR-processed images versus 0–2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001).ConclusionsAll three outcome measures were affected differently by FFR, including failure of analysis methods and both “random” variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants’ privacy.Key Points• Protecting participants’ privacy when sharing MRI data is important.• Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups.• Removing facial features degrades performance of image analysis methods.

We suggest to carry out lattice calculations of current correlators in position space, sandwiched between the vacuum and a hadron state (e.g. pion), in order to access hadronic light-cone distribution amplitudes (DAs). In this way the renormalization problem for composite lattice operators is avoided altogether, and the connection to the DA is done using perturbation theory in the continuum. As an example, the correlation function of two electromagnetic currents is calculated to the next-to-next-to-leading order accuracy in perturbation theory and including the twist-four corrections. We argue that this strategy is fully competitive with direct lattice measurements of the moments of the DA, defined as matrix elements of local operators, and offers new insight in the space-time picture of hard exclusive reactions.

Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) are anchored at the outer leaflet of plasma membranes (PMs) of all eukaryotic organisms studied so far by covalent linkage to a highly conserved glycolipid rather than a transmembrane domain. Since their first description, experimental data have been accumulating for the capability of GPI-APs to be released from PMs into the surrounding milieu. It became evident that this release results in distinct arrangements of GPI-APs which are compatible with the aqueous milieu upon loss of their GPI anchor by (proteolytic or lipolytic) cleavage or in the course of shielding of the full-length GPI anchor by incorporation into extracellular vesicles, lipoprotein-like particles and (lyso)phospholipid- and cholesterol-harboring micelle-like complexes or by association with GPI-binding proteins or/and other full-length GPI-APs. In mammalian organisms, the (patho)physiological roles of the released GPI-APs in the extracellular environment, such as blood and tissue cells, depend on the molecular mechanisms of their release as well as the cell types and tissues involved, and are controlled by their removal from circulation. This is accomplished by endocytic uptake by liver cells and/or degradation by GPI-specific phospholipase D in order to bypass potential unwanted effects of the released GPI-APs or their transfer from the releasing donor to acceptor cells (which will be reviewed in a forthcoming manuscript).

Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand. Extracellular vesicles (EVs) convey inter-organ communication in health and disease. Here, the authors report that adipocyte-derived EVs isolated from insulin-resistant obese but not lean male mice stimulate insulin secretion via the targeted transfer of insulinotropic proteins from adipose tissue to β-cells.

A unique structure in the Earth’s lowermost mantle, the Perm Anomaly, was recently identified beneath Eurasia. It seismologically resembles the large low-shear velocity provinces (LLSVPs) under Africa and the Pacific, but is much smaller. This challenges the current understanding of the evolution of the plate–mantle system in which plumes rise from the edges of the two LLSVPs, spatially fixed in time. New models of mantle flow over the last 230 million years reproduce the present-day structure of the lower mantle, and show a Perm-like anomaly. The anomaly formed in isolation within a closed subduction network ∼22,000 km in circumference prior to 150 million years ago before migrating ∼1,500 km westward at an average rate of 1 cm year −1 , indicating a greater mobility of deep mantle structures than previously recognized. We hypothesize that the mobile Perm Anomaly could be linked to the Emeishan volcanics, in contrast to the previously proposed Siberian Traps. The Perm anomaly is found in the lower mantle beneath Eurasia, but how this structure formed has remained unclear. Here, the authors show that the anomaly has been mobile since it formed in isolation within a closed subduction network and propose that the anomaly is linked to the Emeishan volcanics.