Inhibition of Granulopoiesis in Vivo and in Vitro by β-Lactam Antibiotics

β-Lactam antibiotics can induce severe neutropenia by a hitherto unknown mechanism. Fifty cases of β-lactam antibiotic-induced neutropenia (15% in patients treated for ⩾10 days with large doses of any β-lactam antibiotic but 95% of cases recovery occurred between one to seven days after withdrawal of β-lactam antibiotics. Bone marrow aspirates were characterized by a lack of well-differentiated myeloid elements in the presence of numerous immature granulocyte precursors. Nine penicillins and eight cephalosporins inhibited in vitro granulopoiesis in a dose-dependent manner. There was a good correlation between the inhibitory capacity of β-lactam antibiotics in vitro and the doses inducing neutropenia in vivo. These observations may be relevant for therapy in the granulocytopenic patien

A Global Plate Model Including Lithospheric Deformation Along Major Rifts and Orogens Since the Triassic

Global deep‐time plate motion models have traditionally followed a classical rigid plate approach, even though plate deformation is known to be significant. Here we present a global Mesozoic–Cenozoic deforming plate motion model that captures the progressive extension of all continental margins since the initiation of rifting within Pangea at ~240 Ma. The model also includes major failed continental rifts and compressional deformation along collision zones. The outlines and timing of regional deformation episodes are reconstructed from a wealth of published regional tectonic models and associated geological and geophysical data. We reconstruct absolute plate motions in a mantle reference frame with a joint global inversion using hot spot tracks for the last 80 million years and minimizing global trench migration velocities and net lithospheric rotation. In our optimized model, net rotation is consistently below 0.2°/Myr, and trench migration scatter is substantially reduced. Distributed plate deformation reaches a Mesozoic peak of 30 × 106 km2 in the Late Jurassic (~160–155 Ma), driven by a vast network of rift systems. After a mid‐Cretaceous drop in deformation, it reaches a high of 48 x 106 km2 in the Late Eocene (~35 Ma), driven by the progressive growth of plate collisions and the formation of new rift systems. About a third of the continental crustal area has been deformed since 240 Ma, partitioned roughly into 65% extension and 35% compression. This community plate model provides a framework for building detailed regional deforming plate networks and form a constraint for models of basin evolution and the plate‐mantle system

Decoding Earth’s plate tectonic history using sparse geochemical data

Accurately mapping plate boundary types and locations through time is essential for understanding the evolution of the plate-mantle system and the exchange of material between the solid Earth and surface environments. However, the complexity of the Earth system and the cryptic nature of the geological record make it difficult to discriminate tectonic environments through deep time. Here we present a new method for identifying tectonic paleo-environments on Earth through a data mining approach using global geochemical data. We first fingerprint a variety of present-day tectonic environments utilising up to 136 geochemical data attributes in any available combination. A total of 38301 geochemical analyses from basalts aged from 5–0 Ma together with a well-established plate reconstruction model are used to construct a suite of discriminatory models for the first order tectonic environments of subduction and mid-ocean ridge as distinct from intraplate hotspot oceanic environments, identifying 41, 35, and 39 key discriminatory geochemical attributes, respectively. After training and validation, our model is applied to a global geochemical database of 1547 basalt samples of unknown tectonic origin aged between 1000–410 Ma, a relatively ill-constrained period of Earth's evolution following the breakup of the Rodinia supercontinent, producing 56 unique global tectonic environment predictions throughout the Neoproterozoic and Early Paleozoic. Predictions are used to discriminate between three alternative published Rodinia configuration models, identifying the model demonstrating the closest spatio-temporal consistency with the basalt record, and emphasizing the importance of integrating geochemical data into plate reconstructions. Our approach offers an extensible framework for constructing full-plate, deep-time reconstructions capable of assimilating a broad range of geochemical and geological observations, enabling next generation Earth system models

Topographic asymmetry of the South Atlantic from global models of mantle flow and lithospheric stretching

The relief of the South Atlantic is characterized by elevated passive continental margins along southern Africa and eastern Brazil, and by the bathymetric asymmetry of the southern oceanic basin where the western flank is much deeper than the eastern flank. We investigate the origin of these topographic features in the present and over time since the Jurassic with a model of global mantle flow and lithospheric deformation. The model progressively assimilates plate kinematics, plate boundaries and lithospheric age derived from global tectonic reconstructions with deforming plates, and predicts the evolution of mantle temperature, continental crustal thickness, long-wavelength dynamic topography, and isostatic topography. Mantle viscosity and the kinematics of the opening of the South Atlantic are adjustable parameters in thirteen model cases. Model predictions are compared to observables both for the present-day and in the past. Present-day predictions are compared to topography, mantle tomography, and an estimate of residual topography. Predictions for the past are compared to tectonic subsidence from backstripped borehole data along the South American passive margin, and to dynamic uplift as constrained by thermochronology in southern Africa. Comparison between model predictions and observations suggests that the first-order features of the topography of the South Atlantic are due to long-wavelength dynamic topography, rather than to asthenospheric processes. The uplift of southern Africa is best reproduced with a lower mantle that is at least 40 times more viscous than the upper mantle

Dynamical stability and instability of Ricci-flat metrics

In this short article, we improve the dynamical stability and instability results for Ricci-flat metrics under Ricci flow proved by Sesum and Haslhofer, getting rid of the integrability assumption.Comment: 6 page

The structure of reversible computation determines the self-duality of quantum theory

Predictions for measurement outcomes in physical theories are usually computed by combining two distinct notions: a state, describing the physical system, and an observable, describing the measurement which is performed. In quantum theory, however, both notions are in some sense identical: outcome probabilities are given by the overlap between two state vectors - quantum theory is self-dual. In this paper, we show that this notion of self-duality can be understood from a dynamical point of view. We prove that self-duality follows from a computational primitive called bit symmetry: every logical bit can be mapped to any other logical bit by a reversible transformation. Specifically, we consider probabilistic theories more general than quantum theory, and prove that every bit-symmetric theory must necessarily be self-dual. We also show that bit symmetry yields stronger restrictions on the set of allowed bipartite states than the no-signalling principle alone, suggesting reversible time evolution as a possible reason for limitations of non-locality.Comment: 4 pages, 1 figure. v2: published version. Title slightly changed, interpretation of Theorem 2 correcte

Design and functional analysis of heterobifunctional multivalent phage capsid inhibitors blocking the entry of influenza virus

Multiple conjugation of virus-binding ligands to multivalent carriers is a prominent strategy to construct highly affine virus binders for the inhibition of viral entry into host cells. In a previous study, we introduced rationally designed sialic acid conjugates of bacteriophages (Q beta) that match the triangular binding site geometry on hemagglutinin spike proteins of influenza A virions, resulting in effective infection inhibition in vitro and in vivo. In this work, we demonstrate that even partially sialylated Q beta conjugates retain the inhibitory effect despite reduced activity. These observations not only support the importance of trivalent binding events in preserving high affinity, as supported by computational modeling, but also allow us to construct heterobifunctional modalities. Capsids carrying two different sialic acid ligand-linker structures showed higher viral inhibition than their monofunctional counterparts. Furthermore, capsids carrying a fluorescent dye in addition to sialic acid ligands were used to track their interaction with cells. These findings support exploring broader applications as multivalent inhibitors in the future

Microscopy and chemical analyses reveal flavone-based woolly fibres extrude from micron-sized holes in glandular trichomes of Dionysia tapetodes.

BackgroundDionysia tapetodes, a small cushion-forming mountainous evergreen in the Primulaceae, possesses a vast surface-covering of long silky fibres forming the characteristic "woolly" farina. This contrasts with some related Primula which instead form a fine powder. Farina is formed by specialized cellular factories, a type of glandular trichome, but the precise composition of the fibres and how it exits the cell is poorly understood. Here, using a combination of cell biology (electron and light microscopy) and analytical chemical techniques, we present the principal chemical components of the wool and its mechanism of exit from the glandular trichome.ResultsWe show the woolly farina consists of micron-diameter fibres formed from a mixture of flavone and substituted flavone derivatives. This contrasts with the powdery farina, consisting almost entirely of flavone. The woolly farina in D. tapetodes is extruded through specific sites at the surface of the trichome's glandular head cell, characterised by a small complete gap in the plasma membrane, cell wall and cuticle and forming a tight seal between the fibre and hole. The data is consistent with formation and thread elongation occurring from within the cell.ConclusionsOur results suggest the composition of the D. tapetodes farina dictates its formation as wool rather than powder, consistent with a model of thread integrity relying on intermolecular H-bonding. Glandular trichomes produce multiple wool fibres by concentrating and maintaining their extrusion at specific sites at the cell cortex of the head cell. As the wool is extensive across the plant, there may be associated selection pressures attributed to living at high altitudes

Design and Functional Analysis of Heterobifunctional Multivalent Phage Capsid Inhibitors Blocking the Entry of Influenza Virus

Multiple conjugation of virus-binding ligands to multivalent carriers is a prominent strategy to construct highly affine virus binders for the inhibition of viral entry into host cells. In a previous study, we introduced rationally designed sialic acid conjugates of bacteriophages (Qβ) that match the triangular binding site geometry on hemagglutinin spike proteins of influenza A virions, resulting in effective infection inhibition in vitro and in vivo. In this work, we demonstrate that even partially sialylated Qβ conjugates retain the inhibitory effect despite reduced activity. These observations not only support the importance of trivalent binding events in preserving high affinity, as supported by computational modeling, but also allow us to construct heterobifunctional modalities. Capsids carrying two different sialic acid ligand–linker structures showed higher viral inhibition than their monofunctional counterparts. Furthermore, capsids carrying a fluorescent dye in addition to sialic acid ligands were used to track their interaction with cells. These findings support exploring broader applications as multivalent inhibitors in the future

Theory of Dynamic Stripe Induced Superconductivity

Since the recently reported giant isotope effect on T* [1] could be consistently explained within an anharmonic spin-charge-phonon interaction model, we consider here the role played by stripe formation on the superconducting properties within the same model. This is a two-component scenario and we recast its basic elements into a BCS effective Hamiltonian. We find that the stripe formation is vital to high-Tc superconductivity since it provides the glue between the two components to enhance Tc to the unexpectedly large values observed experimentally.Comment: 7 pages, 2 figure