bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracing the Progression of Sepsis in Critically Ill Children: Clinical Decision Support for Detection of Hematologic Dysfunction
Authors: Bode Louisa , Schamer Sven , Böhnke Julia , Bott Oliver Johannes , Marschollek Michael , Jack Thomas , Wulff Antje ,   ELISE Study Group
Published: September 2022

Background One of the major challenges in pediatric intensive care is the detection of life-threatening health conditions under acute time constraints and performance pressure. This includes the assessment of pediatric organ dysfunction (OD) that demands extraordinary clinical expertise and the clinician's ability to derive a decision based on multiple information and data sources. Clinical decision support systems (CDSS) offer a solution to support medical staff in stressful routine work. Simultaneously, detection of OD by using computerized decision support approaches has been scarcely investigated, especially not in pediatrics.

Objectives The aim of the study is to enhance an existing, interoperable, and rule-based CDSS prototype for tracing the progression of sepsis in critically ill children by augmenting it with the capability to detect SIRS/sepsis-associated hematologic OD, and to determine its diagnostic accuracy.

Methods We reproduced an interoperable CDSS approach previously introduced by our working group: (1) a knowledge model was designed by following the commonKADS methodology, (2) routine care data was semantically standardized and harmonized using openEHR as clinical information standard, (3) rules were formulated and implemented in a business rule management system. Data from a prospective diagnostic study, including 168 patients, was used to estimate the diagnostic accuracy of the rule-based CDSS using the clinicians' diagnoses as reference.

Results We successfully enhanced an existing interoperable CDSS concept with the new task of detecting SIRS/sepsis-associated hematologic OD. We modeled openEHR templates, integrated and standardized routine data, developed a rule-based, interoperable model, and demonstrated its accuracy. The CDSS detected hematologic OD with a sensitivity of 0.821 (95% CI: 0.708–0.904) and a specificity of 0.970 (95% CI: 0.942–0.987).

Conclusion We could confirm our approach for designing an interoperable CDSS as reproducible and transferable to other critical diseases. Our findings are of direct practical relevance, as they present one of the first interoperable CDSS modules that detect pediatric SIRS/sepsis-associated hematologic OD.
The Use of Ultrasound Imaging for Upper Extremity Lymphedema after Breast Cancer: A Systematic Review
Authors: Canales-Lachén Elena , Asunsolo Ángel , Manrique Oscar J. , Blázquez Javier , Holguín Purificación , Maldonado Andrés A.
Published: September 2022

Background The aim of this study was to analyze the different applications of ultrasound (US) in upper extremity lymphedema (UEL) after breast cancer.

Methods A systematic review of the literature was performed in line with the PRISMA statement using MEDLINE/PubMed databases from January 1970 to December 2021. Articles describing the application of US in patients with UEL after breast cancer were included. The quality of the study, the level of reproducibility, and the different applications and type of US technique were analyzed.

Results In total, 30 articles with 1,193 patients were included in the final review. Five different applications were found: (1) diagnosis of UEL (14 studies found a direct correlation between lymphedema and morphological and/or functional parameters); (2) staging/severity of UEL (9 studies found a direct correlation between the clinical stage and the soft-tissue stiffness/texture/thickness); (3) therapeutic assessment (3 studies found an improvement in the circulatory status or in the muscle/subcutaneous thickness after conservative treatments); (4) prognosis assessment of UEL (1 study found a correlation between the venous flow and the risk of UEL); and (5) surgical planning (3 studies determined the location of the lymphatic vessel for lymphovenous anastomosis [LVA] surgery).

Conclusion Morphological and functional parameters have been correlated with the diagnosis, stage, therapeutic effect, prognosis of UEL, and surgical planning of LVA.
Acute Mediastinal Bleeding with Pleural Escape: Case Report of a Rare Interventional Complication with Unusual Resolve
Authors: Widodo Wishnu Aditya , Mansjoer Arif , Dilawar Ismail , Kurnia Andri , Ruslim Daniel
Published: September 2022

Acute mediastinal bleeding is a very rare complication of cardiac intervention. It is a life-threatening situation when this condition causes acute compression of the mediastinal area. A 59-year-old man was diagnosed with inferior ST-elevation myocardial infarction with ongoing chest pain and underwent an urgent percutaneous coronary intervention procedure. After coronary stent was implanted, patient complained of chest tightness, and suffocation, blood pressure dropped, O2 saturation dropped, and was difficultly intubated. Image acquisition by C-arm showed a large bulging in aortic arch area. Contrast-enhanced computed tomography ruled out aortic dissection, but noted a large mediastinal mass that was radiated to the neck. The bulging was spontaneously regressed, and a large left pleural effusion was developed. Left pleural tapping was performed on day 7, and a total of 1.5-L hemorrhagic fluid was evacuated. In our case, unusual drainage from mediastinal to pleural space has probably save the patient.
Abrupt transition of the efficient vaccination strategy in a population with heterogeneous fatality rates
Authors: Jhun Bukyoung , Choi Hoyun
Published: September 2022

An insufficient supply of an effective SARS-CoV-2 vaccine in most countries demands an effective vaccination strategy to minimize the damage caused by the disease. Currently, many countries vaccinate their population in descending order of age (i.e., descending order of fatality rate) to minimize the deaths caused by the disease; however, the effectiveness of this strategy needs to be quantitatively assessed. We employ the susceptible–infected–recovered–dead model to investigate various vaccination strategies. We constructed a metapopulation model with heterogeneous contact and fatality rates and investigated the effectiveness of vaccination strategies to reduce epidemic mortality. We found that the fatality-based strategy, which is currently employed in many countries, is more effective when the contagion rate is high and vaccine supply is low, but the contact-based method outperforms the fatality-based strategy when there is a sufficiently high supply of the vaccine. We identified a discontinuous transition of the optimal vaccination strategy and path-dependency analogous to hysteresis. This transition and path-dependency imply that combining the fatality-based and contact-based strategies is ineffective in reducing the number of deaths. Furthermore, we demonstrate that such phenomena occur in real-world epidemic diseases, such as tuberculosis and COVID-19. We also show that the conclusions of this research are valid even when the complex epidemic stages, efficacy of the vaccine, and reinfection are considered.
Dynamics study of integrable turbulence with fourth-order nonlinear Schrödinger equation
Authors: Tang Yaning , Wang Yan , Wu Dingwei , Zhang Qing , Zhang Yetong
Published: September 2022

In this paper, we focus on the fourth-order nonlinear Schrödinger equation, which can describe the optical system and the Heisenberg spin system. We consider a continuous wave perturbed by the one-dimensional random rough surface as the initial condition. First, we numerically resolve the eigenvalues under different control parameters utilizing the Fourier collocation method. Then, we simulate the evolution of this equation under the above initial conditions via the symmetrical split-step Fourier method. Moreover, we investigate the “steady” chaotic state by evolving a large number of initial conditions for the same control parameters. We find that the control parameters of the initial condition affect the number and intensity of rogue waves (RWs) in integrable turbulence. In particular, we locate the inflection point where the control parameter affects the velocities of solitons and the inconsistency within the parameter of the contribution to the generation of RWs. We further verify that the collision between breathers, solitons, and breathers and solitons can generate RWs. These results will enable us to understand the turbulent state and the formation mechanism of RWs.
Effect of particle arrangement and density on aerodynamic interference between twin particles interacting with a plane shock wave
Authors: Takahashi Shun , Nagata Takayuki , Mizuno Yusuke , Nonomura Taku , Obayashi Shigeru
Published: September 2022

Unsteady drag, unsteady lift, and movement of one or two moving particles caused by the passage of a planar shock wave are investigated using particle-resolved simulations of viscous flows. The particle motion analysis is carried out based on particle-resolved simulations for one or two particles under a shock Mach number of 1.22 and a particle Reynolds number of 49, and the particle migration and fluid forces are investigated. The unsteady drag, unsteady lift, and particle behavior are investigated for different densities and particle configurations. The time evolution of the unsteady drag and lift is changed by interference by the planar shock wave, Mach stem convergence, and the shock wave reflected from the other particle. These two particles become closer after the shock wave passes than in the initial state under most conditions. Two particles placed in an in-line arrangement approach each other very closely due to the passage of a shock wave. On the other hand, two particles placed in a side-by-side arrangement are only slightly closer to each other after the shock wave passes between them. The pressure waves resulting from Mach stem convergence of the upstream particle and the reflected shock waves from the downstream particle are the main factors responsible for the force in the direction that pushes the particles apart. The wide distance between the two particles attenuates these pressure waves, and the particles reduce their motion away from each other.
Measurement of electromagnetic waves from runaway electrons
Authors: Bin W. , Buratti P. , Cardinali A. , Castaldo C. , Napoli F. , Tudisco O. ,   FTU Team
Published: September 2022

Electromagnetic waves emitted during a tokamak discharge can be partially ascribed to coupling with plasma waves. In particular, in the presence of runaway electrons, the electromagnetic waves deliver information, otherwise inaccessible, about kinetic instabilities excited by the fast particles. Experiments aimed at studying radio frequency emissions from runaway electron scenarios during different stages of plasma discharge have been carried out at the Frascati Tokamak Upgrade. Frequencies in the range of lower hybrid and whistler waves have been explored, in the presence of relativistic electrons with different energies, ranging from a few to tens of MeV. A pronounced sensitivity of the radio frequency measurements in detecting driven instabilities is observed, providing the possibility to exploit this kind of technique as a monitor of the instability processes and for studies of the fast electron activity. In particular, in this work, we propose a simplified analysis of the frequency scaling of a specific family of kinetic instabilities arising at the lower hybrid frequency range during the current ramp-up stage. The study is performed with respect to the density profile and the wave vector coupling conditions and is aimed at obtaining a rough estimate of the most likely radial location of the interaction between the runaway electron beam and plasma waves at the emission times of the observed signals.
Upgrade of the helically symmetric experiment Thomson scattering diagnostic suite
Authors: Goodman W. R. , Scott E. R. , Keith Z. , Singh L. , Anderson D. T.
Published: September 2022

The Helically Symmetric eXperiment (HSX) Thomson Scattering (TS) diagnostic is being upgraded to decrease uncertainty in electron temperature and density measurements. Upgrades to the HSX TS diagnostic will consist of a novel redesign of polychromator electronics and digitization of the TS output signal. Here, we also present a study of the benefits of an additional spectral channel that will sample the red-shifted band of the scattered spectrum. To maximize system bandwidth (BW) and gain, while minimizing noise, the existing low-BW polychromator electronics on HSX will be replaced by high-BW, high gain circuitry designed in-house.
Laguerre–Gaussian laser beam guiding and its second harmonics in plasma having density ramp
Authors: Bhatia Aman , Walia Keshav , Singh Arvinder
Published: September 2022

This paper presents the optical guiding of a laser beam in plasma by using a preformed plasma channel. The density ramp in plasma density due to the plasma pressure has also been considered. The effect of ponderomotive force has been taken into account which originates due to the intensity gradient present in the laser beam. This force produces a plasma gradient by expelling plasma electrons from a high-field to a low-field region, providing heavy ions remain immobile. Plasma oscillations result from a gradient in plasma density that excites an electron plasma wave. The equation governing the plasma wave excitation has been found by using linear perturbation theory. An in-phase mixing of an incident laser beam with this plasma wave generates its second harmonics. Laguerre–Gaussian laser profile has been used for harmonic production. Moment theory has been used to obtain a differential equation for beam waist, which has been solved numerically by Runge–Kutta's fourth-order method. The effect of different modes of Laguerre–Gaussian profile, beam intensity, plasma density, channel depth, and slope of density ramp has been explored.
Moiré engineering in van der Waals heterostructures
Authors: Rakib Tawfiqur , Pochet Pascal , Ertekin Elif , Johnson Harley T.
Published: September 2022

Isolated atomic planes can be assembled into a multilayer van der Waals (vdW) heterostructure in a precisely chosen sequence. These heterostructures feature moiré patterns if the constituent 2D material layers are stacked in an incommensurable way, due to a lattice mismatch or twist. This design-by-stacking has opened up the promising area of moiré engineering, a term that can be understood in two different perspectives, namely, (i) structural—engineering a moiré pattern by introducing twist, relative strain, or defects that affect the commensurability of the layers and (ii) functional—exploiting a moiré pattern to find and tune resulting physical properties of a vdW heterostructure. The latter meaning, referring to the application of a moiré pattern, is seen in the literature in the specific context of the observation of correlated electronic states and unconventional superconductivity in twisted bilayer graphene. The former meaning, referring to the design of the moiré pattern itself, is present in the literature but less commonly discussed or less understood. The underlying link between these two perspectives lies in the deformation field of the moiré superlattice. In this Perspective, we describe a path from designing a moiré pattern to employing the moiré pattern to tune physical properties of a vdW heterostructure. We also discuss the concept of moiré engineering in the context of twistronics, strain engineering, and defect engineering in vdW heterostructures. Although twistronics is always associated with moiré superlattices, strain and defect engineering are often not. Here, we demonstrate how strain and defect engineering can be understood within the context of moiré engineering. Adopting this perspective, we note that moiré engineering creates a compelling opportunity to design and develop multiscale electronic devices.
All-fiber switchable orbital angular momentum mode-locked laser based on TM-FBG
Authors: Jiang X. H. , Yao J. N. , Zhang S. Y. , Wang A. T. , Zhan Q. W.
Published: September 2022

In this paper, a simple all-fiber switchable orbital angular momentum (OAM) mode-locked laser is demonstrated. The laser is mainly composed of a single-mode fiber Bragg grating (FBG), a two-mode fiber Bragg grating (TM-FBG), a two-mode circulator, and a nonlinear polarization rotation system. The coupling properties of the TM-FBG are verified, and an OAM mode-locked laser with switchable topological charges of −1, 0, and 1 is realized. When the pump power is 462 mW, the output powers of the fundamental mode and OAM±1 mode-locked lasers are 9.750 and 2.707 mW, respectively. Their repetition rates are both 10.16 MHz, and the signal-to-noise ratios are 60 and 59 dB. When the pump power is increased to 774 mW, the mode-locked laser can operate in the single-pulse, double-pulse, and triple-pulse states. Their output powers are 5.1, 7.4, and 10.1 mW, respectively. The OAM mode purity higher than 98.9% is experimentally realized.
Cluster synchronization induced by manifold deformation
Authors: Wang Ya , Zhang Dapeng , Wang Liang , Li Qing , Cao Hui , Wang Xingang
Published: September 2022

Pinning control of cluster synchronization in a globally connected network of chaotic oscillators is studied. It is found in simulations that when the pinning strength exceeds a critical value, the oscillators are synchronized into two different clusters, one formed by the pinned oscillators and the other one formed by the unpinned oscillators. The numerical results are analyzed by the generalized method of master stability function (MSF), in which it is shown that whereas the method is able to predict the synchronization behaviors of the pinned oscillators, it fails to predict the synchronization behaviors of the unpinned oscillators. By checking the trajectories of the oscillators in the phase space, it is found that the failure is attributed to the deformed synchronization manifold of the unpinned oscillators, which is clearly deviated from that of isolated oscillator under strong pinnings. A similar phenomenon is also observed in the pinning control of cluster synchronization in a complex network of symmetric structures and in the self-organized cluster synchronization of networked neural oscillators. The findings are important complements to the generalized MSF method and provide an alternative approach to the manipulation of synchronization behaviors in complex network systems.
Gradient nano-grained graphene as 2D thermal rectifier: A molecular dynamics based machine learning study
Authors: Xu Ke , Liang Ting , Fu Yuequn , Wang Zhen , Fan Zheyong , Wei Ning , Xu Jianbin , Zhang Zhisen , Wu Jianyang
Published: September 2022

Machine learning has become an excellent tool for scientists and engineers to predict, design, and fabricate next-generation material. Here, we report the thermal conductivity and thermal rectification of gradient-nano-grained graphene (GNGG) by molecular dynamic simulation with machine learning. It is revealed that the thermal conductivity of GNGG is mainly determined by the average grain size, while its thermal rectification factor varies linearly with the gradient of nanograins. Deep neural network-based machine learning models are developed to estimate the thermal transport properties of GNGG using microstructural signatures, such as the location, number, and orientation of 5|7 pairs. The results stress the pivotal roles of 5|7 defects in the planar thermal transports of graphene and indicate that high-performance 2D thermal rectifiers for heat flow control and energy harvesting can be achieved by bio-inspired gradient structure engineering. The findings are expected to supply a theoretical strategy for the design of bio-inspired materials and create a method to predict the potential properties of the material candidates by using machine learning, which can save the abundant expense of developing the material by using the classical method.
Crystal nucleation of highly screened charged colloids
Authors: de Jager Marjolein , Filion Laura
Published: September 2022

We study the nucleation of nearly hard charged colloidal particles. We use Monte Carlo simulations in combination with free-energy calculations to accurately predict the phase diagrams of these particles and map them via the freezing density to hard spheres, then we use umbrella sampling to explore the nucleation process. Surprisingly, we find that even very small amounts of charge repulsion can have a significant effect on the phase behavior. Specifically, we find that phase boundaries and nucleation barriers are mostly dependent on the Debye screening length and that even screening lengths as small as 2% of the particle diameter are sufficient to show marked differences in both. This work demonstrates clearly that even mildly charged colloids are not effectively hard spheres.
Coronavirus peplomer interaction
Authors: Pak Myong Chol , Chakraborty R. , Kanso M. A. , Tontiwattanakul K. , Kim Kwang-Il , Giacomin A. J.
Published: September 2022

By virtue of their lack of motility, viruses rely entirely on their own temperature (Brownian motion) to position themselves properly for cell attachment. Spiked viruses use one or more spikes (called peplomers) to attach. The coronavirus uses adjacent peplomer pairs. These peplomers, identically charged, repel one another over the surface of their convex capsids to form beautiful polyhedra. We identify the edges of these polyhedra with the most important peplomer hydrodynamic interactions. These convex capsids may or may not be spherical, and their peplomer population declines with infection time. These peplomers are short, equidimensional, and bulbous with triangular bulbs. In this short paper, we explore the interactions between nearby peplomer bulbs. By interactions, we mean the hydrodynamic interferences between the velocity profiles caused by the drag of the suspending fluid when the virus rotates. We find that these peplomer hydrodynamic interactions raise rotational diffusivity of the virus, and thus affect its ability to infect.
Reduction pathway of glutaredoxin 1 investigated with QM/MM molecular dynamics using a neural network correction
Authors: Böser Julian , Kubař Tomáš , Elstner Marcus , Maag Denis
Published: September 2022

Glutaredoxins are small enzymes that catalyze the oxidation and reduction of protein disulfide bonds by the thiol–disulfide exchange mechanism. They have either one or two cysteines in their active site, resulting in different catalytic reaction cycles that have been investigated in many experimental studies. However, the exact mechanisms are not yet fully known, and to our knowledge, no theoretical studies have been performed to elucidate the underlying mechanism. In this study, we investigated a proposed mechanism for the reduction of the disulfide bond in the protein HMA4n by a mutated monothiol Homo sapiens glutaredoxin and the co-substrate glutathione. The catalytic cycle involves three successive thiol–disulfide exchanges that occur between the molecules. To estimate the regioselectivity of the different attacks, classical molecular dynamics simulations were performed and the trajectories analyzed regarding the sulfur–sulfur distances and the attack angles between the sulfurs. The free energy profile of each reaction was obtained with hybrid quantum mechanical/molecular mechanical metadynamics simulations. Since this required extensive phase space sampling, the semi-empirical density functional tight-binding method was used to describe the reactive cysteines. For an accurate description, we used specific reaction parameters fitted to B3LYP energies of the thiol–disulfide exchange and a machine learned energy correction that was trained on coupled-cluster single double perturbative triple [CCSD(T)] energies of thiol–disulfide exchanges. Our calculations show the same regiospecificity as observed in the experiment, and the obtained barrier heights are about 12 and 20 kcal/mol for the different reaction steps, which confirms the proposed pathway.
Milankovitch cycles in banded iron formations constrain the Earth–Moon system 2.46 billion years ago
Authors: Lantink Margriet L. , Davies Joshua H. F. L. , Ovtcharova Maria , Hilgen Frederik J.
Published: September 2022

The long-term history of the Earth–Moon system as reconstructed from the geological record remains unclear when based on fossil growth bands and tidal laminations. A possibly more robust method is provided by the sedimentary record of Milankovitch cycles (climatic precession, obliquity, and orbital eccentricity), whose relative ratios in periodicity change over time as a function of a decreasing Earth spin rate and increasing lunar distance. However, for the critical older portion of Earth’s history where information on Earth–Moon dynamics is sparse, suitable sedimentary successions in which these cycles are recorded remain largely unknown, leaving this method unexplored. Here we present results of cyclostratigraphic analysis and high-precision U–Pb zircon dating of the lower Paleoproterozoic Joffre Member of the Brockman Iron Formation, NW Australia, providing evidence for Milankovitch forcing of regular lithological alternations related to Earth’s climatic precession and orbital eccentricity cycles. Combining visual and statistical tools to determine their hierarchical relation, we estimate an astronomical precession frequency of 108.6 ± 8.5 arcsec/y, corresponding to an Earth–Moon distance of 321,800 ± 6,500 km and a daylength of 16.9 ± 0.2 h at 2.46 Ga. With this robust cyclostratigraphic approach, we extend the oldest reliable datum for the lunar recession history by more than 1 billion years and provide a critical reference point for future modeling and geological investigation of Precambrian Earth–Moon system evolution.
Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks
Authors: Marciano Sabina , Ionescu Tudor M. , Saw Ran Sing , Cheong Rachel Y. , Kirik Deniz , Maurer Andreas , Pichler Bernd J. , Herfert Kristina
Published: September 2022

Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of theSlc18a2gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent target for studying the gene network relationships while structurally preserving neuronal integrity and function. We edited theSlc18a2in the substantia nigra pars compacta of adult rats and used in vivo molecular imaging besides behavioral, histological, and biochemical assessments to characterize the CRISPR-Cas9–mediated VMAT2 knockdown. Simultaneous PET/fMRI was performed to investigate molecular and functional brain alterations. We found that stage-specific adaptations of brain functional connectivity follow the selective impairment of presynaptic dopamine storage and release. Our study reveals that recruiting different brain networks is an early response to the dopaminergic dysfunction preceding neuronal cell loss. Our combinatorial approach is a tool to investigate the impact of specific genes on brain molecular and functional dynamics, which will help to develop tailored therapies for normalizing brain function.
Dual roles of β-arrestin 1 in mediating cell metabolism and proliferation in gastric cancer
Authors: Yu Huan , Wang Man , Zhang Ting , Cao Lihua , Li Zhongwu , Du Yang , Hai Yanru , Gao Xiangyu , Ji Jiafu , Wu Jianmin
Published: September 2022

β-Arrestin 1 (ARRB1) has been recognized as a multifunctional adaptor protein in the last decade, beyond its original role in desensitizing G protein-coupled receptor signaling. Here, we identify that ARRB1 plays essential roles in mediating gastric cancer (GC) cell metabolism and proliferation, by combining cohort analysis and functional investigation using patient-derived preclinical models. Overexpression of ARRB1 was associated with poor outcome of GC patients and knockdown of ARRB1 impaired cell proliferation both ex vivo and in vivo. Intriguingly, ARRB1 depicted diverse subcellular localizations during a passage of organoid cultures (7 d) to exert dual functions. Further analysis revealed that nuclear ARRB1 binds with transcription factor E2F1 triggering up-regulation of proliferative genes, while cytoplasmic ARRB1 modulates metabolic flux by binding with the pyruvate kinase M2 isoform (PKM2) and hindering PKM2 tetramerization, which reduces pyruvate kinase activity and leads to cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis. As ARRB1 localization was shown mostly in the cytoplasm in human GC samples, therapeutic potential of the ARRB1–PKM2 axis was tested, and we found tumor proliferation could be attenuated by the PKM2 activator DASA-58, especially in ARRB1highorganoids. Together, the data in our study highlight a spatiotemporally dependent role of ARRB1 in mediating GC cell metabolism and proliferation and implies reactivating PKM2 may be a promising therapeutic strategy in a subset of GC patients.
CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy
Authors: Miller Simon , Kesherwani Manish , Chan Priscilla , Nagai Yoshiko , Yagi Moeri , Cope Jamie , Tama Florence , Kay Steve A. , Hirota Tsuyoshi
Published: September 2022

The mammalian cryptochrome isoforms, CRY1 and CRY2, are core circadian clock regulators that work redundantly. Recent studies revealed distinct roles of these closely related homologs in clock output pathways. Isoform-selective control of CRY1 and CRY2 is critical for further understanding their redundant and distinct roles. KL001 was the first identified small-molecule CRY modulator that activates both CRY1 and CRY2. SHP656 is an orally available KL001 derivative and has shown efficacy in blood glucose control and inhibition of glioblastoma stem cell (GSC) growth in animal models. However, CRY isoform selectivity of SHP656 was uncharacterized, limiting understanding of the roles of CRY1 and CRY2. Here, we report the elucidation of CRY2 selectivity of SHP656. SHP656 lengthened cellular circadian period in a CRY2-dependent manner and selectively interacted with CRY2. By determining the X-ray crystal structure of CRY2 in complex with SHP656 and performing molecular dynamics simulations, we elucidated compound interaction mechanisms. SHP656 binding was compatible with the intrinsic CRY2 gatekeeper W417 “in” orientation and also a close “further in” conformation. Perturbation of W417 interaction with the lid loop resulted in a reduced effect of SHP656 on CRY2, supporting an important role of gatekeeper orientation in isoform selectivity. We also identified the R form of SHP656 (called SHP1703) as the active isomer. Treatment with SHP1703 effectively reduced GSC viability. Our results suggest a direct role of CRY2 in glioblastoma antitumorigenesis and provide a rationale for the selective modulation of CRY isoforms in the therapeutic treatment of glioblastoma and other circadian clock-related diseases.
Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5
Authors: Behrangi Newshan , Heinig Leo , Frintrop Linda , Santrau Emily , Kurth Jens , Krause Bernd , Atanasova Dimitrinka , Clarner Tim , Fragoulis Athanassios , Joksch Markus , Rudolf Henrik , Meuth Sven G. , Joost Sarah , Kipp Markus
Published: September 2022

Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing–remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies inRag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects inS1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon–myelin unit.
Ca2+-dependent phosphorylation of NRAMP1 by CPK21 and CPK23 facilitates manganese uptake and homeostasis inArabidopsis
Authors: Fu Dali , Zhang Zhenqian , Wallrad Lukas , Wang Zhangqing , Höller Stefanie , Ju ChuanFeng , Schmitz-Thom Ina , Huang Panpan , Wang Lei , Peiter Edgar , Kudla Jörg , Wang Cun
Published: September 2022

Homeostasis of the essential micronutrient manganese (Mn) is crucially determined through availability and uptake efficiency in all organisms. Mn deficiency of plants especially occurs in alkaline and calcareous soils, seriously restricting crop yield. However, the mechanisms underlying the sensing and signaling of Mn availability and conferring regulation of Mn uptake await elucidation. Here, we uncover that Mn depletion triggers spatiotemporally defined long-lasting Ca2+oscillations inArabidopsisroots. These Ca2+signals initiate in individual cells, expand, and intensify intercellularly to transform into higher-order multicellular oscillations. Furthermore, through an interaction screen we identified the Ca2+-dependent protein kinases CPK21 and CPK23 as Ca2+signal-decoding components that bring about translation of these signals into regulation of uptake activity of the high-affinity Mn transporter natural resistance associated macrophage proteins 1 (NRAMP1). Accordingly, acpk21/23double mutant displays impaired growth and root development under Mn-limiting conditions, while kinase overexpression confers enhanced tolerance to low Mn supply to plants. In addition, we define Thr498 phosphorylation within NRAMP1 as a pivot mechanistically determining NRAMP1 activity, as revealed by biochemical assays and complementation of yeast Mn uptake andArabidopsis nramp1mutants. Collectively, these findings delineate the Ca2+-CPK21/23-NRAMP1 axis as key for mounting plant Mn homeostasis.
High-harmonic spectroscopy of quantum phase transitions in a high-Tc superconductor
Authors: Alcalà Jordi , Bhattacharya Utso , Biegert Jens , Ciappina Marcelo , Elu Ugaitz , Graß Tobias , Grochowski Piotr T. , Lewenstein Maciej , Palau Anna , Sidiropoulos Themistoklis P. H. , Steinle Tobias , Tyulnev Igor
Published: September 2022

We report on the nonlinear optical signatures of quantum phase transitions in the high-temperature superconductor YBCO, observed through high harmonic generation. While the linear optical response of the material is largely unchanged when cooling across the phase transitions, the nonlinear optical response sensitively imprints two critical points, one at the critical temperature of the cuprate with the exponential growth of the surface harmonic yield in the superconducting phase and another critical point, which marks the transition from strange metal to pseudogap phase. To reveal the underlying microscopic quantum dynamics, a strong-field quasi-Hubbard model was developed, which describes the measured optical response dependent on the formation of Cooper pairs. Further, the theory provides insight into the carrier scattering dynamics and allows us to differentiate between the superconducting, pseudogap, and strange metal phases. The direct connection between nonlinear optical response and microscopic dynamics provides a powerful methodology to study quantum phase transitions in correlated materials. Further implications are light wave control over intricate quantum phases, light–matter hybrids, and application for optical quantum computing.
Chronic stress induces colonic tertiary lymphoid organ formation and protection against secondary injury through IL-23/IL-22 signaling
Authors: Gomez-Nguyen Adrian , Gupta Nikhilesh , Sanaka Harsha , Gruszka Dennis , Pizarro Alaina , DiMartino Luca , Basson Abigail , Menghini Paola , Osme Abdullah , DeSalvo Carlo , Pizarro Theresa , Cominelli Fabio
Published: September 2022

Psychological stress has been previously reported to worsen symptoms of inflammatory bowel disease (IBD). Similarly, intestinal tertiary lymphoid organs (TLOs) are associated with more severe inflammation. While there is active debate about the role of TLOs and stress in IBD pathogenesis, there are no studies investigating TLO formation in the context of psychological stress. Our mouse model of Crohn’s disease–like ileitis, the SAMP1/YitFc (SAMP) mouse, was subjected to 56 consecutive days of restraint stress (RS). Stressed mice had significantly increased colonic TLO formation. However, stress did not significantly increase small or large intestinal inflammation in the SAMP mice. Additionally, 16S analysis of the stressed SAMP microbiome revealed no genus-level changes. Fecal microbiome transplantation into germ-free SAMP mice using stool from unstressed and stressed mice replicated the behavioral phenotype seen in donor mice. However, there was no difference in TLO formation between recipient mice. Stress increased the TLO formation cytokines interleukin-23 (IL-23) and IL-22 followed by up-regulation of antimicrobial peptides. SAMP × IL-23r
−/−
(knockout [KO]) mice subjected to chronic RS did not have increased TLO formation. Furthermore, IL-23, but not IL-22, production was increased in KO mice, and administration of recombinant IL-22 rescued TLO formation. Following secondary colonic insult with dextran sodium sulfate, stressed mice had reduced colitis on both histology and colonoscopy. Our findings demonstrate that psychological stress induces colonic TLOs through intrinsic alterations in IL-23 signaling, not through extrinsic influence from the microbiome. Furthermore, chronic stress is protective against secondary insult from colitis, suggesting that TLOs may function to improve the mucosal barrier.
Opportunistic binding of EcR to open chromatin drives tissue-specific developmental responses
Authors: Uyehara Christopher M. , Leatham-Jensen Mary , McKay Daniel J.
Published: September 2022

Steroid hormones perform diverse biological functions in developing and adult animals. However, the mechanistic basis for their tissue specificity remains unclear. In
Drosophila
, the ecdysone steroid hormone is essential for coordinating developmental timing across physically separated tissues. Ecdysone directly impacts genome function through its nuclear receptor, a heterodimer of the EcR and ultraspiracle proteins. Ligand binding to EcR triggers a transcriptional cascade, including activation of a set of primary response transcription factors. The hierarchical organization of this pathway has left the direct role of EcR in mediating ecdysone responses obscured. Here, we investigate the role of EcR in controlling tissue-specific ecdysone responses, focusing on two tissues that diverge in their response to rising ecdysone titers: the larval salivary gland, which undergoes programmed destruction, and the wing imaginal disc, which initiates morphogenesis. We find that EcR functions bimodally, with both gene repressive and activating functions, even at the same developmental stage. EcR DNA binding profiles are highly tissue-specific, and transgenic reporter analyses demonstrate that EcR plays a direct role in controlling enhancer activity. Finally, despite a strong correlation between tissue-specific EcR binding and tissue-specific open chromatin, we find that EcR does not control chromatin accessibility at genomic targets. We conclude that EcR contributes extensively to tissue-specific ecdysone responses. However, control over access to its binding sites is subordinated to other transcription factors.
Nuclear magnetic resonance diffraction with subangstrom precision
Authors: Haas Holger , Tabatabaei Sahand , Rose William , Sahafi Pardis , Piscitelli Michèle , Jordan Andrew , Priyadarsi Pritam , Singh Namanish , Yager Ben , Poole Philip J. , Dalacu Dan , Budakian Raffi
Published: September 2022

We have combined ultrasensitive force-based spin detection with high-fidelity spin control to achieve NMR diffraction (NMRd) measurement of ~2 million31P spins in a(50 nm)3volume of an indium-phosphide (InP) nanowire. NMRd is a technique originally proposed for studying the structure of periodic arrangements of spins, with complete access to the spectroscopic capabilities of NMR. We describe two experiments that realize NMRd detection with subangstrom precision. In the first experiment, we encode a nanometer-scale spatial modulation of thez-axis magnetization of31P spins and detect the period and position of the modulation with a precision of <0.8 Å. In the second experiment, we demonstrate an interferometric technique, utilizing NMRd, to detect an angstrom-scale displacement of the InP sample with a precision of 0.07 Å. The diffraction-based techniques developed in this work extend the Fourier-encoding capabilities of NMR to the angstrom scale and demonstrate the potential of NMRd as a tool for probing the structure and dynamics of nanocrystalline materials.
TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance
Authors: Peotter Jennifer L. , Pustova Iryna , Lettman Molly M. , Shatadal Shalini , Bradberry Mazdak M. , Winter-Reed Allison D. , Charan Maya , Sharkey Erin E. , Alvin James R. , Bren Alyssa M. , Oie Annika K. , Chapman Edwin R. , Salamat M. Shahriar , Audhya Anjon
Published: September 2022

Molecular pathways that intrinsically regulate neuronal maintenance are poorly understood, but rare pathogenic mutations that underlie neurodegenerative disease can offer important insights into the mechanisms that facilitate lifelong neuronal function. Here, we leverage a rat model to demonstrate directly that the TFG p.R106C variant implicated previously in complicated forms of hereditary spastic paraplegia (HSP) underlies progressive spastic paraparesis with accompanying ventriculomegaly and thinning of the corpus callosum, consistent with disease phenotypes identified in adolescent patients. Analyses of primary cortical neurons obtained from CRISPR-Cas9–edited animals reveal a kinetic delay in biosynthetic secretory protein transport from the endoplasmic reticulum (ER), in agreement with prior induced pluripotent stem cell–based studies. Moreover, we identify an unexpected role for TFG in the trafficking of Rab4A-positive recycling endosomes specifically within axons and dendrites. Impaired TFG function compromises the transport of at least a subset of endosomal cargoes, which we show results in down-regulated inhibitory receptor signaling that may contribute to excitation-inhibition imbalances. In contrast, the morphology and trafficking of other organelles, including mitochondria and lysosomes, are unaffected by the TFG p.R106C mutation. Our findings demonstrate a multifaceted role for TFG in secretory and endosomal protein sorting that is unique to cells of the central nervous system and highlight the importance of these pathways to maintenance of corticospinal tract motor neurons.
What ever happened to thebelles infidèles?
Authors: Buzelin Hélène
Published: September 2022

Over the past thirty years, crime fiction, children’s literature, comics and, to a lesser extent, romance novels have received growing attention from translation scholars. Drawing on an analysis of this translation studies literature and interviews conducted with translators working in different publishing sectors, this paper revisits the hypothesis ofClem Robyns (1990), who proposed that non-canonical literary translations are thebelles infidèlesof the twentieth century. In a spirit reflecting the evolution of the discipline, the author examines not only the textual norms, but also the translators’ viewpoint and their role in the publishing process. The questions at the heart of this reflection are the following: to what extent doesadaptation – to use a less value-laden term thanbelle infidèle – (still) constitute the translation norm of non-canonical literatures? How do the actors participating in the translation of these literatures and their involvement in the publishing process differ from those governing the translation of institutional literature? Finally, what can the study of these literatures teach us about translation and some of the key notions and oppositions in contemporary translation theories?
Enhancement of hot carrier effect and signatures of confinement in terms of thermalization power in quantum well solar cell
Authors: Makhfudz I , Cavassilas N , Giteau M , Esmaielpour H , Suchet D , Daré A-M , Michelini F
Published: September 2022

A theoretical model using electron–phonon scattering rate equations is developed for assessing carrier thermalization under steady-state conditions in two-dimensional systems. The model is applied to investigate the hot carrier effect in III–V hot-carrier solar cells with a quantum well absorber. The question underlying the proposed investigation is: what is the power required to maintain two populations of electron and hole carriers in a quasi-equilibrium state at fixed temperatures and quasi-Fermi level splitting? The obtained answer is that the thermalization power density is reduced in two-dimensional systems compared to their bulk counterpart, which demonstrates a confinement-induced enhancement of the hot carrier effect in quantum wells. This power overall increases with the well thickness, and it is moreover shown that the intra-subband contribution dominates at small thicknesses while the inter-subband contribution increases with thickness and dominates in the bulk limit. Finally, the effects of the thermodynamic state of phonons and screening are clarified. In particular, the two-dimensional thermalization power density exhibits a non-monotonic dependence on the thickness of the quantum well layer, when both out-of-equilibrium longitudinal optical phonons and screening effects are taken into account. Our theoretical and numerical results provide tracks to interpret intriguing experimental observations in quantum well physics. They will also offer guidelines to increase the yield of photovoltaic effect based on the hot carrier effect using quantum well heterostructures, a result critical to the research toward high-efficiency solar cell devices.