bluuebunny/crossref_metadata_2025 huggingface dataset:
Should Weaponised Moral Enhancement Replace Lethal Aggression in War?
Authors: Fabiano Joao
Published: March 2023

Some have proposed the development of technologies that improve our moral behaviour – moral enhancement – in order to address global risks such as pandemics, global warming and nuclear war. I will argue that this technology could be weaponised to manipulate the moral dispositions of enemy combatants. Despite being morally controversial, weaponised moral enhancement would be neither clearly prohibited nor easily prohibitable by international war law. Unlike previous psychochemical weapons, it would be relatively physically harmless. I argue that when combatants are liable to lethal aggression to achieve an aim of war, they are also liable to weaponised moral enhancement to achieve that same aim. Weaponised moral enhancement will loosen just war requirements in both traditional and revisionist normative just war theories. It will particularly affect revisionist theories’ jus ad bellum requirements for humanitarian and preventive wars. For instance, weaponised moral enhancement could be more proportional and efficacious than lethal aggression to effect institutional changes in preventive and humanitarian wars. I will conclude that, despite evading international war laws and loosening normative just war requirements, the intuition that weaponised moral enhancement would gravely harm combatants can be defended by arguing that it would severely disturb personal identity, which could potentially ground future prohibitions.
Viewpointed morphology: A unified account of Spanish verb-complement compounds as fictive interaction structures
Authors: PASCUAL ESTHER , MARQUETA GRACIA BÁRBARA
Published: March 2023

Spanish verb-complement (VC) compounds, one of the most common compound types in Spanish, raise interesting questions, because they are inflected, prototypically containing a verb in the third-person singular of the present indicative. This complexity seems paradoxical, given the strong restrictions of Romance languages on word compounding.

Based on a self-compiled corpus of over 1,400 VC compounds, we show that the compound’s verb may display different persons and illocutionary forces. We claim that all Spanish VC compounds can be parsimoniously accounted for as involving a grammaticalized perspective-indexing structure, setting up a non-actual enunciation. We identify three subtypes of nominal VC compounds according to whether they refer to: (i) the fictive addresser of the non-actual enunciation it is composed of (e.g. metomentodo [I+put+myself+into+everything], ‘meddler’), (ii) the fictive addressee (e.g. tentetieso [hold+yourself+upright], ‘tilting doll’), or (iii) the fictive conversational topic (e.g. pintalabios [paints+lips], ‘lipstick’). We further argue that, despite undeniable morphological constraints, Spanish VC compounds involve a similarly complex semantic and morphological structure as English multi-word compounds like ‘wanna-be(s)’, ‘forget-me-not(s)’, or ‘bring-and-buy sale’. This reveals that intersubjectivity can be central to word formation.
Depression networks: a systematic review of the network paradigm causal assumptions
Authors: Huang Debbie , Susser Ezra , Rudolph Kara E. , Keyes Katherine M.
Published: March 2023

The network paradigm for psychiatric disorder nosology was proposed based on the hypothesis that mental disorders are caused by networks of symptoms that are themselves causally related. Researchers have widely applied and integrated this paradigm to examine a variety of mental disorders, particularly depression. Existing studies generally focus on the correlation structure of symptoms, inferring causal relationships. Thus, presumption of causality may not be justified. The goal of this review was to examine the assumptions necessary for causal inference in network studies of depression. Specifically, we examined whether and how network studies address common violations of causal assumptions (i.e. no measurement error, exchangeability, and positivity). Of the 41 studies reviewed, five (12%) studies discussed sources of confounding unrelated to measurement error; none discussed positivity; and five conducted post-hoc analysis for measurement error. Depression network studies, in principle, are conducted under the assumption that symptom relationships are causal. Yet, in practice, studies seldomly discussed or adequately tested assumptions required to infer causality. Researchers continue to design studies that are unable to support the credibility of the network paradigm for the study of depression. There is a critical need to ensure scientific efforts cease to perpetuate problematic designs and findings to a potentially unsubstantiated paradigm.
Wh-in-situ in child French: Deictic triggers at the syntax-semantics interface
Authors: Palasis Katerina , Faure Richard , Meunier Fanny
Published: March 2023

This article investigates the development of wh-in-situ questions in French by examining a three-year kindergarten dataset of spontaneous productions with 16 children between 2;5 and 5;11. The distribution of the wh-phrases is statistically examined in relation to age, verb form (Fixed be form c’est ‘it is’ vs. Free be forms vs. Free lexical verbs), and grammatical category of the wh-word (Pronoun vs. Adverb). Results show that wh-in-situ remains prevalent throughout the period despite a steady increase in wh-ex-situ. Verb form (Fixed vs. All free forms) is a discriminating variable for the wh-position in all three years, and it interacts with the category of the wh-word. The Fixed be form c’est favours in-situ wh-pronouns (c’est qui Taz ?), whereas the Free forms favour wh-ex-situ questions, and massively co-occur with wh-adverbs (combien ça coûte ?). The emergence of the ex-situ qu’est-ce que ‘what is it that’, as opposed to the in-situ quoi ‘what’, is identified as a factor accounting for the gradual increase in wh-ex-situ. Finally, most outliers (wh-in-situ with Free forms) are shown to belong to the same paradigm as c’est in-situ questions: non-presuppositional questions, which are visible from the frequent use of là ‘there’, like c’est, a deictic item.
Fünf Jahre Psychotherapeutische Sprechstunde: Wer nimmt sie in Anspruch und wie zuverlässig sind die Verdachtsdiagnosen?
Authors: Drewes Emma , Greuel Jan , Job Ann-Katrin
Published: March 2023

Zusammenfassung: Theoretischer Hintergrund: Die Psychotherapeutische Sprechstunde (PTS) wurde eingeführt, um einen zeitnahen, niederschwelligen Zugang zur Psychotherapie zu ermöglichen. Evaluationen im Kinder- und Jugendbereich fehlen bisher. Fragestellung: Welche Patient_innen suchen die PTS auf, wie zuverlässig sind die vergebenen ICD-10-Verdachtsdiagnosen und welche Faktoren beeinflussen die Zuverlässigkeit? Methode: Die PTS-Daten von N = 393 Patient_innen einer ambulanten, juvenilen Stichprobe wurden ausgewertet und mit den Ergebnissen nach einer ausführlichen Psychodiagnostik verglichen. Ergebnisse: Die PTS wurde gleichermaßen von Jungen und Mädchen ( M = 11.7 Jahre; Migrationshintergrund: 23 %) aufgesucht. Die mittlere Wartezeit auf einen PTS-Termin betrug 6.9 Wochen. Die häufigsten Verdachtsdiagnosen waren Hyperkinetische- und Aufmerksamkeitsstörungen sowie Angststörungen. Die Zuverlässigkeit der Verdachtsdiagnosen lag überwiegend im mittleren bis guten Bereich. Am zuverlässigsten waren die Verdachtsdiagnosen bei geringerem Leidensdruck. Schlussfolgerungen: Die PTS scheint die Wartezeit auf einen Erstkontakt zu verkürzen und in einigen Fällen akkurate Diagnosen zu liefern. Der Mehrzahl der Patient_innen ist dennoch eine ausführlichere psychodiagnostische Abklärung zu empfehlen.
Thermoelastic Properties of Liquid Fe‐Rich Alloys Under Martian Core Conditions
Authors: Huang D. , Li Y. , Khan A. , Sossi P. , Giardini D. , Murakami M.
Published: March 2023

Seismic measurements made on Mars indicate that the liquid iron‐nickel core is rich in light elements; however, the effects of these light components on the elasticity of Mars’ core remain poorly constrained. Here, we calculate elastic properties of various liquid Fe‐X (X = Ni, S, C, O and H) mixtures using ab initio molecular dynamics simulations. We find that, at martian core conditions, the addition of S and O most effectively decreases the density of liquid iron, followed by C and H, while Ni has a minimal effect. As for compressional sound velocity (Vp), C increases Vp of liquid Fe throughout Mars’ core, while both S and O reduce Vp, the intensity of which diminishes with increasing pressure. Assuming a martian core made of a binary mixture, the seismically‐inferred density would require the presence of at least 30 wt% S.
The Effect of Secondary‐Phase Fraction on the Deformation of Olivine + Ferropericlase Aggregates: 2. Mechanical Behavior
Authors: Wiesman Harison S. , Zimmerman Mark E. , Kohlstedt David L.
Published: March 2023

To study the mechanical behavior of polymineralic rocks, we performed deformation experiments on two‐phase aggregates of olivine (Ol) + ferropericlase (Per) with periclase fractions (fPer) between 0.1 and 0.8. Each sample was deformed in torsion at T = 1523 K, P = 300 MPa at a constant strain rate to a final shear strain of γ = 6 to 7. The stress‐strain data and calculated values of the stress exponent, n, indicate that Ol in our samples deformed by dislocation‐accommodated sliding along grain interfaces while Per deformed via dislocation creep. At shear strains of γ < 1, the strengths of samples with fPer > 0.5 match model predictions for both phases deforming at the same stress, the lower‐strength bound for two‐phase materials, while the strengths of samples with fPer < 0.5 are greater than predicted by models for both phases deforming at the same strain rate, the upper‐strength bound. These observations suggest a transition from a weak‐phase supported to a strong‐phase supported regime with decreasing fPer. Above γ = 4, however, the strength of all two‐phase samples is greater than those predicted by either the uniform‐stress or the uniform‐strain rate bound. We hypothesize that the high strengths in the Ol + Per system are due to the presence of phase boundaries in two‐phase samples, for which deformation is rate limited by dislocation motion along interfacial boundaries. This observation contrasts with the mechanical behavior of samples consisting of Ol + pyroxene, which are weaker, possibly due to impurities at phase boundaries.
Subduction‐Induced Asthenospheric Flow Around the Songliao Basin in NE China Revealed by Shear Wave Splitting Measurements of Dense Seismic Arrays
Authors: Xu Tao , Ai Yinshuang , Wu Chenglong , Chen Ling , Fan Enbo , Li Long , Dong Weiyu
Published: March 2023

The traditional mantle plume model fails to explain late Cenozoic intraplate volcanism in Northeast China (NEC). We constrained the pattern of upper mantle deformation to study the origin of intraplate volcanism by quantifying the shear wave splitting parameters captured by three NW‐SE linear seismic arrays in NEC. The dense station spacing (10 km) allowed us to image the small‐scale variations in anisotropic structures in unprecedented detail. The WNW‐ESE oriented subduction‐parallel anisotropy is likely induced by the asthenospheric return flow in the big mantle wedge convection associated with Pacific subduction. Therein the most notable feature is a toroidal pattern of anisotropy beneath the Songliao Basin, which is distinguished by a larger splitting time (approximately 1.0 s) relative to weak anisotropy in the center. The toroidal anisotropy pattern coincides with a high‐velocity anomaly extending from uppermost mantle down to ∼300 km depth, presumably indicating early stage foundering lithosphere. The asthenospheric return flow then moved around the foundering lithosphere and induced the corresponding toroidal anisotropy. The decompression partial melting of upwelling asthenospheric materials erupted along weak zones generating late Cenozoic intraplate basalts on both flanks of the Songliao Basin. The high‐density seismic array reveals that the Pacific subduction and early stage lithospheric foundering processes controlled the genesis of late Cenozoic volcanism in NEC.
Earthquakes as Dynamic Fracture Phenomena
Authors: Reches Ze'ev , Fineberg Jay
Published: March 2023

A large earthquake unlocks a fault‐zone via dynamic rupture while releasing part of the elastic energy stored during the interseismic stage. As earthquakes occur at depth, the analyses of earthquake physics rely primarily on experimental observations and conceptual models. A common view is that the earthquake instability is necessarily related to the frictional weakening that is commonly observed in shear experiments under seismic slip velocities. However, recent experiments with frictional interfaces in brittle acrylics (e.g., Svetlizky & Fineberg, 2014, https://doi.org/10.1038/nature13202) and rocks (e.g., Passelegue et al., 2020, https://doi.org/10.1038/s41467-020-18937-0) have explicitly demonstrated that no characteristic frictional strength exists. Namely, prior to nucleation, frictional interfaces can sustain a wide range of applied stresses (“overstresses”) that exceed the residual stresses, which are the stresses along the interface that remain after the sliding. Moreover, the experimentally observed singular stress‐fields and rupture dynamics are precisely those predicted by fracture mechanics (Freund, 1998). We therefore argue here that earthquake dynamics are best understood in terms of dynamic fracture mechanics and not governed by the frictional properties of faults. In this view, rupture dynamics are driven by the release of the elastic energy due to overstresses, whereas the values of the residual stresses and the energy dissipation are determined by fault frictional properties.
Contrasting the Biophysical and Radiative Effects of Rising CO2 Concentrations on Ozone Dry Deposition Fluxes
Authors: Silva Sam J. , Burrows Susannah M. , Calvin Katherine , Cameron‐Smith Philip J. , Shi Xiaoying , Zhou Tian
Published: March 2023

The dry deposition of ozone from the atmosphere to ecosystems is an important coupling mechanism between atmospheric chemistry and terrestrial biogeochemical processes. In most Earth system models, dry deposition is simulated using a resistor‐in‐series approach that aims to parameterize the governing biological, chemical, and physical processes through a series of functional approximations. Here, we evaluate the influence of carbon cycle‐climate responses on this parameterization using the results of the Energy Exascale Earth System Model v1.1 Biogeochemistry simulation campaign. This simulation campaign was designed in part to explore the biophysical and radiative effects of rising historical CO2 concentrations on the Earth system. We find that while the global annual ozone dry deposition is relatively insensitive to these effects, regionally the influence can be up to 10%. The strongest regional sensitivities in ozone dry deposition are predominantly in higher latitudes over land in the northern hemisphere and are dominated by the radiative effect of CO2, with little net influence of biophysical responses. Of all the impacts of the radiative effect of CO2, we point to the potential importance of accurately representing ozone deposition to snow in Earth System Models and provide recommendations for future simulation campaigns.
Grain Shape Evolution of Sand‐Sized Sediments During Transport From Mountains to Dune Fields
Authors: Liang Peng , Yang Xiaoping
Published: March 2023

Grain shape is used less frequently in identifying the origin of sediments than grain size distributions and/or surface microtextures because of technological limitations. In addition, systematic studies on grain shape change of sand‐sized sediments from a source‐to‐sink perspective are lacking, and yet the evolutionary mechanism of grain shape along the sediment transport pathway remains poorly understood. Here, we investigated grain shape changes in sand‐sized sediments ranging from mountains to dune fields using an efficient and quantitative dynamic image analysis technique. By means of the detailed hydro‐geomorphic analysis and field sampling in a quasi‐closed sedimentary system, we collected 41 samples from the Hulunbeier Sandy Land (HSL) in northern China and its potential source region. Also, 21 typical fluvial deposit samples from different river systems in China were collected for comparison. We identify that the sphericity, symmetry, aspect ratio, and mineralogical maturity of the fluvial deposits from mountains are significantly lower than the eolian sand in dune fields. Despite the apparent inheritance of sediments from the mountains to the dune fields, the abrupt changes in the sedimentological and geochemical properties along their pathway suggest that multiple cycles of eolian abrasion within the HSL modify the sediments significantly after they are transported away from the fluvial environments. The well‐defined separation between eolian sand and fluvial deposits by grain shape parameters such as sphericity and symmetry underscores that grain shape can be a powerful tool for tracing sediment transport history in paleoenvironmental or extraterrestrial studies.
Large Variability in Simulated Response of Vegetation Composition and Carbon Dynamics to Variations in Drought‐Heat Occurrence
Authors: Tschumi Elisabeth , Lienert Sebastian , Bastos Ana , Ciais Philippe , Gregor Konstantin , Joos Fortunat , Knauer Jürgen , Papastefanou Philip , Rammig Anja , van der Wiel Karin , Williams Karina , Xu Yidi , Zaehle Sönke , Zscheischler Jakob
Published: March 2023

The frequency of heatwaves, droughts and their co‐occurrence vary greatly in simulations of different climate models. Since these extremes are expected to become more frequent with climate change, it is important to understand how vegetation models respond to different climatologies in heatwave and drought occurrence. In previous work, six climate scenarios featuring different drought‐heat signatures have been developed to investigate how single versus compound extremes affect vegetation and carbon dynamics. Here, we use these scenarios to force six dynamic global vegetation models to investigate model agreement in vegetation and carbon cycle response to these scenarios. We find that global responses to different drought‐heat signatures vary considerably across models. Models agree that frequent compound hot‐dry events lead to a reduction in tree cover and vegetation carbon stocks. However, models show opposite responses in vegetation changes for the scenario with no extremes. We find a strong relationship between the frequency of concurrent hot‐dry conditions and the total carbon pool, suggesting a reduction of the natural land carbon sink for increasing occurrence of hot‐dry events. The effect of frequent compound hot and dry extremes is larger than the sum of the effects when only one extreme occurs, highlighting the importance of studying compound events. Our results demonstrate that uncertainties in the representation of compound hot‐dry event occurrence in climate models propagate to uncertainties in the simulation of vegetation distribution and carbon pools. Therefore, to reduce uncertainties in future carbon cycle projections, the representation of compound events in climate models needs to be improved.
GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program
Authors: Lewis Michael , Terré Berta , Knobel Philip A. , Cheng Tao , Lu Hao , Attolini Camille Stephan-Otto , Smak Jordann , Coyaud Etienne , Garcia-Cao Isabel , Sharma Shalu , Vineethakumari Chithran , Querol Jessica , Gil-Gómez Gabriel , Piergiovanni Gabriele , Costanzo Vincenzo , Peiró Sandra , Raught Brian , Zhao Haotian , Salvatella Xavier , Roy Sudipto , Mahjoub Moe R. , Stracker Travis H.
Published: March 2023

Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.
Evaluating patient-reported outcome measures (PROMs) for future clinical trials in adult patients with optic neuritis
Authors: Panthagani Jesse , O’Donovan Charles , Aiyegbusi Olalekan Lee , Liu Xiaoxuan , Bayliss Susan , Calvert Melanie , Pesudovs Konrad , Denniston Alastair K. , Moore David J. , Braithwaite Tasanee
Published: March 2023

Objective

To search for and critically appraise the psychometric quality of patient-reported outcome measures (PROMs) developed or validated in optic neuritis, in order to support high-quality research and care.

Methods

We systematically searched MEDLINE(Ovid), Embase(Ovid), PsycINFO(Ovid) and CINAHLPlus(EBSCO), and additional grey literature to November 2021, to identify PROM development or validation studies applicable to optic neuritis associated with any systemic or neurologic disease in adults. We included instruments developed using classic test theory or Rasch analysis approaches. We used established quality criteria to assess content development, validity, reliability, and responsiveness, grading multiple domains from A (high quality) to C (low quality).

Results

From 3142 screened abstracts we identified five PROM instruments potentially applicable to optic neuritis: three differing versions of the National Eye Institute (NEI)-Visual Function Questionnaire (VFQ): the 51-item VFQ; the 25-item VFQ and a 10-item neuro-ophthalmology supplement; and the Impact of Visual Impairment Scale (IVIS), a constituent of the Multiple Sclerosis Quality of Life Inventory (MSQLI) handbook, derived from the Functional Assessment of Multiple Sclerosis (FAMS). Psychometric appraisal revealed the NEI-VFQ-51 and 10-item neuro module had some relevant content development but weak psychometric development, and the FAMS had stronger psychometric development using Rasch Analysis, but was only somewhat relevant to optic neuritis. We identified no content or psychometric development for IVIS.

Conclusion

There is unmet need for a PROM with strong content and psychometric development applicable to optic neuritis for use in virtual care pathways and clinical trials to support drug marketing authorisation.
Ultra-low-current driven InGaN blue micro light-emitting diodes for electrically efficient and self-heating relaxed microdisplay
Authors: Baek Woo Jin , Park Juhyuk , Shim Joonsup , Kim Bong Ho , Park Seongchong , Kim Hyun Soo , Geum Dae-Myeong , Kim Sang Hyeon
Published: March 2023

InGaN-based micro-light-emitting diodes have a strong potential as a crucial building block for next-generation displays. However, small-size pixels suffer from efficiency degradations, which increase the power consumption of the display. We demonstrate strategies for epitaxial structure engineering carefully considering the quantum barrier layer and electron blocking layer to alleviate efficiency degradations in low current injection regime by reducing the lateral diffusion of injected carriers via reducing the tunneling rate of electrons through the barrier layer and balanced carrier injection. As a result, the fabricated micro-light-emitting diodes show a high external quantum efficiency of 3.00% at 0.1 A/cm2 for the pixel size of 10 × 10 μm2 and a negligible Jmax EQE shift during size reduction, which is challenging due to the non-radiative recombination at the sidewall. Furthermore, we verify that our epitaxy strategies can result in the relaxation of self-heating of the micro-light-emitting diodes, where the average pixel temperature was effectively reduced.
Large-scale identification of genes involved in septal pore plugging in multicellular fungi
Authors: Mamun Md. Abdulla Al , Cao Wei , Nakamura Shugo , Maruyama Jun-ichi
Published: March 2023

Multicellular filamentous fungi have septal pores that allow cytoplasmic exchange, and thus connectivity, between neighboring cells in the filament. Hyphal wounding and other stress conditions induce septal pore closure to minimize cytoplasmic loss. However, the composition of the septal pore and the mechanisms underlying its function are not well understood. Here, we set out to identify new septal components by determining the subcellular localization of 776 uncharacterized proteins in a multicellular ascomycete,Aspergillus oryzae. The set of 776 uncharacterized proteins was selected on the basis that their genes were present in the genomes of multicellular, septal pore-bearing ascomycetes (threeAspergillusspecies, in subdivision Pezizomycotina) and absent/divergent in the genomes of septal pore-lacking ascomycetes (yeasts). Upon determining their subcellular localization, 62 proteins were found to localize to the septum or septal pore. Deletion of the encoding genes revealed that 23 proteins are involved in regulating septal pore plugging upon hyphal wounding. Thus, this study determines the subcellular localization of many uncharacterized proteins inA. oryzaeand, in particular, identifies a set of proteins involved in septal pore function.
Structural basis for antibody recognition of vulnerable epitopes on Nipah virus F protein
Authors: Byrne Patrick O. , Fisher Brian E. , Ambrozak David R. , Blade Elizabeth G. , Tsybovsky Yaroslav , Graham Barney S. , McLellan Jason S. , Loomis Rebecca J.
Published: March 2023

Nipah virus (NiV) is a pathogenic paramyxovirus that causes fatal encephalitis in humans. Two envelope glycoproteins, the attachment protein (G/RBP) and fusion protein (F), facilitate entry into host cells. Due to its vital role, NiV F presents an attractive target for developing vaccines and therapeutics. Several neutralization-sensitive epitopes on the NiV F apex have been described, however the antigenicity of most of the F protein’s surface remains uncharacterized. Here, we immunize mice with prefusion-stabilized NiV F and isolate ten monoclonal antibodies that neutralize pseudotyped virus. Cryo-electron microscopy reveals eight neutralization-sensitive epitopes on NiV F, four of which have not previously been described. Novel sites span the lateral and basal faces of NiV F, expanding the known library of vulnerable epitopes. Seven of ten antibodies bind the Hendra virus (HeV) F protein. Multiple sequence alignment suggests that some of these newly identified neutralizing antibodies may also bind F proteins across the Henipavirus genus. This work identifies new epitopes as targets for therapeutics, provides a molecular basis for NiV neutralization, and lays a foundation for development of new cross-reactive antibodies targeting Henipavirus F proteins.
Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3
Authors: Cova Giulia , Glaser Juliane , Schöpflin Robert , Prada-Medina Cesar Augusto , Ali Salaheddine , Franke Martin , Falcone Rita , Federer Miriam , Ponzi Emanuela , Ficarella Romina , Novara Francesca , Wittler Lars , Timmermann Bernd , Gentile Mattia , Zuffardi Orsetta , Spielmann Malte , Mundlos Stefan
Published: March 2023

Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture. This leads to ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern induced by AER-specific enhancers of Fgf8. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression in the developing limb. Our results reveal insights into the molecular mechanism underlying SHFM3 and provide conceptual framework for how genomic rearrangements can cause gene misexpression and disease.
Poly(heptazine imide) ligand exchange enables remarkable low catalyst loadings in heterogeneous metallaphotocatalysis
Authors: Xing Liuzhuang , Yang Qian , Zhu Chen , Bai Yilian , Tang Yurong , Rueping Magnus , Cai Yunfei
Published: March 2023

The development of heterogeneous metallaphotocatalysis is of great interest for sustainable organic synthesis. The rational design and controllable preparation of well-defined (site-isolated) metal/photo bifunctional solid catalysts to meet such goal remains a critical challenge. Herein, we demonstrate the incorporation of privileged homogeneous bipyridyl-based Ni-catalysts into highly ordered and crystalline potassium poly(heptazine imide) (K-PHI). A variety of PHI-supported cationic bipyridyl-based Ni-catalysts (LnNi-PHI) have been prepared and fully characterized by various techniques including NMR, ICP-OES, XPS, HAADF-STEM and XAS. The LnNi-PHI catalysts exhibit exceptional chemical stability and recyclability in diverse C−P, C−S, C−O and C−N cross-coupling reactions. The proximity and cooperativity effects in LnNi-PHI significantly enhances the photo/Ni dual catalytic activity, thus resulting in low catalyst loadings and high turnover numbers.
Scale dependence in hydrodynamic regime for jumping on water
Authors: Gwon Minseok , Kim Dongjin , Kim Baekgyeom , Han Seungyong , Kang Daeshik , Koh Je-Sung
Published: March 2023

Momentum transfer from the water surface is strongly related to the dynamical scale and morphology of jumping animals. Here, we investigate the scale-dependent momentum transfer of various jumping organisms and engineered systems at an air-water interface. A simplified analytical model for calculating the maximum momentum transfer identifies an intermediate dynamical scale region highly disadvantageous for jumping on water. The Weber number of the systems should be designed far from 1 to achieve high jumping performance on water. We design a relatively large water-jumping robot in the drag-dominant scale range, having a high Weber number, for maximum jumping height and distance. The jumping robot, around 10 times larger than water striders, has a take-off speed of 3.6 m/s facilitated by drag-based propulsion, which is the highest value reported thus far. The scale-dependent hydrodynamics of water jumpers provides a useful framework for understanding nature and robotic system interacting with the water surface.
A mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination
Authors: Qiang Lihua , Zhang Yong , Lei Zehui , Lu Zhe , Tan Shasha , Ge Pupu , Chai Qiyao , Zhao Mengyuan , Zhang Xinwen , Li Bingxi , Pang Yu , Zhang Lingqiang , Liu Cui Hua , Wang Jing
Published: March 2023

Ferroptosis is a lipid peroxidation-driven and iron-dependent programmed cell death involved in multiple physical processes and various diseases. Emerging evidence suggests that several pathogens manipulate ferroptosis for their pathogenicity and dissemination, but the underlying molecular mechanisms remain elusive. Here, we identify that protein tyrosine phosphatase A (PtpA), an effector secreted by tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis (Mtb), triggers ferroptosis to promote Mtb pathogenicity and dissemination. Mechanistically, PtpA, through its Cys11 site, interacts with host RanGDP to enter host cell nucleus. Then, the nuclear PtpA enhances asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) via targeting protein arginine methyltransferase 6 (PRMT6), thus inhibiting glutathione peroxidase 4 (GPX4) expression, eventually inducing ferroptosis to promote Mtb pathogenicity and dissemination. Taken together, our findings provide insights into molecular mechanisms of pathogen-induced ferroptosis, indicating a potential TB treatment via blocking Mtb PtpA-host PRMT6 interface to target GPX4-dependent ferroptosis.
Data integration across conditions improves turnover number estimates and metabolic predictions
Authors: Wendering Philipp , Arend Marius , Razaghi-Moghadam Zahra , Nikoloski Zoran
Published: March 2023

Turnover numbers characterize a key property of enzymes, and their usage in constraint-based metabolic modeling is expected to increase the prediction accuracy of diverse cellular phenotypes. In vivo turnover numbers can be obtained by integrating reaction rate and enzyme abundance measurements from individual experiments. Yet, their contribution to improving predictions of condition-specific cellular phenotypes remains elusive. Here, we show that available in vitro and in vivo turnover numbers lead to poor prediction of condition-specific growth rates with protein-constrained models ofEscherichia coliandSaccharomyces cerevisiae, particularly when protein abundances are considered. We demonstrate that correction of turnover numbers by simultaneous consideration of proteomics and physiological data leads to improved predictions of condition-specific growth rates. Moreover, the obtained estimates are more precise than corresponding in vitro turnover numbers. Therefore, our approach provides the means to correct turnover numbers and paves the way towards cataloguing kcatomes of other organisms.
Modeling of three-dimensional innervated epidermal like-layer in a microfluidic chip-based coculture system
Authors: Ahn Jinchul , Ohk Kyungeun , Won Jihee , Choi Dong-Hee , Jung Yong Hun , Yang Ji Hun , Jun Yesl , Kim Jin-A , Chung Seok , Lee Sang-Hoon
Published: March 2023

Reconstruction of skin equivalents with physiologically relevant cellular and matrix architecture is indispensable for basic research and industrial applications. As skin-nerve crosstalk is increasingly recognized as a major element of skin physiological pathology, the development of reliable in vitro models to evaluate the selective communication between epidermal keratinocytes and sensory neurons is being demanded. In this study, we present a three-dimensional innervated epidermal keratinocyte layer as a sensory neuron-epidermal keratinocyte co-culture model on a microfluidic chip using the slope-based air-liquid interfacing culture and spatial compartmentalization. Our co-culture model recapitulates a more organized basal-suprabasal stratification, enhanced barrier function, and physiologically relevant anatomical innervation and demonstrated the feasibility of in situ imaging and functional analysis in a cell-type-specific manner, thereby improving the structural and functional limitations of previous coculture models. This system has the potential as an improved surrogate model and platform for biomedical and pharmaceutical research.
Ribozyme-mediated RNA synthesis and replication in a model Hadean microenvironment
Authors: Salditt Annalena , Karr Leonie , Salibi Elia , Le Vay Kristian , Braun Dieter , Mutschler Hannes
Published: March 2023

Enzyme-catalyzed replication of nucleic acid sequences is a prerequisite for the survival and evolution of biological entities. Before the advent of protein synthesis, genetic information was most likely stored in and replicated by RNA. However, experimental systems for sustained RNA-dependent RNA-replication are difficult to realise, in part due to the high thermodynamic stability of duplex products and the low chemical stability of catalytic RNAs. Using a derivative of a group I intron as a model for an RNA replicase, we show that heated air-water interfaces that are exposed to a plausible CO2-rich atmosphere enable sense and antisense RNA replication as well as template-dependent synthesis and catalysis of a functional ribozyme in a one-pot reaction. Both reactions are driven by autonomous oscillations in salt concentrations and pH, resulting from precipitation of acidified dew droplets, which transiently destabilise RNA duplexes. Our results suggest that an abundant Hadean microenvironment may have promoted both replication and synthesis of functional RNAs.
Multiphoton non-local quantum interference controlled by an undetected photon
Authors: Qian Kaiyi , Wang Kai , Chen Leizhen , Hou Zhaohua , Krenn Mario , Zhu Shining , Ma Xiao-song
Published: March 2023

The interference of quanta lies at the heart of quantum physics. The multipartite generalization of single-quanta interference creates entanglement, the coherent superposition of states shared by several quanta. Entanglement allows non-local correlations between many quanta and hence is a key resource for quantum information technology. Entanglement is typically considered to be essential for creating non-local quantum interference. Here, we show that this is not the case and demonstrate multiphoton non-local quantum interference that does not require entanglement of any intrinsic properties of the photons. We harness the superposition of the physical origin of a four-photon product state, which leads to constructive and destructive interference with the photons’ mere existence. With the intrinsic indistinguishability in the generation process of photons, we realize four-photon frustrated quantum interference. This allows us to observe the following noteworthy difference to quantum entanglement: We control the non-local multipartite quantum interference with a photon that we never detect, which does not require quantum entanglement. These non-local properties pave the way for the studies of foundations of quantum physics and potential applications in quantum technologies.
Sustainable application of calcium carbide residue as a filler for 3D printing materials
Authors: Samoylenko Dmitriy E. , Rodygin Konstantin S. , Ananikov Valentine P.
Published: March 2023

Industrial activity results in ton-scale production of calcium carbide and generation of a significant amount of calcium carbide residue (CCR), which is often disposed of in the environment as waste. CCR is an active chemical, and rain washes away alkali from sludge, changing the pH of soils and water and damaging the environment. In this work, we explored new opportunities for the utilization of CCR in view of the coming industrial uptake of digital design and additive technologies. Amazingly, CCR can be successfully used as a filler for the modification of 3D printed materials towards the introduction of hybrid organic/inorganic frameworks. A series of commercially available plastics (PLA, ABS, Nylon, PETG, SBS) were successfully used as matrices for CCR-based composite production with high CCR contents up to 28%. Tensile analyses showed increases in tensile strength and Young’s modulus of 9% and 60%, respectively. Moreover, in comparison with the pure plastics, the CCR-based materials better maintained the digitally designed shape (lower shrinkage). Importantly, CCR-filled materials are 3D printable, making them very promising components in the building sector. Considering the amount of already available CCR stored in the environment, this material is available in large quantities in the near future for hybrid materials, and anticipated opportunities exist in the additive manufacturing sector. The involvement of CCR in practical composite materials is equally important for environmental protection and reuse of already available multiple-ton wastes.
Evaluation of pre-processing methods for tear fluid proteomics using proximity extension assays
Authors: Vergouwen Daphne P. C. , Schotting Amber J. , Endermann Tanja , van de Werken Harmen J. G. , Grashof Dwin G. B. , Arumugam Sinthuja , Nuijts Rudy M. M. A. , ten Berge Josianne C. , Rothova Aniki , Schreurs Marco W. J. , Gijs Marlies
Published: March 2023

Tear fluid forms a potential source for biomarker identification, and can be minimal invasively collected via Schirmer strips. The lack of knowledge on the processing of Schirmer strips however complicates the analysis and between-study comparisons. We studied two different pre-processing methods, specifically the use of punches of the strip versus elution of the strip in a buffer. Tear fluid filled Schirmer strips were collected from 5 healthy participants, and divided into two halves over the length of the strip. In either part, punches or eluates were obtained from 4 different locations, from the first part touching the eye (head) to the end, to assess the protein distribution along the strips. The levels of 92 inflammatory proteins were measured in the punches/eluates using proximity extension assays. The punch method yielded higher protein detectability compared to the elution method (76% vs 66%; p ≤ 0.001). Protein expression level was found to be slightly higher in the head of the strip, however, 3 out of 5 punches from the head failed quality control. Protein expression levels over the remaining parts of the strips were similar. Our study showed beneficial use of punches of any part of the strip except the head in future biomarker research.
The cytotoxic activity of carfilzomib together with nelfinavir is superior to the bortezomib/nelfinavir combination in non-small cell lung carcinoma
Authors: Besse Lenka , Kraus Marianne , Besse Andrej , Driessen Christoph , Tarantino Ignazio
Published: March 2023

Chemotherapy resistance is still a major problem in the treatment of patients with non-small-cell-lung carcinoma (NSCLC), and novel concepts for the induction of cytotoxicity in NSCLC are highly warranted. Proteotoxicity, the induction of cytotoxicity by targeting the ubiquitin proteasome system, represents an appealing innovative strategy. The combination of the proteasome inhibitor bortezomib (BTZ) and the proteotoxic stress-inducing HIV drug nelfinavir (NFV) synergistically induces proteotoxicity and shows encouraging preclinical efficacy in NSCLC. The second-generation proteasome inhibitor carfilzomib (CFZ) is superior to BTZ and overcomes BTZ resistance in multiple myeloma patients. Here, we show that CFZ together with NFV is superior to the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity through the accumulation of excess proteasomal substrate protein in NSCLC in vitro and ex vivo. Interestingly, NFV increases the intracellular availability of CFZ through inhibition of CFZ export from NSCLC cells that express multidrug resistance (MDR) protein. Combining CFZ with NFV may therefore represent a future treatment option for NSCLC, which warrants further investigation.
Information set supported deep learning architectures for improving noisy image classification
Authors: Bhardwaj Saurabh , Wang Yizhi , Yu Guoqiang , Wang Yue
Published: March 2023

Deep learning models have been widely used in many supervised learning applications. However, these models suffer from overfitting due to various types of uncertainty with deteriorating performance when facing data biases, class imbalance, or noise propagation. The Information-Set Deep learning (ISDL) architectures with four variants are developed by integrating information set theory and deep learning principles to address the critical problem of the absence of robust deep learning models. There is a description of the ISDL architectures, learning algorithms, and analytic workflows. The performance of the ISDL models and standard architectures is evaluated using a noise-corrupted benchmark dataset. The experimental results show that the ISDL models can efficiently handle noise-dominated uncertainty and outperform peer architectures.
Fabrication of nitrogen doped TiO2/Fe2O3 nanostructures for photocatalytic oxidation of methanol based wastewater
Authors: Mersal Mai , Zedan Abdallah F. , Mohamed Gehad G. , Hassan Gamal K.
Published: March 2023

An important industrial process that often occurs on the surface of a heterogeneous catalyst using thermochemical or photochemical could help in the oxidation of methanol-based wastewater to formaldehyde. Titania-based photocatalysts have drawn a lot of interest from scientists because they are a reliable and affordable catalyst material for photocatalytic oxidation processes in the presence of light energy. In this study, a straight-forward hydrothermal method for producing n-TiO2@α-Fe2O3 composite photocatalysts and hematite (α-Fe2O3) nanocubes has been done. By adjusting the ratio of n-TiO2 in the prepared composite photocatalysts, the enhancing influence of the nitrogen-doped titania on the photocatalytic characteristics of the prepared materials was investigated. The prepared materials were thoroughly characterized using common physiochemical methods, such as transmission electron microscope (TEM), scanning electron microscope (SEM), X-ray diffraction (XRD), energy dispersive X-ray (EDX), X-ray photoelectrons spectroscopy (XPS), physisorption (BET), and others, in order to learn more about the structure The results obtained showed that nitrogen-doped titania outperforms non-doped titania for methanol photooxidation. The addition of nitrogen-doped titania to their surfaces resulted in an even greater improvement in the photooxidation rates of the methanol coupled with hematite. The photooxidation of methanol in the aqueous solution to simulate its concentration in the wastewater has been occurred. After 3 h, the four weight percent of n-TiO2@α-Fe2O3 photocatalyst showed the highest rate of HCHO production.