bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixed-Functions IoT devices: a Regulatory and Liability Requirements’ Maze. A First Overview
Authors: Gennari Francesca
Published: October 2024

This early-stage research article intends to explore the regulatory and liability requirements of a not yet fully developed subset of consumer Internet of Things (IoT) objects: the mixed-functions IoT devices. These objects could be wearables or not but could perform an e-health function, such as measuring your heartbeat, as well as consumer functions, such as displaying chat notifications. I argue that these mixed-functions devices will play an important role within smart homes as they will interact with new medical IoT devices to carry on rehabilitation and other medical functions at home. That is why it is important to start mapping down all the regulatory and liability requirements that might interest mixed-functions IoT device developers for them to understand which thread to follow in this regulatory and liability requirements maze.
Validation of electronic health record data to identify hospital-associated Clostridioides difficile infections for retrospective research
Authors: Ray Michael J. , Lacanilao Kathleen L. , Lazaro Maela Robyne , Strnad Luke C. , Furuno Jon P. , Royster Kelly , McGregor Jessina C.
Published: October 2024

Clostridioides difficile infection (CDI) research relies upon accurate identification of cases when using electronic health record (EHR) data. We developed and validated a multi-component algorithm to identify hospital-associated CDI using EHR data and determined that the tandem of CDI-specific treatment and laboratory testing has 97% accuracy in identifying HA-CDI cases.
Bouncing behaviour of a particle settling through a density transition layer
Authors: Wang Shuhong , Kandel Prabal , Deng Jian , Caulfield C.P. , Dalziel Stuart B.
Published: October 2024

The present work focuses on a specific bouncing behaviour as a spherical particle settles through a density interface in the absence of a neutral buoyant position. This behaviour was initially discovered by Abaid et al. (Phys. Fluids, vol. 16, issue 5, 2004, pp. 1567–1580) in salinity-induced stratification. Both experimental and numerical investigations are conducted to understand this phenomenon. In our experiments, we employ particle image velocimetry (PIV) to measure the velocity distribution around the particle and to capture the transient wake structure. Our findings reveal that the bouncing process begins after the wake detaches from the particle. The PIV results indicate that an upward jet forms at the central axis behind the particle following wake detachment. By performing a force decomposition procedure, we quantify the contributions from the buoyancy of the wake (

$F_{sb}$

) and the flow structure (

$F_{sj}$

) to the enhanced drag. It is observed that

$F_{sb}$

contributes primarily to the enhanced drag at the early stage, whereas

$F_{sj}$

plays a critical role in reversing the particle's motion. Furthermore, our results indicate that the jet is a necessary condition for the occurrence of the bouncing motion. We also explore the minimum velocities (where negative values denote the occurrence of bouncing) of the particle, while varying the lower Reynolds number

$Re_l$

, the Froude number

$Fr$

, and the upper Reynolds number

$Re_u$

, within the ranges

$1 \leqslant Re_l\leqslant 125$

,

$115 \leqslant Re_u\leqslant 356$

and

$2 \leqslant Fr\leqslant 7$

. Our findings suggest that the bouncing behaviour is influenced primarily by

$Re_l$

. Specifically, we observe that the bouncing motion occurs below a critical lower Reynolds number

$Re^\ast _{l}=30$

in our experiments. In the numerical simulations, the highest value for this critical number is

$Re^\ast _{l}=46.2$

, which is limited to the parametric ranges studied in this work.
Momentum, energy and vorticity balances in deep-water surface gravity waves
Authors: Blaser Aidan , Benamran Raphaël , Villas Bôas Ana B. , Lenain Luc , Pizzo Nick
Published: October 2024

The particle trajectories in irrotational, incompressible and inviscid deep-water surface gravity waves are open, leading to a net drift in the direction of wave propagation commonly referred to as the Stokes drift, which is responsible for catalysing surface wave-induced mixing in the ocean and transporting marine debris. A balance between phase-averaged momentum density, kinetic energy density and vorticity for irrotational, monochromatic and spatially periodic two-dimensional water waves is derived by working directly within the Lagrangian reference frame, which tracks particle trajectories as a function of their labels and time. This balance should be expected as all three of these quantities are conserved following particles in this system. Vorticity in particular is always conserved along particles in two-dimensional inviscid flow, and as such even in its absence it is the value of the vorticity that fundamentally sets the drift, which in the Lagrangian frame is identified as the phase-averaged momentum density of the system. A relationship between the drift and the geometric mean water level of particles is found at the surface, which highlights connections between the geometry and dynamics. Finally, an example of an initially quiescent fluid driven by a wavelike pressure disturbance is considered, showing how the net momentum and energy from the surface pressure disturbance transfer to the wave field, and recognizing the source of the mean Lagrangian drift as the net momentum required to generate an irrotational surface wave by any conservative force.
Lethal and sublethal concentrations spirodiclofen stress may increase the adaptation of Panonychus citri (Acari: Tetranychidae)
Authors: Wang Hongyan , Wang Haifeng , Wen Kexin , Xie Tao , Luo Shigan , Wu Jiawei , Xia Bin
Published: October 2024

Panonychus citri is one of the most destructive pests in citrus orchards, exhibiting varying degrees of tolerance to numerous insecticides, such as spirodiclofen. To effectively manage pests, this study explores the response of P. citri to spirodiclofen stress from the perspectives of life history, enzymatic parameters, and reproduction. The effects of two concentrations (LC30 and LC50) of spirodiclofen on the biological parameters of P. citri were evaluated by the life table method. The results showed that the development duration, fecundity, oviposition days, and lifespan were shortened, though the pre-oviposition period of two treatments was prolonged in comparison with the control. A significant decrease was recorded in the net reproductive rate (R0) and the mean generation time (T) for the two treatments. Nevertheless, the intrinsic rate of increase (r) and the rate of increase (λ) were not significantly affected in the LC30 treatment, whereas they declined in the LC50 treatment. The enzyme activity assay resulted in higher activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), and carboxylesterase (CarE), among the treatments than the control. In contrast, the treatments recorded lower cytochromeP450 (CYP450) and Glutathione S-transferase (GST) activities than the control. Furthermore, the study detected that relative mRNA expression of Vitellogenin (Vg) and Vitellogenin receptor (VgR) for two treatments were lower than the control. In summary, two concentrations of spirodiclofen inhibited progeny growth and fecundity of P. citri. Additionally, the results of this study may support further research on tolerance of P. citri in response to spirodiclofen stress.
Understanding the Good: Medieval Inquisitions and Modern Religion
Authors: Ames Christine Caldwell
Published: October 2024

This essay responds to scholarly arguments that “religion” arose in the particular circumstances of the modern West, distinct chronologically and conceptually from medieval religio. It argues that in the Middle Ages, Christian persecution helped to form that very notion of religion. It does so via the register of heresy inquisitions conducted by Bishop Jacques Fournier in Pamiers (1318–1325), which contains a curious and overlooked Occitan phrase: entendensa del be (“understanding of the good”). In three provocative ways, entendensa del be helps us to reconsider the origins of “religion.” First, one possibility is that the phrase represents an organic proto-religion among the heretics known as Good Christians. A second possibility is, conversely, that scribes presented an insignificant phrase as a technical term, helping to identify the group as heretical. This would highlight coercive inquisitorial agency in reinterpreting language and behavior, anticipating early-modern and modern constructors of “religion.” Third, by its links to troubadour culture, the phrase reminds us how in Occitania, conquest and resistance intertwined with inquisition's policing of “religious” behavior in a way that resembles claims for modernity. Regardless of which possibility, and most importantly, we discover how medieval persecution helped to form modern religion.
Ion-temperature- and density-gradient-driven instabilities and turbulence in Wendelstein 7-X close to the stability threshold
Authors: Podavini L. , Zocco A. , García-Regaña J.M. , Barnes M. , Parra F.I. , Mishchenko A. , Helander P.
Published: October 2024

Electrostatic gyrokinetic instabilities and turbulence in the Wendelstein 7-X stellarator are studied. Particular attention is paid to the ion-temperature-gradient (ITG) instability and its character close to marginal stability [Floquet-type turbulence (Zocco et al., Phys. Rev. E, vol. 106, 2022, p. L013202) with no electron temperature gradient]. The flux tube version of the

$\delta f$

code stella (Barnes et al., J. Comput. Phys., vol. 391, 2019, pp. 365–380) is used to run linear and nonlinear gyrokinetic simulations with kinetic electrons. The nature of the dominant instability depends on the wavelength perpendicular to the magnetic field, and the results are conveniently displayed in stability diagrams that take this dependence into account. This approach highlights the presence of universal instabilities, which are less unstable but have longer wavelengths than other modes. A quasi-linear estimate of the heat flux suggests they are relevant for transport. Close to the stability threshold, the linear eigenmodes and turbulence form highly extended structures along the computational domain if the magnetic shear is small. Numerical experiments and diagnostics are undertaken to assess the resulting radial localisation of the turbulence, which affects the interaction of the latter with zonal flows. Increasing the amplitude of the magnetic shear (e.g.through current drive) has a stabilising effect on the turbulence and, thus, reduces the nonlinear energy transport.
An Altar from Marton, Lincolnshire, and a Soldier of Leg. XI Claudia in Britain
Authors: Buckland Paul C. , Dolby Malcolm J.
Published: October 2024

An altar to Mars dedicated by a soldier of legio XI Claudia is shown to have been removed from the fabric of Marton church during restoration work and, along with much of the other stone for the Romanesque tower, nave and chancel probably derived from the Roman small town of Segelocum, Littleborough on Trent. The name of the dedicator, G. IVLIVS ANTONINUS, is discussed in the context of legio XI Claudia deployment on the Lower Danube.
Lower limb exoskeleton for gait rehabilitation with adaptive nonsingular sliding mode control
Authors: Centeno-Barreda Daniel , Salazar-Cruz Sergio , López-Gutiérrez Ricardo , Rosales-Luengas Yukio , Lozano Rogelio
Published: October 2024

This paper introduces a lower limb exoskeleton for gait rehabilitation, which has been designed to be adjustable to a wide range of patients by incorporating an extension mechanism and series elastic actuators (SEAs). This configuration adapts better to the user’s anatomy and the natural movements of the user’s joints. However, the inclusion of SEAs increases actuator mass and size, while also introducing nonlinearities and changes in the dynamic response of the exoskeletons. To address the challenges related to the human–exoskeleton dynamic interaction, a nonsingular terminal sliding mode control that integrates an adaptive parameter adjustment strategy is proposed, offering a practical solution for trajectory tracking with uncertain exoskeleton dynamics. Simulation results demonstrate the algorithm’s ability to estimate unknown parameters. Experimental tests analyze the performance of the controller against uncertainties and external disturbances.
Neuropsychological outcomes following endovascular clot retrieval and intravenous thrombolysis in ischemic stroke
Authors: Humphrey Sam , Pike Kerryn E. , Long Brian , Ma Henry , Bourke Robert , Wright Bradley J. , Wong Dana
Published: October 2024

Objectives:

Cognitive impairment, anxiety, depression, fatigue, and dependence in instrumental activities of daily living (ADL) are common after stroke; however, little is known about how these outcomes may differ following treatment with endovascular clot retrieval (ECR), intravenous tissue plasminogen activator (t-PA), or conservative management.

Methods:

Patients were recruited after acute treatment and invited to participate in an outcome assessment 90–120 days post-stroke. The assessment included a cognitive test battery and several questionnaires. The COVID-19 pandemic led to significant disruptions in recruitment and data collection, and the t-PA and conservative management groups were combined into a standard medical care (SMC) group.

Results:

Sixty-two participants were included in the study (ECR = 31, SMC = 31). Mean age was 66.5 (20–86) years, and 35 (56.5%) participants were male. Participants treated with ECR had significantly higher National Institutes of Health Stroke Scale scores at presentation and significantly lower education. After adjusting for stroke severity, premorbid intellectual ability, and age, treatment with ECR was associated with significantly better performances on measures of cognitive screening, visual working memory, and verbal learning and memory. Participants treated with ECR also experienced less fatigue and were more likely to achieve independence in basic and instrumental ADLs. Despite this, cognitive impairment and fatigue were still common among participants treated with ECR and anxiety and depression symptoms were experienced similarly by both groups.

Conclusions:

Cognitive impairment and fatigue were less common but still prevalent following treatment with ECR. This has important practical implications for stroke rehabilitation, and routine assessment of cognition, emotion, and fatigue is recommended for all stroke survivors regardless of stroke treatment and functional outcome.
Environmental shocks and agriculture: implications of floods on labor market outcomes
Authors: Kamble Vikrant K. , Paudel Jayash , Mishra Ashok K.
Published: October 2024

Floods often displace people and exacerbate their access to finance, affecting the livelihood of daily wage workers in least-developed countries. In August 2017, Nepal experienced the heaviest rainfall in more than 60 years, severely flooding about 80 per cent of the land in the southern part of the country. Using the two-way fixed effects approach and an event study design, we evaluate the impact of severe flooding on the wages of agricultural workers. We show that the 2017 floods resulted in a 9–10 per cent decrease in cash wages among agricultural households while in-kind wages of agricultural laborers increased significantly after the floods, implying that in-kind wages helped mitigate the adverse effects of floods on cash wages. We also investigate changes in assistance, loan-seeking behavior, loan repayment, and collection behavior as mechanisms leading to the risk-mitigating behavior by farmers.
Women’s Legislative Representation and Human Rights Treaty Ratification
Authors: Senk Kaitlin , Coulombe Nicholas M. , Edry Jessica
Published: October 2024

Do recent increases in women’s representation around the world have implications for international relations? We argue that greater representation of women in legislatures increases the likelihood of human rights treaty ratification for two reasons. First, given their shared gendered experiences of exclusion and discrimination, women legislators will advocate on behalf of marginalized groups on an international scale as transnational surrogate representatives. Second, women legislators may be more inclined to prioritize the ratification of human rights treaties because these treaties align with their domestic policy preferences, which aim to support marginalized groups. We contend that, in countries where ratification depends upon legislative approval, legislatures are more likely to ratify human rights treaties as women’s presence increases. Using an original dataset of 201 multilateral treaties, we find that countries become more likely to ratify human rights treaties as levels of women’s legislative representation increase.
Intersectional Identity and Representative Politics
Authors: Brown Nadia E. , Clark Christopher J. , Mahoney Anna M. , Siow Orly , Strawbridge Michael G.
Published: October 2024

Representation scholarship has drawn from intersectionality theory 0to examine how systemic structures of oppression and privilege have created social groups with distinct political needs. Derived from Black feminist theory that recognizes that identities are mutually constitutive and interconnected, intersectionality research is rooted in the lived experiences of marginalized groups who call attention to social (in)justice. Empirical scholarship building on the insights of Black feminist theorists such as Collins and Bilge (2016), Hill Collins (1990), Crenshaw (1989; 1991), and King (1988) has constituted nothing less than a paradigm shift in the study of gender and politics. Nevertheless, there remain an array of opportunities to expand upon the potential for intersectional frameworks and methods, as well as pressing new questions concerning the operationalization of intersectionality itself. This Critical Perspectives section offers a moment to take stock of these developments and debates, as well as to highlight new pathways for scholarship committed to centering the margins and considering the nexus of multiple power structures that frame our political lives.
Significance of Urea in Sustaining Nitrite Production by Ammonia Oxidizers in the Oligotrophic Ocean
Authors: Wan Xianhui S. , Sheng Hua‐Xia , Shen Hui , Zou Wenbin , Tang Jin‐Ming , Qin Wei , Dai Minhan , Kao Shuh‐Ji , Ward Bess B.
Published: October 2024

Nitrification, the stepwise oxidation of ammonia to nitrate via nitrite, is a key process in the marine nitrogen cycle. Reported nitrite oxidation rates frequently exceed ammonia oxidation rates below the euphotic zone, raising the fundamental question of whether the two steps are balanced and if alternative sources contribute to nitrite production in the dark ocean. Here we present vertically resolved profiles of ammonia, urea, and nitrite oxidation rates and their kinetic traits in the oligotrophic Subtropical North Pacific. Our results show active urea‐derived nitrogen oxidation (urea‐N oxidation) in the presence of experimental ammonium amendment, suggesting direct urea utilization. The depth‐integrated rates of urea‐N oxidation and ammonia oxidation are comparable, demonstrating that urea‐N oxidation is a significant source of nitrite. The additional nitrite from urea‐N oxidation helps to balance the two steps of nitrification in our study region. Nitrifiers exhibit high affinity for their substrates, and the apparent half‐saturation constants for ammonia and nitrite oxidation decrease with depth. The apparent half‐saturation constant for urea‐N oxidation is higher than that for ammonia oxidation and shows no clear vertical trend. Such kinetic traits may account for the relatively higher urea concentration than ammonium concentration in the ocean's interior. Moreover, a compilation of our results and reported data shows a trend of increased urea‐N oxidation relative to ammonia oxidation from the eutrophic coastal zone to the oligotrophic open ocean. This trend reveals a substrate‐dependent biogeographic distribution of urea‐N oxidation across marine environments and provides new information on the balance and flux of the marine nitrification process.
Initiation of Downward Positive Leader Beneath the Negative Leader Channel
Authors: Zhu Jiangwan , Yuan Shanfeng , Qie Xiushu , Jiang Rubin , Liu Mingyuan , Feng Guili , Wang Yu
Published: October 2024

Due to the weak radiation generated by positive leaders, our understanding of how positive leaders are initiated and reach the ground remains limited. This study investigated positive cloud‐to‐ground (CG) lightning induced after the long intracloud lightning based on high‐speed video and fast antenna mapping results. Below the cloud base in the field of view, re‐breakdowns of decayed negative branches occurred consecutively beneath the horizontal negative channel in the form of bidirectional leaders. These bidirectional leaders advanced along the same channel, and eventually, the third reached the ground, generating a positive return stroke (RS) with a peak current of 157 kA. Following the RS, new negative discharges emerge adjacent to the vertical return stroke channel, persisting and propagating to form a continuing current (CC) lasting over 200 milliseconds.
Comparative Impact of Fog and Rainfall on Vegetation in a Foggy Desert
Authors: Qiao Na , Wang Honglang , Li Yue , Wang Lixin
Published: October 2024

Fog is an important water source that alleviates vegetation water stress, especially for dryland ecosystems. Comprehensive knowledge of fog and rainfall effects can help us better understand dryland vegetation responses to current and future climates. However, the differences between fog and rainfall effects on vegetation are poorly understood. This study compared the effects of fog and rainfall on vegetation greenness changes based on the ground‐level meteorological observations in the Namib Desert and the satellite vegetation index. The vegetation index and its first derivative were utilized to indicate vegetation greenness and its change rate, respectively. Results showed that fog played a more significant role than rainfall in explaining vegetation greenness change rates, while accumulated rainfall was more important than fog in determining vegetation greenness. Soil temperature was an important factor in explaining vegetation greenness changes. These findings offer key insights into how fog and rainfall differentially contribute to vegetation greenness changes.
Tandem light-emitting technology accelerates the commercial application of perovskite LEDs
Authors: Zhang Xiang , Luo Jiajun , Chen Enguo , Mohd Yusoff Abd. Rashid bin
Published: October 2024

Hybrid tandem perovskite-organic LED has been developed to achieve high external quantum efficiency, narrow linewidth, and extended device lifespan, which shows great promise for future perovskite-EL-based commercial applications.
Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα–TRAF3–TAK1–MAPK axis
Authors: Xie Lin , Xue Fei , Cheng Cheng , Sui Wenhai , Zhang Jie , Meng Linlin , Lu Yue , Xiong Wenjing , Bu Peili , Xu Feng , Yu Xiao , Xi Bo , Zhong Lin , Yang Jianmin , Zhang Cheng , Zhang Yun
Published: October 2024

The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.
Loss of miR-200c-3p promotes resistance to radiation therapy via the DNA repair pathway in prostate cancer
Authors: Labbé Maureen , Chang Manon , Saintpierre Benjamin , Letourneur Franck , de Beaurepaire Laurence , Véziers Joëlle , Deshayes Sophie , Cotinat Marine , Fonteneau Jean-François , Blanquart Christophe , Potiron Vincent , Supiot Stéphane , Fradin Delphine
Published: October 2024

Radiotherapy represents a major curative treatment for prostate cancer (PCa), but some patients will develop radioresistance (RR) and relapse. The underlying mechanisms remain poorly understood, and miRNAs might be key players in the acquisition and maintenance of RR. Through their encapsulation in small extracellular vesicles (EVs), they can also be relevant biomarkers of radiation response. Using next-generation sequencing, we found that miR-200c-3p was downregulated in PCa RR cells and in their small EVs due to a gain of methylation on its promoter during RR acquisition. We next showed that its exogenous overexpression restores the radiosensitivity of RR cells by delaying DNA repair through the targeting of HP1α. Interestingly, we also observed downregulation of miR-200c-3p expression by DNA methylation in radiation-resistant lung and breast cancer cell lines. In summary, our study demonstrates that the downregulation of miR-200c-3p expression in PCa cells and in their small EVs could help distinguish radioresistant from sensitive tumor cells. This miRNA targets HP1α to delay DNA repair and promote cell death.
Single-cell spatiotemporal analysis of the lungs reveals Slamf9+ macrophages involved in viral clearance and inflammation resolution
Authors: Cong Boyi , Dong Xuan , Yang Zongheng , Yu Pin , Chai Yangyang , Liu Jiaqi , Zhang Meihan , Zang Yupeng , Kang Jingmin , Feng Yu , Liu Yi , Feng Weimin , Wang Dehe , Deng Wei , Li Fengdi , Song Zhiqi , Wang Ziqiao , Chen Xiaosu , Qin Hua , Yu Qinyi , Li Zhiqing , Liu Shuxun , Xu Xun , Zhong Nanshan , Ren Xianwen , Qin Chuan , Liu Longqi , Wang Jian , Cao Xuetao
Published: October 2024

How the lung achieves immune homeostasis after a pulmonary infection is not fully understood. Here, we analyzed the spatiotemporal changes in the lungs over a 2-week natural recovery from severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection. We find that SARS-CoV-2 infects multiple cell types and causes massive cell death at the early stage, including alveolar macrophages. We identify a group of monocyte-derived Slamf9+ macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9+ macrophages contain SARS-CoV-2, recruit and interact with Isg12+Cst7+ neutrophils to clear the viruses. After viral clearance, Slamf9+ macrophages differentiate into Trem2+ and Fbp1+ macrophages, contributing to inflammation resolution at the late stage, and finally replenish alveolar macrophages. These findings are validated in a SARS-CoV-2-infected hACE2 mouse model and confirmed with publicly available human autopsy single-cell RNA-seq data, demonstrating the potential role of Slamf9+ macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution.
Engineered cross-feeding creates inter- and intra-species synthetic yeast communities with enhanced bioproduction
Authors: Park Young-Kyoung , Peng Huadong , Hapeta Piotr , Sellés Vidal Lara , Ledesma-Amaro Rodrigo
Published: October 2024

Microorganisms can be engineered to sustainably produce a variety of products including fuels, pharmaceuticals, materials, and food. However, highly engineered strains often result in low production yield, due to undesired effects such as metabolic burden and the toxicity of intermediates. Drawing inspiration from natural ecosystems, the construction of a synthetic community with division of labor can offer advantages for bioproduction. This approach involves dividing specific tasks among community members, thereby enhancing the functionality of each member. In this study, we identify six pairs out of fifteen composed of six auxotrophs of Yarrowia lipolytica that spontaneously form robust syntrophic and synergistic communities. We characterize the stability and growth dynamics of these communities. Furthermore, we validate the existence of syntrophic interactions between two yeast species, Y. lipolytica and Saccharomyces cerevisiae, and find a strain combination, Δtrp2 and Δtrp4, forming a stable syntrophic community between two species. Subsequently, we introduce a 3-hydroxypropionic acid (3-HP) biosynthesis pathway into the syntrophic community by dividing the pathway among different strains. Our results demonstrate improved production of 3-HP in both intra- and interspecies communities compared to monocultures. Our results show the stable formation of synthetic syntrophic communities, and their potential in improving bioproduction processes.
Active state structures of a bistable visual opsin bound to G proteins
Authors: Tejero Oliver , Pamula Filip , Koyanagi Mitsumasa , Nagata Takashi , Afanasyev Pavel , Das Ishita , Deupi Xavier , Sheves Mordechai , Terakita Akihisa , Schertler Gebhard F. X. , Rodrigues Matthew J. , Tsai Ching-Ju
Published: October 2024

Opsins are G protein-coupled receptors (GPCRs) that have evolved to detect light stimuli and initiate intracellular signaling cascades. Their role as signal transducers is critical to light perception across the animal kingdom. Opsins covalently bind to the chromophore 11-cis retinal, which isomerizes to the all-trans isomer upon photon absorption, causing conformational changes that result in receptor activation. Monostable opsins, responsible for vision in vertebrates, release the chromophore after activation and must bind another retinal molecule to remain functional. In contrast, bistable opsins, responsible for non-visual light perception in vertebrates and for vision in invertebrates, absorb a second photon in the active state to return the chromophore and protein to the inactive state. Structures of bistable opsins in the activated state have proven elusive, limiting our understanding of how they function as bidirectional photoswitches. Here we present active state structures of a bistable opsin, jumping spider rhodopsin isoform-1 (JSR1), in complex with its downstream signaling partners, the Gi and Gq heterotrimers. These structures elucidate key differences in the activation mechanisms between monostable and bistable opsins, offering essential insights for the rational engineering of bistable opsins into diverse optogenetic tools to control G protein signaling pathways.
Streamlined analysis of drug targets by proteome integral solubility alteration indicates organ-specific engagement
Authors: Batth Tanveer Singh , Locard-Paulet Marie , Doncheva Nadezhda T. , Lopez Mendez Blanca , Jensen Lars Juhl , Olsen Jesper Velgaard
Published: October 2024

Proteins are the primary targets of almost all small molecule drugs. However, even the most selectively designed drugs can potentially target several unknown proteins. Identification of potential drug targets can facilitate design of new drugs and repurposing of existing ones. Current state-of-the-art proteomics methodologies enable screening of thousands of proteins against a limited number of drug molecules. Here we report the development of a label-free quantitative proteomics approach that enables proteome-wide screening of small organic molecules in a scalable, reproducible, and rapid manner by streamlining the proteome integral solubility alteration (PISA) assay. We used rat organs ex-vivo to determine organ specific targets of medical drugs and enzyme inhibitors to identify drug targets for common drugs such as Ibuprofen. Finally, global drug profiling revealed overarching trends of how small molecules affect the proteome through either direct or indirect protein interactions.
Rumicidins are a family of mammalian host-defense peptides plugging the 70S ribosome exit tunnel
Authors: Panteleev Pavel V. , Pichkur Eugene B. , Kruglikov Roman N. , Paleskava Alena , Shulenina Olga V. , Bolosov Ilia A. , Bogdanov Ivan V. , Safronova Victoria N. , Balandin Sergey V. , Marina Valeriya I. , Kombarova Tatiana I. , Korobova Olga V. , Shamova Olga V. , Myasnikov Alexander G. , Borzilov Alexander I. , Osterman Ilya A. , Sergiev Petr V. , Bogdanov Alexey A. , Dontsova Olga A. , Konevega Andrey L. , Ovchinnikova Tatiana V.
Published: October 2024

The antimicrobial resistance crisis along with challenges of antimicrobial discovery revealed the vital necessity to develop new antibiotics. Many of the animal proline-rich antimicrobial peptides (PrAMPs) inhibit the process of bacterial translation. Genome projects allowed to identify immune-related genes encoding animal host defense peptides. Here, using genome mining approach, we discovered a family of proline-rich cathelicidins, named rumicidins. The genes encoding these peptides are widespread among ruminant mammals. Biochemical studies indicated that rumicidins effectively inhibited the elongation stage of bacterial translation. The cryo-EM structure of the Escherichia coli 70S ribosome in complex with one of the representatives of the family revealed that the binding site of rumicidins span the ribosomal A-site cleft and the nascent peptide exit tunnel interacting with its constriction point by the conservative Trp23-Phe24 dyad. Bacterial resistance to rumicidins is mediated by knockout of the SbmA transporter or modification of the MacAB-TolC efflux pump. A wide spectrum of antibacterial activity, a high efficacy in the animal infection model, and lack of adverse effects towards human cells in vitro make rumicidins promising molecular scaffolds for development of ribosome-targeting antibiotics.
Ex vivo imaging reveals the spatiotemporal control of ovulation
Authors: Thomas Christopher , Marx Tabea Lilian , Penir Sarah Mae , Schuh Melina
Published: October 2024

During ovulation, an egg is released from an ovarian follicle, ready for fertilization. Ovulation occurs inside the body, impeding direct studies of its progression. Therefore, the exact mechanisms that control ovulation have remained unclear. Here we devised live imaging methods to study the entire process of ovulation in isolated mouse ovarian follicles. We show that ovulation proceeds through three distinct phases, follicle expansion (I), contraction (II) and rupture (III), culminating in the release of the egg. Follicle expansion is driven by hyaluronic acid secretion and an osmotic gradient-directed fluid influx into the follicle. Then, smooth muscle cells in the outer follicle drive follicle contraction. Follicle rupture begins with stigma formation, followed by the exit of follicular fluid and cumulus cells and the rapid release of the egg. These results establish a mechanistic framework for ovulation, a process of fundamental importance for reproduction.
The dynamics of blaTEM resistance genes in Salmonella Typhi
Authors: Nuanmuang Narong , Leekitcharoenphon Pimlapas , Njage Patrick Murigu Kamau , Thorn Alix Vincent , Aarestrup Frank M.
Published: October 2024

Salmonella Typhi (S. Typhi) is an important pathogen causing typhoid fever worldwide. The emergence of antibiotic resistance, including that of blaTEM genes encoding to TEM $$\:\beta\:$$-lactamases has been observed. This study aimed to investigate the dynamics of blaTEM genes in S. Typhi by analyzing the phylogeny and flanking region patterns and phylogenetic associating them with metadata (year, country) and genomic data (genotypes, antibiotic resistance genes (ARGs), plasmids). Genomic sequences of publicly available S. Typhi harboring blaTEM (n = 6079), spanning from 1983 to 2023, were downloaded and analyzed using CSIPhylogeny for phylogeny, Flankophile for identifying genetic contexts around blaTEM genes and GenoTyphi for determining genotypes, ARGs and plasmid replicons. We found that blaTEM-positive isolates occurred most commonly in specific location, especially in Asia and Africa and clustered among a limited number of genotypes. Flankophile identified 740 isolates (12.2%) with distinct flanking region patterns, which were categorized into 13 patterns. Notably, 7 patterns showed a predominantly phylogenetic association with genotypes. Additionally, these 7 patterns exhibited relation to the country, ARGs and plasmid replicons. Further examination of the flanking region patterns provided association with mobile genetic elements (MGEs). Taken together, this study suggests that blaTEM has been acquired by S. Typhi isolates a limited number of times and subsequently spread clonally with specific genotypes.
The value of systemic immune inflammation index, white blood cell to platelet ratio, and homocysteine in predicting the instability of small saccular intracranial aneurysms
Authors: Zhang Wanwan , Xiang Chao , Liu Boliang , Hou Fandi , Zheng Zhanqiang , Chen Zhongcan , Suo Lina , Feng Guang , Gu Jianjun
Published: October 2024

Inflammation has a destructive effect on the homeostasis of the vascular wall, which is involved in the formation, growth, and rupture of human intracranial aneurysms (IAs) disease progression. However, inflammation-related markers have not been well studied in the risk stratification of unruptured IAs. The purpose of this study was to investigate the predictive value of serum inflammatory markers in the unstable progression of small saccular intracranial aneurysms (SIAs). This study retrospectively included 275 patients with small SIAs (aneurysm diameter less than or equal to 7 mm), to compare the level difference of serum inflammatory complex marker systemic immune-inflammatory index (SII), white blood cell to platelet ratio (WPR), and homocysteine (Hcy) in patients with stable (asymptomatic unruptured) and unstable (symptomatic unruptured, ruptured) small SIAs. 187 patients (68%) had aneurysm-related compression symptoms and rupture outcomes. In the multivariate logistic regression after adjusting for baseline differences, SII, WPR, and Hcy were independent risk factors for the instability of small SIAs, the prediction model combined with other risk factors (previous stroke history, aneurysm irregularity) showed good predictive ability for the instability of small SIAs, with an area under the curve of 0.905. In addition, correlation analysis showed that SII, WPR, and Hcy also had significant differences in patients with symptomatic unruptured and ruptured small SIAs, and higher inflammation levels often promoted the disease progression of small SIAs. Higher levels of SII, WPR and Hcy can be used as independent predictors of instability of small SIAs. As an economical and convenient biomarker, it is crucial for clinical treatment strategies of stable small SIAs.
Lessons learned from 12 years using the Woven Endobridge for the treatment of cerebral aneurysms in a multi-center series
Authors: Goertz Lukas , Liebig Thomas , Siebert Eberhard , Zopfs David , Pennig Lenhard , Pflaeging Muriel , Schlamann Marc , Radomi Alexandra , Dorn Franziska , Kabbasch Christoph
Published: October 2024

Intrasaccular flow disruption with the Woven Endobridge (WEB) has become a well-established endovascular technique for the treatment of intracranial aneurysms. This study presents our 12-year experience with the WEB and evaluates its evolving indications, procedures, and outcomes. A consecutive series of 324 aneurysms treated with WEB between 2011 and 2023 at three neurovascular centers was retrospectively analyzed and the study group was divided into four treatment periods. Uni- and multivariate analyses were performed to evaluate factors associated with technical success, thromboembolic complications, and angiographic outcome. The mean aneurysm size was 7.0 ± 3.6 mm and decreased during the study period, while the proportion of atypical sites for WEB implantation increased. WEB implantation was technically successful in 96.0%, and the ratio of WEB width to dome width increased during the study period, indicating oversizing. The neurological complication rate was 4.9% (1.5% major, 3.4% minor) and the mid-term complete occlusion rate was 60.6% (81.9% adequate occlusion), with no statistical differences in either outcome measure between the study periods. In multivariate analyses, the use of WEB 17 was associated with increased technical success (HR: 7.4, 95%CI: 2.4-23.6, p<0.01), whereas ruptured aneurysm status (HR: 2.5, 95%CI: 1.0-6.0, p=0.04) and the use of additional stents (HR: 4.8, 95%CI: 1.6-14.4, p<0.01) predicted thromboembolic complications. Appropriate oversizing of the WEB favored mid-term complete occlusion (HR: 10.5, 95%CI: 1.3-83.3, p=0.03). The results suggest an expansion of the indications for WEB implantation and highlight the importance of oversizing for treatment efficacy.
Effects of inorganic phosphate on stem cells isolated from human exfoliated deciduous teeth
Authors: Suwittayarak Ravipha , Nowwarote Nunthawan , Kornsuthisopon Chatvadee , Sukarawan Waleerat , Foster Brian L , Egusa Hiroshi , Osathanon Thanaphum
Published: October 2024

Calcium phosphate-based materials (CaP) are introduced as potential dental pulp capping materials for deciduous teeth. The present study investigated the influence of inorganic phosphate (Pi) on regulating stem cells isolated from human exfoliated deciduous teeth (SHED). SHEDs were treated with Pi. Cell cycle progression and apoptosis were examined using flow cytometry analysis. Osteo/odontogenic and adipogenic differentiation were analyzed using alizarin red S and oil red O staining, respectively. The mRNA expression profile was investigated using a high-throughput RNA sequencing technique. Pi increased the late apoptotic cell population while cell cycle progression was not altered. Pi upregulated osteo/odontoblastic gene expression and enhanced calcium deposition. Pi-induced mineralization was reversed by pretreatment of cells with Foscarnet, or p38 inhibitor. Pi treatment inhibited adipogenic differentiation as determined by decreased PPARγ expression and reduced intracellular lipid accumulation. Bioinformatic analysis of gene expression profiles demonstrated several involved pathways, including PI3K/AKT, MAPK, EGFR, and VEGF signaling. In conclusion, Pi enhanced osteo/odontogenic but inhibited adipogenic differentiation in SHED.
Acceptance as a possible link between past psychedelic experiences and psychological flexibility
Authors: Krabbe Andreas , Sikka Pilleriin , Jylkkä Jussi
Published: October 2024

Increased psychological flexibility (PF) may underlie the lasting positive effects of psychedelic experiences on mental well-being. The associations between different components of PF, psychological inflexibility (PI), and well-being with psychedelic use are not well understood. We conducted a cross-sectional internet survey of participants (N = 629) with experience of classical psychedelics. Using network analysis, we examined how aspects of a single psychedelic experience (mystical-type features and psychological insights) and the frequency of past psychedelic use, were associated with current PF and PI components, as well as with mental well-being and ill-being. Mediation analyses explored whether PF mediated the relationship between past psychedelic use and well-being or ill-being. The network analysis linked psychological insight to the PF component Acceptance, with no association found between the frequency of past use and PF. Mediation analyses showed PF mediates the association between past psychedelic use and well-being and ill-being. These results suggest that the quality and depth of the psychedelic experience, rather than the frequency of use, are primarily linked to psychological flexibility, particularly Acceptance, and overall well-being. This underscores the importance of treating PF as a multidimensional construct to better understand the long-term mental health benefits of psychedelics.
Immunomodulatory effect of IFN-γ licensed adipose-mesenchymal stromal cells in an in vitro model of inflammation generated by SARS-CoV-2 antigens
Authors: Bispo Elizabete Cristina Iseke , Argañaraz Enrique Roberto , Neves Franscisco de Assis Rocha , de Carvalho Juliana Lott , Saldanha-Araujo Felipe
Published: October 2024

In recent years, clinical studies have shown positive results of the application of Mesenchymal Stromal Cells (MSCs) in severe cases of COVID-19. However, the mechanisms of immunomodulation of IFN-γ licensed MSCs in SARS-CoV-2 infection are only partially understood. In this study, we first tested the effect of IFN-γ licensing in the MSC immunomodulatory profile. Then, we established an in vitro model of inflammation by exposing Calu-3 lung cells to SARS-CoV-2 nucleocapsid and spike (NS) antigens, and determined the toxicity of SARS-CoV-2 NS antigen and/or IFN-γ stimulation to Calu-3. The conditioned medium (iCM) generated by Calu-3 cells exposed to IFN-γ and SARS-CoV-2 NS antigens was used to stimulate T-cells, which were then co-cultured with IFN-γ-licensed MSCs. The exposure to IFN-γ and SARS-CoV-2 NS antigens compromised the viability of Calu-3 cells and induced the expression of the inflammatory mediators ICAM-1, CXCL-10, and IFN-β by these cells. Importantly, despite initially stimulating T-cell activation, IFN-γ-licensed MSCs dramatically reduced IL-6 and IL-10 levels secreted by T-cells exposed to NS antigens and iCM. Moreover, IFN-γ-licensed MSCs were able to significantly inhibit T-cell apoptosis induced by SARS-CoV-2 NS antigens. Taken together, our data show that, in addition to reducing the level of critical cytokines in COVID-19, IFN-γ-licensed MSCs protect T-cells from SARS-CoV-2 antigen-induced apoptosis. Such observations suggest that MSCs may contribute to COVID-19 management by preventing the lymphopenia and immunodeficiency observed in critical cases of the disease.