bluuebunny/crossref_metadata_2025 huggingface dataset:
The Volunteer State: Latinx youth and the making of membership in Nashville, Tennessee
Authors: Flores Andrea
Published: July 2023

Volunteering has long held a vaunted position in the United States, which has only increased in the wake of welfare reform and the state's retraction from the provision of public goods. This article explores how immigrant‐origin Latinx youth in Nashville, Tennessee, who are active community volunteers, linked volunteering to moral personhood and their claims to national membership. This linkage is based on an internalized deficit perception of the Latinx immigrant person as an immoral national interloper and a concurrent stigmatization and racialization of economic need. However, youth also reframed membership and volunteering's meanings rooted in their relational commitments to each other and their undocumented peers' blocked paths to citizenship. These socially reproductive and more transformative understandings of volunteering, and their links to self‐as‐citizen, reveal the contingent value of civic engagement for immigrant‐origin Latinx youth. It also reveals their central roles in defining the parameters of membership in an era of increased nativist racism and decreased state social service provision in the United States.
Modulation of carcinogenesis with selected GRAS nutraceuticals via Keap1‐Nrf2 signaling pathway
Authors: Nair Bhagyalakshmi , Adithya Jayaprakash K. , Chandrababu Gopika , Lakshmi P. K. , Koshy Joel Joy , Manoj Sreedharan Vilasini , Ambiliraj D. B. , Vinod Balachandran S. , Sethi Gautam , Nath Lekshmi R.
Published: July 2023

Keap1‐Nrf2 is a fundamental signaling cascade known to promote or prevent carcinogenesis. Extensive studies identify the key target of modulatory aspects of Keap1‐Nrf2 signaling against cancer. Nutraceuticals are those dietary agents with many health benefits that have immense potential for cancer chemoprevention. The nutritional supplements known as nutraceuticals are found to be one of the most promising chemoprevention agents. Upon investigating the dual nature of Nrf2, it became clear that, in addition to shielding normal cells from numerous stresses, Nrf2 may also promote the growth of tumors. In the present review, we performed a systematic analysis of the role of 12 different nutraceuticals like curcumin, sulforaphane, resveratrol, polyunsaturated fatty acids (PUFA) from fish oil, lycopene, soybean, kaempferol, allicin, thymoquinone, quercetin, gingerol, and piperine in modulating the Nrf2/Keap1 signaling mechanism. Among these, 12 Generally Recognized As Safe (GRAS) certified nutraceuticals, sulforaphane is the most extensively studied compound in modulating Keap1‐Nrf signaling. Even though there is much evidence at preclinical levels, further high‐quality research is still required to validate the potential role of these nutraceuticals in Keap1‐Nrf2 modulation.
Scalable Synthesis of ZrO2 Nanoparticles through Imidazolic Precursor and Evaluation of its Energy Storage Performance
Authors: Raj Benjamin , Pandurangan Perumal , Basu Suddhasatwa , Sourav Smruti , Padhy Arun Kumar , Mohapatra Mamata
Published: July 2023

Herein, we reported the facile synthesis of zirconium oxide (ZrO2) nanoparticles from an imidazole based organic precursor followed by calcination of 750 °C in the thermostat. The bonding properties of the as‐synthesized nanoparticles were examined by FTIR and Raman spectroscopy. X‐Ray Diffraction (XRD) analysed the phase formation of nanoparticles, and spherical‐shaped nanoparticles were examined by Field Emission Scanning Electron Microscope (FESEM) and Transmission Electron Microscope (TEM) spectroscopy. The high surface area of 65 m2 g−1 was analysed by the N2 adsorption‐desorption isotherm using a Brunauer‐Emmett‐Teller (BET) surface analyser. The electrochemical performance, like cyclic voltammetry (CV), galvanometric charging‐discharging (GCD) and impedance spectroscopy (EIS), were analysed. The electrochemical performances were carried out by using aqueous electrolytes of 1 M KOH. The specific capacitance was observed 246.98 F g−1. The asymmetric supercapacitor device (ASC) is fabricated using synthesized ZrO2 nanoparticles/activated charcoal (AC). The device exhibits utmost specific capacitance of 29.15 F g−1, and energy density of 13 Wh kg−1 with a power of 3201 W kg−1, respectively. The device maintains excellent coulombic efficiency, and the value is more than 98 % after the 3000 charge‐discharge cycles. The enhanced electrochemical properties of zirconium oxide are due to the high surface area and porous nature.
Sunda pangolins show inconsistent responses to disturbances across multiple scales
Authors: Nursamsi Ilyas , Amir Zachary , Decoeur Henri , Moore Jonathan H. , Luskin Matthew Scott
Published: July 2023

Pangolins are the most trafficked animals worldwide and are presumed to be restricted to pristine habitats due to poaching intensity in more accessible degraded areas or intrinsic habitat preferences. We tested the hypothesis that pangolins' could persist in degraded areas and near humans if poaching is controlled. We used occurrence records from new and published camera trapping studies from across Southeast Asia to conduct a multiscale analysis of habitat associations for the Critically Endangered Sunda pangolin, encompassing poached and non‐poached areas. Our results were highly influenced by Singapore, where pangolins are common in urban settings and there is minimal poaching. Excluding Singapore, there were no significant landscape‐level habitat associations, reflecting pangolins are habitat generalists. At local scales (including and excluding Singapore), occupancy was negatively correlated with active deforestation but not previously degraded forests. We conclude that with strong antipoaching enforcement, pangolins are unexpectedly adaptable, with Singapore exemplifying the potential for species recovery.
Analysis of the As-Cast Microstructure and Properties of the Ni-Based Superalloy MAR-M247® Produced Via Directional Solidification
Authors: Rakoczy Łukasz , Grudzień-Rakoczy Małgorzata , Cygan Rafał , Kargul Tomasz , Maj Łukasz , Zielińska-Lipiec Anna
Published: July 2023

The presented research investigates MAR-M247® Ni-based superalloy castings produced via directional solidification at various mold preheating temperatures (1510, 1566 °C) and withdrawal rates (3.4, 5.0 mm/min). Casting analyses were carried out via thermodynamic simulations, differential scanning calorimetry (DSC), X-ray diffraction (XRD), light microscopy (LM), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), scanning transmission electron microscopy (STEM), and tensile testing. On DSC curve, four effects have been registered during cooling: liquidus (1337 °C), formation of eutectic γ − γ′ (1315 °C), precipitation of Ni7(Hf, Zr)2 (1244 °C), and M5B3 borides (1201 °C). The castings’ primary and secondary dendrite arm spacing decreases with increasing withdrawal rates for both shell mold temperatures. The dendritic regions of the castings are characterized by a relatively homogenous microstructure, consisting of γ′ precipitates surrounded by the matrix, with a mean size in the range of 0.437 to 0.481 μm, depending on the casting parameters. In the interdendritic spaces, γ − γ′ eutectic, MC carbides, M5B3, Ni7(Hf, Zr)2, and M3C2 phases were identified. The ultimate tensile strength of the produced castings was in the range of 970 to 1088 MPa.
Extracellular vesicles derived from umbilical cord mesenchymal stromal cells show enhanced anti-inflammatory properties via upregulation of miRNAs after pro-inflammatory priming
Authors: Hyland Mairead , Mennan Claire , Davies Rebecca , Wilson Emma , Tonge Daniel P. , Clayton Aled , Kehoe Oksana
Published: July 2023

Autoimmune conditions, such as rheumatoid arthritis, are characterised by a loss of immune tolerance, whereby the immune cells attack self-antigens causing pain and inflammation. These conditions can be brought into remission using pharmaceutical treatments, but often have adverse side effects and some patients do not respond favourably to them. Human umbilical cord mesenchymal stromal cells (UCMSCs) present a promising alternative therapeutic due to their innate anti-inflammatory properties which can be strengthened using pro-inflammatory conditions. Their therapeutic mechanism of action has been attributed to paracrine signalling, by which nanosized acellular particles called ‘extracellular vesicles’ (EVs) are one of the essential components. Therefore, this research analysed the anti-inflammatory properties of UCMSC-EVs ‘primed’ with pro-inflammatory cytokines and at baseline with no inflammatory cytokines (control). Both control and primed EVs were co-cultured with un-pooled peripheral blood mononuclear cells (PBMCs; n = 6) from healthy donors. Neither control nor primed EVs exerted a pro-inflammatory effect on PBMCs. Instead, the primed EVs showed the immunosuppressive potential by increasing the expression of the anti-inflammatory protein FoxP3 in PBMCs. This may be attributed to the upregulated miRNAs identified in primed EVs in comparison to control EVs (miR-139-5p, miR-140-5p, miR-214-5p). These findings aid in understanding how UCMSC-EVs mediate immunosuppression and support their potential use in treating autoimmune conditions.

Graphical Abstract
SCN5A-1795insD founder variant: a unique Dutch experience spanning 7 decades
Authors: Proost Virginnio M. , van den Berg Maarten P. , Remme Carol Ann , Wilde Arthur A. M.
Published: July 2023

The SCN5A-1795insD founder variant is a unique SCN5A gene variant found in a large Dutch pedigree that first came to attention in the late 1950s. To date, this is still one of the largest and best described SCN5A founder families worldwide. It was the first time that a single pathogenic variant in SCN5A proved to be sufficient to cause a sodium channel overlap syndrome. Affected family members displayed features of Brugada syndrome, cardiac conduction disease and long QT syndrome type 3, thus encompassing features of both loss and gain of sodium channel function. This brief summary takes us past 70 years of clinical experience and over 2 decades of research. It is remarkable to what extent researchers and clinicians have managed to gain understanding of this complex phenotype in a relatively short time. Extensive clinical, genetic, electrophysiological and molecular studies have provided fundamental insights into SCN5A and the cardiac sodium channel Nav1.5.
Exercise does not influence development of phenotype in PLN p.(Arg14del) cardiomyopathy
Authors: van Lint Freyja H. M. , Hassanzada Fahima , Verstraelen Tom E. , Wang Weijia , Bosman Laurens P. , van der Zwaag Paul A. , Oomen Toon , Calkins Hugh , Murray Brittney , Tichnell Crystal , Beuren Thais M. A. , Asselbergs Folkert W. , Houweling Arjan , van den Berg Maarten P. , Wilde Arthur A. M. , James Cynthia A. , van Tintelen J. Peter
Published: July 2023

Background

Endurance and frequent exercise are associated with earlier onset of arrhythmogenic right ventricular cardiomyopathy (ARVC) and ventricular arrhythmias (VA) in desmosomal gene variant carriers. Individuals with the pathogenic c.40_42del; p.(Arg14del) variant in the PLN gene are frequently diagnosed with ARVC or dilated cardiomyopathy (DCM). The aim of this study was to evaluate the effect of exercise in PLN p.(Arg14del) carriers.

Methods

In total, 207 adult PLN p.(Arg14del) carriers (39.1% male; mean age 53 ± 15 years) were interviewed on their regular physical activity since the age of 10 years. The association of exercise with diagnosis of ARVC, DCM, sustained VA and hospitalisation for heart failure (HF) was studied.

Results

Individuals participated in regular physical activities with a median of 1661 metabolic equivalent of task (MET) hours per year (31.9 MET-hours per week) until clinical presentation. The 50% most and least active individuals had a similar frequency of sustained VA (18.3% vs 18.4%; p = 0.974) and hospitalisation for HF (9.6% vs 8.7%; p = 0.827). There was no relationship between exercise and survival free from (incident) sustained VA (p = 0.65), hospitalisation for HF (p = 0.81), diagnosis of ARVC (p = 0.67) or DCM (p = 0.39) during follow-up. In multivariate analyses, exercise was not associated with sustained VA or HF hospitalisation during follow-up in this relatively not-active cohort.

Conclusion

There was no association between the amount of exercise and the susceptibility to develop ARVC, DCM, VA or HF in PLN p.(Arg14del) carriers. This suggested unaffected PLN p.(Arg14del) carriers can safely perform mild-moderate exercise, in contrast to desmosomal variant carriers and ARVC patients.
Individual and combined effects of deoxynivalenol (DON) with other Fusarium mycotoxins on rainbow trout (Oncorhynchus mykiss) growth performance and health
Authors: Koletsi Paraskevi , Wiegertjes Geert F. , Graat Elisabeth A. M. , de Kool Marijn , Lyons Philip , Schrama Johan W.
Published: July 2023

This study assessed whether the toxicological effects of deoxynivalenol (DON) produced by Fusarium graminearum in rainbow trout (Oncorhynchus mykiss) are altered by the co-exposure to a mixture of toxins produced by Fusarium verticillioides (FUmix). This FUmix contained fusaric acid and fumonisin B1, B2 and B3. Four diets were formulated according to a 2 × 2 factorial design: CON-CON; CON-FUmix; DON-CON; and DON-FUmix. Diets with and without DON contained on average 2700 and 0 µg/kg feed, respectively. The sum of the analysed FUmix toxins was 12,700 and 100 µg/kg feed in the diets with and without FUmix, respectively. The experiment consisted of a 6-week restrictive feeding period immediately followed by a 2-week ad libitum feeding period. Growth performance measurements were taken per feeding period. Histopathological measurements in the liver and gastrointestinal tract (pyloric caeca, midgut and hindgut) were assessed at the end of week 1 and week 6 of the restrictive feeding period and at week 8, the last day of the ad libitum feeding period. During both restrictive and ad libitum feeding, the effects of FUmix and DON on growth performance were additive (no interaction effect; p > 0.05). During the restrictive feeding period, exposure to DON (p ≤ 0.001) and FUmix (p ≤ 0.01) inhibited growth and increased feed conversion ratio (FCR). During this period, DON exposure decreased the protein (p ≤ 0.001) and energy retention (p ≤ 0.05) in the trout. During the ad libitum feeding period, FUmix affected HSI (p ≤ 0.01), while DON exposure reduced feed intake (p ≤ 0.001) and growth (p ≤ 0.001) and increased FCR (p ≤ 0.01). In general, for both liver and intestinal tissue measurements, no interaction effects between DON and FUmix were observed. In the liver, histopathological analysis revealed mild alterations, increased necrosis score by DON (p ≤ 0.01), increased glycogen vacuolization by FUmix (p ≤ 0.05) and decreased percentage of pleomorphic nuclei by FUmix (p ≤ 0.01). DON had a minor impact on the intestinal histological measurements. Over time, some of the liver (glycogen vacuolization score, pleomorphic nuclei; p ≤ 0.01) and intestinal measurements (mucosal fold and enterocyte width; p ≤ 0.01) were aggravated in fish fed the FUmix contaminated diets, with the most severe alterations being noted at week 8. Overall, the co-exposure to FUmix and DON gave rise to additive effects but showed no synergistic or antagonistic effects for the combination of DON with other Fusarium mycotoxins.
DEM study on the effect of particle shape on the shear behaviour of granular materials
Authors: Adesina Peter , O’Sullivan Catherine , Wang Teng
Published: July 2023

This study investigates the effects of particle convexity, sphericity and aspect ratio (AR) on the behaviour of sheared granular materials using two-dimensional discrete element method simulations. Isotropic, dense and loose assemblies with different particle shapes were prepared and subjected to drained shearing via biaxial compression until the critical state was reached. Macroscopic characteristics such as strength and dilatancy are presented. The factors underlying the macroscopic behaviour are then investigated by considering the coordination number, fabric anisotropy, particle moment, friction mobilisation at contacts and particle rotation. For the range of shapes considered here, the data indicate that the shear strength decreases as particle convexity and sphericity increases while the shear strength increases with increasing AR. The shear strength and convexity are weakly correlated, however a stronger correlation is observed between AR and strength. The volumetric strain at large strains tends to increase with increasing AR. There is a stronger correlation between the critical state strength and both the critical state coordination number and the critical state mechanical void ratio than there is between the critical state void ratio and the critical state strength. The contact fabric anisotropy, the magnitude of the moment transmitted by particles and the friction mobilised at the contacts are important factors underlying strength. The critical state strength increases as both the mean particle moment and the mean mobilised friction increased. Analysis of particle rotation provides insights into the response of the granular materials to shearing.
Novel C-Shaped Shape Memory Alloy Connectors for Vacuum Flanges: Modeling and Tests
Authors: Niccoli F. , Scalet G. , Giovinco V. , Garion C. , Maletta C. , Chiggiato P. , Auricchio F.
Published: July 2023

Shape memory alloy (SMA)-based fasteners and connectors represent a class of successful SMA components that are increasingly used especially in marine or aerospace applications. The present paper aims to investigate novel C-Shaped SMA connectors for room-temperature vacuum pipes within particle accelerators. The proposed connectors exhibit the two-way shape memory effect (TW-SME), so they can generate significant axial recovery forces and they can be dismounted by temperature variations. Proper thermo-mechanical training procedures were performed to tune the mechanical and functional response of the connectors to make them suitable for the investigated application. The thermo-mechanical and functional response of the SMA fasteners in both free and constrained recovery conditions were assessed by strain gauge and extensometer tests as well as by finite element analyses based on a constitutive model, recently developed by the authors, accounting for TW-SME and plasticity. Comparison between experimental and numerical results validates the proposed model. Moreover, results give useful, important information in terms of SMA transformation temperatures, generated recovery forces as well as shape recovery capabilities.
A Hybrid Strategy Enhanced Sub-Sampled Recursive Second Order Algorithm for Chemical Process Intelligent Identification
Authors: Wang Yaxin , Xu Baochang
Published: July 2023

The accurate dynamic model of the chemical process is an important condition for the successful implementation of advanced control in the plant. In this paper, an efficient second order algorithm for long short-term memory (LSTM) network training is proposed for chemical process intelligent identification. A novel Hessian inverse recursion method is adopted to achieve fast convergence and avoid the high-cost operation of the classic second order optimization method. Besides, more information is back propagated since the proposed method retains the real curvature information of the neural network. Considering the large amount of chemical process data, a sub-sampled recursive second order-stochastic gradient descent (SRSO-SGD) algorithm which uses sub-sampling method and hybrid strategy is proposed. The identification experiment on a delayed coker fractionator shows that the proposed sub-sampled neural network second order training algorithm has better performance than other learning algorithms in terms of model identification accuracy and convergence speed. By adopting a hybrid strategy that performing Hessian inverse estimation every 3 training epochs, the expensive Hessian inverse calculation cost in the identification process is further reduced while low training and testing errors are maintained.
Trustworthy AI: a plea for modest anthropocentrism
Authors: Nyrup Rune
Published: July 2023

Simion and Kelp defend a non-anthropocentric account of trustworthy AI, based on the idea that the obligations of AI systems should be sourced in purely functional norms. In this commentary, I highlight some pressing counterexamples to their account, involving AI systems that reliably fulfil their functions but are untrustworthy because those functions are antagonistic to the interests of the trustor. Instead, I outline an alternative account, based on the idea that AI systems should not be considered primarily as tools but as technological participants in social practices. Specifically, I propose to source the obligations of an AI system in the norms that should govern the role it plays within the social practices it participates in, taking into account any changes to the social practices that its participation may bring about. This proposal is anthropocentric insofar as it ascribes obligations to AI systems that are similar to those of human participants in social practices, but only modestly so, as it does not require trustworthy AI to have contentious anthropomorphic capacities (e.g. for consciousness or moral responsibility).
Mathematical Analysis of Machine Learning Algorithms
Authors: Zhang Tong
Published: July 2023

The mathematical theory of machine learning not only explains the current algorithms but can also motivate principled approaches for the future. This self-contained textbook introduces students and researchers of AI to the main mathematical techniques used to analyze machine learning algorithms, with motivations and applications. Topics covered include the analysis of supervised learning algorithms in the iid setting, the analysis of neural networks (e.g. neural tangent kernel and mean-field analysis), and the analysis of machine learning algorithms in the sequential decision setting (e.g. online learning, bandit problems, and reinforcement learning). Students will learn the basic mathematical tools used in the theoretical analysis of these machine learning problems and how to apply them to the analysis of various concrete algorithms. This textbook is perfect for readers who have some background knowledge of basic machine learning methods, but want to gain sufficient technical knowledge to understand research papers in theoretical machine learning.
What counts as a multimodal metaphor and metonymy? Evolution of inter-rater reliability across rounds of annotation
Authors: Pérez Sobrino Paula , Ford Samantha
Published: July 2023

An open question in research on multimodal figuration is how to mitigate the analyst’s bias in identifying and interpreting metaphor and metonymy; an issue that determines the generalizability of the findings. Little is known about the causes that motivate different annotations. Inter-rater reliability tests are useful to investigate the sources of variation in annotations by independent researchers that can help inform and refine protocols.

Inspired by existing procedures for verbal, visual, and filmic metaphor identification, we formulated instructions to identify multimodal metaphor and metonymy and tested it against a corpus of 21 generic advertisements and 21 genre-specific advertisements (mobile phones). Two independent researchers annotated the advertisements in six rounds. A joint discussion followed each round to consider conflicting annotations and refine the protocol for the ensuing round.

By examining the evolution of inter-rater reliability results, we found that (1) we reached similar levels of agreement for the identification of metaphor and metonymy, although converging on the interpretation of metonymy was more difficult; (2) some genre specificities made it easier to agree on the annotations for mobile advertisements than for the general advertisements; and (3) there was a consistent increase in the kappa scores reaching substantial agreement by the sixth round.
Impact of implementing a free varicella vaccination policy on incidence in Wuxi City, China: an interrupted time series analysis
Authors: Xiu Shixin , Wang Xuwen , Wang Qiang , Jin Hui , Shen Yuan
Published: July 2023

Varicella vaccination is optional and requires self-payment. On 1 December 2018, Wuxi City launched a free varicella vaccination program for children. This study aimed to evaluate the changes in varicella incidence before and after the implementation of the policy. The data were obtained from official information systems and statistical yearbooks. We divided the period into chargeable (January 2017 to November 2018) and free (December 2018 to December 2021) periods. Interrupt time series analysis was used to conduct a generalised least-squares regression analysis for the two periods. A total of 51,071 varicella cases were reported between January 2017 and December 2021. After the implementation of the policy, there was a statistically significant decrease in the incidence of varicella (β2 = −0.140, P = 0.017), and the slope of the incidence also decreased by 0.012 (P = 0.015). Following policy implementation, the incidence decreased in all age groups, with the largest decline observed among children aged 8–14 years (β2 = −1.109, P = 0.009), followed by children aged ≤7 years (β2 = −0.894, P = 0.013). Our study found a significant reduction in the incidence of varicella in the total population after the introduction of free varicella vaccination in Wuxi City.
Hydrogeomorphology of Asymmetric Meandering Channels: Experiments and Field Evidence
Authors: Abad J. D. , Motta D. , Guerrero L. , Paredes M. , Kuroiwa J. M. , Garcia M. H.
Published: July 2023

Meandering channels display complex planform configurations with upstream (US)‐ and downstream (DS)‐skewed bends. Bend orientation is linked to hydrodynamics, bed morphodynamic regime, bank characteristics, riparian vegetation, and geological environment, which are the modulating factors that act specially in high‐amplitude and high‐sinuosity conditions. Based on the interaction between hydrodynamics and morphodynamics, previous studies have suggested that sub‐ (β < βR) and super‐resonant (β > βR) morphodynamic regimes (where β is the half width‐to‐depth ratio of the channel, and βR is the resonance condition) may trigger a particular bend orientation (upstream‐ and downstream‐skewed, respectively). However, natural rivers exhibit both US‐skewed and DS‐skewed bend patterns along the same reach, independently of the morphodynamic regime. Little is known about the hydrogeomorphology (forced and free morphodynamic patterns) under these bend orientations. Herein, using the asymmetric Kinoshita laboratory channel, experiments under sub‐ and super‐resonant conditions (with presence or absence of free bars) for upstream‐and downstream‐skewed conditions are performed. The experiments with migrating bars (β = 10, 15) are compared with previous experiments where only migrating dunes (β = 2) under sub‐resonant condition were observed. Additional, detailed field measurements at US‐ and DS‐skewed bends of different skewness along the Tigre River in Peru are also presented. Conditions at field scale filter out the influence of the morphodynamic regime in high‐sinuosity and high amplitude bends, where nonlinear processes (width variation, bedform dynamics) can directly affect the development of the three‐dimensional flow structure, and consequently the erosional and depositional patterns, and the lateral migration patterns.
Causal associations of brain structure with bone mineral density: a large-scale genetic correlation study
Authors: Guo Bin , Wang Chao , Zhu Yong , Liu Zhi , Long Haitao , Ruan Zhe , Lin Zhangyuan , Fan Zhihua , Li Yusheng , Zhao Shushan
Published: July 2023

In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs “Volume of normalized brain,” “Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis,” “Volume of Estimated Total Intra Cranial” and “Volume-ratio of brain segmentation/estimated total intracranial” had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.
Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
Authors: Leonhardt Susan A. , Purdy Michael D. , Grover Jonathan R. , Yang Ziwei , Poulos Sandra , McIntire William E. , Tatham Elizabeth A. , Erramilli Satchal K. , Nosol Kamil , Lai Kin Kui , Ding Shilei , Lu Maolin , Uchil Pradeep D. , Finzi Andrés , Rein Alan , Kossiakoff Anthony A. , Mothes Walther , Yeager Mark
Published: July 2023

The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). Here, we determine cryoEM maps of full-length human SERINC3 and an ICL4 deletion construct, which reveal that hSERINC3 is comprised of two α-helical bundles connected by a ~ 40-residue, highly tilted, “crossmember” helix. The design resembles non-ATP-dependent lipid transporters. Consistently, purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. Furthermore, SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity, with similar results in MLV. SERINC effects in HIV-1 and MLV are counteracted by Nef and GlycoGag, respectively. Our results demonstrate that SERINCs are membrane transporters that flip lipids, resulting in a loss of membrane asymmetry that is strongly correlated with changes in Env conformation and loss of infectivity.
Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma
Authors: Wang Shiqun , Yan Wei , Kong Lingkai , Zuo Shuguang , Wu Jingyi , Zhu Chunxiao , Huang Huaping , He Bohao , Dong Jie , Wei Jiwu
Published: July 2023

The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.
Arbitrary aperture synthesis with nonlocal leaky-wave metasurface antennas
Authors: Xu Gengyu , Overvig Adam , Kasahara Yoshiaki , Martini Enrica , Maci Stefano , Alù Andrea
Published: July 2023

The emergence of new technological needs in 5 G/6 G networking and broadband satellite internet access amplifies the demand for innovative wireless communication hardware, including high-performance low-profile transceivers. In this context, antennas based on metasurfaces – artificial surfaces engineered to manipulate electromagnetic waves at will – represent highly promising solutions. In this article, we introduce leaky-wave metasurface antennas operating at micro/millimeter-wave frequencies that are designed using the principles of quasi-bound states in the continuum, exploiting judiciously tailored spatial symmetries that enable fully customized radiation. Specifically, we unveil additional degrees of control over leaky-wave radiation by demonstrating pointwise control of the amplitude, phase and polarization state of the metasurface aperture fields by carefully breaking relevant symmetries with tailored perturbations. We design and experimentally demonstrate metasurface antenna prototypes showcasing a variety of functionalities advancing capabilities in wireless communications, including single-input multi-output and multi-input multi-output near-field focusing, as well as far-field beam shaping.
Insertion sequence transposition inactivates CRISPR-Cas immunity
Authors: Sheng Yong , Wang Hengyu , Ou Yixin , Wu Yingying , Ding Wei , Tao Meifeng , Lin Shuangjun , Deng Zixin , Bai Linquan , Kang Qianjin
Published: July 2023

CRISPR-Cas immunity systems safeguard prokaryotic genomes by inhibiting the invasion of mobile genetic elements. Here, we screened prokaryotic genomic sequences and identified multiple natural transpositions of insertion sequences (ISs) into cas genes, thus inactivating CRISPR-Cas defenses. We then generated an IS-trapping system, using Escherichia coli strains with various ISs and an inducible cas nuclease, to monitor IS insertions into cas genes following the induction of double-strand DNA breakage as a physiological host stress. We identified multiple events mediated by different ISs, especially IS1 and IS10, displaying substantial relaxed target specificity. IS transposition into cas was maintained in the presence of DNA repair machinery, and transposition into other host defense systems was also detected. Our findings highlight the potential of ISs to counter CRISPR activity, thus increasing bacterial susceptibility to foreign DNA invasion.
Genome-scale metabolic modeling of Aspergillus fumigatus strains reveals growth dependencies on the lung microbiome
Authors: Mirhakkak Mohammad H. , Chen Xiuqiang , Ni Yueqiong , Heinekamp Thorsten , Sae-Ong Tongta , Xu Lin-Lin , Kurzai Oliver , Barber Amelia E. , Brakhage Axel A. , Boutin Sebastien , Schäuble Sascha , Panagiotou Gianni
Published: July 2023

Aspergillus fumigatus, an opportunistic human pathogen, frequently infects the lungs of people with cystic fibrosis and is one of the most common causes of infectious-disease death in immunocompromised patients. Here, we construct 252 strain-specific, genome-scale metabolic models of this important fungal pathogen to study and better understand the metabolic component of its pathogenic versatility. The models show that 23.1% of A. fumigatus metabolic reactions are not conserved across strains and are mainly associated with amino acid, nucleotide, and nitrogen metabolism. Profiles of non-conserved reactions and growth-supporting reaction fluxes are sufficient to differentiate strains, for example by environmental or clinical origin. In addition, shotgun metagenomics analysis of sputum from 40 cystic fibrosis patients (15 females, 25 males) before and after diagnosis with an A. fumigatus colonization suggests that the fungus shapes the lung microbiome towards a more beneficial fungal growth environment associated with aromatic amino acid availability and the shikimate pathway. Our findings are starting points for the development of drugs or microbiome intervention strategies targeting fungal metabolic needs for survival and colonization in the non-native environment of the human lung.
Identification of transcriptional programs using dense vector representations defined by mutual information with GeneVector
Authors: Ceglia Nicholas , Sethna Zachary , Freeman Samuel S. , Uhlitz Florian , Bojilova Viktoria , Rusk Nicole , Burman Bharat , Chow Andrew , Salehi Sohrab , Kabeer Farhia , Aparicio Samuel , Greenbaum Benjamin D. , Shah Sohrab P. , McPherson Andrew
Published: July 2023

Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with respect to gene co-expression, low-dimensional features can model these gene-specific relationships and leverage shared signal to overcome sparsity. We describe GeneVector, a scalable framework for dimensionality reduction implemented as a vector space model using mutual information between gene expression. Unlike other methods, including principal component analysis and variational autoencoders, GeneVector uses latent space arithmetic in a lower dimensional gene embedding to identify transcriptional programs and classify cell types. In this work, we show in four single cell RNA-seq datasets that GeneVector was able to capture phenotype-specific pathways, perform batch effect correction, interactively annotate cell types, and identify pathway variation with treatment over time.
Comparative genomics reveals a unique nitrogen-carbon balance system in Asteraceae
Authors: Shen Fei , Qin Yajuan , Wang Rui , Huang Xin , Wang Ying , Gao Tiangang , He Junna , Zhou Yue , Jiao Yuannian , Wei Jianhua , Li Lei , Yang Xiaozeng
Published: July 2023

The Asteraceae (daisy family) is one of the largest families of plants. The genetic basis for its high biodiversity and excellent adaptability has not been elucidated. Here, we compare the genomes of 29 terrestrial plant species, including two de novo chromosome-scale genome assemblies for stem lettuce, a member of Asteraceae, and Scaevola taccada, a member of Goodeniaceae that is one of the closest outgroups of Asteraceae. We show that Asteraceae originated ~80 million years ago and experienced repeated paleopolyploidization. PII, the universal regulator of nitrogen-carbon (N-C) assimilation present in almost all domains of life, has conspicuously lost across Asteraceae. Meanwhile, Asteraceae has stepwise upgraded the N-C balance system via paleopolyploidization and tandem duplications of key metabolic genes, resulting in enhanced nitrogen uptake and fatty acid biosynthesis. In addition to suggesting a molecular basis for their ecological success, the unique N-C balance system reported for Asteraceae offers a potential crop improvement strategy.
Fungal small RNAs ride in extracellular vesicles to enter plant cells through clathrin-mediated endocytosis
Authors: He Baoye , Wang Huan , Liu Guosheng , Chen Angela , Calvo Alejandra , Cai Qiang , Jin Hailing
Published: July 2023

Small RNAs (sRNAs) of the fungal pathogen Botrytis cinerea can enter plant cells and hijack host Argonaute protein 1 (AGO1) to silence host immunity genes. However, the mechanism by which these fungal sRNAs are secreted and enter host cells remains unclear. Here, we demonstrate that B. cinerea utilizes extracellular vesicles (EVs) to secrete Bc-sRNAs, which are then internalized by plant cells through clathrin-mediated endocytosis (CME). The B. cinerea tetraspanin protein, Punchless 1 (BcPLS1), serves as an EV biomarker and plays an essential role in fungal pathogenicity. We observe numerous Arabidopsis clathrin-coated vesicles (CCVs) around B. cinerea infection sites and the colocalization of B. cinerea EV marker BcPLS1 and Arabidopsis CLATHRIN LIGHT CHAIN 1, one of the core components of CCV. Meanwhile, BcPLS1 and the B. cinerea-secreted sRNAs are detected in purified CCVs after infection. Arabidopsis knockout mutants and inducible dominant-negative mutants of key components of the CME pathway exhibit increased resistance to B. cinerea infection. Furthermore, Bc-sRNA loading into Arabidopsis AGO1 and host target gene suppression are attenuated in those CME mutants. Together, our results demonstrate that fungi secrete sRNAs via EVs, which then enter host plant cells mainly through CME.
Multi-campaign ship and aircraft observations of marine cloud condensation nuclei and droplet concentrations
Authors: Sanchez Kevin J. , Painemal David , Brown Matthew D. , Crosbie Ewan C. , Gallo Francesca , Hair Johnathan W. , Hostetler Chris A. , Jordan Carolyn E. , Robinson Claire E. , Scarino Amy Jo , Shingler Taylor J. , Shook Michael A. , Thornhill Kenneth L. , Wiggins Elizabeth B. , Winstead Edward L. , Ziemba Luke D. , Chambers Scott , Williams Alastair , Humphries Ruhi S , Keywood Melita D. , Ward Jason P. , Cravigan Luke , McRobert Ian M. , Flynn Connor , Kulkarni Gourihar R. , Russell Lynn M. , Roberts Gregory C. , McFarquhar Greg M. , Nenes Athanasios , Woods Sarah F. , Reid Jeffery S. , Small-Griswold Jennifer , Brooks Sarah , Kirschler Simon , Voigt Christianne , Wang Jian , Delene David J. , Quinn Patricia K. , Moore Richard H.
Published: July 2023

In-situmarine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates.
Citizens’ Perceptions of Research and Innovation Dilemmas: Insights from a Large-Scale Survey in Four European Regions
Authors: Fellnhofer Katharina , Angelidou Margarita , Bakratsas Thomas , Buongiovanni Chiara , Eiser Toni , Hörndler Elena , Panori Anastasia , Wintjes Rene , Quaranta Gabriella
Published: July 2023

This study presents a valuable dataset supporting regional research and innovation systems in four European regions: Vestland (Norway), Kriti (Greece), Galicia (Spain), and Overijssel (Netherlands). It focuses on understanding citizens’ perceptions of research and innovation dilemmas within these regions. The dataset comprises 14 questions aligned with the Responsible Research and Innovation framework, evaluating stakeholders’ techno-moral attitudes towards technological change and socio-economic outcomes. A survey conducted between April and July 2020 gathered responses from 7,729 individuals, ensuring broad age and gender representation. This dataset is highly valuable for regional policymaking and policymakers’ engagement strategies, enhancing equity and effectiveness in addressing grand societal challenges. Research outcomes reveal citizens’ aspirations for developmental trajectories prioritizing quality-of-life, renewable energy, and support for innovative SMEs in their regions. The study contributes to existing research by highlighting limited citizen trust and expectations of effective government actions in addressing societal challenges at the regional level.
Pharmacokinetic–pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia
Authors: Gebhard Anna , Lilienthal Patrick , Metzler Markus , Rauh Manfred , Sager Sebastian , Schmiegelow Kjeld , Toksvang Linea Natalie , Zierk Jakob
Published: July 2023

In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient. We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic–pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization.
Measuring electro-adhesion pressure before and after contact
Authors: Schaller Sylvain , Shea Herbert
Published: July 2023

Electro-adhesion (EA) is a low-power, tunable, fast and reversible electrically-controlled adhesion method, effective on both conducting and insulating objects. Typically, only the electro-adhesive detachment force, i.e., the force required to separate an object from the EA patch, is measured. Here, we report a method that enables comparing the pre-contact EA attachment forces with post-contact EA detachment forces. We observe that pre-contact pressures are 1 to 100 times lower than post-contact detachment pressures, indicating the large role played by surface forces, charge injection, and polarization inertia. We characterize the time-dependence of pre- and post-contact EA forces as a function of the applied voltage waveform, observing that using an AC drive allowing for much faster release than DC operation. We measure both EA forces on conductive and insulating objects, using over 100 different EA patches covering a wide range of electrode dimensions. At 400 V, the EA release pressures for conductive objects range from 1 to 100 kPa, and are 1 to 10 times higher than pre-contact adhesion force. For dielectric objects, release pressures are 1 to 100 higher than pre-contact adhesion pressures. The methodology presented in this paper can enable standardized EA characterization while varying numerous parameters.