bluuebunny/crossref_metadata_2025 huggingface dataset:
Fostering Students’ Situational Interest in Physics: Results from a Classroom-Based Intervention Study
Authors: Brakhage Henriette , Gröschner Alexander , Gläser-Zikuda Michaela , Hagenauer Gerda
Published: July 2023

Research indicates that students’ interest in science decreases during their school years. To counteract this, a quasi-experimental instructional intervention was designed in which we addressed students’ leisure interests to foster their (situational) interest in physics. Students in the intervention group got the opportunity to choose topics matching their leisure interests (e.g. sports, music) and were encouraged to reflect on and discuss the application of principles of semiconductor physics to those topics throughout the intervention with a duration over 11 lessons. The intervention group consisted of 60 students from German high-track schools; another 55 students comprised the control group. The results of a MANCOVA analysis indicate that the instructional intervention succeeded in triggering students’ catch and hold component of situational interest during all four phases of the lesson series. Furthermore, behavioural disengagement developed more positively for students in the intervention group, while no significant effects were found for their behavioural engagement, their interest in physics-related activities in leisure or their general interest in physics classes in school. The results suggest that addressing students’ leisure interests in physics classes can promote their situational interest and reduce their behavioural disengagement in physics.
Anomaly and change point detection for time series with concept drift
Authors: Liu Jiayi , Yang Donghua , Zhang Kaiqi , Gao Hong , Li Jianzhong
Published: July 2023

Anomaly detection is one of the most important research contents in time series data analysis, which is widely used in many fields. In real world, the environment is usually dynamically changing, and the distribution of data changes over time, namely concept drift. The accuracy of static anomaly detection methods is bound to be reduced by concept drift. In addition, there is a sudden concept drift, which is manifested as a abrupt variation in a data point that changes the statistical properties of data. Such a point is called a change point, and it has very similar behavior to an anomaly. However, the existing methods cannot distinguish between anomaly and change point, so the existence of change point will affect the result of anomaly detection. In this paper, we propose an unsupervised method to simultaneously detect anomaly and change point for time series with concept drift. The method is based on the fluctuation features of data and converts the original data into the rate of change of data. It not only solves the concept drift, but also effectively detects and distinguishes anomalies and change points. Experiments on both public and synthetic datasets show that compared with the state-of-the-art anomaly detection methods, our method is superior to most of the existing works and significantly superior to existing methods for change point detection. It fully demonstrates the superiority of our method in detecting anomalies and change points simultaneously.
NMR metabolite quantification of a synthetic urine sample: an inter-laboratory comparison of processing workflows
Authors: Canlet Cécile , Deborde Catherine , Cahoreau Edern , Da Costa Grégory , Gautier Roselyne , Jacob Daniel , Jousse Cyril , Lacaze Mélia , Le Mao Inès , Martineau Estelle , Peyriga Lindsay , Richard Tristan , Silvestre Virginie , Traïkia Mounir , Moing Annick , Giraudeau Patrick
Published: July 2023

Introduction

Absolute quantification of individual metabolites in complex biological samples is crucial in targeted metabolomic profiling.

Objectives

An inter-laboratory test was performed to evaluate the impact of the NMR software, peak-area determination method (integration vs. deconvolution) and operator on quantification trueness and precision.

Methods

A synthetic urine containing 32 compounds was prepared. One site prepared the urine and calibration samples, and performed NMR acquisition. NMR spectra were acquired with two pulse sequences including water suppression used in routine analyses. The pre-processed spectra were sent to the other sites where each operator quantified the metabolites using internal referencing or external calibration, and his/her favourite in-house, open-access or commercial NMR tool.

Results

For 1D NMR measurements with solvent presaturation during the recovery delay (zgpr), 20 metabolites were successfully quantified by all processing strategies. Some metabolites could not be quantified by some methods. For internal referencing with TSP, only one half of the metabolites were quantified with a trueness below 5%. With peak integration and external calibration, about 90% of the metabolites were quantified with a trueness below 5%. The NMRProcFlow integration module allowed the quantification of several additional metabolites. The number of quantified metabolites and quantification trueness improved for some metabolites with deconvolution tools. Trueness and precision were not significantly different between zgpr- and NOESYpr-based spectra for about 70% of the variables.

Conclusion

External calibration performed better than TSP internal referencing. Inter-laboratory tests are useful when choosing to better rationalize the choice of quantification tools for NMR-based metabolomic profiling and confirm the value of spectra deconvolution tools.
Spaces of Phylogenetic Diversity Indices: Combinatorial and Geometric Properties
Authors: Manson Kerry , Steel Mike
Published: July 2023

Biodiversity is a concept most naturally quantified and measured across sets of species. However, for some applications, such as prioritising species for conservation efforts, a species-by-species approach is desirable. Phylogenetic diversity indices are functions that apportion the total biodiversity value of a set of species across its constituent members. As such, they aim to measure each species’ individual contribution to, and embodiment of, the diversity present in that set. However, no clear definition exists that encompasses the diversity indices in current use. This paper presents conditions that define diversity indices arising from the phylogenetic diversity measure on rooted phylogenetic trees. In this context, the diversity index ‘score’ given to a species represents a measure of its unique and shared evolutionary history as displayed in the underlying phylogenetic tree. Our definition generalises the diversity index notion beyond the popular Fair Proportion and Equal-Splits indices. These particular indices may now be seen as two points in a convex space of possible diversity indices, for which the boundary conditions are determined by the underlying shape of each phylogenetic tree. We calculated the dimension of the convex space associated with each tree shape and described the extremal points.
Fachberatung in familienanalogen Wohnformen als „eierlegende Wollmilchsau“?
Authors: Flack Nina
Published: July 2023

Die familienanalogen Wohnformen als eine Form der stationären Erziehungshilfen erlangen im wissenschaftlichen Diskurs zunehmend an Aufmerksamkeit. Durch das Zusammenleben der pädagogischen Fachkräfte mit den jungen Menschen wird für die professionelle Fremdbetreuung eine kontinuierliche Reflexion von den Fachkräften erwartet. Aufgrund einer fehlenden Eingebundenheit in Teamstrukturen werden die Fachkräfte von Fachberater*innen unterstützt. Die Fachberatung ist ein konstitutives Merkmal für dieses Setting, allerdings stellt sie bisher eine eklatante Forschungslücke dar. Ihre Bedeutsamkeit wird zwar hervorgehoben, was konkret Fachberatung bedeutet und welche Aufgaben Fachberater*innen in der Praxis übernehmen, ist jedoch nicht bekannt. Dieser Artikel zeigt empirische Ergebnisse einer ethnografischen Studie, in deren Rahmen der Alltag von Fachberater*innen beobachtet wurde. Mithilfe des Soziale-Welten-Ansatzes wird analytisch gefasst, wie komplex Fachberatung ist. Dadurch wird der bisherige Fokus auf der Beziehung zwischen pädagogischer Fachkraft und Fachberater*in erweitert. In diesem Artikel wird zusätzlich das Grenzobjekt von Star und Griesemer (2017) als analytische Betrachtung hinzugezogen, um aufzuzeigen, wie die Akteur*innen der differenten Sozialen Welten zusammenarbeiten. Durch dieses Vorgehen kann erklärt werden, wie Fachberatung funktioniert und warum sie für den Fallverlauf in den stationären Erziehungshilfen relevant ist. Somit ist nachvollziehbar, warum verschiedene Perspektiven auf Fachberatung existieren können und dennoch eine Zusammenarbeit möglich ist.
Effects of an enhanced fibre–matrix adhesion on the fatigue behaviour of composite materials under very high cycle fatigue
Authors: Bartelt M. , Horst P. , Heimbs S.
Published: July 2023

The fatigue behaviour of two glass fibre-reinforced epoxy composite materials with a cross-ply layup is investigated in the very high cycle fatigue (VHCF) regime with up to $$10^8$$

10
8

load cycles. In addition to the influence on the fatigue lifetime, different materials can also cause a different damage phenomenology. One reference fibre (OC111A) and one fibre with increased fibre–matrix adhesion (SE2020) are tested. The experimental and numerical investigations show that the damage threshold is shifted to higher loads with increased fibre–matrix adhesion, but the damage mode of delaminations becomes more important.
Mechanical behavior of basalt-reinforced epoxy composites modified with biomass-derived seashell powder
Authors: Hiremath Anupama , Nayak Suhas Yeshwant , Heckadka Srinivas Shenoy , Pramod Jaideep Jeppu
Published: July 2023

The effect of resin modification through the incorporation of the biomass waste in the form of seashell powder on the mechanical properties of basalt fiber–reinforced epoxy/seashell composites is examined through experimental investigations. The resin modification is done through the addition of seashell powder in 5, 10, 15, and 20 wt.%. The modified resin is then reinforced with basalt fiber mat and the required laminate is obtained through compression molding technique. The specimens required for various mechanical tests, such as flexural, tensile, inter laminar shear (ILSS), and the impact strengths, are cut from the laminate as per the standard ASTM dimensions. The mechanical test results indicate that through the addition of the seashell filler additional toughening mechanisms are introduced which improves the strength of the composite laminate. The improvement in the flexural modulus value for all the laminates made from modified resin indicates the ability of the laminate to deflect the applied load effectively and efficiently. The optimum wt.% addition of seashell filler into the resin is found to be 5% for flexural, ILSS, and impact strength while for tensile strength it was observed to be 10%. The addition of higher wt.% loading of seashell filler into the resin has rendered the resin too thick and viscous with minimum flowability. Thus, there is a reduced wettability of the modified resin with the basalt fibers due to which the strength of the laminates reduces. The SEM analysis indicates widespread delamination for higher wt.% addition of the seashell filler into the resin.
Wiener–Hopf technique for a fractional mixed boundary value problem in cylindrical layer
Authors: Ansari Alireza , Masomi Mohammad Rasool
Published: July 2023

In this paper, we study the heat transfer modeling during freezing of a biological tissue and present an analytical approach for solving the heat transfer problem in cryosurgery. We consider a time-fractional bio-heat equation in the cylindrical coordinate and employ the Wiener–Hopf technique to find the temperature of tissue in two different domains by the factorization of associated Wiener–Hopf kernel. We discuss the fundamental roles of the Bessel and Wright functions in determining the analytical solution of fractional cryosurgery problem.
Flexible Nanocomposite Conductors for Electromagnetic Interference Shielding
Authors: Nan Ze , Wei Wei , Lin Zhenhua , Chang Jingjing , Hao Yue
Published: July 2023

Highlights

Convincing candidates of flexible (stretchable/compressible) electromagnetic interference shielding nanocomposites are discussed in detail from the views of fabrication, mechanical elasticity and shielding performance.

Detailed summary of the relationship between deformation of materials and electromagnetic shielding performance.

The future directions and challenges in developing flexible (particularly elastic) shielding nanocomposites are highlighted.

With the extensive use of electronic communication technology in integrated circuit systems and wearable devices, electromagnetic interference (EMI) has increased dramatically. The shortcomings of conventional rigid EMI shielding materials include high brittleness, poor comfort, and unsuitability for conforming and deformable applications. Hitherto, flexible (particularly elastic) nanocomposites have attracted enormous interest due to their excellent deformability. However, the current flexible shielding nanocomposites present low mechanical stability and resilience, relatively poor EMI shielding performance, and limited multifunctionality. Herein, the advances in low-dimensional EMI shielding nanomaterials-based elastomers are outlined and a selection of the most remarkable examples is discussed. And the corresponding modification strategies and deformability performance are summarized. Finally, expectations for this quickly increasing sector are discussed, as well as future challenges.
Nanofiber Composite Reinforced Organohydrogels for Multifunctional and Wearable Electronics
Authors: Wen Jing , Wu Yongchuan , Gao Yuxin , Su Qin , Liu Yuntao , Wu Haidi , Zhang Hechuan , Liu Zhanqi , Yao Hang , Huang Xuewu , Tang Longcheng , Shi Yongqian , Song Pingan , Xue Huaiguo , Gao Jiefeng
Published: July 2023

Composite organohydrogels have been widely used in wearable electronics. However, it remains a great challenge to develop mechanically robust and multifunctional composite organohydrogels with good dispersion of nanofillers and strong interfacial interactions. Here, multifunctional nanofiber composite reinforced organohydrogels (NCROs) are prepared. The NCRO with a sandwich-like structure possesses excellent multi-level interfacial bonding. Simultaneously, the synergistic strengthening and toughening mechanism at three different length scales endow the NCRO with outstanding mechanical properties with a tensile strength (up to 7.38 ± 0.24 MPa), fracture strain (up to 941 ± 17%), toughness (up to 31.59 ± 1.53 MJ m−3) and fracture energy (up to 5.41 ± 0.63 kJ m−2). Moreover, the NCRO can be used for high performance electromagnetic interference shielding and strain sensing due to its high conductivity and excellent environmental tolerance such as anti-freezing performance. Remarkably, owing to the organohydrogel stabilized conductive network, the NCRO exhibits superior long-term sensing stability and durability compared to the nanofiber composite itself. This work provides new ideas for the design of high-strength, tough, stretchable, anti-freezing and conductive organohydrogels with potential applications in multifunctional and wearable electronics.
Are Character Strengths and Attitudes towards Vegetarian Food Related?
Authors: Jansen Petra , Rahe Martina , Hoja Sabine , Jost Leonardo
Published: July 2023

One aspect of sustainable consumption behavior is the shift to a vegetarian diet. This study investigates if individual factors, like character strengths, are related to attitudes toward vegetarian food. Additionally, the study examines potential variations in character strengths between vegetarians/vegans and omnivores, as well as whether there are differences in explicit and implicit affective attitudes towards vegetarian and meat-based diets. A total of 210 participants filled out a demographic questionnaire, a scale measuring character strength, an explicit rating task, and an affective priming task that involved images of both vegetarian and meat-based food. The results showed that there was no difference in the explicit and implicit rating of meat-based food compared to vegetarian food for omnivore people. Vegetarians/vegans rated vegetarian food explicitly and implicitly more positively than meat-based food. Only the four character strengths of prudence, appreciation of beauty and excellence, humor, and teamwork, besides the diet type (vegetarians/vegans vs. omnivores), predicted the explicit attitudes toward vegetarian food. Vegetarians/vegans and omnivores only differed in the character strengths of love of learning and forgiveness. This study provides evidence that the explicit and implicit attitudes towards vegetarian food are concordant for vegetarians and vegans with their diet choice. Furthermore, the relationship between character strengths and explicit attitudes toward vegetarian food is weak, which hints that those individual transformative qualities (Woiwode et al., 2021) toward sustainable attitude and behavior should be investigated carefully and in-depth.
INFINITE SERIES CONCERNING HARMONIC NUMBERS AND QUINTIC CENTRAL BINOMIAL COEFFICIENTS
Authors: LI CHUNLI , CHU WENCHANG
Published: July 2023

By examining two hypergeometric series transformations, we establish several remarkable infinite series identities involving harmonic numbers and quintic central binomial coefficients, including five conjectured recently by Z.-W. Sun [‘Series with summands involving harmonic numbers’, Preprint, 2023, arXiv:2210.07238v7]. This is realised by ‘the coefficient extraction method’ implemented byMathematicacommands.
A Case of Multiple Identities: Uncanny Histories of the Arabic Typewriter
Authors: Scott Deuchar Hannah
Published: July 2023

Little is known today about the Arabic typewriter. American typewriters revolutionized clerical labor and became literary icons, but the Arabic typewriter is largely absent from scholarship and popular culture. Only one story about it recurs, namely that of its origins. It was reportedly invented multiple times: in 1890s Beirut by, among others, a portrait painter named Salim Haddad; in 1900s Vienna by Theodor Herzl, founding father of political Zionism; and in 1940s Cairo by Wadie Said, father of the pioneering postcolonial theorist Edward Said. Bringing three competing accounts of the machine's invention together, I find that in each the Arabic typewriter was turned to very different purposes. Consistently, however, it was co-opted into intensifying struggles over territory and language. Repeatedly, it exceeded its representations, unsettling the narratives into which it was written and provoking a sense of strangeness, even unease. And across the accounts, diverse names and places reappear: New York, Palestine, Sherlock Holmes. Taking seriously the doublings and coincidences that connect the typewriter's origin-stories, I ask finally whether they might alert us to the possibility of another mode of cultural history—one that is itself uncanny and estranged.
Activation of distinct inflammatory pathways in subgroups of LR-MDS
Authors: Schneider Marie , Rolfs Clara , Trumpp Matthias , Winter Susann , Fischer Luise , Richter Mandy , Menger Victoria , Nenoff Kolja , Grieb Nora , Metzeler Klaus H. , Kubasch Anne Sophie , Sockel Katja , Thiede Christian , Wu Jincheng , Woo Janghee , Brüderle Andreas , Hofbauer Lorenz C. , Lützner Jörg , Roth Andreas , Cross Michael , Platzbecker Uwe
Published: July 2023

Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large, clinically and genetically well-characterized cohort of treatment-naïve MDS patients confirms intrinsic activation of inflammatory pathways in general mediated by caspase-1, interleukin (IL)-1β and IL-18 in low-risk (LR)-MDS bone marrow and reveals a previously unrecognized heterogeneity of inflammation between genetically defined LR-MDS subgroups. Principal component analysis resolved two LR-MDS phenotypes with low (cluster 1) and high (cluster 2) levels of IL1B gene expression, respectively. Cluster 1 contained 14/17 SF3B1-mutated cases, while cluster 2 contained 8/8 del(5q) cases. Targeted gene expression analysis of sorted cell populations showed that the majority of the inflammasome-related genes, including IL1B, were primarily expressed in the monocyte compartment, consistent with a dominant role in determining the inflammatory bone marrow environment. However, the highest levels of IL18 expression were found in hematopoietic stem and progenitor cells (HSPCs). The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1β-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies.
Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis
Authors: Skorda Aikaterini , Lauridsen Anna Røssberg , Wu Chengnan , Huang Jinrong , Mrackova Monika , Winther Nuggi Ingholt , Jank Vanessa , Sztupinszki Zsofia , Strauss Robert , Bilgin Mesut , Maeda Kenji , Liu Bin , Luo Yonglun , Jäättelä Marja , Kallunki Tuula
Published: July 2023

Cancer cells are dependent on cholesterol, and they possess strictly controlled cholesterol homeostasis mechanisms. These allow them to smoothly switch between cholesterol synthesis and uptake to fulfill their needs and to adapt environmental changes. Here we describe a mechanism of how cancer cells employ oncogenic growth factor signaling to promote uptake and utilization of extracellular cholesterol via Myeloid Zinc Finger 1 (MZF1)-mediated Niemann Pick C1 (NPC1) expression and upregulated macropinocytosis. Expression of p95ErbB2, highly oncogenic, standard-treatment resistant form of ErbB2 mobilizes lysosomes and activates EGFR, invasion and macropinocytosis. This is connected to a metabolic shift from cholesterol synthesis to uptake due to macropinocytosis-enabled flow of extracellular cholesterol. NPC1 increase facilitates extracellular cholesterol uptake and is necessary for the invasion of ErbB2 expressing breast cancer spheroids and ovarian cancer organoids, indicating a regulatory role for NPC1 in the process. The ability to obtain cholesterol as a byproduct of increased macropinocytosis allows cancer cells to direct the resources needed for the energy-consuming cholesterol synthesis towards other activities such as invasion. These results demonstrate that macropinocytosis is not only an alternative energy source for cancer cells but also an efficient way to provide building material, such as cholesterol, for its macromolecules and membranes.
E3 ligase MG53 suppresses tumor growth by degrading cyclin D1
Authors: Fang Meng , Wu Hong-Kun , Pei Yumeng , Zhang Yan , Gao Xiangyu , He Yanyun , Chen Gengjia , Lv Fengxiang , Jiang Peng , Li Yumei , Li Wenwen , Jiang Peng , Wang Lin , Ji Jiafu , Hu Xinli , Xiao Rui-Ping
Published: July 2023

Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.
Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression
Authors: Asraf Kfir , Zaidan Hiba , Natoor Baylasan , Gaisler-Salomon Inna
Published: July 2023

Glutamate abnormalities in the medial prefrontal cortex (mPFC) are associated with cognitive deficits. We previously showed that homozygous deletion of CNS glutamate dehydrogenase 1 (Glud1), a metabolic enzyme critical for glutamate metabolism, leads to schizophrenia-like behavioral abnormalities and increased mPFC glutamate; mice heterozygous for CNSGlud1deletion (C-Glud1+/−mice) showed no cognitive or molecular abnormalities. Here, we examined the protracted behavioral and molecular effects of mild injection stress on C-Glud1+/−mice. We found spatial and reversal learning deficits, as well as large-scale mPFC transcriptional changes in pathways associated with glutamate and GABA signaling, in stress-exposed C-Glud1+/−mice, but not in their stress-naïve or C-Glud1+/+littermates. These effects were observed several weeks following stress exposure, and the expression levels of specific glutamatergic and GABAergic genes differentiated between high and low reversal learning performance. An increase in miR203-5p expression immediately following stress may provide a translational regulatory mechanism to account for the delayed effect of stress exposure on cognitive function. Our findings show that chronic glutamate abnormalities interact with acute stress to induce cognitive deficits, and resonate with gene x environment theories of schizophrenia. Stress-exposed C-Glud1+/−mice may model a schizophrenia high-risk population, which is uniquely sensitive to stress-related ‘trigger’ events.
Quality of life, mentalization, and perception of challenging patient encounters in dentistry: A cross-sectional study
Authors: Johnsen Jan-Are K. , Haukefer Sunniva B. , Korsan Sofie. J. , Larsen Maria , Holde Gro Eirin
Published: July 2023

Objective

This study investigated how exposure to challenging patient encounters influenced participants’ self-reported quality of life, and how participants’ mentalization capabilities affected the perceptions of challenging patients encounters among Norwegian dentists and dental students.

Materials and Methods

Data was collected with an online questionnaire, and a total of 165 dentists (n = 126) and dental students (n = 39) responded.

Results

Participants who reported higher total exposure of challenging encounters reported lower quality of life (QoL). Mentalization tendencies affected the perception of challenging encounters with specific types of patients; critical and anxious; as well as the estimation of the total exposure to challenging patient encounters. Participants that were overconfident with regards to the mental states of others found these patient types less challenging and they reported less overall exposure to challenging patients than underconfident participants. Also, overconfident participants reported higher QoL than underconfident participants.

Conclusions

Mentalization capabilities of dental practitioners interact with the perception of challenging encounters in dental practice, and how practitioners respond to these challenges. Measures should be undertaken to increase the awareness of metacognitive skills in dentistry with the dual goal of improving patient care as well as the quality of life of dental practitioners.
A novel CTLA-4 blocking strategy based on nanobody enhances the activity of dendritic cell vaccine-stimulated antitumor cytotoxic T lymphocytes
Authors: Yang Wenli , Pang Yanyang , Wang Xi , Lai Zhiheng , Lu Yanda , Zheng Shaojiang , Wang Wu
Published: July 2023

Despite the great success of CTLA-4 blocking in cancer treatment, the use of anti-CTLA-4 monoclonal antibodies still faces many limitations. Now, immune checkpoint blocking coupled with adoptive cell therapy is gaining much attention. In this paper, we reported a strategy on the basis of anti-CTLA-4 nanobody (Nb)-modified liposomes to improve these obstacles. An Nb36/liposome complex was constructed and utilized as a blocker of the CTLA-4/B7 signal pathway in a combination with dendritic cell (DC)/tumor fusion vaccine to enhance the CD8+ T cell cytokine secretion, activation, proliferation, as well as specific cytotoxicity. Moreover, the CD8+ T cells induced by LPS-Nb36 and DC/tumor fusion vaccine led to higher CD8+ T cell effector function in vivo, which significantly retarded tumor growth and lengthened survival of tumor-bearing mice (HepG2, A549, and MGC-803). Our data demonstrate that the anti-CTLA-4 Nb-modified liposomes in connection with DC/tumor fusion vaccines enhance the CD8+ T cell antitumor activity in vitro and in vivo, and is expected to be an alternative therapy for patients with malignancies that have T cell dysfunction or have poor treatment against anti-CTLA-4 mAb.
Central macular choriocapillaris impairment as a manifestation of microvascular disease in eyes with subretinal drusenoid deposits
Authors: Abdolrahimzadeh Solmaz , Zweifel Sandrine Anne , Di Pippo Mariachiara , Bajka Anahita , Scuderi Gianluca , Lotery Andrew John
Published: July 2023

Background/Objectives

Microvascular alterations and choroidal impairment are emerging as a pathologic pathway in age-related macular degeneration (AMD). This study aimed to evaluate the central macular choriocapillaris (CC) in eyes with subretinal drusenoid deposits (SDD) and the retinal microvasculature in patients with early AMD phenotypes.

Subjects/Methods

This was an institutional, multicentric observational cross-sectional study. Ninety-nine eyes of 99 subjects; 33 eyes with SDD only, 33 eyes with conventional drusen (CD) only, and 33 eyes of healthy age-matched subjects were included. Comprehensive ophthalmologic examination and optical coherence tomography angiography (OCTA) was performed. The central macular flow area of the CC was analysed in the SDD group and the vessel density of the retinal superficial capillary plexus (SCP) and deep capillary plexus (DCP) was analysed in the SDD and CD groups using automated OCTA output parameters.

Results

The flow area of the CC in the SDD group was significantly reduced (p ≤ 0.001) with respect to the healthy control group. There was a trend of reduction of vessel density of the SCP and the DCP in the SDD and CD group with respect to controls, although this did not reach statistical significance.

Conclusions

OCTA data in the present report corroborate the role of vascular damage in early AMD with CC impairment in the central macular area in eyes with SDD.
Highly efficient platelet generation in lung vasculature reproduced by microfluidics
Authors: Zhao Xiaojuan , Alibhai Dominic , Walsh Tony G. , Tarassova Nathalie , Englert Maximilian , Birol Semra Z. , Li Yong , Williams Christopher M. , Neal Chris R. , Burkard Philipp , Cross Stephen J. , Aitken Elizabeth W. , Waller Amie K. , Beltrán José Ballester , Gunning Peter W. , Hardeman Edna C. , Agbani Ejaife O. , Nieswandt Bernhard , Hers Ingeborg , Ghevaert Cedric , Poole Alastair W.
Published: July 2023

Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms remain unclear. Outside the body, however, our ability to generate large number of functional platelets is poor. Here we show that perfusion of megakaryocytes ex vivo through the mouse lung vasculature generates substantial platelet numbers, up to 3000 per megakaryocyte. Despite their large size, megakaryocytes are able repeatedly to passage through the lung vasculature, leading to enucleation and subsequent platelet generation intravascularly. Using ex vivo lung and an in vitro microfluidic chamber we determine how oxygenation, ventilation, healthy pulmonary endothelium and the microvascular structure support thrombopoiesis. We also show a critical role for the actin regulator Tropomyosin 4 in the final steps of platelet formation in lung vasculature. This work reveals the mechanisms of thrombopoiesis in lung vasculature and informs approaches to large-scale generation of platelets.
Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers
Authors: Schuster Eugene F. , Lopez-Knowles Elena , Alataki Anastasia , Zabaglo Lila , Folkerd Elizabeth , Evans David , Sidhu Kally , Cheang Maggie Chon U. , Tovey Holly , Salto-Tellez Manuel , Maxwell Perry , Robertson John , Smith Ian , Bliss Judith M. , Dowsett Mitch
Published: July 2023

Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.
Expanded vacuum-stable gels for multiplexed high-resolution spatial histopathology
Authors: Bai Yunhao , Zhu Bokai , Oliveria John-Paul , Cannon Bryan J. , Feyaerts Dorien , Bosse Marc , Vijayaragavan Kausalia , Greenwald Noah F. , Phillips Darci , Schürch Christian M. , Naik Samuel M. , Ganio Edward A. , Gaudilliere Brice , Rodig Scott J. , Miller Michael B. , Angelo Michael , Bendall Sean C. , Rovira-Clavé Xavier , Nolan Garry P. , Jiang Sizun
Published: July 2023

Cellular organization and functions encompass multiple scales in vivo. Emerging high-plex imaging technologies are limited in resolving subcellular biomolecular features. Expansion Microscopy (ExM) and related techniques physically expand samples for enhanced spatial resolution, but are challenging to be combined with high-plex imaging technologies to enable integrative multiscaled tissue biology insights. Here, we introduce Expand and comPRESS hydrOgels (ExPRESSO), an ExM framework that allows high-plex protein staining, physical expansion, and removal of water, while retaining the lateral tissue expansion. We demonstrate ExPRESSO imaging of archival clinical tissue samples on Multiplexed Ion Beam Imaging and Imaging Mass Cytometry platforms, with detection capabilities of > 40 markers. Application of ExPRESSO on archival human lymphoid and brain tissues resolved tissue architecture at the subcellular level, particularly that of the blood-brain barrier. ExPRESSO hence provides a platform for extending the analysis compatibility of hydrogel-expanded biospecimens to mass spectrometry, with minimal modifications to protocols and instrumentation.
Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice
Authors: Reynolds Lauren M. , Hernandez Giovanni , MacGowan Del , Popescu Christina , Nouel Dominique , Cuesta Santiago , Burke Samuel , Savell Katherine E. , Zhao Janet , Restrepo-Lozano Jose Maria , Giroux Michel , Israel Sonia , Orsini Taylor , He Susan , Wodzinski Michael , Avramescu Radu G. , Pokinko Matthew , Epelbaum Julia G. , Niu Zhipeng , Pantoja-Urbán Andrea Harée , Trudeau Louis-Éric , Kolb Bryan , Day Jeremy J. , Flores Cecilia
Published: July 2023

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual’s sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.
Photoswitchable dynamic conjugate addition-elimination reactions as a tool for light-mediated click and clip chemistry
Authors: Lu Hanwei , Ye Hebo , Zhang Meilan , Liu Zimu , Zou Hanxun , You Lei
Published: July 2023

Phototriggered click and clip reactions can endow chemical processes with high spatiotemporal resolution and sustainability, but are challenging with a limited scope. Herein we report photoswitchable reversible covalent conjugate addition-elimination reactions toward light-addressed modular covalent connection and disconnection. By coupling between photochromic dithienylethene switch and Michael acceptors, the reactivity of Michael reactions was tuned through closed-ring and open-ring forms of dithienylethene, allowing switching on and off dynamic exchange of a wide scope of thiol and amine nucleophiles. The breaking of antiaromaticity in transition states and enol intermediates of addition-elimination reactions provides the driving force for photoinduced change in kinetic barriers. To showcase the versatile application, light-mediated modification of solid surfaces, regulation of amphiphilic assemblies, and creation/degradation of covalent polymers on demand were achieved. The manipulation of dynamic click/clip reactions with light should set the stage for future endeavors, including responsive assemblies, biological delivery, and intelligent materials.
Signatures of VH1-69-derived hepatitis C virus neutralizing antibody precursors defined by binding to envelope glycoproteins
Authors: Capella-Pujol Joan , de Gast Marlon , Radić Laura , Zon Ian , Chumbe Ana , Koekkoek Sylvie , Olijhoek Wouter , Schinkel Janke , van Gils Marit J. , Sanders Rogier W. , Sliepen Kwinten
Published: July 2023

An effective preventive vaccine for hepatitis C virus (HCV) remains a major unmet need. Antigenic region 3 (AR3) on the E1E2 envelope glycoprotein complex overlaps with the CD81 receptor binding site and represents an important epitope for broadly neutralizing antibodies (bNAbs) and is therefore important for HCV vaccine design. Most AR3 bNAbs utilize the VH1-69 gene and share structural features that define the AR3C-class of HCV bNAbs. In this work, we identify recombinant HCV glycoproteins based on a permuted E2E1 trimer design that bind to the inferred VH1-69 germline precursors of AR3C-class bNAbs. When presented on nanoparticles, these recombinant E2E1 glycoproteins efficiently activate B cells expressing inferred germline AR3C-class bNAb precursors as B cell receptors. Furthermore, we identify critical signatures in three AR3C-class bNAbs that represent two subclasses of AR3C-class bNAbs that will allow refined protein design. These results provide a framework for germline-targeting vaccine design strategies against HCV.
Ultra-short pulse laser acceleration of protons to 80 MeV from cryogenic hydrogen jets tailored to near-critical density
Authors: Rehwald Martin , Assenbaum Stefan , Bernert Constantin , Brack Florian-Emanuel , Bussmann Michael , Cowan Thomas E. , Curry Chandra B. , Fiuza Frederico , Garten Marco , Gaus Lennart , Gauthier Maxence , Göde Sebastian , Göthel Ilja , Glenzer Siegfried H. , Huang Lingen , Huebl Axel , Kim Jongjin B. , Kluge Thomas , Kraft Stephan , Kroll Florian , Metzkes-Ng Josefine , Miethlinger Thomas , Loeser Markus , Obst-Huebl Lieselotte , Reimold Marvin , Schlenvoigt Hans-Peter , Schoenwaelder Christopher , Schramm Ulrich , Siebold Mathias , Treffert Franziska , Yang Long , Ziegler Tim , Zeil Karl
Published: July 2023

Laser plasma-based particle accelerators attract great interest in fields where conventional accelerators reach limits based on size, cost or beam parameters. Despite the fact that particle in cell simulations have predicted several advantageous ion acceleration schemes, laser accelerators have not yet reached their full potential in producing simultaneous high-radiation doses at high particle energies. The most stringent limitation is the lack of a suitable high-repetition rate target that also provides a high degree of control of the plasma conditions required to access these advanced regimes. Here, we demonstrate that the interaction of petawatt-class laser pulses with a pre-formed micrometer-sized cryogenic hydrogen jet plasma overcomes these limitations enabling tailored density scans from the solid to the underdense regime. Our proof-of-concept experiment demonstrates that the near-critical plasma density profile produces proton energies of up to 80 MeV. Based on hydrodynamic and three-dimensional particle in cell simulations, transition between different acceleration schemes are shown, suggesting enhanced proton acceleration at the relativistic transparency front for the optimal case.
Quantifying disorder one atom at a time using an interpretable graph neural network paradigm
Authors: Chapman James , Hsu Tim , Chen Xiao , Heo Tae Wook , Wood Brandon C.
Published: July 2023

Quantifying the level of atomic disorder within materials is critical to understanding how evolving local structural environments dictate performance and durability. Here, we leverage graph neural networks to define a physically interpretable metric for local disorder, called SODAS. This metric encodes the diversity of the local atomic configurations as a continuous spectrum between the solid and liquid phases, quantified against a distribution of thermal perturbations. We apply this methodology to four prototypical examples with varying levels of disorder: (1) grain boundaries, (2) solid-liquid interfaces, (3) polycrystalline microstructures, and (4) tensile failure/fracture. We also compare SODAS to several commonly used methods. Using elemental aluminum as a case study, we show how our paradigm can track the spatio-temporal evolution of interfaces, incorporating a mathematically defined description of the spatial boundary between order and disorder. We further show how to extract physics-preserved gradients from our continuous disorder fields, which may be used to understand and predict materials performance and failure. Overall, our framework provides a simple and generalizable pathway to quantify the relationship between complex local atomic structure and coarse-grained materials phenomena.
Molecular mechanism of plasmid-borne resistance to sulfonamide antibiotics
Authors: Venkatesan Meenakshi , Fruci Michael , Verellen Lou Ann , Skarina Tatiana , Mesa Nathalie , Flick Robert , Pham Chester , Mahadevan Radhakrishnan , Stogios Peter J. , Savchenko Alexei
Published: July 2023

The sulfonamides (sulfas) are the oldest class of antibacterial drugs and inhibit the bacterial dihydropteroate synthase (DHPS, encoded by folP), through chemical mimicry of its co-substrate p-aminobenzoic acid (pABA). Resistance to sulfa drugs is mediated either by mutations in folP or acquisition of sul genes, which code for sulfa-insensitive, divergent DHPS enzymes. While the molecular basis of resistance through folP mutations is well understood, the mechanisms mediating sul-based resistance have not been investigated in detail. Here, we determine crystal structures of the most common Sul enzyme types (Sul1, Sul2 and Sul3) in multiple ligand-bound states, revealing a substantial reorganization of their pABA-interaction region relative to the corresponding region of DHPS. We use biochemical and biophysical assays, mutational analysis, and in trans complementation of E. coli ΔfolP to show that a Phe-Gly sequence enables the Sul enzymes to discriminate against sulfas while retaining pABA binding and is necessary for broad resistance to sulfonamides. Experimental evolution of E. coli results in a strain harboring a sulfa-resistant DHPS variant that carries a Phe-Gly insertion in its active site, recapitulating this molecular mechanism. We also show that Sul enzymes possess increased active site conformational dynamics relative to DHPS, which could contribute to substrate discrimination. Our results reveal the molecular foundation for Sul-mediated drug resistance and facilitate the potential development of new sulfas less prone to resistance.
A supramolecular metalloenzyme possessing robust oxidase-mimetic catalytic function
Authors: Xu Shichao , Wu Haifeng , Liu Siyuan , Du Peidong , Wang Hui , Yang Haijun , Xu Wenjie , Chen Shuangming , Song Li , Li Jikun , Shi Xinghua , Wang Zhen-Gang
Published: July 2023

Enzymes fold into unique three-dimensional structures to distribute their reactive amino acid residues, but environmental changes can disrupt their essential folding and lead to irreversible activity loss. The de novo synthesis of enzyme-like active sites is challenging due to the difficulty of replicating the spatial arrangement of functional groups. Here, we present a supramolecular mimetic enzyme formed by self-assembling nucleotides with fluorenylmethyloxycarbonyl (Fmoc)-modified amino acids and copper. This catalyst exhibits catalytic functions akin those of copper cluster-dependent oxidases, and catalytic performance surpasses to date-reported artificial complexes. Our experimental and theoretical results reveal the crucial role of periodic arrangement of amino acid components, enabled by fluorenyl stacking, in forming oxidase-mimetic copper clusters. Nucleotides provide coordination atoms that enhance copper activity by facilitating the formation of a copper-peroxide intermediate. The catalyst shows thermophilic behavior, remaining active up to 95 °C in an aqueous environment. These findings may aid the design of advanced biomimetic catalysts and offer insights into primordial redox enzymes.
Artificially controlled nanoscale chemical reduction in VO2 through electron beam illumination
Authors: Zhang Yang , Wang Yupu , Wu Yongshun , Shu Xinyu , Zhang Fan , Peng Huining , Shen Shengchun , Ogawa Naoki , Zhu Junyi , Yu Pu
Published: July 2023

Chemical reduction in oxides plays a crucial role in engineering the material properties through structural transformation and electron filling. Controlling the reduction at nanoscale forms a promising pathway to harvest functionalities, which however is of great challenge for conventional methods (e.g., thermal treatment and chemical reaction). Here, we demonstrate a convenient pathway to achieve nanoscale chemical reduction for vanadium dioxide through the electron-beam illumination. The electron beam induces both surface oxygen desorption through radiolytic process and positively charged background through secondary electrons, which contribute cooperatively to facilitate the vacancy migration from the surface toward the sample bulk. Consequently, the VO2 transforms into a reduced V2O3 phase, which is associated with a distinct insulator to metal transition at room temperature. Furthermore, this process shows an interesting facet-dependence with the pronounced transformation observed for the c-facet VO2 as compared with the a-facet, which is attributed to the intrinsically different oxygen vacancy formation energy between these facets. Remarkably, we readily achieve a lateral resolution of tens nanometer for the controlled structural transformation with a commercial scanning electron microscope. This work provides a feasible strategy to manipulate the nanoscale chemical reduction in complex oxides for exploiting functionalities.