bluuebunny/crossref_metadata_2025 huggingface dataset:
Lola-I is a promoter pioneer factor that establishes de novo Pol II pausing during development
Authors: Ramalingam Vivekanandan , Yu Xinyang , Slaughter Brian D. , Unruh Jay R. , Brennan Kaelan J. , Onyshchenko Anastasiia , Lange Jeffrey J. , Natarajan Malini , Buck Michael , Zeitlinger Julia
Published: September 2023

While the accessibility of enhancers is dynamically regulated during development, promoters tend to be constitutively accessible and poised for activation by paused Pol II. By studying Lola-I, a Drosophila zinc finger transcription factor, we show here that the promoter state can also be subject to developmental regulation independently of gene activation. Lola-I is ubiquitously expressed at the end of embryogenesis and causes its target promoters to become accessible and acquire paused Pol II throughout the embryo. This promoter transition is required but not sufficient for tissue-specific target gene activation. Lola-I mediates this function by depleting promoter nucleosomes, similar to the action of pioneer factors at enhancers. These results uncover a level of regulation for promoters that is normally found at enhancers and reveal a mechanism for the de novo establishment of paused Pol II at promoters.
Proof of crystal-field-perturbation-enhanced luminescence of lanthanide-doped nanocrystals through interstitial H+ doping
Authors: Li Guowei , Jiang Shihui , Liu Aijun , Ye Lixiang , Ke Jianxi , Liu Caiping , Chen Lian , Liu Yongsheng , Hong Maochun
Published: September 2023

Crystal-field perturbation is theoretically the most direct and effective method of achieving highly efficient photoluminescence from trivalent lanthanide (Ln3+) ions through breaking the parity-forbidden nature of their 4f-transitions. However, exerting such crystal-field perturbation remains an arduous task even in well-developed Ln3+-doped luminescent nanocrystals (NCs). Herein, we report crystal-field perturbation through interstitial H+-doping in orthorhombic-phase NaMgF3:Ln3+ NCs and achieve a three-orders-of-magnitude emission amplification without a distinct lattice distortion. Mechanistic studies reveal that the interstitial H+ ions perturb the local charge density distribution, leading to anisotropic polarization of the F− ligand, which affects the highly symmetric Ln3+-substituted [MgF6]4− octahedral clusters. This effectively alleviates the parity-forbidden selective rule to enhance the 4f–4 f radiative transition rate of the Ln3+ emitter and is directly corroborated by the apparent shortening of the radiative recombination lifetime. The interstitially H+-doped NaMgF3:Yb/Er NCs are successfully used as bioimaging agents for real-time vascular imaging. These findings provide concrete evidence for crystal-field perturbation effects and promote the design of Ln3+-doped luminescent NCs with high brightness.
Self-organized and directed branching results in optimal coverage in developing dermal lymphatic networks
Authors: Uçar Mehmet Can , Hannezo Edouard , Tiilikainen Emmi , Liaqat Inam , Jakobsson Emma , Nurmi Harri , Vaahtomeri Kari
Published: September 2023

Branching morphogenesis is a ubiquitous process that gives rise to high exchange surfaces in the vasculature and epithelial organs. Lymphatic capillaries form branched networks, which play a key role in the circulation of tissue fluid and immune cells. Although mouse models and correlative patient data indicate that the lymphatic capillary density directly correlates with functional output, i.e., tissue fluid drainage and trafficking efficiency of dendritic cells, the mechanisms ensuring efficient tissue coverage remain poorly understood. Here, we use the mouse ear pinna lymphatic vessel network as a model system and combine lineage-tracing, genetic perturbations, whole-organ reconstructions and theoretical modeling to show that the dermal lymphatic capillaries tile space in an optimal, space-filling manner. This coverage is achieved by two complementary mechanisms: initial tissue invasion provides a non-optimal global scaffold via self-organized branching morphogenesis, while VEGF-C dependent side-branching from existing capillaries rapidly optimizes local coverage by directionally targeting low-density regions. With these two ingredients, we show that a minimal biophysical model can reproduce quantitatively whole-network reconstructions, across development and perturbations. Our results show that lymphatic capillary networks can exploit local self-organizing mechanisms to achieve tissue-scale optimization.
Pick and place process for uniform shrinking of 3D printed micro- and nano-architected materials
Authors: Mori Tomohiro , Wang Hao , Zhang Wang , Ser Chern Chia , Arora Deepshikha , Pan Cheng-Feng , Li Hao , Niu Jiabin , Rahman M. A. , Mori Takeshi , Koishi Hideyuki , Yang Joel K. W.
Published: September 2023

Two-photon polymerization lithography is promising for producing three-dimensional structures with user-defined micro- and nanoscale features. Additionally, shrinkage by thermolysis can readily shorten the lattice constant of three-dimensional photonic crystals and enhance their resolution and mechanical properties; however, this technique suffers from non-uniform shrinkage owing to substrate pinning during heating. Here, we develop a simple method using poly(vinyl alcohol)-assisted uniform shrinking of three-dimensional printed structures. Microscopic three-dimensional printed objects are picked and placed onto a receiving substrate, followed by heating to induce shrinkage. We show the successful uniform heat-shrinking of three-dimensional prints with various shapes and sizes, without sacrificial support structures, and observe that the surface properties of the receiving substrate are important factors for uniform shrinking. Moreover, we print a three-dimensional mascot model that is then uniformly shrunk, producing vivid colors from colorless woodpile photonic crystals. The proposed method has significant potential for application in mechanics, optics, and photonics.
Nonlinear El Niño impacts on the global economy under climate change
Authors: Liu Yi , Cai Wenju , Lin Xiaopei , Li Ziguang , Zhang Ying
Published: September 2023

The El Niño-Southern Oscillation (ENSO) is a consequential climate phenomenon affecting global extreme weather events often with largescale socioeconomic impacts. To what extent the impact affects the macroeconomy, how long the impact lasts, and how the impact may change in a warming climate are important questions for the field. Using a smooth nonlinear climate-economy model fitted with historical data, here we find a damaging impact from an El Niño which increases for a further three years after initial shock, amounting to multi-trillion US dollars in economic loss; we attribute a loss of US$2.1 T and US$3.9 T globally to the 1997-98 and 2015-16 extreme El Niño events, far greater than that based on tangible losses. We find impacts from La Niña are asymmetric and weaker, and estimate a gain of only US$0.06 T from the 1998-99 extreme La Niña event. Under climate change, economic loss grows exponentially with increased ENSO variability. Under a high-emission scenario, increased ENSO variability causes an additional median loss of US$33 T to the global economy at a 3% discount rate aggregated over the remainder of the 21st century. Thus, exacerbated economic damage from changing ENSO in a warming climate should be considered in assessments of mitigation strategies.
Benchmarking universal quantum gates via channel spectrum
Authors: Gu Yanwu , Zhuang Wei-Feng , Chai Xudan , Liu Dong E.
Published: September 2023

Noise remains the major obstacle to scalable quantum computation. Quantum benchmarking provides key information on noise properties and is an important step for developing more advanced quantum processors. However, current benchmarking methods are either limited to a specific subset of quantum gates or cannot directly describe the performance of the individual target gate. To overcome these limitations, we propose channel spectrum benchmarking (CSB), a method to infer the noise properties of the target gate, including process fidelity, stochastic fidelity, and some unitary parameters, from the eigenvalues of its noisy channel. Our CSB method is insensitive to state-preparation and measurement errors, and importantly, can benchmark universal gates and is scalable to many-qubit systems. Unlike standard randomized schemes, CSB can provide direct noise information for both target native gates and circuit fragments, allowing benchmarking and calibration of global entangling gates and frequently used modules in quantum algorithms like Trotterized Hamiltonian evolution operator in quantum simulation.
SRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis
Authors: Barbayianni Ilianna , Kanellopoulou Paraskevi , Fanidis Dionysios , Nastos Dimitris , Ntouskou Eleftheria-Dimitra , Galaris Apostolos , Harokopos Vaggelis , Hatzis Pantelis , Tsitoura Eliza , Homer Robert , Kaminski Naftali , Antoniou Katerina M. , Crestani Bruno , Tzouvelekis Argyrios , Aidinis Vassilis
Published: September 2023

The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of Idiopathic Pulmonary Fibrosis patients and bleomycin-treated mice. Τhe profibrotic milieu is found to induceTKS5expression and the formation of prominent podosome rosettes in lung fibroblasts, that are retained ex vivo, culminating in increased extracellular matrix invasion.Tks5+/-mice are found resistant to bleomycin-induced pulmonary fibrosis, largely attributed to diminished podosome formation in fibroblasts and decreased extracellular matrix invasion. As computationally predicted, inhibition of src kinase is shown to potently attenuate podosome formation in lung fibroblasts and extracellular matrix invasion, and bleomycin-induced pulmonary fibrosis, suggesting pharmacological targeting of podosomes as a very promising therapeutic option in pulmonary fibrosis.
Causal inference from cross-sectional earth system data with geographical convergent cross mapping
Authors: Gao Bingbo , Yang Jianyu , Chen Ziyue , Sugihara George , Li Manchun , Stein Alfred , Kwan Mei-Po , Wang Jinfeng
Published: September 2023

Causal inference in complex systems has been largely promoted by the proposal of some advanced temporal causation models. However, temporal models have serious limitations when time series data are not available or present insignificant variations, which causes a common challenge for earth system science. Meanwhile, there are few spatial causation models for fully exploring the rich spatial cross-sectional data in Earth systems. The generalized embedding theorem proves that observations can be combined together to construct the state space of the dynamic system, and if two variables are from the same dynamic system, they are causally linked. Inspired by this, here we show a Geographical Convergent Cross Mapping (GCCM) model for spatial causal inference with spatial cross-sectional data-based cross-mapping prediction in reconstructed state space. Three typical cases, where clearly existing causations cannot be measured through temporal models, demonstrate that GCCM could detect weak-moderate causations when the correlation is not significant. When the coupling between two variables is significant and strong, GCCM is advantageous in identifying the primary causation direction and better revealing the bidirectional asymmetric causation, overcoming the mirroring effect.
Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies
Authors: Yanik Sean , Venkatesh Varsha , Parker Michelle L. , Ramaswamy Raghavendran , Diouf Ababacar , Sarkar Deepti , Miura Kazutoyo , Long Carole A. , Boulanger Martin J. , Srinivasan Prakash
Published: September 2023

Invasion of human erythrocytes by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins: apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2). While antibodies to AMA1 provide limited protection against Pf in non-human primate malaria models, clinical trials using recombinant AMA1 alone (apoAMA1) yielded no protection due to insufficient functional antibodies. Immunization with AMA1 bound to RON2L, a 49-amino acid peptide from its ligand RON2, has shown superior protection by increasing the proportion of neutralizing antibodies. However, this approach relies on the formation of a complex in solution between the two vaccine components. To advance vaccine development, here we engineered chimeric antigens by replacing the AMA1 DII loop, displaced upon ligand binding, with RON2L. Structural analysis confirmed that the fusion chimera (Fusion-FD12) closely mimics the binary AMA1-RON2L complex. Immunization studies in female rats demonstrated that Fusion-FD12 immune sera, but not purified IgG, neutralized vaccine-type parasites more efficiently compared to apoAMA1, despite lower overall anti-AMA1 titers. Interestingly, Fusion-FD12 immunization enhanced antibodies targeting conserved epitopes on AMA1, leading to increased neutralization of non-vaccine type parasites. Identifying these cross-neutralizing antibody epitopes holds promise for developing an effective, strain-transcending malaria vaccine.
DeepSlice: rapid fully automatic registration of mouse brain imaging to a volumetric atlas
Authors: Carey Harry , Pegios Michael , Martin Lewis , Saleeba Chris , Turner Anita J. , Everett Nicholas A. , Bjerke Ingvild E. , Puchades Maja A. , Bjaalie Jan G. , McMullan Simon
Published: September 2023

Registration of data to a common frame of reference is an essential step in the analysis and integration of diverse neuroscientific data. To this end, volumetric brain atlases enable histological datasets to be spatially registered and analyzed, yet accurate registration remains expertise-dependent and slow. In order to address this limitation, we have trained a neural network, DeepSlice, to register mouse brain histological images to the Allen Brain Common Coordinate Framework, retaining registration accuracy while improving speed by >1000 fold.
Decoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Authors: Santamaria Xavier , Roson Beatriz , Perez-Moraga Raul , Venkatesan Nandakumar , Pardo-Figuerez Maria , Gonzalez-Fernandez Javier , Llera-Oyola Jaime , Fernández Estefania , Moreno Inmaculada , Salumets Andres , Vankelecom Hugo , Vilella Felipe , Simon Carlos
Published: September 2023

Asherman’s Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. The pathophysiology of this syndrome remains unknown, with treatment restricted to recurrent surgical removal of intrauterine scarring, which has limited success. Here, we decode the Asherman’s Syndrome endometrial cell niche by analyzing data from over 200,000 cells with single-cell RNA-sequencing in patients with this condition and through in vitro analyses of Asherman’s Syndrome patient-derived endometrial organoids. Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation. We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment.
The CBL1/9-CIPK1 calcium sensor negatively regulates drought stress by phosphorylating the PYLs ABA receptor
Authors: You Zhang , Guo Shiyuan , Li Qiao , Fang Yanjun , Huang Panpan , Ju Chuanfeng , Wang Cun
Published: September 2023

The stress hormone, Abscisic acid (ABA), is crucial for plants to respond to changes in their environment. It triggers changes in cytoplasmic Ca2+ levels, which activate plant responses to external stresses. However, how Ca2+ sensing and signaling feeds back into ABA signaling is not well understood. Here we reveal a calcium sensing module that negatively regulates drought stress via modulating ABA receptor PYLs. Mutants cbl1/9 and cipk1 exhibit hypersensitivity to ABA and drought resilience. Furthermore, CIPK1 is shown to interact with and phosphorylate 7 of 14 ABA receptors at the evolutionarily conserved site corresponding to PYL4 Ser129, thereby suppressing their activities and promoting PP2C activities under normal conditions. Under drought stress, ABA impedes PYLs phosphorylation by CIPK1 to respond to ABA signaling and survive in unfavorable environment. These findings provide insights into a previously unknown negative regulatory mechanism of the ABA signaling pathway, which is mediated by CBL1/9-CIPK1-PYLs, resulting in plants that are more sensitive to drought stress. This discovery expands our knowledge about the interplay between Ca2+ signaling and ABA signaling.
Deep generative modeling of transcriptional dynamics for RNA velocity analysis in single cells
Authors: Gayoso Adam , Weiler Philipp , Lotfollahi Mohammad , Klein Dominik , Hong Justin , Streets Aaron , Theis Fabian J. , Yosef Nir
Published: September 2023

RNA velocity has been rapidly adopted to guide interpretation of transcriptional dynamics in snapshot single-cell data; however, current approaches for estimating RNA velocity lack effective strategies for quantifying uncertainty and determining the overall applicability to the system of interest. Here, we present veloVI (velocity variational inference), a deep generative modeling framework for estimating RNA velocity. veloVI learns a gene-specific dynamical model of RNA metabolism and provides a transcriptome-wide quantification of velocity uncertainty. We show that veloVI compares favorably to previous approaches with respect to goodness of fit, consistency across transcriptionally similar cells and stability across preprocessing pipelines for quantifying RNA abundance. Further, we demonstrate that veloVI’s posterior velocity uncertainty can be used to assess whether velocity analysis is appropriate for a given dataset. Finally, we highlight veloVI as a flexible framework for modeling transcriptional dynamics by adapting the underlying dynamical model to use time-dependent transcription rates.
EzMechanism: an automated tool to propose catalytic mechanisms of enzyme reactions
Authors: Ribeiro Antonio J. M. , Riziotis Ioannis G. , Tyzack Jonathan D. , Borkakoti Neera , Thornton Janet M.
Published: September 2023

Over the years, hundreds of enzyme reaction mechanisms have been studied using experimental and simulation methods. This rich literature on biological catalysis is now ripe for use as the foundation of new knowledge-based approaches to investigate enzyme mechanisms. Here, we present a tool able to automatically infer mechanistic paths for a given three-dimensional active site and enzyme reaction, based on a set of catalytic rules compiled from the Mechanism and Catalytic Site Atlas, a database of enzyme mechanisms. EzMechanism (pronounced as ‘Easy’ Mechanism) is available to everyone through a web user interface. When studying a mechanism, EzMechanism facilitates and improves the generation of hypotheses, by making sure that relevant information is considered, as derived from the literature on both related and unrelated enzymes. We validated EzMechanism on a set of 62 enzymes and have identified paths for further improvement, including the need for additional and more generic catalytic rules.
Time-resolved cryo-EM (TR-EM) analysis of substrate polyubiquitination by the RING E3 anaphase-promoting complex/cyclosome (APC/C)
Authors: Bodrug Tatyana , Welsh Kaeli A. , Bolhuis Derek L. , Paulаkonis Ethan , Martinez-Chacin Raquel C. , Liu Bei , Pinkin Nicholas , Bonacci Thomas , Cui Liying , Xu Pengning , Roscow Olivia , Amann Sascha Josef , Grishkovskaya Irina , Emanuele Michael J. , Harrison Joseph S. , Steimel Joshua P. , Hahn Klaus M. , Zhang Wei , Zhong Ellen D. , Haselbach David , Brown Nicholas G.
Published: September 2023

Substrate polyubiquitination drives a myriad of cellular processes, including the cell cycle, apoptosis and immune responses. Polyubiquitination is highly dynamic, and obtaining mechanistic insight has thus far required artificially trapped structures to stabilize specific steps along the enzymatic process. So far, how any ubiquitin ligase builds a proteasomal degradation signal, which is canonically regarded as four or more ubiquitins, remains unclear. Here we present time-resolved cryogenic electron microscopy studies of the 1.2 MDa E3 ubiquitin ligase, known as the anaphase-promoting complex/cyclosome (APC/C), and its E2 co-enzymes (UBE2C/UBCH10 and UBE2S) during substrate polyubiquitination. Using cryoDRGN (Deep Reconstructing Generative Networks), a neural network-based approach, we reconstruct the conformational changes undergone by the human APC/C during polyubiquitination, directly visualize an active E3–E2 pair modifying its substrate, and identify unexpected interactions between multiple ubiquitins with parts of the APC/C machinery, including its coactivator CDH1. Together, we demonstrate how modification of substrates with nascent ubiquitin chains helps to potentiate processive substrate polyubiquitination, allowing us to model how a ubiquitin ligase builds a proteasomal degradation signal.
Impact of elastic substrate on the dynamic heterogeneity of WC256 Walker carcinosarcoma cells
Authors: Mielnicka Aleksandra , Kołodziej Tomasz , Dziob Daniel , Lasota Sławomir , Sroka Jolanta , Rajfur Zenon
Published: September 2023

Cellular heterogeneity is a phenomenon in which cell populations are composed of subpopulations that vary in their behavior. Heterogeneity is particularly pronounced in cancer cells and can affect the efficacy of oncological therapies. Previous studies have considered heterogeneity dynamics to be indicative of evolutionary changes within subpopulations; however, these studies do not consider the short-time morphological plasticity of cells. Physical properties of the microenvironment elasticity have also been poorly investigated within the context of cellular heterogeneity, despite its role in determining cellular behavior. This article demonstrates that cellular heterogeneity can be highly dynamic and dependent on the micromechanical properties of the substrate. During observation, migrating Walker carcinosarcoma WC256 cells were observed to belong to different subpopulations, in which their morphologies and migration strategies differed. Furthermore, the application of an elastic substrate (E = 40 kPa) modified three aspects of cellular heterogeneity: the occurrence of subpopulations, the occurrence of transitions between subpopulations, and cellular migration and morphology. These findings provide a new perspective in the analysis of cellular heterogeneity, whereby it may not be a static feature of cancer cell populations, instead varying over time. This helps further the understanding of cancer cell behavior, including their phenotype and migration strategy, which may help to improve cancer therapies by extending their suitability to investigate tumor heterogeneity.
Synthesis and in situ oxidation of copper micro- and nanoparticles by arc discharge plasma in liquid
Authors: Zhakypov Alibek S. , Nemkayeva Renata R. , Yerlanuly Yerassyl , Tulegenova Malika A. , Kurbanov Beibarys Y. , Aitzhanov Madi B. , Markhabayeva Aiymkul A. , Gabdullin Maratbek T.
Published: September 2023

This work presents a one-step controlled method for the synthesis of copper oxide nanoparticles using an arc discharge in deionized water without subsequent thermal annealing. The synthesis conditions were varied by changing the arc discharge current from 2 to 4 A. Scanning electron microscopy images of samples synthesized at discharge current of 2 A revealed the formation of tenorite (CuO) nanopetals with an average length of 550 nm and a width of 100 nm, which had a large surface area. Arc discharge synthesis at 3 and 4 A current modes provides the formation of a combination of CuO nanopetals with spherical cuprite (Cu2O) nanoparticles with sizes ranging from 30 to 80 nm. The crystalline phase and elemental composition of the synthesized particles were identified by X-ray diffraction analysis, Raman spectroscopy and Energy dispersive analysis. As the arc discharge current was raised from 2 to 4 A, two notable changes occurred in the synthesized particles: the Cu/O ratio increased, and the particle sizes decreased. At 4 A, the synthesized particles were from 30 to 80 nm in size and had a spherical shape, indicating an increase in the amount of cuprite (Cu2O) phase. The optical band gap of the aqueous solutions of copper oxide particles also increased from 2 to 2.34 eV with increasing synthesis current from 2 to 4 A, respectively. This suggests that the proposed synthesis method can be used to tune the band gap of the final material by controlling the Cu/O ratio through the current of arc discharge. Overall, this work demonstrates a novel approach to the synthesis of copper oxide nanoparticles with controllable CuO/Cu2O/Cu ratios, which has the potential to be useful in a variety of applications, particularly due to the significant enhancement of photocatalytic abilities and widen the working spectral range.
MSFC: a new feature construction method for accurate diagnosis of mass spectrometry data
Authors: Feng Xin , Dong Zheyuan , Li Yingrui , Cheng Qian , Xin Yongxian , Lu Qiaolin , Xin Ruihao
Published: September 2023

Mass spectrometry technology can realize dynamic detection of many complex matrix samples in a simple, rapid, compassionate, precise, and high-throughput manner and has become an indispensable tool in accurate diagnosis. The mass spectrometry data analysis is mainly to analyze all metabolites in the organism quantitatively and to find the relative relationship between metabolites and physiological and pathological changes. A feature construction of mass spectrometry data (MSFS) method is proposed to construct the features of the original mass spectrometry data, so as to reduce the noise in the mass spectrometry data, reduce the redundancy of the original data and improve the information content of the data. Chi-square test is used to select the optimal non-redundant feature subset from high-dimensional features. And the optimal feature subset is visually analyzed and corresponds to the original mass spectrum interval. Training in 10 kinds of supervised learning models, and evaluating the classification effect of the models through various evaluation indexes. Taking two public mass spectrometry datasets as examples, the feasibility of the method proposed in this paper is verified. In the coronary heart disease dataset, during the identification process of mixed batch samples, the classification accuracy on the test set reached 1.000; During the recognition process, the classification accuracy on the test set advanced to 0.979. On the colorectal liver metastases data set, the classification accuracy on the test set reached 1.000. This paper attempts to use a new raw mass spectrometry data preprocessing method to realize the alignment operation of the raw mass spectrometry data, which significantly improves the classification accuracy and provides another new idea for mass spectrometry data analysis. Compared with MetaboAnalyst software and existing experimental results, the method proposed in this paper has obtained better classification results.
A cross-sectional case–control study on the structural connectome in recovered hospitalized COVID-19 patients
Authors: Lathouwers Elke , Radwan Ahmed , Blommaert Jeroen , Stas Lara , Tassignon Bruno , Allard Sabine D. , De Ridder Filip , De Waele Elisabeth , Hoornaert Nicole , Lacor Patrick , Mertens Rembert , Naeyaert Maarten , Raeymaekers Hubert , Seyler Lucie , Vanbinst Anne-Marie , Van Liedekerke Lien , Van Schependom Jeroen , Van Schuerbeek Peter , Provyn Steven , Roelands Bart , Vandekerckhove Marie , Meeusen Romain , Sunaert Stefan , Nagels Guy , De Mey Johan , De Pauw Kevin
Published: September 2023

COVID-19 can induce neurological sequelae, negatively affecting the quality of life. Unravelling this illness's impact on structural brain connectivity, white-matter microstructure (WMM), and cognitive performance may help elucidate its implications. This cross-sectional study aimed to investigate differences in these factors between former hospitalised COVID-19 patients (COV) and healthy controls. Group differences in structural brain connectivity were explored using Welch-two sample t-tests and two-sample Mann–Whitney U tests. Multivariate linear models were constructed (one per region) to examine fixel-based group differences. Differences in cognitive performance between groups were investigated using Wilcoxon Rank Sum tests. Possible effects of bundle-specific FD measures on cognitive performance were explored using a two-group path model. No differences in whole-brain structural organisation were found. Bundle-specific metrics showed reduced fiber density (p = 0.012, Hedges’ g = 0.884) and fiber density cross-section (p = 0.007, Hedges’ g = 0.945) in the motor segment of the corpus callosum in COV compared to healthy controls. Cognitive performance on the motor praxis and digit symbol substitution tests was worse in COV than healthy controls (p < 0.001, r = 0.688; p = 0.013, r = 422, respectively). Associations between the cognitive performance and bundle-specific FD measures differed significantly between groups. WMM and cognitive performance differences were observed between COV and healthy controls.
Stem cells-derived exosomes alleviate neurodegeneration and Alzheimer’s pathogenesis by ameliorating neuroinflamation, and regulating the associated molecular pathways
Authors: Khan Muhammad Imran , Jeong Eun Sun , Khan Muhammad Zubair , Shin Jin Hyuk , Kim Jong Deog
Published: September 2023

Amyloid beta (Aβ) aggregation and tau hyper phosphorylation (p-tau) are key molecular factors in Alzheimer’s disease (AD). The abnormal formation and accumulation of Aβ and p-tau lead to the formation of amyloid plaques and neurofibrillary tangles (NFTs) which ultimately leads to neuroinflammation and neurodegeneration. β- and γ-secretases produce Aβ peptides via the amyloidogenic pathway, and several kinases are involved in tau phosphorylation. Exosomes, a recently developed method of intercellular communication, derived from neuronal stem cells (NSC-exos), are intriguing therapeutic options for AD. Exosomes have ability to cross the BBB hence highly recommended for brain related diseases and disorders. In the current study, we examined how NSC-exos could protect human neuroblastoma cells SH-SY5Y (ATCC CRL-2266). NSC-exos were derived from Human neural stem cells (ATCC-BYS012) by ultracentrifugation and the therapeutic effects of the NSC-exos were then investigated in vitro. NSC-exos controlled the associated molecular processes to drastically lower Aβ and p-tau. A dose dependent reduction in β- and γ-secretase, acetylcholinesterase, GSK3β, CDK5, and activated α-secretase activities was also seen. We further showed that BACE1, PSEN1, CDK5, and GSK-3β mRNA expression was suppressed and downregulated, while ADAM10 mRNA was increased. NSC- Exos downregulate NF-B/ERK/JNK-related signaling pathways in activated glial cells HMC3 (ATCC-CRL-3304) and reduce inflammatory mediators such iNOS, IL-1β, TNF-α, and IL-6, which are associated with neuronal inflammation. The NSC-exos therapy ameliorated the neurodegeneration of human neuroblastoma cells SH-SY5Y by enhancing viability. Overall, these findings support that exosomes produced from stem cells can be a neuro-protective therapy to alleviate AD pathology.
Dermoscopy of acute radiation-induced dermatitis in patients with head and neck cancers treated with radiotherapy
Authors: Pilśniak Aleksandra , Szlauer-Stefańska Anastazja , Tukiendorf Andrzej , Rutkowski Tomasz , Składowski Krzysztof , Kamińska-Winciorek Grażyna
Published: September 2023

Head and neck cancer (HNC) was the seventh most common cancer in the world in 2018. Treatment of a patient may include surgery, radiotherapy (RT), chemotherapy, targeted therapy, immunotherapy, or a combination of these methods. Ionizing radiation used during RT covers relatively large volumes of healthy tissue surrounding the tumor. The acute form of radiation-induced dermatitis (ARD) are skin lesions that appear usually within 90 days of the start of RT. This is a prospective study which compares 2244 dermoscopy images and 374 clinical photographs of irradiated skin and healthy skin of 26 patients at on average 15 time points. Dermoscopy pictures were evaluated independently by 2 blinded physicians. Vessels in reticular distribution, white, yellow or brown scale in a patchy distribution, perifollicular pigmentation and follicular plugs arranged in rosettes were most often observed. For these dermoscopic features, agreement with macroscopic features was observed. Two independent predictors of severe acute toxicity were identified: gender and concurrent chemotherapy. Knowledge of dermoscopic features could help in the early assessment of acute toxicity and the immediate implementation of appropriate therapeutic strategies. This may increase the tolerance of RT in these groups of patients.
FAT4 expression in peripheral blood mononuclear cells is associated with prognosis and immune cell infiltration in hepatocellular carcinoma
Authors: Li Jing , Lv Minling , Huang Qi , Hu Rui , Zhong Xin , Sun Xinfeng , Feng Wenxing , Han Zhiyi , Ma MengQing , Zhang Wei , Zhou Xiaozhou
Published: September 2023

Peripheral blood mononuclear cell (PBMC) genes reflect the host immune status and could be suitable for evaluating the prognosis of patients with hepatocellular carcinoma (HCC), for which a reliable biomarker is unavailable and the host immune responses to cancer cells. This study aimed to investigate prognostically relevant genes in HCC PBMCs and assessed whether their expression represents tumor immune infiltration. Gene expression in PBMCs from patients with advanced or terminal HCC who had survived or died was examined. Correlations among FAT atypical cadherin 4 (FAT4) expression, cancer immune characteristics, and infiltrated immune cell gene marker sets were analyzed. FAT4 expression was lower in the PBMCs of patients with advanced or terminal HCC who had died than that in patients who survived. Kaplan–Meier analysis indicated that FAT4 downregulation was associated with a relatively poor prognosis while overexpression was positively correlated with immune cell infiltration, several immune cell markers, and immune checkpoint expression. Hsa-miR-93-5p represented the most probable upstream microRNA of FAT4. Thus, upregulated FAT4 in PBMCs and HCC tissues might indicate a favorable prognosis and increased immune cell infiltration, while miRNA-93-5p could be a modulator of FAT4 expression. Collectively, these findings suggest novel immunotherapy targets for HCC.
Flow phenomena in laminar flow through streamlined and sharp-edged short monolithic structures
Authors: Korpyś Mateusz , Iwaniszyn Marzena , Sindera Katarzyna , Suwak Mikołaj , Gancarczyk Anna , Kołodziej Andrzej
Published: September 2023

Monolithic structures of catalytic reactors offer low flow resistance, but their drawback is weak heat and mass transport. For transport intensification, innovative streamlined structures were designed, the walls of which are shaped like an airplane wing. Extensive CFD (Computer Fluid Dynamics) studies were performed for the streamlined and—for comparison—classic (sharp-edged) structures, covered flow phenomena, and heat transfer to channel walls. The streamlined structures were made using the SLM (Selective Laser Melting) method to perform heat transfer experiments that gave a satisfactory agreement with the CFD. Heat transfer for streamlined structures was, by CFD, more intensive than for the classical ones. CFD simulations showed a significant reduction of vortices in streamlined structures. The lack of an inlet vortex was demonstrated, for classic structures strongly limiting transfer properties. For the streamlined structures the outlet vortex even intensifies heat transport near the outlet of the channel. The CFD showed the flow patterns for the structures as well as the distribution of transport coefficients within the millimetre-sized channels.
The transfer of 137Cs and heavy metals to tissues within the organs of snails
Authors: Baigazinov Zhanat , Lukashenko Sergey , Silybayeva Batiyash , Zharykbasova Klara , Bukabayeva Zhanylkhan , Muhamediarov Nurlan , Kantbayeva Bagdat , Kozhakhmetova Balzhan , Ganbaatar Tuvshinsaikhan , Toth-Bodrogi Edit , Hegedus Miklos , Kovacs Tibor
Published: September 2023

This paper describes the dynamics of 137Cs accumulation and its concentration ratio as well as that of some stable elements in the body, shell, gastrointestinal tract and albumin gland of a particular species of snail (terrestrial gastropod), namely the Giant African snail (Lissachatina fulica), after the long-term ingestion of contaminated forage and/or soil. The activity concentration of 137Cs in the their bodies increased over the first 40 days of the experiment, after which the increase in the activity of this radionuclide significantly reduced. The distribution of 137Cs in the body of a snail decreases as follows: gastrointestinal tract ˃ body = albumin gland ˃ shell. It was found that the contribution of soil towards the contamination of their bodies by 137Cs is far less than that of forage. Although the biological availability of Pb and U in forage is one order of magnitude higher than in soil, the main contribution to the contamination of snails originates from soil.
Effects of bone-conducted vibration stimulation of various frequencies on the vertical vection
Authors: Kondo Tetsuta , Hirao Yutaro , Narumi Takuji , Amemiya Tomohiro
Published: September 2023

Illusory self-motion (“vection”) has been used to present a sense of movement in virtual reality (VR) and other similar applications. It is crucial in vection research to present a stronger sense of movement. Bone-conducted vibration (BCV) is a small and generally acceptable method for enhancing the sense of movement in VR. However, its effects on vection have not been extensively studied. Here, we conducted two experiments to investigate the effect of BCV on the vection, which generates an upward sensation under the hypothesis that BCV stimulation to the mastoid processes causes noise in the vestibular system and enhances visually-induced self-motion perception. The experiments focused on the effects of BCV stimuli of different frequencies on the vection experience. The results suggested that 500 Hz BCV was more effective as noise to the vestibular system than other frequency BCVs and improved self-motion sensation. This study examines the effects of BCV with different frequencies on the vection experience and designs a theory for using BCV in VR.
Homeology of sex chromosomes in Amazonian Harttia armored catfishes supports the X-fission hypothesis for the X1X2Y sex chromosome system origin
Authors: de Menezes Cavalcante Sassi Francisco , Sember Alexandr , Deon Geize Aparecida , Liehr Thomas , Padutsch Niklas , Oyakawa Osvaldo Takeshi , Vicari Marcelo Ricardo , Bertollo Luiz Antonio Carlos , Moreira-Filho Orlando , de Bello Cioffi Marcelo
Published: September 2023

The Neotropical monophyletic catfish genus Harttia represents an excellent model to study karyotype and sex chromosome evolution in teleosts. Its species split into three phylogenetic clades distributed along the Brazilian territory and they differ widely in karyotype traits, including the presence of standard or multiple sex chromosome systems in some members. Here, we investigate the chromosomal rearrangements and associated synteny blocks involved in the origin of a multiple X1X2Y sex chromosome system present in three out of six sampled Amazonian-clade species. Using 5S and 18S ribosomal DNA fluorescence in situ hybridization and whole chromosome painting with probes corresponding to X1 and X2 chromosomes of X1X2Y system from H. punctata, we confirm previous assumptions that X1X2Y sex chromosome systems of H. punctata, H. duriventris and H. villasboas represent the same linkage groups which also form the putative XY sex chromosomes of H. rondoni. The shared homeology between X1X2Y sex chromosomes suggests they might have originated once in the common ancestor of these closely related species. A joint arrangement of mapped H. punctata X1 and X2 sex chromosomes in early diverging species of different Harttia clades suggests that the X1X2Y sex chromosome system may have formed through an X chromosome fission rather than previously proposed Y-autosome fusion.
Plasticity of cone photoreceptors in adult zebrafish revealed by thyroid hormone exposure
Authors: Farre Ashley A. , Thomas Preston , Huang Johnson , Poulsen Rachel A. , Owusu Poku Emmanuel , Stenkamp Deborah L.
Published: September 2023

Vertebrate color vision is predominantly mediated by the presence of multiple cone photoreceptor subtypes that are each maximally sensitive to different wavelengths of light. Thyroid hormone (TH) has been shown to be essential in the spatiotemporal patterning of cone subtypes in many species, including cone subtypes that express opsins that are encoded by tandemly replicated genes. TH has been shown to differentially regulate the tandemly replicated lws opsin genes in zebrafish, and exogenous treatments alter the expression levels of these genes in larvae and juveniles. In this study, we sought to determine whether gene expression in cone photoreceptors remains plastic to TH treatment in adults. We used a transgenic lws reporter line, multiplexed fluorescence hybridization chain reaction in situ hybridization, and qPCR to examine the extent to which cone gene expression can be altered by TH in adults. Our studies revealed that opsin gene expression, and the expression of other photoreceptor genes, remains plastic to TH treatment in adult zebrafish. In addition to retinal plasticity, exogenous TH treatment alters skin pigmentation patterns in adult zebrafish after 5 days. Taken together, our results show a remarkable level of TH-sensitive plasticity in the adult zebrafish.
Binary code similarity analysis based on naming function and common vector space
Authors: Xia Bing , Pang Jianmin , Zhou Xin , Shan Zheng , Wang Junchao , Yue Feng
Published: September 2023

Binary code similarity analysis is widely used in the field of vulnerability search where source code may not be available to detect whether two binary functions are similar or not. Based on deep learning and natural processing techniques, several approaches have been proposed to perform cross-platform binary code similarity analysis using control flow graphs. However, existing schemes suffer from the shortcomings of large differences in instruction syntaxes across different target platforms, inability to align control flow graph nodes, and less introduction of high-level semantics of stability, which pose challenges for identifying similar computations between binary functions of different platforms generated from the same source code. We argue that extracting stable, platform-independent semantics can improve model accuracy, and a cross-platform binary function similarity comparison model N_Match is proposed. The model elevates different platform instructions to the same semantic space to shield their underlying platform instruction differences, uses graph embedding technology to learn the stability semantics of neighbors, extracts high-level knowledge of naming function to alleviate the differences brought about by cross-platform and cross-optimization levels, and combines the stable graph structure as well as the stable, platform-independent API knowledge of naming function to represent the final semantics of functions. The experimental results show that the model accuracy of N_Match outperforms the baseline model in terms of cross-platform, cross-optimization level, and industrial scenarios. In the vulnerability search experiment, N_Match significantly improves hit@N, the mAP exceeds the current graph embedding model by 66%. In addition, we also give several interesting observations from the experiments. The code and model are publicly available at https://www.github.com/CSecurityZhongYuan/Binary-Name_Match.
Wnt activation as a potential therapeutic approach to treat partial limbal stem cell deficiency
Authors: Bonnet Clémence , González Sheyla , Deng Sophie X. , Zheng Jie J.
Published: September 2023

Limbal epithelial stem/progenitor cells (LSCs) are adult stem cells located at the limbus, tightly regulated by their niche involving numerous signaling pathways, such as Wnt. Wnt proteins are secreted morphogens that play critical roles in embryonic development, stem cell proliferation, self-renewal, tissue regeneration, and remodeling in adults. It has been shown that a small molecule Wnt mimic could improve LSCs expansion ex vivo. Damage to the LSCs and/or their niche can lead to limbal stem cell deficiency (LSCD), a condition that can cause corneal blindness and is difficult to treat. This study explored if repopulating residual LSCs in partial LSCD through Wnt activation could be a novel therapeutic approach. To mimic LSCD due to a chemical injury, single cultured LSCs were exposed to various concentrations of sodium hydroxide. A progressive loss of the LSCs phenotype was observed: the percentage of p63bright cells and cytokeratin (K)14+ cells decreased while the percentage of K12+ increased. Wnt activation was attained by treating the LSCs with lithium chloride (LiCl) and a small-molecule Wnt mimic, respectively. After 18 h of treatment, LSCs proliferation was increased, and the LSCs phenotype was recovered, while the untreated cells did not proliferate and lost their phenotype. The percentage of p63bright cells was significantly higher in the Wnt mimic-treated cells compared with untreated cells, while the percentage of K12+ cells was significantly lower. These findings suggest that local Wnt activation may rescue LSCs upon alkaline injury.
Distinct patterns of copy number alterations may predict poor outcome in central nervous system germ cell tumors
Authors: Takami Hirokazu , Satomi Kaishi , Fukuoka Kohei , Nakamura Taishi , Tanaka Shota , Mukasa Akitake , Saito Nobuhito , Suzuki Tomonari , Yanagisawa Takaaki , Sugiyama Kazuhiko , Kanamori Masayuki , Kumabe Toshihiro , Tominaga Teiji , Tamura Kaoru , Maehara Taketoshi , Nonaka Masahiro , Asai Akio , Yokogami Kiyotaka , Takeshima Hideo , Iuchi Toshihiko , Kobayashi Keiichi , Yoshimoto Koji , Sakai Keiichi , Nakazato Yoichi , Matsutani Masao , Nagane Motoo , Nishikawa Ryo , Ichimura Koichi
Published: September 2023

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.