bluuebunny/crossref_metadata_2025 huggingface dataset:
Notch3 inhibits cell proliferation and tumorigenesis and predicts better prognosis in breast cancer through transactivating PTEN
Authors: Zhang Yong-Qu , Liang Yuan-Ke , Wu Yang , Chen Min , Chen Wei-Ling , Li Rong-Hui , Zeng Yun-Zhu , Huang Wen-He , Wu Jun-Dong , Zeng De , Gao Wen-Liang , Chen Chun-Fa , Lin Hao-Yu , Yang Rui-Qin , Zhu Jiang-Wen , Liu Wan-Ling , Bai Jing-Wen , Wei Min , Wei Xiao-Long , Zhang Guo-Jun
Published: May 2021

Notch receptors (Notch1–4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.
Nicotine aggravates vascular adiponectin resistance via ubiquitin-mediated adiponectin receptor degradation in diabetic Apolipoprotein E knockout mouse
Authors: Gao Jia , Fan Jianghong , Meng Zhijun , Wang Rui , Liu Caihong , Liu Jing , Liang Bin , Wang Jing , Xie Yaoli , Zhao Jing , Guo Rui , Zhao Jianli , Ma Xinliang , Jiao Xiangying , Cao Jimin , Wang Yajing
Published: May 2021

There is limited and discordant evidence on the role of nicotine in diabetic vascular disease. Exacerbated endothelial cell dysregulation in smokers with diabetes is associated with the disrupted adipose function. Adipokines possess vascular protective, anti-inflammatory, and anti-diabetic properties. However, whether and how nicotine primes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of adiponectin (APN) level in high-fat diet (HFD) mice with nicotine (NIC) administration. The vascular pathophysiological response was evaluated with vascular ring assay. Confocal and co-immunoprecipitation analysis were applied to identify the signal interaction and transduction. These results indicated that the circulating APN level in nicotine-administrated diabetic Apolipoprotein E-deficient (ApoE−/−) mice was elevated in advance of 2 weeks of diabetic ApoE−/− mice. NIC and NIC addition in HFD groups (NIC + HFD) reduced the vascular relaxation and signaling response to APN at 6 weeks. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while elevated suppressor of cytokine signaling 3 (SOCS3) expression was induced by NIC and further augmented in NIC + HFD group. Additionally, nicotine provoked SOCS3, degraded AdipoR1, and attenuated APN-activated ERK1/2 in the presence of high glucose and high lipid (HG/HL) in human umbilical vein endothelial cells (HUVECs). MG132 (proteasome inhibitor) administration manifested that AdipoR1 was ubiquitinated, while inhibited SOCS3 rescued the reduced AdipoR1. In summary, this study demonstrated for the first time that nicotine primed vascular APN resistance via SOCS3-mediated degradation of ubiquitinated AdipoR1, accelerating diabetic endothelial dysfunction. This discovery provides a potential therapeutic target for preventing nicotine-accelerated diabetic vascular dysfunction.
Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells
Authors: Chen Xi , Saccon Elisa , Appelberg K. Sofia , Mikaeloff Flora , Rodriguez Jimmy Esneider , Vinhas Beatriz Sá , Frisan Teresa , Végvári Ákos , Mirazimi Ali , Neogi Ujjwal , Gupta Soham
Published: May 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce the susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV, and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon-stimulated genes and their role in the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.
ROS induces NETosis by oxidizing DNA and initiating DNA repair
Authors: Azzouz Dhia , Khan Meraj A. , Palaniyar Nades
Published: May 2021

Reactive oxygen species (ROS) are essential for neutrophil extracellular trap (NET) formation or NETosis. Nevertheless, how ROS induces NETosis is unknown. Neutrophil activation induces excess ROS production and a meaningless genome-wide transcription to facilitate chromatin decondensation. Here we show that the induction of NADPH oxidase-dependent NETosis leads to extensive DNA damage, and the subsequent translocation of proliferating cell nuclear antigen (PCNA), a key DNA repair protein, stored in the cytoplasm into the nucleus. During the activation of NETosis (e.g., by phorbol myristate acetate,Escherichia coliLPS,Staphylococcus aureus(RN4220), orPseudomonas aeruginosa), preventing the DNA-repair-complex assembly leading to nick formation that decondenses chromatin causes the suppression of NETosis (e.g., by inhibitors to, or knockdown of, Apurinic endonuclease APE1, poly ADP ribose polymerase PARP, and DNA ligase). The remaining repair steps involving polymerase activity and PCNA interactions with DNA polymerases β/δ do not suppress agonist-induced NETosis. Therefore, excess ROS produced during neutrophil activation induces NETosis by inducing extensive DNA damage (e.g., oxidising guanine to 8-oxoguanine), and the subsequent DNA repair pathway, leading to chromatin decondensation.
Spatio-temporal landscape of mouse epididymal cells and specific mitochondria-rich segments defined by large-scale single-cell RNA-seq
Authors: Shi Jianwu , Fok Kin Lam , Dai Pengyuan , Qiao Feng , Zhang Mengya , Liu Huage , Sang Mengmeng , Ye Mei , Liu Yang , Zhou Yiwen , Wang Chengniu , Sun Fei , Xie Gangcai , Chen Hao
Published: May 2021

Spermatozoa acquire their fertilizing ability and forward motility during epididymal transit, suggesting the importance of the epididymis. Although the cell atlas of the epididymis was reported recently, the heterogeneity of the cells and the gene expression profile in the epididymal tube are still largely unknown. Considering single-cell RNA sequencing results, we thoroughly studied the cell composition, spatio-temporal differences in differentially expressed genes (DEGs) in epididymal segments and mitochondria throughout the epididymis with sufficient cell numbers. In total, 40,623 cells were detected and further clustered into 8 identified cell populations. Focused analyses revealed the subpopulations of principal cells, basal cells, clear/narrow cells, and halo/T cells. Notably, two subtypes of principal cells, the Prc7 and Prc8 subpopulations were enriched as stereocilia-like cells according to GO analysis. Further analysis demonstrated the spatially specific pattern of the DEGs in each cell cluster. Unexpectedly, the abundance of mitochondria and mitochondrial transcription (MT) was found to be higher in the corpus and cauda epididymis than in the caput epididymis by scRNA-seq, immunostaining, and qPCR validation. In addition, the spatio-temporal profile of the DEGs from the P42 and P56 epididymis, including transiting spermatozoa, was depicted. Overall, our study presented the single-cell transcriptome atlas of the mouse epididymis and revealed the novel distribution pattern of mitochondria and key genes that may be linked to sperm functionalities in the first wave and subsequent wave of sperm, providing a roadmap to be emulated in efforts to achieve sperm maturation regulation in the epididymis.
Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens
Authors: Walter Nicholas D. , Born Sarah E. M. , Robertson Gregory T. , Reichlen Matthew , Dide-Agossou Christian , Ektnitphong Victoria A. , Rossmassler Karen , Ramey Michelle E. , Bauman Allison A. , Ozols Victor , Bearrows Shelby C. , Schoolnik Gary , Dolganov Gregory , Garcia Benjamin , Musisi Emmanuel , Worodria William , Huang Laurence , Davis J. Lucian , Nguyen Nhung V. , Nguyen Hung V. , Nguyen Anh T. V. , Phan Ha , Wilusz Carol , Podell Brendan K. , Sanoussi N’ Dira , de Jong Bouke C. , Merle Corinne S. , Affolabi Dissou , McIlleron Helen , Garcia-Cremades Maria , Maidji Ekaterina , Eshun-Wilson Franceen , Aguilar-Rodriguez Brandon , Karthikeyan Dhuvarakesh , Mdluli Khisimuzi , Bansbach Cathy , Lenaerts Anne J. , Savic Radojka M. , Nahid Payam , Vásquez Joshua J. , Voskuil Martin I.
Published: May 2021

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.
The effect of generic market entry on antibiotic prescriptions in the United States
Authors: Kållberg Cecilia , Hudson Jemma , Salvesen Blix Hege , Årdal Christine , Klein Eili , Lindbæk Morten , Outterson Kevin , Røttingen John-Arne , Laxminarayan Ramanan
Published: May 2021

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)—aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin—and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.
A well-timed shift from local to global agreements accelerates climate change mitigation
Authors: Karatayev Vadim A. , Vasconcelos Vítor V. , Lafuite Anne-Sophie , Levin Simon A. , Bauch Chris T. , Anand Madhur
Published: May 2021

Recent attempts at cooperating on climate change mitigation highlight the limited efficacy of large-scale negotiations, when commitment to mitigation is costly and initially rare. Deepening existing voluntary mitigation pledges could require more stringent, legally-binding agreements that currently remain untenable at the global scale. Building-blocks approaches promise greater success by localizing agreements to regions or few-nation summits, but risk slowing mitigation adoption globally. Here, we show that a well-timed policy shift from local to global legally-binding agreements can dramatically accelerate mitigation compared to using only local, only global, or both agreement types simultaneously. This highlights the scale-specific roles of mitigation incentives: local agreements promote and sustain mitigation commitments in early-adopting groups, after which global agreements rapidly draw in late-adopting groups. We conclude that focusing negotiations on local legally-binding agreements and, as these become common, a renewed pursuit of stringent, legally-binding world-wide agreements could best overcome many current challenges facing climate mitigation.
Low coordination number copper catalysts for electrochemical CO2 methanation in a membrane electrode assembly
Authors: Xu Yi , Li Fengwang , Xu Aoni , Edwards Jonathan P. , Hung Sung-Fu , Gabardo Christine M. , O’Brien Colin P. , Liu Shijie , Wang Xue , Li Yuhang , Wicks Joshua , Miao Rui Kai , Liu Yuan , Li Jun , Huang Jianan Erick , Abed Jehad , Wang Yuhang , Sargent Edward H. , Sinton David
Published: May 2021

The electrochemical conversion of CO2 to methane provides a means to store intermittent renewable electricity in the form of a carbon-neutral hydrocarbon fuel that benefits from an established global distribution network. The stability and selectivity of reported approaches reside below technoeconomic-related requirements. Membrane electrode assembly-based reactors offer a known path to stability; however, highly alkaline conditions on the cathode favour C-C coupling and multi-carbon products. In computational studies herein, we find that copper in a low coordination number favours methane even under highly alkaline conditions. Experimentally, we develop a carbon nanoparticle moderator strategy that confines a copper-complex catalyst when employed in a membrane electrode assembly. In-situ XAS measurements confirm that increased carbon nanoparticle loadings can reduce the metallic copper coordination number. At a copper coordination number of 4.2 we demonstrate a CO2-to-methane selectivity of 62%, a methane partial current density of 136 mA cm−2, and > 110 hours of stable operation.
Spectral bias and task-model alignment explain generalization in kernel regression and infinitely wide neural networks
Authors: Canatar Abdulkadir , Bordelon Blake , Pehlevan Cengiz
Published: May 2021

A theoretical understanding of generalization remains an open problem for many machine learning models, including deep networks where overparameterization leads to better performance, contradicting the conventional wisdom from classical statistics. Here, we investigate generalization error for kernel regression, which, besides being a popular machine learning method, also describes certain infinitely overparameterized neural networks. We use techniques from statistical mechanics to derive an analytical expression for generalization error applicable to any kernel and data distribution. We present applications of our theory to real and synthetic datasets, and for many kernels including those that arise from training deep networks in the infinite-width limit. We elucidate an inductive bias of kernel regression to explain data with simple functions, characterize whether a kernel is compatible with a learning task, and show that more data may impair generalization when noisy or not expressible by the kernel, leading to non-monotonic learning curves with possibly many peaks.
Superconductor-insulator transition in space charge doped one unit cell Bi2.1Sr1.9CaCu2O8+x
Authors: Wang Fang , Biscaras Johan , Erb Andreas , Shukla Abhay
Published: May 2021

The superconductor-insulator transition in two dimensions is a prototype continuous quantum phase transition at absolute zero, driven by a parameter other than temperature. Here we reveal this transition in one unit-cell Bi2.1Sr1.9CaCu2O8+x by space charge doping, a field effect electrostatic doping technique. We determine the related critical parameters and develop a reliable way to estimate doping in the nonsuperconducting region, a crucial and central problem in these materials. Finite-size scaling analysis yields a critical doping of 0.057 holes/Cu, a critical resistance of ~6.85 kΩ and a scaling exponent product νz ~ 1.57. These results, together with earlier work in other materials, provide a coherent picture of the superconductor-insulator transition and its bosonic nature in the underdoped regime of emerging superconductivity in high critical temperature superconductors.
Biomimetic high performance artificial muscle built on sacrificial coordination network and mechanical training process
Authors: Tu Zhikai , Liu Weifeng , Wang Jin , Qiu Xueqing , Huang Jinhao , Li Jinxing , Lou Hongming
Published: May 2021

Artificial muscle materials promise incredible applications in actuators, robotics and medical apparatus, yet the ability to mimic the full characteristics of skeletal muscles into synthetic materials remains a huge challenge. Herein, inspired by the dynamic sacrificial bonds in biomaterials and the self-strengthening of skeletal muscles by physical exercise, high performance artificial muscle material is prepared by rearrangement of sacrificial coordination bonds in the polyolefin elastomer via a repetitive mechanical training process. Biomass lignin is incorporated as a green reinforcer for the construction of interfacial coordination bonds. The prepared artificial muscle material exhibits high actuation strain (>40%), high actuation stress (1.5 MPa) which can lift more than 10,000 times its own weight with 30% strain, characteristics of excellent self-strengthening by mechanical training, strain-adaptive stiffening, and heat/electric programmable actuation performance. In this work, we show a facile strategy for the fabrication of intelligent materials using easily available raw materials.
Guiding functions of the C-terminal domain of topoisomerase IIα advance mitotic chromosome assembly
Authors: Shintomi Keishi , Hirano Tatsuya
Published: May 2021

Topoisomerase II (topo II) is one of the six proteins essential for mitotic chromatid reconstitution in vitro. It is not fully understood, however, mechanistically how this enzyme regulates this process. In an attempt to further refine the reconstitution assay, we have found that chromosomal binding of Xenopus laevis topo IIα is sensitive to buffer conditions and depends on its C-terminal domain (CTD). Enzymological assays using circular DNA substrates supports the idea that topo IIα first resolves inter-chromatid entanglements to drive individualization and then generates intra-chromatid entanglements to promote thickening. Importantly, only the latter process requires the CTD. By using frog egg extracts, we also show that the CTD contributes to proper formation of nucleosome-depleted chromatids by competing with a linker histone for non-nucleosomal DNA. Our results demonstrate that topo IIα utilizes its CTD to deliver the enzymatic core to crowded environments created during mitotic chromatid assembly, thereby fine-tuning this process.
CD8+ T cell landscape in Indigenous and non-Indigenous people restricted by influenza mortality-associated HLA-A*24:02 allomorph
Authors: Hensen Luca , Illing Patricia T. , Bridie Clemens E. , Nguyen Thi H. O. , Koutsakos Marios , van de Sandt Carolien E. , Mifsud Nicole A. , Nguyen Andrea T. , Szeto Christopher , Chua Brendon Y. , Halim Hanim , Rizzetto Simone , Luciani Fabio , Loh Liyen , Grant Emma J. , Saunders Phillipa M. , Brooks Andrew G. , Rockman Steve , Kotsimbos Tom C. , Cheng Allen C. , Richards Michael , Westall Glen P. , Wakim Linda M. , Loudovaris Thomas , Mannering Stuart I. , Elliott Michael , Tangye Stuart G. , Jackson David C. , Flanagan Katie L. , Rossjohn Jamie , Gras Stephanie , Davies Jane , Miller Adrian , Tong Steven Y. C. , Purcell Anthony W. , Kedzierska Katherine
Published: May 2021

Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. Here, we define CD8+ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8+ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2550–558-specific CD8+ T cells being cross-reactive between IAV and IBV. Memory CD8+ T cells towards these specificities are present in blood (CD27+CD45RA− phenotype) and tissues (CD103+CD69+ phenotype) of healthy individuals, and effector CD27−CD45RA−PD-1+CD38+CD8+ T cells in IAV/IBV patients. Our data show influenza-specific CD8+ T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8+ T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.
PLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy
Authors: Koerner Julia , Horvath Dennis , Herrmann Valerie L. , MacKerracher Anna , Gander Bruno , Yagita Hideo , Rohayem Jacques , Groettrup Marcus
Published: May 2021

With emerging supremacy, cancer immunotherapy has evolved as a promising therapeutic modality compared to conventional antitumor therapies. Cancer immunotherapy composed of biodegradable poly(lactic-co-glycolic acid) (PLGA) particles containing antigens and toll-like receptor ligands induces vigorous antitumor immune responses in vivo. Here, we demonstrate the supreme adjuvant effect of the recently developed and pharmaceutically defined double-stranded (ds)RNA adjuvant Riboxxim especially when incorporated into PLGA particles. Encapsulation of Riboxxim together with antigens potently activates murine and human dendritic cells, and elevated tumor-specific CD8+ T cell responses are superior to those obtained using classical dsRNA analogues. This PLGA particle vaccine affords primary tumor growth retardation, prevention of metastases, and prolonged survival in preclinical tumor models. Its advantageous therapeutic potency was further enhanced by immune checkpoint blockade that resulted in reinvigoration of cytotoxic T lymphocyte responses and tumor ablation. Thus, combining immune checkpoint blockade with immunotherapy based on Riboxxim-bearing PLGA particles strongly increases its efficacy.
Localized corrosion induced surface modifications of Al-Cu-Li alloy studied by ToF-SIMS 3D imaging
Authors: Li Meicheng , Seyeux Antoine , Wiame Frédéric , Marcus Philippe , Światowska Jolanta
Published: May 2021

Three-dimensional (3D) time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging is a promising tool in the analysis of surface modifications of alloy matrix and intermetallic particles induced by localized corrosion due to its good spatial resolution and very high sensitivity to chemical identification especially involving light mass elements like Li. In this paper, ToF-SIMS 3D chemical mapping combined with scanning electron microscopy was performed to study the localized corrosion of Al-Cu-Li alloy (AA2050-T8) in a region around an Al-Cu-Fe-Mn intermetallic particles (IMPs) in 0. 1 M NaCl solution. Initiation of corrosion was locally observed on the IMPs and between IMPs and matrix substrate. Moreover, a modified oxide/hydroxide layer was observed over IMPs compared to the matrix. This new corrosion layer was enriched with chlorides and Cu hydroxides. ToF-SIMS 3D imaging revealed that Li was present over the alloy matrix, while no Li was present over the IMPs in regions where localized corrosion occurred.
Experimental realization of phase-controlled dynamics with hybrid digital–analog approach
Authors: Tao Ziyu , Zhang Libo , Li Xiaole , Niu Jingjing , Luo Kai , Yi Kangyuan , Zhou Yuxuan , Jia Hao , Zhang Xu , Liu Song , Yan Tongxing , Chen Yuanzhen , Yu Dapeng
Published: May 2021

Quantum simulation can be implemented in pure digital or analog ways, each with their pros and cons. By taking advantage of the universality of a digital route and the efficiency of analog simulation, hybrid digital–analog approaches can enrich the possibilities for quantum simulation. We use a hybrid approach to experimentally perform a quantum simulation of phase-controlled dynamics resulting from a closed-contour interaction (CCI) within certain multi-level systems in superconducting quantum circuits. Due to symmetry constraints, such systems cannot host an inherent CCI. Nevertheless, by assembling analog modules corresponding to their natural evolutions and specially designed digital modules constructed from standard quantum logic gates, we can bypass such constraints and realize an effective CCI in these systems. Based on this realization, we demonstrate a variety of related and interesting phenomena, including phase-controlled chiral dynamics, separation of chiral enantiomers, and a mechanism to generate entangled states based on CCI.
Multiple sclerosis patients have reduced resting and increased activated CD4+CD25+FOXP3+T regulatory cells
Authors: Verma Nirupama D. , Lam Andrew D. , Chiu Christopher , Tran Giang T. , Hall Bruce M. , Hodgkinson Suzanne J.
Published: May 2021

Resting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared. Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer. CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells. Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells. Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg. Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors. Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors. Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD. Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III. In MS, CCR6+Treg were lower in Population III. This study found MS is associated with significant shifts in CD4+T cells subpopulations. MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment. Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.
Highly stabilized flexible transparent capacitive photodetector based on silver nanowire/graphene hybrid electrodes
Authors: Hwang Yooji , Hwang Young Hyun , Choi Kwang Wook , Lee Seungwon , Kim Soojin , Park Soo Jong , Ju Byeong-Kwon
Published: May 2021

The need for photodetectors in various fields has gradually emerged, and several studies in this area are therefore being conducted. For photodetectors to be used in various environments, their transparency, flexibility, and durability must be ensured. However, the development of flexible photodetectors based on the current measurement techniques of conventional photodetectors has been difficult owing to the limitations of semiconductor materials. In this study, a new type of flexible and transparent capacitive photodetector was fabricated to address the shortcomings of conventional photodetectors. In addition, by introducing graphene electrodes to a new type of manufactured photodetector, devices with excellent overall chemical, thermal, and mechanical durability have been developed. Compared to photodetectors based on pristine Ag nanowire (AgNW) electrodes, AgNW/graphene hybrid electrode-based photodetectors exhibit a 20% higher photosensitivity. Also, the hybrid AgNW/graphene electrode on the dielectric layer exhibited low sheet resistance (~ 8 Ω/sq) and relatively high transmittance (~ 45%).
Processing of novel food reveals payoff and rank-biased social learning in a wild primate
Authors: Canteloup Charlotte , Cera Mabia B. , Barrett Brendan J. , van de Waal Erica
Published: May 2021

Social learning—learning from others—is the basis for behavioural traditions. Different social learning strategies (SLS), where individuals biasedly learn behaviours based on their content or who demonstrates them, may increase an individual’s fitness and generate behavioural traditions. While SLS have been mostly studied in isolation, their interaction and the interplay between individual and social learning is less understood. We performed a field-based open diffusion experiment in a wild primate. We provided two groups of vervet monkeys with a novel food, unshelled peanuts, and documented how three different peanut opening techniques spread within the groups. We analysed data using hierarchical Bayesian dynamic learning models that explore the integration of multiple SLS with individual learning. We (1) report evidence of social learning compared to strictly individual learning, (2) show that vervets preferentially socially learn the technique that yields the highest observed payoff and (3) also bias attention toward individuals of higher rank. This shows that behavioural preferences can arise when individuals integrate social information about the efficiency of a behaviour alongside cues related to the rank of a demonstrator. When these preferences converge to the same behaviour in a group, they may result in stable behavioural traditions.
Evolution of altruistic punishments among heterogeneous conditional cooperators
Authors: Battu Balaraju
Published: May 2021

It has been known that altruistic punishments solve the free rider problem in public goods games. Considering spatial structure and considering pure strategies significant advances have been made in understanding the evolution of altruistic punishments. However, these models have not considered key behavior regularities observed in experimental and field settings, where the individuals behave like conditional cooperators who are more willing to donate and are also more willing to punish free riders. Considering these behavioral regularities, without imposing a spatial structure on the population, I propose an evolutionary agent-based model in which agents behave like conditional cooperators, each agent’s donation conditional on the difference between the number of donations in the past and the threshold value and the propensity value of the agent. Altruistic punishment depends on the difference between the threshold value of the focal agent and the randomly matched another agent. The simulations show that, for certain inflicted costs of punishments, generous altruistic punishments evolve and stabilize cooperation. The results show that, unlike previous models, it is not necessary to punish all free riders equally; it is necessary to do so in the case of the selfish free riders but not in the case of negative reciprocators.
Pathologies affect the performance of ECG signals compression
Authors: Nemcova Andrea , Smisek Radovan , Vitek Martin , Novakova Marie
Published: May 2021

The performance of ECG signals compression is influenced by many things. However, there is not a single study primarily focused on the possible effects of ECG pathologies on the performance of compression algorithms. This study evaluates whether the pathologies present in ECG signals affect the efficiency and quality of compression. Single-cycle fractal-based compression algorithm and compression algorithm based on combination of wavelet transform and set partitioning in hierarchical trees are used to compress 125 15-leads ECG signals from CSE database. Rhythm and morphology of these signals are newly annotated as physiological or pathological. The compression performance results are statistically evaluated. Using both compression algorithms, physiological signals are compressed with better quality than pathological signals according to 8 and 9 out of 12 quality metrics, respectively. Moreover, it was statistically proven that pathological signals were compressed with lower efficiency than physiological signals. Signals with physiological rhythm and physiological morphology were compressed with the best quality. The worst results reported the group of signals with pathological rhythm and pathological morphology. This study is the first one which deals with effects of ECG pathologies on the performance of compression algorithms. Signal-by-signal rhythm and morphology annotations (physiological/pathological) for the CSE database are newly published.
Effects of posed smiling on memory for happy and sad facial expressions
Authors: Kuehne Maria , Zaehle Tino , Lobmaier Janek S.
Published: May 2021

The perception and storage of facial emotional expressions constitutes an important human skill that is essential for our daily social interactions. While previous research revealed that facial feedback can influence the perception of facial emotional expressions, it is unclear whether facial feedback also plays a role in memory processes of facial emotional expressions. In the present study we investigated the impact of facial feedback on the performance in emotional visual working memory (WM). For this purpose, 37 participants underwent a classical facial feedback manipulation (FFM) (holding a pen with the teeth—inducing a smiling expression vs. holding a pen with the non-dominant hand—as a control condition) while they performed a WM task on varying intensities of happy or sad facial expressions. Results show that the smiling manipulation improved memory performance selectively for happy faces, especially for highly ambiguous facial expressions. Furthermore, we found that in addition to an overall negative bias specifically for happy faces (i.e. happy faces are remembered as more negative than they initially were), FFM induced a positivity bias when memorizing emotional facial information (i.e. faces were remembered as being more positive than they actually were). Finally, our data demonstrate that men were affected more by FFM: during induced smiling men showed a larger positive bias than women did. These data demonstrate that facial feedback not only influences our perception but also systematically alters our memory of facial emotional expressions.
Comparative antler proteome of sika deer from different developmental stages
Authors: Zhang Ranran , Li Yang , Xing Xiumei
Published: May 2021

Antler is a special bone tissue that has the ability to regenerate completely periodically. It is the fastest growing bone in the animal kingdom. Antler provides a valuable research model for bone growth and mineralization. Antler grows longitudinally by endochondral ossification with their growth center located in its tip. Many scholars have carried out detailed studies on morphology and gene expression of antler tip. However, few scholars have analyzed the protein expression patterns of antler tip at different development stages. This study used label-free proteomics approach to analyze the protein expression dynamics of the antler tip in six developmental periods (15, 25, 45, 65, 100 and 130 days after the previous antler cast) and costal cartilage. In result, 2052 proteins were confidently quantified, including 1937 antler proteins and 1044 costal cartilage proteins. Moreover, 913 antler core proteins and 132 antler-special proteins were obtained. Besides, the stages special proteins and differentially expressed proteins (DEPs) in different development stages were analyzed. A total of 875 DEPs were determined by one-way AVOVA. It is found that the growth period (15, 25, 45 and 65 days) showed more up-regulated protein including several chondrogenesis-associated proteins (collagen types II, collagen types XI, HAPLN1, PAPSS1 and PAPSS2). In ossification stages, the up-regulated proteins related with lysosome (CTSD, CTSB, MMP9, CAII) indicated that the antler has higher bone remodeling activity. Given the up-regulated expression of immune-related molecules (S100A7, CATHL7, LTF, AZU1, ELANE and MPO), we speculate that the local immune system may contribute to the ossification of antler tip. In conclusion, proteomics technology was used to deeply analyze the protein expression patterns of antler at different development stages. This provides a strong support for the research on the molecular regulation mechanism of rapid growth and ossification of velvet antler.
Vagal reactivation after a cardiac rehabilitation session associated with hydration in coronary artery disease patients: crossover clinical trial
Authors: Laurino Maria Júlia Lopez , da Silva Anne Kastelianne França , Santos Lorena Altafin , Ribeiro Felipe , Vanzella Laís Manata , Corazza Dayane Andrade Genoni , Vanderlei Luiz Carlos Marques
Published: May 2021

This study aimed to investigate the hydration influence on the autonomic responses of coronary artery disease subjects in the immediate recovery period after a cardiovascular rehabilitation session, in view of the risks of a delayed autonomic recovery for this population. 28 males with coronary artery disease were submitted to: (I) Maximum effort test; (II) Control protocol (CP), composed by initial rest, warm-up, exercise and passive recovery; (III) Hydration protocol (HP) similar to CP, but with rehydration during exercise. The recovery was evaluated through the heart rate (HR) variability, HR recovery and by the rate of perceived exertion and recovery. The main results revealed that the vagal reactivation occurred at the first 30 s of recovery in HP and after the first minute in CP. A better behavior of the HR at the first minute of recovery was observed in HP. The rate of perceived exertion had a significant decrease in the first minute of recovery in HP, while in CP this occurred after the third minute. In conclusion, despite an anticipated vagal reactivation found at HP, these results should be analyzed with caution as there were no significant differences between protocols for all variables and the effect sizes were small.
Tubulin binding potentially clears up Bortezomib and Carfilzomib differential neurotoxic effect
Authors: Malacrida A. , Semperboni S. , Di Domizio A. , Palmioli A. , Broggi L. , Airoldi C. , Meregalli C. , Cavaletti G. , Nicolini G.
Published: May 2021

Proteasome inhibitors (PIs) represent the gold standard in the treatment of multiple myeloma. Among PIs, Bortezomib (BTZ) is frequently used as first line therapy, but peripheral neuropathy (PN), occurring approximately in 50% of patients, impairs their life, representing a dose-limiting toxicity. Carfilzomib (CFZ), a second-generation PI, induces a significantly less severe PN. We investigated possible BTZ and CFZ off-targets able to explain their different neurotoxicity profiles. In order to identify the possible PIs off-targets we used the SPILLO-PBSS software that performs a structure-based in silico screening on a proteome-wide scale. Among the top-ranked off-targets of BTZ identified by SPILLO-PBSS we focused on tubulin which, by contrast, did not turn out to be an off-target of CFZ. We tested the hypothesis that the direct interaction between BTZ and microtubules would inhibit the tubulin alfa GTPase activity, thus reducing the microtubule catastrophe and consequently furthering the microtubules polymerization. This hypothesis was validated in a cell-free model, since BTZ (but not CFZ) reduces the concentration of the free phosphate released during GTP hydrolysis. Moreover, NMR binding studies clearly demonstrated that BTZ, unlike CFZ, is able to interact with both tubulin dimers and polymerized form. Our data suggest that different BTZ and CFZ neurotoxicity profiles are independent from their proteasome inhibition, as demonstrated in adult mice dorsal root ganglia primary sensory neurons, and, first, we demonstrate, in a cell free model, that BTZ is able to directly bind and perturb microtubules.
Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells
Authors: Alhourani Abdelnour H. , Tidwell Tia R. , Bokil Ansooya A. , Røsland Gro V. , Tronstad Karl Johan , Søreide Kjetil , Hagland Hanne R.
Published: May 2021

Cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg. However, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Metformin, a metabolic drug commonly used to treat type 2 diabetes, has been associated with lower cancer incidence, although studies are inconclusive concerning effectiveness of the drug in treatment or cancer prevention. The aim of this study was to determine how glucose concentration influences cancer cells’ response to metformin, highlighting why metformin studies are inconsistent. We used two colorectal cancer cell lines with different growth rates and clinically achievable metformin concentrations. We found that fast growing SW948 are more glycolytic in terms of metabolism, while the slower growing SW1116 are reliant on mitochondrial respiration. Both cell lines show inhibitory growth after metformin treatment under physiological glucose conditions, but not in high glucose conditions. Furthermore, SW1116 converges with SW948 at a more glycolytic phenotype after metformin treatment. This metabolic shift is supported by changed GLUT1 expression. Thus, cells having different metabolic phenotypes, show a clear differential response to metformin treatment based on glucose concentration. This demonstrates the importance of growth conditions for experiments or clinical studies involving metabolic drugs such as metformin.
Prediction model for sap flow in cacao trees under different radiation intensities in the western Colombian Amazon
Authors: Suárez Juan Carlos , Casanoves Fernando , Bieng Marie Ange Ngo , Melgarejo Luz Marina , Di Rienzo Julio A. , Armas Cristina
Published: May 2021

In this study, we measured diurnal patterns of sap flow (Vs) in cacao trees growing in three types of agroforestry systems (AFs) that differ in the incident solar radiation they receive. We modeled the relationship of Vs with several microclimatic characteristics of the AFs using mixed linear models. We characterized microclimatic variables that may have an effect on diurnal patterns of sap flow: air relative humidity, air temperature, photosynthetically active radiation and vapor pressure deficit. Overall, our model predicted the differences between cacao Vs in the three different AFs, with cacao plants with dense Musaceae plantation and high mean diurnal incident radiation (HPAR) displaying the highest differences compared to the other agroforestry arrangements. The model was also able to predict situations such as nocturnal transpiration in HPAR and inverse nocturnal sap flows indicative of hydraulic redistribution in the other AFs receiving less incident radiation. Overall, the model we present here can be a useful and cost-effective tool for predicting transpiration and water use in cacao trees, as well as for managing cacao agroforestry systems in the Amazon rainforest.
Implementing a method for engineering multivalency to substantially enhance binding of clinical trial anti-SARS-CoV-2 antibodies to wildtype spike and variants of concern proteins
Authors: Leach Adam , Miller Ami , Bentley Emma , Mattiuzzo Giada , Thomas Jemima , McAndrew Craig , Van Montfort Rob , Rabbitts Terence
Published: May 2021

Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes COVID-19 disease. Therapeutic antibodies are being developed that interact with the viral spike proteins to limit viral infection of epithelium. We have applied a method to dramatically improve the performance of anti-SARS-CoV-2 antibodies by enhancing avidity through multimerization using simple engineering to yield tetrameric antibodies. We have re-engineered six anti-SARS-CoV-2 antibodies using the human p53 tetramerization domain, including three clinical trials antibodies casirivimab, imdevimab and etesevimab. The method yields tetrameric antibodies, termed quads, that retain efficient binding to the SARS-CoV-2 spike protein, show up to two orders of magnitude enhancement in neutralization of pseudovirus infection and retain potent interaction with virus variant of concern spike proteins. The tetramerization method is simple, general and its application is a powerful methodological development for SARS-CoV-2 antibodies that are currently in pre-clinical and clinical investigation.