bluuebunny/crossref_metadata_2025 huggingface dataset:
The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression
Authors: Ho Nicole Pui Yu , Leung Carmen Oi Ning , Wong Tin Lok , Lau Eunice Yuen Ting , Lei Martina Mang Leng , Mok Etienne Ho Kit , Leung Hoi Wing , Tong Man , Ng Irene Oi Lin , Yun Jing Ping , Ma Stephanie , Lee Terence Kin Wah
Published: February 2021

Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.
Osteomodulin positively regulates osteogenesis through interaction with BMP2
Authors: Lin Wenzhen , Zhu Xiaohan , Gao Li , Mao Mengying , Gao Daming , Huang Zhengwei
Published: February 2021

Osteomodulin (OMD), a member of the small leucine-rich proteoglycan family, distributes in mineralized tissues and is positively regulated by bone morphogenetic protein 2 (BMP2). However, the exact function of OMD during mineralization and its association with BMP2 remain poorly understood. Herein, the expression pattern of OMD during osteogenesis was investigated in human dental pulp stem cells. Silencing OMD gene significantly suppressed the alkaline phosphatase activity, mineralized nodule formation and osteogenesis-associated gene transcription. Besides, OMD could enhance BMP2-induced expression of SP7 and RUNX2 with concentration dependence in vitro. Rat mandibular bone defect model revealed that scaffolds injected with the combination of OMD and suboptimal BMP2 exhibited more mature and abundant mineralized bone than that treated with OMD or suboptimal BMP2 alone. Mechanistically, OMD could bind to BMP2 via its terminal leucine-rich repeats and formed complexes with BMP2 and its membrane receptors, thus promoting BMP/SMAD signal transduction. In addition, OMD was a putative target gene of SMAD4, which plays a pivotal role in this pathway. Collectively, these data elucidate that OMD may act as a positive coordinator in osteogenesis through BMP2/SMADs signaling.
Double-targeting CDCA8 and E2F1 inhibits the growth and migration of malignant glioma
Authors: Wang Xiaoxiong , Wang Heping , Xu Jiajun , Hou Xu , Zhan Haoqiang , Zhen Yunbo
Published: February 2021

High-grade glioma is the most common and aggressive primary brain tumor in adults with poor therapeutic efficiency and survival prognosis. Cell division cycle associated 8 (CDCA8) has been well known as a cell cycle regulator and tumor promotor in various malignant tumors. However, its biological role in glioma still remains unclear. Our results showed that high level of CDCA8 was significantly correlated with advanced WHO grade and poor overall survival and disease-free survival prognosis. In vitro and in vivo investigations demonstrated that CDCA8 promoted the glioma malignancy by promoting cell proliferation, cell migration, and inhibiting cell apoptosis. Moreover, we found its synergetic biological protein—E2F1 by the gene microarray chip. In this study, we revealed that CDCA8 synergized with E2F1 facilitated the proliferation and migration of glioma. In conclusion, our study provides a novel promising therapeutic targets and prognostic biomarkers for malignant glioma treatment.
The N-terminal BRCT domain determines MCPH1 function in brain development and fertility
Authors: Liu Xiaoqian , Schneble-Löhnert Nadine , Kristofova Martina , Qing Xiaobing , Labisch Jan , Hofmann Susanne , Ehrenberg Sandra , Sannai Mara , Jörß Tjard , Ori Alessandro , Godmann Maren , Wang Zhao-Qi
Published: February 2021

MCPH1 is a causal gene for the neurodevelopmental disorder, human primary microcephaly (MCPH1, OMIM251200). Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N’-BRCT domain of MCPH1 (referred as Mcph1-ΔBR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. Mcph1-ΔBR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. Mcph1-ΔBR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with Mcph1 complete knockout mice, Mcph1-ΔBR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes.
The ATPase Pontin is a key cell cycle regulator by amplifying E2F1 transcription response in glioma
Authors: Wang Run , Li Xuebing , Sun Cuiyun , Yu Lin , Hua Dan , Shi Cuijuan , Wang Qian , Rao Chun , Luo Wenjun , Jiang Zhendong , Zhou Xuexia , Yu Shizhu
Published: February 2021

Pontin (RUVBL1) is a highly conserved ATPase of the AAA + (ATPases Associated with various cellular Activities) superfamily and is implicated in various biological processes crucial for oncogenesis. Its overexpression is observed in multiple human cancers, whereas the relevance of Pontin to gliomagenesis remains obscure. To gain insights into Pontin involvement in glioma, we performed bioinformatics analyses of Pontin co-expressed genes, Pontin-affected genes, and carried out experimental studies. The results verified that Pontin was upregulated in gliomas. Its higher levels might predict the worse prognosis of glioma patients. The Pontin co-expressed genes were functionally enriched in cell cycle progression and RNA processing. In the nucleus, Pontin promoted cell growth via facilitating cell cycle progression. Using RNA-seq, we found that Pontin knockdown resulted in altered expression of multiple genes, among which the E2F1 targets accounted for a large proportion. Mechanistic studies found that Pontin interacted with E2F1 and markedly amplified the E2F1 transcription response in an ATPase domain-dependent manner. By analyzing the RNA-seq data, we also found that Pontin could impact on the alternative splicing (AS). Both differential expressed genes and AS events affected by Pontin were associated with cell cycle regulation. Taken together, our findings provide novel insights of the importance of Pontin in gliomagenesis by regulating cell cycle and AS, and shed light on the possible application of Pontin as an antineoplastic target in glioma.
Role of microRNA-335 carried by bone marrow mesenchymal stem cells-derived extracellular vesicles in bone fracture recovery
Authors: Hu Haifeng , Wang Dong , Li Lihong , Yin Haiyang , He Guoyu , Zhang Yonghong
Published: February 2021

Mesenchymal stem cells (MSCs) have the potential to reduce healing time and treat nonunion in fracture patients. In this study, bone marrow MSCs-derived extracellular vesicles (B-EVs) were firstly extracted and identified. CD9−/− and normal mice were enrolled for the establishment of fracture models and then injected with B-EVs. Osteoblast differentiation and fracture recovery were estimated. The levels of osteoblast-related genes were detected, and differentially expressed microRNAs (miRs) in B-EVs-treated normal fracture mice were screened and verified. The downstream mechanisms of miR were predicted and assessed. The loss-of functions of miR-335 in B-EV and gain-of-functions of VapB were performed in animal and cell experiments to evaluate their roles in bone fracture. Collectively, B-EVs promoted bone fracture recovery and osteoblast differentiation by releasing miR-335. miR-335 downregulation in B-EVs impaired B-EV functions in fracture recovery and osteoblast differentiation. miR-335 could target VapB, and VapB overexpression reversed the effects of B-EVs on osteoblast differentiation. B-EV treatment activated the Wnt/β-catenin pathway in fracture mice and osteoblasts-like cells. Taken together, the study suggested that B-EVs carry miR-335 to promote bone fracture recovery via VapB and the Wnt/β-catenin pathway. This study may offer insights into bone fracture treatment.
HNRNPD interacts with ZHX2 regulating the vasculogenic mimicry formation of glioma cells via linc00707/miR-651-3p/SP2 axis
Authors: Yu Sifei , Ruan Xuelei , Liu Xiaobai , Zhang Fangfang , Wang Di , Liu Yunhui , Yang Chunqing , Shao Lianqi , Liu Qianshuo , Zhu Lu , Lin Yang , Xue Yixue
Published: February 2021

Studies have found that RNA-binding proteins (RBPs) are dysfunctional and play a significant regulatory role in the development of glioma. Based on The Cancer Genome Atlas database and the previous studies, we selected heterogeneous nuclear ribonucleoprotein (HNRNPD) as the research candidate and sought its downstream targeted genes. In the present study, HNRNPD, linc00707, and specific protein 2 (SP2) were highly expressed, while zinc fingers and homeboxes 2 (ZHX2) and miR-651-3p were remarkedly downregulated in glioma tissues and cells. HNRNPD, linc00707, and SP2 knockdown or ZHX2 and miR-651-3p overexpression suppressed glioma cells proliferation, migration, and invasion and vasculogenic mimicry (VM) formation. Knockdown of HNRNPD increased the stability of ZHX2 mRNA. ZHX2 bound to the promoter region of linc00707 and negatively regulate its expression. Linc00707 could bind with miR-651-3p, while miR-651-3p bound to the 3′ untranslated region (3′UTR) of SP2 mRNA to negatively regulate its expression. The transcription factor SP2 directly bound to the promoter regions of the VM formation-related proteins MMP2, MMP9, and VE-cadherin, playing a role in promoting transcription in order to regulate the VM formation ability of glioma cells.
Targeting Aurora B kinase with Tanshinone IIA suppresses tumor growth and overcomes radioresistance
Authors: Li Ming , Liu Haidan , Zhao Qin , Han Shuangze , Zhou Li , Liu Wenbin , Li Wei , Gao Feng
Published: February 2021

Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.
Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish
Authors: Zhao Ting , Ye Shengfan , Tang Zimu , Guo Liwei , Ma Zhipeng , Zhang Yuxi , Yang Chun , Peng Jinrong , Chen Jun
Published: February 2021

Reactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed thatΔ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly,Δ113p53M/Mmutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability,Δ113p53M/Mzebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate thatΔ113p53protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.
Origins of human genetics. A personal perspective
Authors: Passarge Eberhard
Published: February 2021

Genetics evolved as a field of science after 1900 with new theories being derived from experiments obtained in fruit flies, bacteria, and viruses. This personal account suggests that the origins of human genetics can best be traced to the years 1949 to 1959. Several genetic scientific advances in genetics in 1949 yielded results directly relating to humans for the first time, except for a few earlier observations. In 1949 the first textbook of human genetics was published, the American Journal of Human Genetics was founded, and in the previous year the American Society of Human Genetics. In 1940 in Britain a textbook entitledIntroduction to Medical Geneticsserved as a foundation for introducing genetic aspects into medicine. The introduction of new methods for analyzing chromosomes and new biochemical assays using cultured cells in 1959 and subsequent years revealed that many human diseases, including cancer, have genetic causes. It became possible to arrive at a precise cause-related genetic diagnosis. As a result the risk of occurrence or re-occurrence of a disease within a family could be assessed correctly. Genetic counseling as a new concept became a basis for improved patient care. Taken together the advances in medically orientated genetic research and patient care since 1949 have resulted in human genetics being both, a basic medical and a basic biological science. Prior to 1949 genetics was not generally viewed in a medical context. Although monogenic human diseases were recognized in 1902, their occurrence and distribution were considered mainly at the population level.
More accurate quantification of model-to-model agreement in externally forced climatic responses over the coming century
Authors: Maher Nicola , Power Scott B. , Marotzke Jochem
Published: February 2021

Separating how model-to-model differences in the forced response (UMD) and internal variability (UIV) contribute to the uncertainty in climate projections is important, but challenging. ReducingUMDincreases confidence in projections, whileUIVcharacterises the range of possible futures that might occur purely by chance. Separating these uncertainties is limited in traditional multi-model ensembles because most models have only a small number of realisations; furthermore, some models are not independent. Here, we use six largely independent single model initial-condition large ensembles to separate the contributions ofUMDandUIVin projecting 21st-century changes of temperature, precipitation, and their temporal variability under strong forcing (RCP8.5). We provide a method that produces similar results using traditional multi-model archives. WhileUMDis larger thanUIVfor both temperature and precipitation changes,UIVis larger thanUMDfor the changes in temporal variability of both temperature and precipitation, between 20° and 80° latitude in both hemispheres. Over large regions and for all variables considered here except temporal temperature variability, models agree on the sign of the forced response whereas they disagree widely on the magnitude. Our separation method can readily be extended to other climate variables.
Nanoscopic subcellular imaging enabled by ion beam tomography
Authors: Coskun Ahmet F. , Han Guojun , Ganesh Shambavi , Chen Shih-Yu , Clavé Xavier Rovira , Harmsen Stefan , Jiang Sizun , Schürch Christian M. , Bai Yunhao , Hitzman Chuck , Nolan Garry P.
Published: February 2021

Multiplexed ion beam imaging (MIBI) has been previously used to profile multiple parameters in two dimensions in single cells within tissue slices. Here, a mathematical and technical framework for three-dimensional (3D) subcellular MIBI is presented. Ion-beam tomography (IBT) compiles ion beam images that are acquired iteratively across successive, multiple scans, and later assembled into a 3D format without loss of depth resolution. Algorithmic deconvolution, tailored for ion beams, is then applied to the transformed ion image series, yielding 4-fold enhanced ion beam data cubes. To further generate 3D sub-ion-beam-width precision visuals, isolated ion molecules are localized in the raw ion beam images, creating an approach coined as SILM, secondary ion beam localization microscopy, providing sub-25 nm accuracy in original ion images. Using deep learning, a parameter-free reconstruction method for ion beam tomograms with high accuracy is developed for low-density targets. In cultured cancer cells and tissues, IBT enables accessible visualization of 3D volumetric distributions of genomic regions, RNA transcripts, and protein factors with 5 nm axial resolution using isotope-enrichments and label-free elemental analyses. Multiparameter imaging of subcellular features at near macromolecular resolution is implemented by the IBT tools as a general biocomputation pipeline for imaging mass spectrometry.
An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine
Authors: Song Guang , Wang Guohua , Luo Ximei , Cheng Ying , Song Qifeng , Wan Jun , Moore Cedric , Song Hongjun , Jin Peng , Qian Jiang , Zhu Heng
Published: February 2021

Epigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides. Many proteins that recognize consensus sequences carrying these modifications in symmetric and/or hemi-modified forms are identified. We further demonstrate that the modifications in different sequence contexts could either enhance or suppress TF binding activity. Moreover, many modifications can affect TF binding specificity. Furthermore, symmetric modifications show a stronger effect in either enhancing or suppressing TF-DNA interactions than hemi-modifications. Finally, in vivo evidence suggests that USF1 and USF2 might regulate transcription via hydroxymethylcytosine-binding activity in weak enhancers in human embryonic stem cells.
Morphology and mechanism of highly selective Cu(II) oxide nanosheet catalysts for carbon dioxide electroreduction
Authors: Wang Xingli , Klingan Katharina , Klingenhof Malte , Möller Tim , Ferreira de Araújo Jorge , Martens Isaac , Bagger Alexander , Jiang Shan , Rossmeisl Jan , Dau Holger , Strasser Peter
Published: February 2021

Cu oxides catalyze the electrochemical carbon dioxide reduction reaction (CO2RR) to hydrocarbons and oxygenates with favorable selectivity. Among them, the shape-controlled Cu oxide cubes have been most widely studied. In contrast, we report on novel 2-dimensional (2D) Cu(II) oxide nanosheet (CuO NS) catalysts with high C2+ products, selectivities (> 400 mA cm−2) in gas diffusion electrodes (GDE) at industrially relevant currents and neutral pH. Under applied bias, the (001)-orientated CuO NS slowly evolve into highly branched, metallic Cu0 dendrites that appear as a general dominant morphology under electrolyte flow conditions, as attested by operando X-ray absorption spectroscopy and in situ electrochemical transmission electron microscopy (TEM). Millisecond-resolved differential electrochemical mass spectrometry (DEMS) track a previously unavailable set of product onset potentials. While the close mechanistic relation between CO and C2H4 was thereby confirmed, the DEMS data help uncover an unexpected mechanistic link between CH4 and ethanol. We demonstrate evidence that adsorbed methyl species, *CH3, serve as common intermediates of both CH3H and CH3CH2OH and possibly of other CH3-R products via a previously overlooked pathway at (110) steps adjacent to (100) terraces at larger overpotentials. Our mechanistic conclusions challenge and refine our current mechanistic understanding of the CO2 electrolysis on Cu catalysts.
Discovery of an ene-reductase for initiating flavone and flavonol catabolism in gut bacteria
Authors: Yang Gaohua , Hong Sen , Yang Pengjie , Sun Yuwei , Wang Yong , Zhang Peng , Jiang Weihong , Gu Yang
Published: February 2021

Gut microbial transformations of flavonoids, an enormous class of polyphenolic compounds abundant in plant-based diets, are closely associated with human health. However, the enzymes that initiate the gut microbial metabolism of flavones and flavonols, the two most abundant groups of flavonoids, as well as their underlying molecular mechanisms of action remain unclear. Here, we discovered a flavone reductase (FLR) from the gut bacterium, Flavonifractor plautii ATCC 49531 (originally assigned as Clostridium orbiscindens DSM 6740), which specifically catalyses the hydrogenation of the C2–C3 double bond of flavones/flavonols and initiates their metabolism as a key step. Crystal structure analysis revealed the molecular basis for the distinct catalytic property of FLR. Notably, FLR and its widespread homologues represent a class of ene-reductases that has not been previously identified. Genetic and biochemical analyses further indicated the importance of FLR in gut microbial consumption of dietary and medicinal flavonoids, providing broader insight into gut microbial xenobiotic transformations and possible guidance for personalized nutrition and medicine.
The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases
Authors: Mäkinen Janne J. , Shin Yeonoh , Vieras Eeva , Virta Pasi , Metsä-Ketelä Mikko , Murakami Katsuhiko S. , Belogurov Georgiy A.
Published: February 2021

RNA polymerases (RNAPs) synthesize RNA from NTPs, whereas DNA polymerases synthesize DNA from 2′dNTPs. DNA polymerases select against NTPs by using steric gates to exclude the 2′OH, but RNAPs have to employ alternative selection strategies. In single-subunit RNAPs, a conserved Tyr residue discriminates against 2′dNTPs, whereas selectivity mechanisms of multi-subunit RNAPs remain hitherto unknown. Here, we show that a conserved Arg residue uses a two-pronged strategy to select against 2′dNTPs in multi-subunit RNAPs. The conserved Arg interacts with the 2′OH group to promote NTP binding, but selectively inhibits incorporation of 2′dNTPs by interacting with their 3′OH group to favor the catalytically-inert 2′-endo conformation of the deoxyribose moiety. This deformative action is an elegant example of an active selection against a substrate that is a substructure of the correct substrate. Our findings provide important insights into the evolutionary origins of biopolymers and the design of selective inhibitors of viral RNAPs.
Somatic deficiency causes reproductive parasitism in a fungus
Authors: Grum-Grzhimaylo Alexey A. , Bastiaans Eric , van den Heuvel Joost , Berenguer Millanes Cristina , Debets Alfons J. M. , Aanen Duur K.
Published: February 2021

Some multicellular organisms can fuse because mergers potentially provide mutual benefits. However, experimental evolution in the fungus Neurospora crassa has demonstrated that free fusion of mycelia favours cheater lineages, but the mechanism and evolutionary dynamics of this exploitation are unknown. Here we show, paradoxically, that all convergently evolved cheater lineages have similar fusion deficiencies. These mutants are unable to initiate fusion but retain access to wild-type mycelia that fuse with them. This asymmetry reduces cheater-mutant contributions to somatic substrate-bound hyphal networks, but increases representation of their nuclei in the aerial reproductive hyphae. Cheaters only benefit when relatively rare and likely impose genetic load reminiscent of germline senescence. We show that the consequences of somatic fusion can be unequally distributed among fusion partners, with the passive non-fusing partner profiting more. We discuss how our findings may relate to the extensive variation in fusion frequency of fungi found in nature.
Engineering advanced logic and distributed computing in human CAR immune cells
Authors: Cho Jang Hwan , Okuma Atsushi , Sofjan Katri , Lee Seunghee , Collins James J. , Wong Wilson W.
Published: February 2021

The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.
Ratio of the interferon-γ signature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma
Authors: Cui Chuanliang , Xu Canqiang , Yang Wenxian , Chi Zhihong , Sheng Xinan , Si Lu , Xie Yihong , Yu Jinyu , Wang Shun , Yu Rongshan , Guo Jun , Kong Yan
Published: February 2021

Immune checkpoint inhibitor (ICI) treatments produce clinical benefit in many patients. However, better pretreatment predictive biomarkers for ICI are still needed to help match individual patients to the treatment most likely to be of benefit. Existing gene expression profiling (GEP)-based biomarkers for ICI are primarily focused on measuring a T cell-inflamed tumor microenvironment that contributes positively to the response to ICI. Here, we identified an immunosuppression signature (IMS) through analyzing RNA sequencing data from a combined discovery cohort (n = 120) consisting of three publicly available melanoma datasets. Using the ratio of an established IFN-γsignature and IMS led to consistently better prediction of the ICI therapy outcome compared to a collection of nine published GEP signatures from the literature on a newly generated internal validation cohort (n = 55) and three published datasets of metastatic melanoma treated with anti-PD-1 (n = 54) and anti-CTLA-4 (n = 42), as well as in patients with gastric cancer treated with anti-PD-1 (n = 45), demonstrating the potential utility of IMS as a predictive biomarker that complements existing GEP signatures for immunotherapy.
A universal molecular prognostic score for gastrointestinal tumors
Authors: Shimizu Hideyuki , Nakayama Keiichi I.
Published: February 2021

Colorectal and gastric cancers are a leading cause of cancer deaths in developed countries. Precise estimation of prognosis is important with regard to clinical decision making for individuals with such cancers. We here comprehensively compiled a complete atlas of prognostic genes based on an integrated meta-analysis of one of the largest assembled colorectal cancer cohorts. A simple yet robust machine learning approach was then applied to establish a universal molecular prognostic score (mPS_colon) that relies on the expression status of only 16 genes and which was validated with independent data sets. This score was found to be an independent prognostic indicator in multivariate models including cancer stage, to be valid independent of tumor characteristics or patient ethnicity, and to be also applicable to gastric cancer. We conclude that mPS_colon is a universal prognostic classifier for patients with gastrointestinal cancers and that it should prove informative for optimization of personalized therapy for such patients.
Case-finding for COPD clinic acceptability to patients in GPs across Hampshire: a qualitative study
Authors: Rose Danielle , Ray Emma , Summers Rachael H. , Taylor Melinda , Kruk Helen , North Mal , Gillett Kate , Thomas Mike , Wilkinson Tom M. A.
Published: February 2021

Despite high mortality and morbidity, COPD remains under-diagnosed. Case-finding strategies are possible, but patients’ perspectives are unexplored. Using qualitative methods, we explored the patient perspective of a case-finding intervention among at-risk patients in primary care. Semi-structured telephone interviews were transcribed and thematic analysis utilised. Seven patients without (mean age 64.5 years (58–74), n = 4) and 8 with obstructed spirometry (mean age 63.5 (53–75), n = 4) were interviewed. Themes identified were motives, challenges and concerns regarding attending the clinic. These included wanting to be well; to help with research; concern over negative impact to life from COPD diagnosis; perceived utility of the clinic; quality of information given; staff manner, approachability and knowledge; and perceived effects of the clinic on lifestyle, self-management and symptoms. The intervention was generally deemed useful and reassuring, although shared information was too detailed or irrelevant for some. Several reported positive lifestyle changes, improved symptoms and improved self-management.
Two-dimensional centrosymmetrical antiferromagnets for spin photogalvanic devices
Authors: Jiang Peng , Tao Xixi , Hao Hua , Liu Yushen , Zheng Xiaohong , Zeng Zhi
Published: February 2021

Spin-dependent photogalvanic effect (PGE) in low-dimensional magnetic systems has recently attracted intensive attention. Based on first-principle transport calculations and symmetry analyses, we propose a robust scheme to generate pure spin current by PGE in centrosymmetric materials with spin polarization antisymmetry. As a demonstration, the idea is successfully applied to a photoelectric device constructed with a zigzag graphene nanoribbon (ZGNR), which has intrinsic antiferromagnetic coupling between the two edges and spin degenerate band structure. It suggests that spin splitting is not a prerequisite for pure spin current generation. More interestingly, by further introducing external transverse electric fields to the two leads to lift the spin degeneracy, the device may behave multifunctionally, capable of producing fully spin-polarized current or pure spin current, depending on whether the fields in the two leads are parallel or antiparallel. Very importantly, our scheme of pure spin current generation with PGE is not limited to ZGNR and can be extended to other two-dimensional (2D) centrosymmetric magnetic materials with spin polarization antisymmetry, suggesting a promising category of 2D platforms for PGE-based pure spin current generation.
Waveguide bandgap engineering with an array of superconducting qubits
Authors: Brehm Jan David , Poddubny Alexander N. , Stehli Alexander , Wolz Tim , Rotzinger Hannes , Ustinov Alexey V.
Published: February 2021

Waveguide quantum electrodynamics offers a wide range of possibilities to effectively engineer interactions between artificial atoms via a one-dimensional open waveguide. While these interactions have been experimentally studied in the few qubit limit, the collective properties of such systems for larger arrays of qubits in a metamaterial configuration has so far not been addressed. Here, we experimentally study a metamaterial made of eight superconducting transmon qubits with local frequency control coupled to the mode continuum of a waveguide. By consecutively tuning the qubits to a common resonance frequency we observe the formation of super- and subradiant states, as well as the emergence of a polaritonic bandgap. Making use of the qubits quantum nonlinearity, we demonstrate control over the latter by inducing a transparency window in the bandgap region of the ensemble. The circuit of this work extends experiments with one and two qubits toward a full-blown quantum metamaterial, thus paving the way for large-scale applications in superconducting waveguide quantum electrodynamics.
Evidence for metastable photo-induced superconductivity in K3C60
Authors: Budden M. , Gebert T. , Buzzi M. , Jotzu G. , Wang E. , Matsuyama T. , Meier G. , Laplace Y. , Pontiroli D. , Riccò M. , Schlawin F. , Jaksch D. , Cavalleri A.
Published: February 2021

Excitation of high-Tc cuprates and certain organic superconductors with intense far-infrared optical pulses has been shown to create non-equilibrium states with optical properties that are consistent with transient high-temperature superconductivity. These non-equilibrium phases have been generated using femtosecond drives, and have been observed to disappear immediately after excitation, which is evidence of states that lack intrinsic rigidity. Here we make use of a new optical device to drive metallic K3C60 with mid-infrared pulses of tunable duration, ranging between one picosecond and one nanosecond. The same superconducting-like optical properties observed over short time windows for femtosecond excitation are shown here to become metastable under sustained optical driving, with lifetimes in excess of ten nanoseconds. Direct electrical probing, which becomes possible at these timescales, yields a vanishingly small resistance with the same relaxation time as that estimated by terahertz conductivity. We provide a theoretical description of the dynamics after excitation, and justify the observed slow relaxation by considering randomization of the order-parameter phase as the rate-limiting process that determines the decay of the light-induced superconductor.
Clinically-identified C-terminal mutations in fibulin-3 are prone to misfolding and destabilization
Authors: Woodard DaNae R. , Nakahara Emi , Hulleman John D.
Published: February 2021

Distinct mutations in the secreted extracellular matrix protein, fibulin-3 (F3), have been associated with a number of ocular diseases ranging from primary open angle glaucoma to cuticular age-related macular degeneration to a rare macular dystrophy, Malattia Leventinese (ML). The R345W F3 mutation that causes ML leads to F3 misfolding, inefficient secretion and accumulation at higher intracellular steady state levels in cultured cells. Herein, we determined whether fifteen other clinically-identified F3 mutations also led to similar levels of misfolding and secretion defects, which might provide insight into their potential pathogenicity. Surprisingly, we found that only a single F3 variant, L451F, presented with a significant secretion defect (69.5 ± 2.4% of wild-type (WT) F3 levels) and a corresponding increase in intracellular levels (226.8 ± 25.4% of WT F3 levels). Upon follow-up studies, when this conserved residue (L451) was mutated to a charged (Asp or Arg) or bulky (Pro, Trp, Tyr) residue, F3 secretion was also compromised, indicating the importance of small side chains (Leu, Ala, or Gly) at this residue. To uncover potential inherent F3 instability not easily observed under typical culture conditions, we genetically eliminated the sole stabilizing N-linked glycosylation site (N249) from select clinically-identified F3 mutants. This removal exacerbated R345W and L451F secretion defects (19.8 ± 3.0% and 12.4 ± 1.2% of WT F3 levels, respectively), but also revealed a previously undiscovered secretion defect in another C-terminal variant, Y397H (42.0 ± 10.1% of WT F3 levels). Yet, glycan removal did not change the relative secretion of the N-terminal mutants tested (D49A, R140W, I220F). These results highlight the uniqueness and molecular similarities between the R345W and L451F variants and also suggest that previously identified disease-associated mutations (e.g., R140W) are indistinguishable from WT with respect to secretion, hinting that they may lead to disease by an alternative mechanism.
A novel diagnostic method based on filter bank theory for fast and accurate detection of thermoacoustic instability
Authors: Joo Seongpil , Choi Jongwun , Kim Namkeun , Lee Min Chul
Published: February 2021

This study proposes and analyzes a novel methodology that can effectively detect multi-mode combustion instability (CI) in a gas turbine combustor. The experiment is conducted in a model gas turbine combustor, and dynamic pressure (DP) and flame images are examined during the transition from stable to unstable flame, which is driven by changing fuel compositions. As a powerful technique for early detection of CI in multi-mode as well as in single mode, a new filter bank (FB) method based on spectral analysis of DP is proposed. Sequential processing using a triangular filter with Mel-scaling and a Hamming window is applied to increase the accuracy of the FB method, and the instability criterion is determined by calculating the magnitude of FB components. The performance of the FB method is compared with that of two conventional methods that are based on the root-mean-squared DP and temporal kurtosis. From the results, the FB method shows comparable performance in detection speed, sensitivity, and accuracy with other parameters. In addition, the FB components enable the analysis of various frequencies and multi-mode frequencies. Therefore, the FB method can be considered as an additional prognosis tool to determine the multi-mode CI in a monitoring system for gas turbine combustors.
Cell and tissue system capable of automated culture, stimulation, and monitor with the aim of feedback control of organs-on-a-chip
Authors: Konishi Satoshi , Hashimoto Takeshi , Nakabuchi Tsubasa , Ozeki Takatoshi , Kajita Hiroki
Published: February 2021

This paper presents progress in the automation of cell and tissue systems and attempts toward the in situ feedback control of organs-on-a-chip. Our study aims to achieve feedback control of a cell and tissue system by a personal computer (PC), whereas most studies on organs-on-a-chip focus on the automation of status monitoring. The implemented system is composed of subsystems including automated culture, stimulation, and monitoring. The monitoring function provides imaging as well as sampling and dispensing in combination with an external analyzer. Individual subsystems can be combined accordingly. First, monitoring of skeletal muscle (SM) and adipose tissues using this system was demonstrated. The highlight of this paper is the application of the system to the feedback control of the lipid droplet (LD) size, where biochemical stimulation using insulin and adrenaline is controlled by a PC according to the obtained LD imaging data. In this study, the system demonstrated its function of maintaining the desired size of LDs. Our results expand the possibility of PC-controllable cell and tissue systems by addressing the challenge of feedback control of organs-on-a-chip. The PC-controllable cell and tissue systems will contribute to living systems-on-a-chip based on homeostasis phenomena involving interactions between organs or tissues.
Polycrystalline texture causes magnetic instability in greigite
Authors: Lesniak Barbara , Koulialias Dimitrios , Charilaou Michalis , Weidler Peter G. , Rhodes Jordan M. , Macdonald Janet E. , Gehring Andreas U.
Published: February 2021

Magnetic stability of iron mineral phases is a key for their use as paleomagnetic information carrier and their applications in nanotechnology, and it critically depends on the size of the particles and their texture. Ferrimagnetic greigite (Fe3S4) in nature and synthesized in the laboratory forms almost exclusively polycrystalline particles. Textural effects of inter-grown, nano-sized crystallites on the macroscopic magnetization remain unresolved because their experimental detection is challenging. Here, we use ferromagnetic resonance (FMR) spectroscopy and static magnetization measurements in concert with micromagnetic simulations to detect and explain textural effects on the magnetic stability in synthetic, polycrystalline greigite flakes. We demonstrate that these effects stem from inter-grown crystallites with mean coherence length (MCL) of about 20 nm in single-domain magnetic state, which generate modifiable coherent magnetization volume (CMV) configurations in the flakes. At room temperature, the instability of the CVM configuration is exhibited by the angular dependence of the FMR spectra in fields of less than 100 mT and its reset by stronger fields. This finding highlights the magnetic manipulation of polycrystalline greigite, which is a novel trait to detect this mineral phase in Earth systems and to assess its fidelity as paleomagnetic information carrier. Additionally, our magneto-spectroscopic approach to analyse instable CMV opens the door for a new more rigorous magnetic assessment and interpretation of polycrystalline nano-materials.
Repetitive visual cortex transcranial random noise stimulation in adults with amblyopia
Authors: Donkor Richard , Silva Andrew E. , Teske Caroline , Wallis-Duffy Margaret , Johnson Aaron P. , Thompson Benjamin
Published: February 2021

We tested the hypothesis that five daily sessions of visual cortex transcranial random noise stimulation would improve contrast sensitivity, crowded and uncrowded visual acuity in adults with amblyopia. Nineteen adults with amblyopia (44.2 ± 14.9 years, 10 female) were randomly allocated to active or sham tRNS of the visual cortex (active, n = 9; sham, n = 10). Sixteen participants completed the study (n = 8 per group). tRNS was delivered for 25 min across five consecutive days. Monocular contrast sensitivity, uncrowded and crowded visual acuity were measured before, during, 5 min and 30 min post stimulation on each day. Active tRNS significantly improved contrast sensitivity and uncrowded visual acuity for both amblyopic and fellow eyes whereas sham stimulation had no effect. An analysis of the day by day effects revealed large within session improvements on day 1 for the active group that waned across subsequent days. No long-lasting (multi-day) improvements were observed for contrast sensitivity, however a long-lasting improvement in amblyopic eye uncrowded visual acuity was observed for the active group. This improvement remained at 28 day follow up. However, between-group differences in baseline uncrowded visual acuity complicate the interpretation of this effect. No effect of tRNS was observed for amblyopic eye crowded visual acuity. In agreement with previous non-invasive brain stimulation studies using different techniques, tRNS induced short-term contrast sensitivity improvements in adult amblyopic eyes, however, repeated sessions of tRNS did not lead to enhanced or long-lasting effects for the majority of outcome measures.
Small mammal glucocorticoid concentrations vary with forest fragment size, trap type, and mammal taxa in the Interior Atlantic Forest
Authors: Boyle Sarah A. , de la Sancha Noé U. , Pérez Pastor , Kabelik David
Published: February 2021

Species that live in degraded habitats often show signs of physiological stress. Glucocorticoid hormones (e.g., corticosterone and cortisol) are often assessed as a proxy of the extent of physiological stress an animal has experienced. Our goal was to quantify glucocorticoids in free-ranging small mammals in fragments of Interior Atlantic Forest. We extracted glucocorticoids from fur samples of 106 small mammals (rodent genera Akodon and Oligoryzomys, and marsupial genera Gracilinanus and Marmosa) from six forest fragments (2–1200 ha) in the Reserva Natural Tapytá, Caazapá Department, Paraguay. To our knowledge, this is the first publication of corticosterone and cortisol levels for three of the four sampled genera (Akodon, Oligoryzomys, and Marmosa) in this forest system. We discovered three notable results. First, as predicted, glucocorticoid levels were higher in individuals living withing small forest fragments. Second, animals captured live using restraint trapping methods (Sherman traps) had higher glucocorticoid levels than those animals captured using kill traps (Victor traps), suggesting that hair glucocorticoid measures can reflect acute stress levels in addition to long-term glucocorticoid incorporation. These acute levels are likely due to urinary steroids diffusing into the hair shaft. This finding raises a concern about the use of certain trapping techniques in association with fur hormone analysis. Finally, as expected, we also detected genus-specific differences in glucocorticoid levels, as well as cortisol/corticosterone ratios.