bluuebunny/crossref_metadata_2025 huggingface dataset:
Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development
Authors: Morandell Jasmin , Schwarz Lena A. , Basilico Bernadette , Tasciyan Saren , Dimchev Georgi , Nicolas Armel , Sommer Christoph , Kreuzinger Caroline , Dotter Christoph P. , Knaus Lisa S. , Dobler Zoe , Cacci Emanuele , Schur Florian K. M. , Danzl Johann G. , Novarino Gaia
Published: May 2021

De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). In mouse, constitutive Cul3 haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.
Nutrient content and stoichiometry of pelagic Sargassum reflects increasing nitrogen availability in the Atlantic Basin
Authors: Lapointe B. E. , Brewton R. A. , Herren L. W. , Wang M. , Hu C. , McGillicuddy D. J. , Lindell S. , Hernandez F. J. , Morton P. L.
Published: May 2021

The pelagic brown macroalgaeSargassumspp. have grown for centuries in oligotrophic waters of the North Atlantic Ocean supported by natural nutrient sources, such as excretions from associated fishes and invertebrates, upwelling, and N2fixation. Using a unique historical baseline, we show that since the 1980s the tissue %N ofSargassumspp. has increased by 35%, while %P has decreased by 44%, resulting in a 111% increase in the N:P ratio (13:1 to 28:1) and increased P limitation. The highest %N and δ15N values occurred in coastal waters influenced by N-rich terrestrial runoff, while lower C:N and C:P ratios occurred in winter and spring during peak river discharges. These findings suggest that increased N availability is supporting blooms ofSargassumand turning a critical nursery habitat into harmful algal blooms with catastrophic impacts on coastal ecosystems, economies, and human health.
The role of drop shape in impact and splash
Authors: Liu Qingzhe , Lo Jack Hau Yung , Li Ye , Liu Yuan , Zhao Jinyu , Xu Lei
Published: May 2021

The impact and splash of liquid drops on solid substrates are ubiquitous in many important fields. However, previous studies have mainly focused on spherical drops while the non-spherical situations, such as raindrops, charged drops, oscillating drops, and drops affected by electromagnetic field, remain largely unexplored. Using ferrofluid, we realize various drop shapes and illustrate the fundamental role of shape in impact and splash. Experiments show that different drop shapes produce large variations in spreading dynamics, splash onset, and splash amount. However, underlying all these variations we discover universal mechanisms across various drop shapes: the impact dynamics is governed by the superellipse model, the splash onset is triggered by the Kelvin-Helmholtz instability, and the amount of splash is determined by the energy dissipation before liquid taking off. Our study generalizes the drop impact research beyond the spherical geometry, and reveals the potential of using drop shape to control impact and splash.
Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
Authors: Nath Aritro , Cosgrove Patrick A. , Mirsafian Hoda , Christie Elizabeth L. , Pflieger Lance , Copeland Benjamin , Majumdar Sumana , Cristea Mihaela C. , Han Ernest S. , Lee Stephen J. , Wang Edward W. , Fereday Sian , Traficante Nadia , Salgia Ravi , Werner Theresa , Cohen Adam L. , Moos Philip , Chang Jeffrey T. , Bowtell David D. L. , Bild Andrea H.
Published: May 2021

The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy.
Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility
Authors: Dhara S. , Chhangawala S. , Chintalapudi H. , Askan G. , Aveson V. , Massa A. L. , Zhang L. , Torres D. , Makohon-Moore A. P. , Lecomte N. , Melchor J. P. , Bermeo J. , Cardenas A. , Sinha S. , Glassman D. , Nicolle R. , Moffitt R. , Yu K. H. , Leppanen S. , Laderman S. , Curry B. , Gui J. , Balachandran V. P. , Iacobuzio-Donahue C. , Chandwani R. , Leslie C. S. , Leach S. D.
Published: May 2021

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed “ATAC-array”, an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.
Clump sequencing exposes the spatial expression programs of intestinal secretory cells
Authors: Manco Rita , Averbukh Inna , Porat Ziv , Bahar Halpern Keren , Amit Ido , Itzkovitz Shalev
Published: May 2021

Single-cell RNA sequencing combined with spatial information on landmark genes enables reconstruction of spatially-resolved tissue cell atlases. However, such approaches are challenging for rare cell types, since their mRNA contents are diluted in the spatial transcriptomics bulk measurements used for landmark gene detection. In the small intestine, enterocytes, the most common cell type, exhibit zonated expression programs along the crypt-villus axis, but zonation patterns of rare cell types such as goblet and tuft cells remain uncharacterized. Here, we present ClumpSeq, an approach for sequencing small clumps of attached cells. By inferring the crypt-villus location of each clump from enterocyte landmark genes, we establish spatial atlases for all epithelial cell types in the small intestine. We identify elevated expression of immune-modulatory genes in villus tip goblet and tuft cells and heterogeneous migration patterns of enteroendocrine cells. ClumpSeq can be applied for reconstructing spatial atlases of rare cell types in other tissues and tumors.
Identification of microbial markers across populations in early detection of colorectal cancer
Authors: Wu Yuanqi , Jiao Na , Zhu Ruixin , Zhang Yida , Wu Dingfeng , Wang An-Jun , Fang Sa , Tao Liwen , Li Yichen , Cheng Sijing , He Xiaosheng , Lan Ping , Tian Chuan , Liu Ning-Ning , Zhu Lixin
Published: May 2021

Associations between gut microbiota and colorectal cancer (CRC) have been widely investigated. However, the replicable markers for early-stage adenoma diagnosis across multiple populations remain elusive. Here, we perform an integrated analysis on 1056 public fecal samples, to identify adenoma-associated microbial markers for early detection of CRC. After adjusting for potential confounders, Random Forest classifiers are constructed with 11 markers to discriminate adenoma from control (area under the ROC curve (AUC) = 0.80), and 26 markers to discriminate adenoma from CRC (AUC = 0.89), respectively. Moreover, we validate the classifiers in two independent cohorts achieving AUCs of 0.78 and 0.84, respectively. Functional analysis reveals that the altered microbiome is characterized with increased ADP-l-glycero-beta-d-manno-heptose biosynthesis in adenoma and elevated menaquinone-10 biosynthesis in CRC. These findings are validated in a newly-collected cohort of 43 samples using quantitative real-time PCR. This work proves the validity of adenoma-specific markers across multi-populations, which would contribute to the early diagnosis and treatment of CRC.
PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling
Authors: Ma Ning , Wang Yi-Kang , Xu Sheng , Ni Qian-Zhi , Zheng Qian-Wen , Zhu Bing , Cao Hui-Jun , Jiang Hao , Zhang Feng-Kun , Yuan Yan-Mei , Zhang Er-Bin , Chen Tian-Wei , Xia Ji , Ding Xu-Fen , Chen Zhen-Hua , Zhang Xiu-Ping , Wang Kang , Cheng Shu-Qun , Qiu Lin , Li Zhi-Gang , Yu Yong-Chun , Wang Xiao-Fan , Zhou Bin , Li Jing-Jing , Xie Dong
Published: May 2021

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.
Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase
Authors: Hayes Robert P. , Heo Mee Ra , Mason Mark , Reid John , Burlein Christine , Armacost Kira A. , Tellers David M. , Raheem Izzat , Shaw Anthony W. , Murray Edward , McKenna Philip M. , Abeywickrema Pravien , Sharma Sujata , Soisson Stephen M. , Klein Daniel
Published: May 2021

All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition.
Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives
Authors: Amporndanai Kangsa , Meng Xiaoli , Shang Weijuan , Jin Zhenmig , Rogers Michael , Zhao Yao , Rao Zihe , Liu Zhi-Jie , Yang Haitao , Zhang Leike , O’Neill Paul M. , Samar Hasnain S.
Published: May 2021

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.
Distinct EH domains of the endocytic TPLATE complex confer lipid and protein binding
Authors: Yperman Klaas , Papageorgiou Anna C. , Merceron Romain , De Munck Steven , Bloch Yehudi , Eeckhout Dominique , Jiang Qihang , Tack Pieter , Grigoryan Rosa , Evangelidis Thomas , Van Leene Jelle , Vincze Laszlo , Vandenabeele Peter , Vanhaecke Frank , Potocký Martin , De Jaeger Geert , Savvides Savvas N. , Tripsianes Konstantinos , Pleskot Roman , Van Damme Daniel
Published: May 2021

Clathrin-mediated endocytosis (CME) is the gatekeeper of the plasma membrane. In contrast to animals and yeasts, CME in plants depends on the TPLATE complex (TPC), an evolutionary ancient adaptor complex. However, the mechanistic contribution of the individual TPC subunits to plant CME remains elusive. In this study, we used a multidisciplinary approach to elucidate the structural and functional roles of the evolutionary conserved N-terminal Eps15 homology (EH) domains of the TPC subunit AtEH1/Pan1. By integrating high-resolution structural information obtained by X-ray crystallography and NMR spectroscopy with all-atom molecular dynamics simulations, we provide structural insight into the function of both EH domains. Both domains bind phosphatidic acid with a different strength, and only the second domain binds phosphatidylinositol 4,5-bisphosphate. Unbiased peptidome profiling by mass-spectrometry revealed that the first EH domain preferentially interacts with the double N-terminal NPF motif of a previously unidentified TPC interactor, the integral membrane protein Secretory Carrier Membrane Protein 5 (SCAMP5). Furthermore, we show that AtEH/Pan1 proteins control the internalization of SCAMP5 via this double NPF peptide interaction motif. Collectively, our structural and functional studies reveal distinct but complementary roles of the EH domains of AtEH/Pan1 in plant CME and connect the internalization of SCAMP5 to the TPLATE complex.
When timing matters—misdesigned dam filling impacts hydropower sustainability
Authors: Zaniolo Marta , Giuliani Matteo , Sinclair Scott , Burlando Paolo , Castelletti Andrea
Published: May 2021

Decades of sustainable dam planning efforts have focused on containing dam impacts in regime conditions, when the dam is fully filled and operational, overlooking potential disputes raised by the filling phase. Here, we argue that filling timing and operations can catalyze most of the conflicts associated with a dam’s lifetime, which can be mitigated by adaptive solutions that respond to medium-to-long term hydroclimatic fluctuations. Our retrospective analysis of the contested recent filling of Gibe III in the Omo-Turkana basin provides quantitative evidence of the benefits generated by adaptive filling strategies, attaining levels of hydropower production comparable with the historical ones while curtailing the negative impacts to downstream users. Our results can inform a more sustainable filling of the new megadam currently under construction downstream of Gibe III, and are generalizable to the almost 500 planned dams worldwide in regions influenced by climate feedbacks, thus representing a significant scope to reduce the societal and environmental impacts of a large number of new hydropower reservoirs.
Molecular insights of exceptionally photostable electron acceptors for organic photovoltaics
Authors: Liu Zhi-Xi , Yu Zhi-Peng , Shen Ziqiu , He Chengliang , Lau Tsz-Ki , Chen Zeng , Zhu Haiming , Lu Xinhui , Xie Zengqi , Chen Hongzheng , Li Chang-Zhi
Published: May 2021

Photo-degradation of organic semiconductors remains as an obstacle preventing their durable practice in optoelectronics. Herein, we disclose that volume-conserving photoisomerization of a unique series of acceptor-donor-acceptor (A-D-A) non-fullerene acceptors (NFAs) acts as a surrogate towards their subsequent photochemical reaction. Among A-D-A NFAs with fused, semi-fused and non-fused backbones, fully non-fused PTIC, representing one of rare existing samples, exhibits not only excellent photochemical tolerance in aerobic condition, but also efficient performance in solar cells. Along with a series of in-depth investigations, we identify that the structural confinement to inhibit photoisomerization of these unique A-D-A NFAs from molecular level to macroscopic condensed solid helps enhancing the photochemical stabilities of molecules, as well as the corresponding OSCs. Although other reasons associating with the photostabilities of molecules and devices should not excluded, we believe this work provides helpful structure-property information toward new design of stable and efficient photovoltaic molecules and solar cells.
Modifying redox properties and local bonding of Co3O4 by CeO2 enhances oxygen evolution catalysis in acid
Authors: Huang Jinzhen , Sheng Hongyuan , Ross R. Dominic , Han Jiecai , Wang Xianjie , Song Bo , Jin Song
Published: May 2021

Developing efficient and stable earth-abundant electrocatalysts for acidic oxygen evolution reaction is the bottleneck for water splitting using proton exchange membrane electrolyzers. Here, we show that nanocrystalline CeO2 in a Co3O4/CeO2 nanocomposite can modify the redox properties of Co3O4 and enhances its intrinsic oxygen evolution reaction activity, and combine electrochemical and structural characterizations including kinetic isotope effect, pH- and temperature-dependence, in situ Raman and ex situ X-ray absorption spectroscopy analyses to understand the origin. The local bonding environment of Co3O4 can be modified after the introduction of nanocrystalline CeO2, which allows the CoIII species to be easily oxidized into catalytically active CoIV species, bypassing the potential-determining surface reconstruction process. Co3O4/CeO2 displays a comparable stability to Co3O4 thus breaks the activity/stability tradeoff. This work not only establishes an efficient earth-abundant catalysts for acidic oxygen evolution reaction, but also provides strategies for designing more active catalysts for other reactions.
Cryo-EM structure of the mature and infective Mayaro virus at 4.4 Å resolution reveals features of arthritogenic alphaviruses
Authors: Ribeiro-Filho Helder V. , Coimbra Lais D. , Cassago Alexandre , Rocha Rebeca P. F. , Guerra João Victor da Silva , de Felicio Rafael , Carnieli Carolina Moretto , Leme Luiza , Padilha Antonio Cláudio , Paes Leme Adriana F. , Trivella Daniela B. B. , Portugal Rodrigo Villares , Lopes-de-Oliveira Paulo Sérgio , Marques Rafael Elias
Published: May 2021

Mayaro virus (MAYV) is an emerging arbovirus of the Americas that may cause a debilitating arthritogenic disease. The biology of MAYV is not fully understood and largely inferred from related arthritogenic alphaviruses. Here, we present the structure of MAYV at 4.4 Å resolution, obtained from a preparation of mature, infective virions. MAYV presents typical alphavirus features and organization. Interactions between viral proteins that lead to particle formation are described together with a hydrophobic pocket formed between E1 and E2 spike proteins and conformational epitopes specific of MAYV. We also describe MAYV glycosylation residues in E1 and E2 that may affect MXRA8 host receptor binding, and a molecular “handshake” between MAYV spikes formed by N262 glycosylation in adjacent E2 proteins. The structure of MAYV is suggestive of structural and functional complexity among alphaviruses, which may be targeted for specificity or antiviral activity.
Ecology and molecular targets of hypermutation in the global microbiome
Authors: Roux Simon , Paul Blair G. , Bagby Sarah C. , Nayfach Stephen , Allen Michelle A. , Attwood Graeme , Cavicchioli Ricardo , Chistoserdova Ludmila , Gruninger Robert J. , Hallam Steven J. , Hernandez Maria E. , Hess Matthias , Liu Wen-Tso , McAllister Tim A. , O’Malley Michelle A. , Peng Xuefeng , Rich Virginia I. , Saleska Scott R. , Eloe-Fadrosh Emiley A.
Published: May 2021

Changes in the sequence of an organism’s genome, i.e., mutations, are the raw material of evolution. The frequency and location of mutations can be constrained by specific molecular mechanisms, such as diversity-generating retroelements (DGRs). DGRs have been characterized from cultivated bacteria and bacteriophages, and perform error-prone reverse transcription leading to mutations being introduced in specific target genes. DGR loci were also identified in several metagenomes, but the ecological roles and evolutionary drivers of these DGRs remain poorly understood. Here, we analyze a dataset of >30,000 DGRs from public metagenomes, establish six major lineages of DGRs including three primarily encoded by phages and seemingly used to diversify host attachment proteins, and demonstrate that DGRs are broadly active and responsible for >10% of all amino acid changes in some organisms. Overall, these results highlight the constraints under which DGRs evolve, and elucidate several distinct roles these elements play in natural communities.
Fast widefield scan provides tunable and uniform illumination optimizing super-resolution microscopy on large fields
Authors: Mau Adrien , Friedl Karoline , Leterrier Christophe , Bourg Nicolas , Lévêque-Fort Sandrine
Published: May 2021

Non-uniform illumination limits quantitative analyses of fluorescence imaging techniques. In particular, single molecule localization microscopy (SMLM) relies on high irradiances, but conventional Gaussian-shaped laser illumination restricts the usable field of view to around 40 µm × 40 µm. We present Adaptable Scanning for Tunable Excitation Regions (ASTER), a versatile illumination technique that generates uniform and adaptable illumination. ASTER is also highly compatible with optical sectioning techniques such as total internal reflection fluorescence (TIRF). For SMLM, ASTER delivers homogeneous blinking kinetics at reasonable laser power over fields-of-view up to 200 µm × 200 µm. We demonstrate that ASTER improves clustering analysis and nanoscopic size measurements by imaging nanorulers, microtubules and clathrin-coated pits in COS-7 cells, and β2-spectrin in neurons. ASTER’s sharp and quantitative illumination paves the way for high-throughput quantification of biological structures and processes in classical and super-resolution fluorescence microscopies.
Metabolic plasticity enables lifestyle transitions of Porphyromonas gingivalis
Authors: Moradali M. Fata , Davey Mary E.
Published: May 2021

Our understanding of how the oral anaerobe Porphyromonas gingivalis can persist below the gum line, induce ecological changes, and promote polymicrobial infections remains limited. P. gingivalis has long been described as a highly proteolytic and asaccharolytic pathogen that utilizes protein substrates as the main source for energy production and proliferation. Here, we report that P. gingivalis displays a metabolic plasticity that enables the exploitation of non-proteinaceous substrates, specifically the monocarboxylates pyruvate and lactate, as well as human serum components, for colonization and biofilm formation. We show that anabolism of carbohydrates from pyruvate is powered by catabolism of amino acids. Concomitantly, the expression of fimbrial adhesion is upregulated, leading to the enhancement of biofilm formation, stimulation of multispecies biofilm development, and increase of colonization and invasion of the primary gingival epithelial cells by P. gingivalis. These studies provide the first glimpse into the metabolic plasticity of P. gingivalis and its adaptation to the nutritional condition of the host niche. Our findings support the model that in response to specific nutritional parameters, P. gingivalis has the potential to promote host colonization and development of a pathogenic community.
Quantum Zeno effects across a parity-time symmetry breaking transition in atomic momentum space
Authors: Chen Tao , Gou Wei , Xie Dizhou , Xiao Teng , Yi Wei , Jing Jun , Yan Bo
Published: May 2021

We experimentally study quantum Zeno effects in a parity-time (PT) symmetric cold atom gas periodically coupled to a reservoir. Based on the state-of-the-art control of inter-site couplings of atoms in a momentum lattice, we implement a synthetic two-level system with passive PT symmetry over two lattice sites, where an effective dissipation is introduced through repeated couplings to the rest of the lattice. Quantum Zeno (anti-Zeno) effects manifest in our experiment as the overall dissipation of the two-level system becoming suppressed (enhanced) with increasing coupling intensity or frequency. We demonstrate that quantum Zeno regimes exist in the broken PT symmetry phase, and are bounded by exceptional points separating the PT symmetric and PT broken phases, as well as by a discrete set of critical coupling frequencies. Our experiment establishes the connection between PT-symmetry-breaking transitions and quantum Zeno effects, and is extendable to higher dimensions or to interacting regimes, thanks to the flexible control with atoms in a momentum lattice.
Multimodal assessment of communicative-pragmatic features in schizophrenia: a machine learning approach
Authors: Parola Alberto , Gabbatore Ilaria , Berardinelli Laura , Salvini Rogerio , Bosco Francesca M.
Published: May 2021

An impairment in pragmatic communication is a core feature of schizophrenia, often associated with difficulties in social interactions. The pragmatic deficits regard various pragmatic phenomena, e.g., direct and indirect communicative acts, deceit, irony, and include not only the use of language but also other expressive means such as non-verbal/extralinguistic modalities, e.g., gestures and body movements, and paralinguistic cues, e.g., prosody and tone of voice. The present paper focuses on the identification of those pragmatic features, i.e., communicative phenomena and expressive modalities, that more reliably discriminate between individuals with schizophrenia and healthy controls. We performed a multimodal assessment of communicative-pragmatic ability, and applied a machine learning approach, specifically a Decision Tree model, with the aim of identifying the pragmatic features that best separate the data into the two groups, i.e., individuals with schizophrenia and healthy controls, and represent their configuration. The results indicated good overall performance of the Decision Tree model, with mean Accuracy of 82%, Sensitivity of 76%, and Precision of 91%. Linguistic irony emerged as the most relevant pragmatic phenomenon in distinguishing between the two groups, followed by violation of the Gricean maxims, and then extralinguistic deceitful and sincere communicative acts. The results are discussed in light of the pragmatic theoretical literature, and their clinical relevance in terms of content and design of both assessment and rehabilitative training.
The inhibition of ABCB1/MDR1 or ABCG2/BCRP enables doxorubicin to eliminate liver cancer stem cells
Authors: Yin Wang , Xiang Dongxi , Wang Tao , Zhang Yumei , Pham Cuong V. , Zhou Shufeng , Jiang Guoqin , Hou Yingchun , Zhu Yimin , Han Yinglu , Qiao Liang , Tran Phuong H.-L. , Duan Wei
Published: May 2021

Two ATP-binding cassette transporters, ABCB1/MDR1 and ABCG2/BCRP, are considered the most critical determinants for chemoresistance in hepatocellular carcinoma. However, their roles in the chemoresistance in liver cancer stem cells remain elusive. Here we explored the role of inhibition of MDR1 or ABCG2 in sensitizing liver cancer stem cells to doxorubicin, the most frequently used chemotherapeutic agent in treating liver cancer. We show that the inhibition of MDR1 or ABCG2 in Huh7 and PLC/PRF/5 cells using either pharmacological inhibitors or RNAi resulted in the elevated level of intracellular concentration of doxorubicin and the accompanied increased apoptosis as determined by confocal microscopy, high-performance liquid chromatography, flow cytometry, and annexin V assay. Notably, the inhibition of MDR1 or ABCG2 led to the reversal of the chemoresistance, as evident from the enhanced death of the chemoresistant liver cancer stem cells in tumorsphere-forming assays. Thus, the elevation of effective intracellular concentration of doxorubicin via the inhibition of MDR1 or ABCG2 represents a promising future strategy that transforms doxorubicin from a traditional chemotherapy agent into a robust killer of liver cancer stem cells for patients undergoing transarterial chemoembolization.
Improved methods for RNAseq-based alternative splicing analysis
Authors: Halperin Rebecca F. , Hegde Apurva , Lang Jessica D. , Raupach Elizabeth A. ,   C4RCD Research Group, Narayanan Vinodh , Huentelman Matt , Belnap Newell , Aziz Anne-Marie , Ramsey Keri , Legendre Christophe , Liang Winnie S. , LoRusso Patricia M. , Sekulic Aleksandar , Sosman Jeffrey A. , Trent Jeffrey M. , Rangasamy Sampathkumar , Pirrotte Patrick , Schork Nicholas J.
Published: May 2021

The robust detection of disease-associated splice events from RNAseq data is challenging due to the potential confounding effect of gene expression levels and the often limited number of patients with relevant RNAseq data. Here we present a novel statistical approach to splicing outlier detection and differential splicing analysis. Our approach tests for differences in the percentages of sequence reads representing local splice events. We describe a software package called Bisbee which can predict the protein-level effect of splice alterations, a key feature lacking in many other splicing analysis resources. We leverage Bisbee’s prediction of protein level effects as a benchmark of its capabilities using matched sets of RNAseq and mass spectrometry data from normal tissues. Bisbee exhibits improved sensitivity and specificity over existing approaches and can be used to identify tissue-specific splice variants whose protein-level expression can be confirmed by mass spectrometry. We also applied Bisbee to assess evidence for a pathogenic splicing variant contributing to a rare disease and to identify tumor-specific splice isoforms associated with an oncogenic mutation. Bisbee was able to rediscover previously validated results in both of these cases and also identify common tumor-associated splice isoforms replicated in two independent melanoma datasets.
Distributed abstraction and verification of an installed optical fibre network
Authors: Ives D. J. , Yan S. , Galdino L. , Wang R. , Elson D. J. , Wakayama Y. , Vaquero-Caballero F. J. , Saavedra G. , Lavery D. , Nejabati R. , Bayvel P. , Simeonidou D. , Savory S. J.
Published: May 2021

The management of wavelength routed optical mesh networks is complex with many potential light path routes and numerous physical layer impairments to transmission performance. This complexity can be reduced by applying the ideas of abstraction from computer science where different equipment is described in the same basic terms. The noise-to-signal ratio can be used as a metric to describe the quality of transmission performance of a signal propagated through a network element and accumulates additively through a sequence of such elements allowing the estimation of end-to-end performance. This study aims to explore the robustness of the noise-to-signal ratio metric in an installed fibre infrastructure. We show that the abstracted noise-to-signal ratio is independent of the observers and their location. We confirm that the abstracted noise-to-signal ratio can reasonably predict the performance of light-paths subsequently set in our network. Having a robust network element abstraction that can be incorporated into routeing engines allows the network management controller to make decisions on the most effective way to use the network resources in terms of the routeing and data coding format.
The pest kill rate of thirteen natural enemies as aggregate evaluation criterion of their biological control potential of Tuta absoluta
Authors: van Lenteren Joop C. , Lanzoni Alberto , Hemerik Lia , Bueno Vanda H. P. , Bajonero Cuervo Johanna G. , Biondi Antonio , Burgio Giovanni , Calvo Francisco J. , de Jong Peter W. , López Silvia N. , Luna M. Gabriela , Montes Flavio C. , Nieves Eliana L. , Aigbedion-Atalor Pascal Osa , Riquelme Virgala Maria B. , Sánchez Norma E. , Urbaneja Alberto
Published: May 2021

Ecologists study how populations are regulated, while scientists studying biological pest control apply population regulation processes to reduce numbers of harmful organisms: an organism (a natural enemy) is used to reduce the population density of another organism (a pest). Finding an effective biological control agent among the tens to hundreds of natural enemies of a pest is a daunting task. Evaluation criteria help in a first selection to remove clearly ineffective or risky species from the list of candidates. Next, we propose to use an aggregate evaluation criterion, the pest kill rate, to compare the pest population reduction capacity of species not eliminated during the first selection. The pest kill rate is the average daily lifetime killing of the pest by the natural enemy under consideration. Pest kill rates of six species of predators and seven species of parasitoids of Tuta absoluta were calculated and compared. Several natural enemies had pest kill rates that were too low to be able to theoretically reduce the pest population below crop damaging densities. Other species showed a high pest reduction capacity and their potential for practical application can now be tested under commercial crop production conditions.
The limit of tolerable micromotion for implant osseointegration: a systematic review
Authors: Kohli Nupur , Stoddart Jennifer C. , van Arkel Richard J.
Published: May 2021

Much research effort is being invested into the development of porous biomaterials that enhance implant osseointegration. Large micromotions at the bone-implant interface impair this osseointegration process, resulting in fibrous capsule formation and implant loosening. This systematic review compiled all the in vivo evidence available to establish if there is a universal limit of tolerable micromotion for implant osseointegration. The protocol was registered with the International Prospective Register for Systematic Reviews (ID: CRD42020196686). Pubmed, Scopus and Web of Knowledge databases were searched for studies containing terms relating to micromotion and osseointegration. The mean value of micromotion for implants that osseointegrated was 32% of the mean value for those that did not (112 ± 176 µm versus 349 ± 231 µm, p < 0.001). However, there was a large overlap in the data ranges with no universal limit apparent. Rather, many factors were found to combine to affect the overall outcome including loading time, the type of implant and the material being used. The tables provided in this review summarise these factors and will aid investigators in identifying the most relevant micromotion values for their biomaterial and implant development research.
Association of Candida albicans and Cbp+ Streptococcus mutans with early childhood caries recurrence
Authors: Garcia B. A. , Acosta N. C. , Tomar S. L. , Roesch L. F. W. , Lemos J. A. , Mugayar L. R. F. , Abranches J.
Published: May 2021

Early childhood caries (ECC) recurrence occurs in approximately 40% of treated cases within one year. The association of Streptococcus mutans and Candida albicans with the onset of ECC is well known. Also, S. mutans strains harboring collagen-binding proteins (Cbps) avidly bind to collagen-rich dentin and are linked to increased caries risk. Here, we investigated the presence of Cbp+S. mutans and C. albicans in saliva and dental plaque of children with varying caries statuses, and their salivary microbiome. In this cross-sectional study, 143 children who were caries-free (n = 73), treated for ECC with no signs of recurrence after 6 months (n = 45), or treated for ECC and experiencing recurrence within 6 months following treatment (n = 25) were enrolled. Co-infection with C. albicans and S. mutans, especially Cbp+S. mutans, was strongly associated with caries recurrence. Subjects of the recurrence group infected with Cbp+S. mutans showed a greater burden of Candida spp. and of Mutans streptococci in dentin than those infected with Cbp- strains. Salivary microbiome analysis revealed that Streptococcus parasanguinis was overrepresented in the caries recurrence group. Our findings indicate that Cbp+S. mutans and C. albicans are intimately associated with caries recurrence, contributing to the establishment of recalcitrant biofilms.
Topical arginase inhibition decreases growth of cutaneous squamous cell carcinoma
Authors: Mittal Amit , Wang Mike , Vidyarthi Aurobind , Yanez Diana , Pizzurro Gabriela , Thakral Durga , Tracy Erin , Colegio Oscar R.
Published: May 2021

Cutaneous squamous cell carcinomas (cSCC) are among the most commonly diagnosed malignancies, causing significant morbidity and mortality. Tumor-associated macrophage (TAM) expression of arginase is implicated in tumor progression, and therapeutic use of arginase inhibitors has been studied in various cancers. However, investigating potential cSCC immunotherapies including arginase inhibition in pre-clinical models is hampered by the lack of appropriate tumor models in immunocompetent mice. PDV is a cSCC cell line derived from chemical carcinogenesis of mouse keratinocytes. PDVC57 cells were derived from a PDV tumor in C57BL/6 (B6) mice. Unlike PDV, PDVC57 tumors grow consistently in B6 mice, and have increased TAMs, decreased dendritic and T cell intra-tumor infiltration. Arginase inhibition in cSCC tumors using Nω-hydroxy-nor-arginine (nor-NOHA) reduced tumor growth in B6 mice but not immunodeficient Rag1-deficient mice. nor-NOHA administration increased dendritic and T cell tumor-infiltration and PD-1 expression. The combination of nor-NOHA and anti-PD-1 therapy with nivolumab enhanced anti-PD-1 therapeutic efficacy. This study demonstrates the therapeutic potential of transcutaneous arginase inhibition in cSCC. A competent immune microenvironment is required for tumor growth inhibition using this arginase inhibitor. Synergistic co-inhibition of tumor growth in these results, supports further examination of transcutaneous arginase inhibition as a therapeutic modality for cSCC.
Green synthesis of multifunctional carbon coated copper oxide nanosheets and their photocatalytic and antibacterial activities
Authors: Bibi Hamida , Iqbal Mudassar , Wahab Hassan , Öztürk Mehmet , Ke Fei , Iqbal Zafar , Khan Muhammad Ishfaq , Alghanem Suliman Mohammed
Published: May 2021

The studies of metal oxides in environmental remediation of chemical and biological pollutants are gaining colossal importance. Herein, we report the facile synthesis of multifunctional copper oxide nanosheets (CuO NS) using an aqueous extract of Rhazya stricta. The phytochemical investigation of R. stricta indicated the presence of saponins, tannins, and reducing sugars, responsible for the reduction and stabilization of CuO NS. A UV–Visible spectrophotometer initially confirmed the fabrication of CuO NS with specific Surface Plasmon Resonance at 294 nm. Field Emission Scanning Electron Microscopy (FE-SEM), Fourier-transform infrared spectroscopy FTIR, and XRD were further used to characterize the CuO NS. The obtained CuO NS were poly-dispersed with an average size of 20 nm. Interestingly these particles were aligned together in 3D cubical sheets layered above each other via self-assembly. The as-synthesized CuO NS showed enhanced antibacterial potential (17.63 mm, overall mean inhibition zone) in comparison to the known antibiotics (11.51 mm, overall mean inhibition zone) against both Solanaceous crop's wilt-causing bacteria (Ralstonia solanacearum and Clavibacter michiganensis). Furthermore, the appreciable photocatalytic potential of CuO NS has also been observed, causing 83% degradation of methylene blue (MB) upon solar irradiation. The synthesis methodology is devoid of any toxic waste or by-products. It could be used to produce eco-friendly CuO nanomaterial for industrial uses.
Air-ozonolysis activation of polyolefins versus use of laden finishing to form contact-active nonwoven materials
Authors: Kiel Stella , Klein Miri , Kroupitski Yulia , Peiper Uri M. , Sela Saldinger Shlomo , Poverenov Elena
Published: May 2021

Two synthetic approaches were explored for modification of the polyolefins polyethylene/polypropylene (PE/PP) to form contact-active nonwoven materials. In the first approach, polymer surfaces were activated by O2-free air-ozonolysis, and then the active agent (trimethoxysilyl) propyl-octadecyl-dimethyl-ammonium chloride (C18-TSA) was covalently bound. In the second approach, the active agent was directly conjugated to the commercial ‘finishing’ that was then applied to the polymer. The chemical, physical and microscopic properties of the modified polymers were comprehensively studied, and their active site density was quantified by fluorescein sodium salt-cetyltrimethylammonium chloride reaction. The antimicrobial activity of the prepared nonwovens against Bacillus subtilis (Gram-positive) and Salmonella enterica (Gram-negative), and their stability at various pHs and temperatures were examined. The two approaches conferred antimicrobial properties to the modified polymers and demonstrated stable linkage of C18-TSA. However, the performance of the nonwovens formed by the first approach was superior. The study suggests two feasible and safe pathways for the modification of polyolefins to form contact-active nonwoven materials that can be further applied in various fields, such as hygiene products, medical fabrics, sanitizing wipes, and more.
Temperature dependency of excitonic effective mass and charge carrier conduction mechanism in CH3NH3PbI3−xClx thin films
Authors: Karim A. M. M. Tanveer , Khan M. K. R. , Hossain M. S.
Published: May 2021

In this paper we explain the temperature dependence of excitonic effective mass and charge carrier conduction mechanism occurs in CH3NH3PbI3−xClx thin films prepared by chemical dip coating (CDC), spray pyrolysis (Spray) and repeated dipping-withdrawing (Dipping). Hall Effect study confirmed that prepared CH3NH3PbI3−xClx samples are p-type semiconductor having carrier concentration of the order of ~ 1016 cm−3. The charge carrier mobility, mean free path and mean free life time were found to decrease with increasing temperature due to polaronic effect. The excitonic effective mass is estimated to (0.090–0.196)me and excitonic binding energy (15–33) meV, well consistent with Wannier-Mott hydrogenic model and the nature of exciton is likely to be Mott-Wannier type. From electrical measurement, it was observed that charge carrier conduction in CH3NH3PbI3−xClx is governed by migration of $${\mathrm{I}}^{-}$$

I

-

and CH3N $${\mathrm{H}}_{3}^{+}$$

H

3

+

vacancies and vacancy-assisted diffusion processes depending on temperature.
Facilitation of oral sensitivity by electrical stimulation of the faucial pillars
Authors: Braun Tobias , Hamzic Samra , Doerr Johanna M. , Peters Laura , Viard Maxime , Reuter Iris , Prosiegel Mario , Weber Susanne , Yenigün Mesut , Tschernatsch Marlene , Gerriets Tibo , Juenemann Martin
Published: May 2021

Dysphagia is common in neurological disease. However, our understanding of swallowing and its central nervous control is limited. Sensory information plays a vital role in the initiation of the swallowing reflex and is often reduced in stroke patients. We hypothesized that the sensitivity threshold of the anterior faucial pillar could be facilitated by either electrical stimulation (ES) or taste and smell information. The sensitivity threshold was measured by ES in the anterior faucial pillar region. The measurement was repeated 5 min after baseline. Thirty minutes after baseline, the participants underwent a test for taste and smell. Immediately after the test, the ES was repeated. Thirty healthy volunteers with a mean age of 27 ± 5.1 participated in the trial. Mean sensitivity threshold at baseline was 1.9 ± 0.59 mA. The values 5 min after baseline (1.74 ± 0.56 mA, p = 0.027) and 30 min after baseline (1.67 ± 0.58 mA, p = 0.011) were significantly lower compared to the baseline, but there was no difference between the latter (p = 0.321). After 5 min, a potentially facilitating effect was found on oral sensitivity by ES of the faucial pillar area. Thirty minutes later, this effect was still present.

Trial registration Clinicaltrials.gov, NCT03240965. Registered 7th August 2017—https://clinicaltrials.gov/ct2/show/NCT03240965.