bluuebunny/crossref_metadata_2025 huggingface dataset:
Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II-trial
Authors: Hölig Kristina , Schmidt Helmuth , Hütter Gero , Kramer Michael , Teipel Raphael , Heidrich Katharina , Zimmer Kristin , Heidenreich Falk , Blechschmidt Matthias , Torosian Tigran , Ordemann Rainer , Kroschinsky Frank , Rücker-Braun Elke , Gopsca Laszlo , Wagner-Drouet Eva Maria , Oelschlaegel Uta , Schmidt Alexander H. , Bornhäuser Martin , Ehninger Gerhard , Schetelig Johannes
Published: October 2020

We conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to standard-dose granulocyte colony-stimulating factor (G-CSF), defined by <2 × 106CD34 + cells/kg recipient body-weight (CD34+/kg RBW) after 1st apheresis. A single dose of 240 µg/kg P was injected subcutaneously at 10 p.m. on the day of the 1st apheresis. Thirty-seven allogeneic PBSC donors underwent study treatment. The median CD34+ count in peripheral blood was 15/µl on Day 1 after G-CSF alone, versus 44/µl on Day 2 after G-CSF plus P (p < 0.001). The median yield of CD34+ cells was 1.1 × 108on Day 1 and 2.8 × 108on Day 2. In contrast to a median yield of only 1.31 × 106CD CD34+/kg RBW on Day 1, triggering study inclusion, a median of 3.74 × 106CD CD34+/kg RBW were collected with G-CSF plus P on Day 2. Of 37 donors, 21 reached the target cell count of >4.5 × 106CD34+/kg RBW (57%, 95%CI 40–73%). No donor experienced a severe adverse event requiring treatment. In conclusion, P might be considered on a case-by-case basis for healthy allogeneic donors with very poor stem cell mobilization success after G-CSF.
Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer
Authors: Siddiqui Mohammad Aarif , Gollavilli Paradesi Naidu , Ramesh Vignesh , Parma Beatrice , Schwab Annemarie , Vazakidou Maria Eleni , Natesan Ramakrishnan , Saatci Ozge , Rapa Ida , Bironzo Paolo , Schuhwerk Harald , Asangani Irfan Ahmed , Sahin Ozgur , Volante Marco , Ceppi Paolo
Published: October 2020

Background

Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis. Little is known about how various pathways coordinate to elicit EMT’s different functional aspects in non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) has been previously correlated with EMT transcription factor ZEB1 in NSCLC and imparts resistance against anti-folate chemotherapy. In this study, we establish a functional correlation between TS, EMT, chemotherapy and metastasis and propose a network for TS mediated EMT.

Methods

Published datasets were analysed to evaluate the significance of TS in NSCLC fitness and prognosis. Promoter reporter assay was used to sort NSCLC cell lines in TSHIGH and TSLOW. Metastasis was assayed in a syngeneic mouse model.

Results

TS levels were prognostic and predicted chemotherapy response. Cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq identified EMT as one of the most differentially regulated pathways in connection to TS expression. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS, and AXL, SPARC and FOSL1 as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo.

Conclusion

These results establish TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be targeted in EMT-driven NSCLC.
Sequence-to-function deep learning frameworks for engineered riboregulators
Authors: Valeri Jacqueline A. , Collins Katherine M. , Ramesh Pradeep , Alcantar Miguel A. , Lepe Bianca A. , Lu Timothy K. , Camacho Diogo M.
Published: October 2020

While synthetic biology has revolutionized our approaches to medicine, agriculture, and energy, the design of completely novel biological circuit components beyond naturally-derived templates remains challenging due to poorly understood design rules. Toehold switches, which are programmable nucleic acid sensors, face an analogous design bottleneck; our limited understanding of how sequence impacts functionality often necessitates expensive, time-consuming screens to identify effective switches. Here, we introduce Sequence-based Toehold Optimization and Redesign Model (STORM) and Nucleic-Acid Speech (NuSpeak), two orthogonal and synergistic deep learning architectures to characterize and optimize toeholds. Applying techniques from computer vision and natural language processing, we ‘un-box’ our models using convolutional filters, attention maps, and in silico mutagenesis. Through transfer-learning, we redesign sub-optimal toehold sensors, even with sparse training data, experimentally validating their improved performance. This work provides sequence-to-function deep learning frameworks for toehold selection and design, augmenting our ability to construct potent biological circuit components and precision diagnostics.
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
Authors: Douangamath Alice , Fearon Daren , Gehrtz Paul , Krojer Tobias , Lukacik Petra , Owen C. David , Resnick Efrat , Strain-Damerell Claire , Aimon Anthony , Ábrányi-Balogh Péter , Brandão-Neto José , Carbery Anna , Davison Gemma , Dias Alexandre , Downes Thomas D. , Dunnett Louise , Fairhead Michael , Firth James D. , Jones S. Paul , Keeley Aaron , Keserü György M. , Klein Hanna F. , Martin Mathew P. , Noble Martin E. M. , O’Brien Peter , Powell Ailsa , Reddi Rambabu N. , Skyner Rachael , Snee Matthew , Waring Michael J. , Wild Conor , London Nir , von Delft Frank , Walsh Martin A.
Published: October 2020

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.
Suppressing material loss in the visible and near-infrared range for functional nanophotonics using bandgap engineering
Authors: Wang Mingsong , Krasnok Alex , Lepeshov Sergey , Hu Guangwei , Jiang Taizhi , Fang Jie , Korgel Brian A. , Alù Andrea , Zheng Yuebing
Published: October 2020

All-dielectric nanostructures have recently opened exciting opportunities for functional nanophotonics, owing to their strong optical resonances along with low material loss in the near-infrared range. Pushing these concepts to the visible range is hindered by their larger absorption coefficient, thus encouraging the search for alternative dielectrics for nanophotonics. Here, we employ bandgap engineering to synthesize hydrogenated amorphous Si nanoparticles (a-Si:H NPs) offering ideal features for functional nanophotonics. We observe significant material loss suppression in a-Si:H NPs in the visible range caused by hydrogenation-induced bandgap renormalization, producing strong higher-order resonant modes in single NPs with Q factors up to ~100 in the visible and near-IR range. We also realize highly tunable all-dielectric meta-atoms by coupling a-Si:H NPs to photochromic spiropyran molecules. ~70% reversible all-optical tuning of light scattering at the higher-order resonant mode under a low incident light intensity is demonstrated. Our results promote the development of high-efficiency visible nanophotonic devices.
PilY1 and minor pilins form a complex priming the type IVa pilus in Myxococcus xanthus
Authors: Treuner-Lange Anke , Chang Yi-Wei , Glatter Timo , Herfurth Marco , Lindow Steffi , Chreifi Georges , Jensen Grant J. , Søgaard-Andersen Lotte
Published: October 2020

Type IVa pili are ubiquitous and versatile bacterial cell surface filaments that undergo cycles of extension, adhesion and retraction powered by the cell-envelope spanning type IVa pilus machine (T4aPM). The overall architecture of the T4aPM and the location of 10 conserved core proteins within this architecture have been elucidated. Here, using genetics, cell biology, proteomics and cryo-electron tomography, we demonstrate that the PilY1 protein and four minor pilins, which are widely conserved in T4aP systems, are essential for pilus extension in Myxococcus xanthus and form a complex that is an integral part of the T4aPM. Moreover, these proteins are part of the extended pilus. Our data support a model whereby the PilY1/minor pilin complex functions as a priming complex in T4aPM for pilus extension, a tip complex in the extended pilus for adhesion, and a cork for terminating retraction to maintain a priming complex for the next round of extension.
A fluoride-responsive genetic circuit enables in vivo biofluorination in engineered Pseudomonas putida
Authors: Calero Patricia , Volke Daniel C. , Lowe Phillip T. , Gotfredsen Charlotte H. , O’Hagan David , Nikel Pablo I.
Published: October 2020

Fluorine is a key element in the synthesis of molecules broadly used in medicine, agriculture and materials. Addition of fluorine to organic structures represents a unique strategy for tuning molecular properties, yet this atom is rarely found in Nature and approaches to integrate fluorometabolites into the biochemistry of living cells are scarce. In this work, synthetic gene circuits for organofluorine biosynthesis are implemented in the platform bacterium Pseudomonas putida. By harnessing fluoride-responsive riboswitches and the orthogonal T7 RNA polymerase, biochemical reactions needed for in vivo biofluorination are wired to the presence of fluoride (i.e. circumventing the need of feeding expensive additives). Biosynthesis of fluoronucleotides and fluorosugars in engineered P. putida is demonstrated with mineral fluoride both as only fluorine source (i.e. substrate of the pathway) and as inducer of the synthetic circuit. This approach expands the chemical landscape of cell factories by providing alternative biosynthetic strategies towards fluorinated building-blocks.
Reconstructing lost BOLD signal in individual participants using deep machine learning
Authors: Yan Yuxiang , Dahmani Louisa , Ren Jianxun , Shen Lunhao , Peng Xiaolong , Wang Ruiqi , He Changgeng , Jiang Changqing , Gong Chen , Tian Ye , Zhang Jianguo , Guo Yi , Lin Yuanxiang , Li Shijun , Wang Meiyun , Li Luming , Hong Bo , Liu Hesheng
Published: October 2020

Signal loss in blood oxygen level-dependent (BOLD) functional neuroimaging is common and can lead to misinterpretation of findings. Here, we reconstructed compromised fMRI signal using deep machine learning. We trained a model to learn principles governing BOLD activity in one dataset and reconstruct artificially compromised regions in an independent dataset, frame by frame. Intriguingly, BOLD time series extracted from reconstructed frames are correlated with the original time series, even though the frames do not independently carry any temporal information. Moreover, reconstructed functional connectivity maps exhibit good correspondence with the original connectivity maps, indicating that the model recovers functional relationships among brain regions. We replicated this result in two healthy datasets and in patients whose scans suffered signal loss due to intracortical electrodes. Critically, the reconstructions capture individual-specific information. Deep machine learning thus presents a unique opportunity to reconstruct compromised BOLD signal while capturing features of an individual’s own functional brain organization.
Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ
Authors: Barski Michał S. , Minnell Jordan J. , Hodakova Zuzana , Pye Valerie E. , Nans Andrea , Cherepanov Peter , Maertens Goedele N.
Published: October 2020

Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.
Proteasomal degradation of polycomb-group protein CBX6 confers MMP-2 expression essential for mesothelioma invasion
Authors: Sakai Katsuya , Nishiuchi Takumi , Tange Shoichiro , Suzuki Yoshinori , Yano Seiji , Terashima Minoru , Suzuki Takeshi , Matsumoto Kunio
Published: October 2020

The aggressive invasiveness of malignant mesothelioma limits cancer therapy, however, the molecular mechanisms underlying the invasiveness remain largely unknown. Here we found that the matrix metalloproteinase-2 (MMP-2) was required for the invasion of mesothelioma cells in the collagen matrix and the gene expression of MMP-2 was correlated with the invasive phenotype. The MMP-2 gene expression was regulated by DNA and histone methylation around the transcription start site, implicating the involvement of the polycomb repressive complex (PRC). Knockdown of PRC component chromobox 6 (CBX6) promoted MMP-2 expression and invasion of mesothelioma cells. Transcriptome analysis suggested that CBX6 regulates sets of genes involved in cancer cell migration and metastasis. In invasive but not non-invasive cells, CBX6 was constantly unstable owing to ubiquitination and protein degradation. In human tissues, CBX6 localized in the nuclei of normal mesothelium and benign mesothelioma, but the nuclear staining of CBX6 was lost in malignant mesothelioma. These results suggest involvement of proteasomal degradation of CBX6 in mesothelioma progression.
The global biological microplastic particle sink
Authors: Kvale K. , Prowe A. E. F. , Chien C.-T. , Landolfi A. , Oschlies A.
Published: October 2020

Every year, about four percent of the plastic waste generated worldwide ends up in the ocean. What happens to the plastic there is poorly understood, though a growing body of evidence suggests it is rapidly spreading throughout the global ocean. The mechanisms of this spread are straightforward for buoyant larger plastics that can be accurately modelled using Lagrangian particle models. But the fate of the smallest size fractions (the microplastics) are less straightforward, in part because they can aggregate in sinking marine snow and faecal pellets. This biologically-mediated pathway is suspected to be a primary surface microplastic removal mechanism, but exactly how it might work in the real ocean is unknown. We search the parameter space of a new microplastic model embedded in an earth system model to show that biological uptake can significantly shape global microplastic inventory and distributions and even account for the budgetary “missing” fraction of surface microplastic, despite being an inefficient removal mechanism. While a lack of observational data hampers our ability to choose a set of “best” model parameters, our effort represents a first tool for quantitatively assessing hypotheses for microplastic interaction with ocean biology at the global scale.
The comparison of MRN, electrophysiology and progression among typical CIDP and atypical CIDP subtypes
Authors: Feng Yuan , Zhang Yu , Su Xiaoyun , Zheng Chuansheng , Lu Zuneng
Published: October 2020

We aimed to compare the electrophysiology and magnetic resonance neurography (MRN) results of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) subtypes and to explore the progression from atypical CIDP to typical CIDP. We collected the medical records of 45 CIDP patients to analyse the rate of progression from atypical CIDP to typical CIDP subtypes. The cerebrospinal fluid (CSF) protein (p = 0.024) and overall disability sum score (ODSS) (p = 0.000) differed among patients with typical CIDP, distal acquired demyelinating symmetric neuropathy (DADS) and Lewis-Sumner syndrome (LSS). The compound motor action potential (CMAP) of typical CIDP was lower than that of the other subtypes (p = 0.016, p = 0.022 and p = 0.012). The cross-sectional area (CSA) of nerve roots in typical CIDP was significantly thicker than that of nerve roots in DADS and LSS. There were fewer DADS and LSS patients who progressed to typical CIDP than those who progressed to pure motor and pure sensory CIDP (p = 0.000), and the progression from pure motor to typical CIDP required a significantly longer time than the progression from pure sensory to typical CIDP (p = 0.007). Typical CIDP was more severe than the other subtypes not only in terms of clinical and electrophysiology factors but also in terms of MRN factors.
Projections of heat stress and associated work performance over India in response to global warming
Authors: Koteswara Rao K. , Lakshmi Kumar T. V. , Kulkarni Ashwini , Ho Chang-Hoi , Mahendranath B. , Desamsetti Srinivas , Patwardhan Savita , Dandi Appala Ramu , Barbosa Humberto , Sabade Sudhir
Published: October 2020

Summertime heat stress future projections from multi-model mean of 18 CMIP5 models show unprecedented increasing levels in the RCP 4.5 and RCP 8.5 emission scenarios over India. The estimated heat stress is found to have more impact on the coastal areas of India having exposure to more frequent days of extreme caution to danger category along with the increased probability of occurrence. The explicit amount of change in temperature, increase in the duration and intensity of warm days along with the modulation in large scale circulation in future are seemingly connected to the increasing levels of heat stress over India. A decline of 30 to 40% in the work performance is projected over India by the end of the century due to the elevated heat stress levels which pose great challenges to the country policy makers to design the safety mechanisms and to protect people working under continuous extreme hot weather conditions.
Explicit integration of dispersal-related metrics improves predictions of SDM in predatory arthropods
Authors: Monsimet Jérémy , Devineau Olivier , Pétillon Julien , Lafage Denis
Published: October 2020

Fishing spiders (Dolomedes spp.) make an interesting model to predict the impact of global changes because they are generalist, opportunistic predators, whose distribution is driven mostly by abiotic factors. Yet, the two European species are expected to react differently to forthcoming environmental changes, because of habitat specialization and initial range. We used an original combination of habitat and dispersal data to revisit these predictions under various climatic scenarios. We used the future range of suitable habitat, predicted with habitat variables only, as a base layer to further predict the range or reachable habitat by accounting for both dispersal ability and landscape connectivity. Our results confirm the northward shift in range and indicate that the area of co-occurrences should also increase. However, reachable habitat should expand less than suitable habitat, especially when accounting for landscape connectivity. In addition, the potential range expansion was further limited for the red-listed D. plantarius, which is more of a habitat specialist and has a lower ability to disperse. This study highlights the importance of looking beyond habitat variables to produce more accurate predictions for the future of arthropods populations.
Graph-based exploitation of gene ontology using GOxploreR for scrutinizing biological significance
Authors: Manjang Kalifa , Tripathi Shailesh , Yli-Harja Olli , Dehmer Matthias , Emmert-Streib Frank
Published: October 2020

Gene ontology (GO) is an eminent knowledge base frequently used for providing biological interpretations for the analysis of genes or gene sets from biological, medical and clinical problems. Unfortunately, the interpretation of such results is challenging due to the large number of GO terms, their hierarchical and connected organization as directed acyclic graphs (DAGs) and the lack of tools allowing to exploit this structural information explicitly. For this reason, we developed the package . The main features of are (I) easy and direct access to structural features of GO, (II) structure-based ranking of GO-terms, (III) mapping to reduced GO-DAGs including visualization capabilities and (IV) prioritizing of GO-terms. The underlying idea of is to exploit a graph-theoretical perspective of GO as manifested by its DAG-structure and the containing hierarchy levels for cumulating semantic information. That means all these features enhance the utilization of structural information of GO and complement existing analysis tools. Overall, provides exploratory as well as confirmatory tools for complementing any kind of analysis resulting in a list of GO-terms, e.g., from differentially expressed genes or gene sets, GWAS or biomarkers. Our package is freely available from CRAN.
Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells
Authors: Almasoud Nuha , Binhamdan Sarah , Younis Ghaydaa , Alaskar Hanouf , Alotaibi Amal , Manikandan Muthurangan , Alfayez Musaad , Kassem Moustapha , AlMuraikhi Nihal
Published: October 2020

Tankyrase is part of poly (ADP-ribose) polymerase superfamily required for numerous cellular and molecular processes. Tankyrase inhibition negatively regulates Wnt pathway. Thus, Tankyrase inhibitors have been extensively investigated for the treatment of clinical conditions associated with activated Wnt signaling such as cancer and fibrotic diseases. Moreover, Tankyrase inhibition has been recently reported to upregulate osteogenesis through the accumulation of SH3 domain-binding protein 2, an adaptor protein required for bone metabolism. In this study, we investigated the effect of Tankyrase inhibition in osteoblast differentiation of human skeletal (mesenchymal) stem cells (hMSCs). A Tankyrase inhibitor, XAV-939, identified during a functional library screening of small molecules. Alkaline phosphatase activity and Alizarin red staining were employed as markers for osteoblastic differentiation and in vitro mineralized matrix formation, respectively. Global gene expression profiling was performed using the Agilent microarray platform. XAV-939, a Tankyrase inhibitor, enhanced osteoblast differentiation of hBMSCs as evidenced by increased ALP activity, in vitro mineralized matrix formation, and upregulation of osteoblast-related gene expression. Global gene expression profiling of XAV-939-treated cells identified 847 upregulated and 614 downregulated mRNA transcripts, compared to vehicle-treated control cells. It also points towards possible changes in multiple signaling pathways, including TGFβ, insulin signaling, focal adhesion, estrogen metabolism, oxidative stress, RANK-RANKL (receptor activator of nuclear factor κB ligand) signaling, Vitamin D synthesis, IL6, and cytokines and inflammatory responses. Further bioinformatic analysis, employing Ingenuity Pathway Analysis identified significant enrichment in XAV-939-treated cells of functional categories and networks involved in TNF, NFκB, and STAT signaling. We identified a Tankyrase inhibitor (XAV-939) as a powerful enhancer of osteoblastic differentiation of hBMSC that may be useful as a therapeutic option for treating conditions associated with low bone formation.
Fabrication of monodispersed copper oxide nanoparticles with potential application as antimicrobial agents
Authors: Bezza Fisseha A. , Tichapondwa Shepherd M. , Chirwa Evans M. N.
Published: October 2020

Cuprous oxide nanoparticles (Cu2O NPs) were fabricated in reverse micellar templates by using lipopeptidal biosurfactant as a stabilizing agent. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive x-ray spectrum (EDX) and UV–Vis analysis were carried out to investigate the morphology, size, composition and stability of the nanoparticles synthesized. The antibacterial activity of the as-synthesized Cu2O NPs was evaluated against Gram-positive B. subtilis CN2 and Gram-negative P. aeruginosa CB1 strains, based on cell viability, zone of inhibition and minimal inhibitory concentration (MIC) indices. The lipopeptide stabilized Cu2O NPs with an ultra-small size of 30 ± 2 nm diameter exhibited potent antimicrobial activity against both Gram-positive and Gram-negative bacteria with a minimum inhibitory concentration of 62.5 µg/mL at pH5. MTT cell viability assay displayed a median inhibition concentration (IC50) of 21.21 μg/L and 18.65 μg/mL for P. aeruginosa and B. subtilis strains respectively. Flow cytometric quantification of intracellular reactive oxygen species (ROS) using 2,7-dichlorodihydrofluorescein diacetate staining revealed a significant ROS generation up to 2.6 to 3.2-fold increase in the cells treated with 62.5 µg/mL Cu2O NPs compared to the untreated controls, demonstrating robust antibacterial activity. The results suggest that lipopeptide biosurfactant stabilized Cu2O NPs could have promising potential for biocompatible bactericidal and therapeutic applications.
The liposomal delivery of hydrophobic oxidovanadium complexes imparts highly effective cytotoxicity and differentiating capacity in neuroblastoma tumour cells
Authors: Irving Elsa , Tagalakis Aristides D. , Maeshima Ruhina , Hart Stephen L. , Eaton Simon , Lehtonen Ari , Stoker Andrew W.
Published: October 2020

Oxidovanadium complexes with organic ligands are well known to have cytotoxic or differentiating capabilities against a range of cancer cell types. Their limited use in clinical testing though has resulted largely from uncertainties about the long-term toxicities of such complexes, due in part to the speciation to vanadate ions in the circulation. We hypothesised that more highly stable complexes, delivered using liposomes, may provide improved opportunities for oxidovanadium applications against cancer. In this study we sourced specifically hydrophobic forms of oxidovanadium complexes with the explicit aim of demonstrating liposomal encapsulation, bioavailability in cultured neuroblastoma cells, and effective cytotoxic or differentiating activity. Our data show that four ethanol-solubilised complexes with amine bisphenol, aminoalcohol bisphenol or salan ligands are equally or more effective than a previously used complex bis(maltolato)oxovanadium(V) in neuroblastoma cell lines. Moreover, we show that one of these complexes can be stably incorporated into cationic liposomes where it retains very good bioavailability, apparently low speciation and enhanced efficacy compared to ethanol delivery. This study provides the first proof-of-concept that stable, hydrophobic oxidovanadium complexes retain excellent cellular activity when delivered effectively to cancer cells with nanotechnology. This offers the improved prospect of applying oxidovanadium-based drugs in vivo with increased stability and reduced off-target toxicity.
Palaeoproteomic analysis of Pleistocene cave hyenas from east Asia
Authors: Rao Huiyun , Yang Yimin , Liu Jinyi , Westbury Michael V. , Zhang Chi , Shao Qingfeng
Published: October 2020

The spotted hyena (Crocuta crocuta) is the only extant species of the genusCrocuta, which once occupied a much wider range during the Pliocene and Pleistocene. However, its origin and evolutionary history is somewhat contentious due to discordances between morphological, nuclear, and mitochondrial data. Due to the limited molecular data from east AsianCrocuta,also known as cave hyena, and the difficulty of extracting ancient DNA from this area, here we present proteomic analysis of cave hyenas from three locations in northern China. This marks the first proteomic data generated from cave hyenas, adding new molecular data to the east Asian populations. Phylogenetic analysis based on these protein sequences reveals two different groups of cave hyenas in east Asia, one of which could not be distinguished from modern spotted hyenas from northern Africa, tentatively the result of previously suggested gene flow between these lineages. With developments of instrumentation and analytical methods, proteomics holds promising potential for molecular phylogenetic reconstructions of ancient fauna previously thought to be unreachable using ancient DNA.
The spatial and temporal dynamics of global meat trade networks
Authors: Chung Min Gon , Kapsar Kelly , Frank Kenneth A. , Liu Jianguo
Published: October 2020

Rapid increases in meat trade generate complex global networks across countries. However, there has been little research quantifying the dynamics of meat trade networks and the underlying forces that structure them. Using longitudinal network data for 134 countries from 1995 to 2015, we combined network modeling and cluster analysis to simultaneously identify the structural changes in meat trade networks and the factors that influence the networks themselves. The integrated network approach uncovers a general consolidation of global meat trade networks over time, although some global events may have weakened this consolidation both regionally and globally. In consolidated networks, the presence of trade agreements and short geographic distances between pairs of countries are associated with increases in meat trade. Countries with rapid population and income growth greatly depend on meat imports. Furthermore, countries with high food availability import large quantities of meat products to satisfy their various meat preferences. The findings from this network approach provide key insights that can be used to better understand the social and environmental consequences of increasing global meat trade.
Century-long cod otolith biochronology reveals individual growth plasticity in response to temperature
Authors: Smoliński Szymon , Deplanque-Lasserre Julie , Hjörleifsson Einar , Geffen Audrey J. , Godiksen Jane A. , Campana Steven E.
Published: October 2020

Otolith biochronologies combine growth records from individual fish to produce long-term growth sequences, which can help to disentangle individual from population-level responses to environmental variability. This study assessed individual thermal plasticity of Atlantic cod (Gadus morhua) growth in Icelandic waters based on measurements of otolith increments. We applied linear mixed-effects models and developed a century-long growth biochronology (1908–2014). We demonstrated interannual and cohort-specific changes in the growth of Icelandic cod over the last century which were mainly driven by temperature variation. Temperature had contrasting relationships with growth—positive for the fish during the youngest ages and negative during the oldest ages. We decomposed the effects of temperature on growth observed at the population level into within-individual effects and among‐individual effects and detected significant individual variation in the thermal plasticity of growth. Variance in the individual plasticity differed across cohorts and may be related to the mean environmental conditions experienced by the group. Our results underscore the complexity of the relationships between climatic conditions and the growth of fish at both the population and individual level, and highlight the need to distinguish between average population responses and growth plasticity of the individuals for accurate growth predictions.
Membrane stiffness and myelin basic protein binding strength as molecular origin of multiple sclerosis
Authors: Krugmann Benjamin , Radulescu Aurel , Appavou Marie-Sousai , Koutsioubas Alexandros , Stingaciu Laura R. , Dulle Martin , Förster Stephan , Stadler Andreas M.
Published: October 2020

Myelin basic protein (MBP) and its interaction with lipids of the myelin sheath plays an important part in the pathology of multiple sclerosis (MS). Previous studies observed that changes in the myelin lipid composition lead to instabilities and enhanced local curvature of MBP-lipid multilayer structures. We investigated the molecular origin of the instability and found that the diseased lipid membrane has a 25% lower bending rigidity, thus destabilizing smooth $$>1\,$$

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1

µm curvature radius structures such as in giant unilamellar vesicles. MBP-mediated assembling of lipid bilayers proceeds in two steps, with a slow second step occurring over many days where native lipid membranes assemble into well-defined multilayer structures, whereas diseased lipid membranes form folded assemblies with high local curvature. For both native and diseased lipid mixtures we find that MBP forms dense liquid phases on top of the lipid membranes mediating attractive membrane interactions. Furthermore, we observe MBP to insert into its bilayer leaflet side in case of the diseased lipid mixture, whereas there is no insertion for the native mixture. Insertion increases the local membrane curvature, and could be caused by a decrease of the sphingomyelin content of the diseased lipid mixture. These findings can help to open a pathway to remyelination strategies.
Acrylamide alters CREB and retinoic acid signalling pathways during differentiation of the human neuroblastoma SH-SY5Y cell line
Authors: Attoff Kristina , Johansson Ylva , Cediel-Ulloa Andrea , Lundqvist Jessica , Gupta Rajinder , Caiment Florian , Gliga Anda , Forsby Anna
Published: October 2020

Acrylamide (ACR) is a known neurotoxicant which crosses the blood–brain barrier, passes the placenta and has been detected in breast milk. Hence, early-life exposure to ACR could lead to developmental neurotoxicity. The aim of this study was to elucidate if non-cytotoxic concentrations of ACR alter neuronal differentiation by studying gene expression of markers significant for neurodevelopment in the human neuroblastoma SH-SY5Y cell model. Firstly, by using RNASeq we identified two relevant pathways that are activated during 9 days of retinoic acid (RA) induced differentiation i.e. RA receptor (RAR) activation and the cAMP response element-binding protein (CREB) signalling pathways. Next, by qPCR we showed that 1 and 70 µM ACR after 9 days exposure alter the expression of 13 out of 36 genes in the RAR activation pathway and 18 out of 47 in the CREB signalling pathway. Furthermore, the expression of established neuronal markers i.e. BDNF, STXBP2, STX3, TGFB1 and CHAT were down-regulated. Decreased protein expression of BDNF and altered ratio of phosphorylated CREB to total CREB were confirmed by western blot. Our results reveal that micromolar concentrations of ACR sustain proliferation, decrease neurite outgrowth and interfere with signalling pathways involved in neuronal differentiation in the SH-SY5Y cell model.
Electron cyclotron motion excited surface plasmon and radiation with orbital angular momentum on a semiconductor thin film
Authors: Lan Yung-Chiang , Shen Chia-Hui , Chen Chih-Min
Published: October 2020

In this work, surface plasmons (SPs) on a germanium (Ge) thin film in terahertz (THz) region that are excited by electron cyclotron motion (ECM) and the subsequent SP emission (SPE) by adding Ge gratings on the film are explored by finite-difference time-domain (FDTD) and particle-in-cell FDTD (PIC-FDTD) simulations. The optical properties of ECM-excited SPs are the same as those of SPs that are excited by electron straight motion (ESM). For operating at the flat band of SPs’ dispersion curve on the Ge film, changing the electron energy will only change the wavevector of SPs and hence the number of periods of SPs on the circular orbital. When the periodic gratings are deposited on the Ge film along the circular orbital of electrons, the emitted SPE contains the orbital angular momentum (OAM). The number of arms and chirality of the spiral patterns in phase map (i.e. the quantum number of OAM) of SPE are determined by the difference between the number of SPs’ periods and the number of gratings. Manipulations of the quantum number of OAM by changing the number of gratings for a fixed electron energy and by changing the electron energy for a fixed number of gratings are also demonstrated. This work provides an active OAM source and it is not required to launch circularly polarized beams or pumping beams into the structure.
Low noise all-fiber amplification of a coherent supercontinuum at 2 µm and its limits imposed by polarization noise
Authors: Heidt Alexander M. , Modupeh Hodasi Joanna , Rampur Anupamaa , Spangenberg Dirk-Mathys , Ryser Manuel , Klimczak Mariusz , Feurer Thomas
Published: October 2020

We report a low noise, broadband, ultrafast Thulium/Holmium co-doped all-fiber chirped pulse amplifier, seeded by an Erbium-fiber system spectrally broadened via coherent supercontinuum generation in an all-normal dispersion photonic crystal fiber. The amplifier supports a − 20 dB bandwidth of more than 300 nm and delivers high quality 66 fs pulses with more than 70 kW peak power directly from the output fiber. The total relative intensity noise (RIN) integrated from 10 Hz to 20 MHz is 0.07%, which to our knowledge is the lowest reported RIN for wideband ultrafast amplifiers operating at 2 µm to date. This is achieved by eliminating noise-sensitive anomalous dispersion nonlinear dynamics from the spectral broadening stage. In addition, we identify the origin of the remaining excess RIN as polarization modulational instability (PMI), and propose a route towards complete elimination of this excess noise. Hence, our work paves the way for a next generation of ultra-low noise frequency combs and ultrashort pulse sources in the 2 µm spectral region that rival or even outperform the excellent noise characteristics of Erbium-fiber technology.
Author Correction: Respective influence of vertical mountain differentiation on debris flow occurrence in the Upper Min River, China
Authors: Ding Mingtao , Huang Tao , Zheng Hao , Yang Guohui
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Effects of fibrillin mutations on the behavior of heart muscle cells in Marfan syndrome
Authors: Aalders Jeffrey , Léger Laurens , Van der Meeren Louis , Van den Vreken Natasja , Skirtach Andre G. , Sinha Sanjay , De Backer Julie , van Hengel Jolanda
Published: October 2020

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Myocardial dysfunction has been demonstrated in MFS patients and mouse models, but little is known about the intrinsic effect on the cardiomyocytes (CMs). In this study, both induced pluripotent stem cells derived from a MFS-patient and the line with the corrected FBN1 mutation were differentiated to CMs. Several functional analyses are performed on this model to study MFS related cardiomyopathy. Atomic force microscopy revealed that MFS CMs are stiffer compared to corrected CMs. The contraction amplitude of MFS CMs is decreased compared to corrected CMs. Under normal culture conditions, MFS CMs show a lower beat-to-beat variability compared to corrected CMs using multi electrode array. Isoproterenol-induced stress or cyclic strain demonstrates lack of support from the matrix in MFS CMs. This study reports the first cardiac cell culture model for MFS, revealing abnormalities in the behavior of MFS CMs that are related to matrix defects. Based on these results, we postulate that impaired support from the extracellular environment plays a key role in the improper functioning of CMs in MFS.
Dietary inflammatory index and metabolic syndrome in Iranian population (Fasa Persian Cohort Study)
Authors: Ariya Mohammad , Shahraki Hadi Raeisi , Farjam Mojtaba , Ehrampoush Elham , Bahramali Ehsan , Homayounfar Reza , Shivappa Nitin , Hebert James R.
Published: October 2020

Metabolic syndrome (MetS) is one of the risk factors for all causes of mortality. Inflammation is an important risk factor for MetS. The present cross-sectional study aimed to investigate the relationship between MetS and pro-inflammatory diet by using the food inflammation index (DII). This study consists of 10,017 participants with an age range of 35 to 70 years. The Fasa Cohort Study (FACS) population (Fars Province, Iran) was used to collect data. The DII was estimated according to Shivappa et al. method using a validated 125-item FFQ. To determine the association between MetS components and DII Logistic regression was used (P > 0.05). The overall mean of DII was − 0.89 ± 1.74. However, adjusted multinomial logistic regression indicates each unit increase in waist circumference (WC) (OR 0.98, 95% CI 0.96–0.99) and HDL-C (OR 0.99, 95% CI 0.98–0.99) was associated with significantly decreased odds of being in the 4th DII quartile in men and all participations respectively, there is no statistically significant relationship between MetS and DII. Overall, although people in the highest quartile of inflammatory food consumption had more likely to develop MetS, this relationship was not statistically significant among males and females.
Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
Authors: Kwan Thaddaeus , Kazamel Mohamed , Thoenes Kristina , Si Ying , Jiang Nan , King Peter H.
Published: October 2020

Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signature represents an intersection of signaling pathways including Smads, TGF-β, and vitamin D. Here, we show that the Wnt antagonist, Frizzled Related Protein (FRZB), was increased in ALS muscle samples and to a variable extent other denervating disease but only minimally in acquired myopathies. In the SOD1G93A mouse, FRZB was upregulated in the early stages of disease (between 40 and 60 days) until end-stage. By immunohistochemistry, FRZB was predominantly localized to endomysial connective tissue and to a lesser extent muscle membrane. There was a significant increase in immunoreactivity surrounding atrophied myofibers. Because FRZB is a Wnt antagonist, we assessed β-catenin, the canonical transducer of Wnt signaling, and found increased levels mainly at the muscle membrane. In summary, we show that FRZB is part of a molecular signature of muscle denervation that may reflect disease progression in ALS. Our findings open up avenues for future investigation as to what roles FRZB and Wnt signaling might be playing in muscle denervation/reinnervation.
Vascular density with optical coherence tomography angiography and systemic biomarkers in low and high cardiovascular risk patients
Authors: Hannappe Marc-Antoine , Arnould Louis , Méloux Alexandre , Mouhat Basile , Bichat Florence , Zeller Marianne , Cottin Yves , Binquet Christine , Vergely Catherine , Creuzot-Garcher Catherine , Guenancia Charles
Published: October 2020

We aimed to compare retinal vascular density in Optical Coherence Tomography Angiography (OCT-A) between patients hospitalized for acute coronary syndrome (ACS) and control patients and to investigate correlation with angiogenesis biomarkers. Patients hospitalized for an acute coronary syndrome (ACS) in the Intensive Care Unit were included in the “high cardiovascular risk” group while patients without cardiovascular risk presenting in the Ophthalmology department were included as “control”. Both groups had blood sampling and OCT-A imaging. Retina microvascularization density in the superficial capillary plexus was measured on 3 × 3 mm angiograms centered on the macula. Angiopoietin-2, TGF-β1, osteoprotegerin, GDF-15 and ST-2 were explored with ELISA or multiplex method. Overall, 62 eyes of ACS patients and 42 eyes of controls were included. ACS patients had significantly lower inner vessel length density than control patients (p = 0.004). A ROC curve found that an inner vessel length density threshold below 20.05 mm−1 was moderately associated with ACS. Significant correlation was found between serum levels of angiopoietin-2 and osteoprotegerin, and retinal microvascularization in OCT-A (R = − 0.293, p = 0.003; R = − 0.310, p = 0.001). Lower inner vessel length density measured with OCT-A was associated with ACS event and was also correlated with higher concentrations of angiopoietin-2 and osteoprotegerin.
Deep neural networks detect suicide risk from textual facebook posts
Authors: Ophir Yaakov , Tikochinski Refael , Asterhan Christa S. C. , Sisso Itay , Reichart Roi
Published: October 2020

Detection of suicide risk is a highly prioritized, yet complicated task. Five decades of research have produced predictions slightly better than chance (AUCs = 0.56–0.58). In this study, Artificial Neural Network (ANN) models were constructed to predict suicide risk from everyday language of social media users. The dataset included 83,292 postings authored by 1002 authenticated Facebook users, alongside valid psychosocial information about the users. Using Deep Contextualized Word Embeddings for text representation, two models were constructed: A Single Task Model (STM), to predict suicide risk from Facebook postings directly (Facebook texts → suicide) and a Multi-Task Model (MTM), which included hierarchical, multilayered sets of theory-driven risk factors (Facebook texts → personality traits → psychosocial risks → psychiatric disorders → suicide). Compared with the STM predictions (0.621 ≤ AUC ≤ 0.629), the MTM produced significantly improved prediction accuracy (0.697 ≤ AUC ≤ 0.746), with substantially larger effect sizes (0.729 ≤ d ≤ 0.936). Subsequent content analyses suggested that predictions did not rely on explicit suicide-related themes, but on a range of text features. The findings suggest that machine learning based analyses of everyday social media activity can improve suicide risk predictions and contribute to the development of practical detection tools.
Mode hybridization analysis in thin film lithium niobate strip multimode waveguides
Authors: Kaushalram Archana , Hegde Gopalkrishna , Talabattula Srinivas
Published: October 2020

Mode hybridization phenomenon in air-cladded X-cut Y-propagating and Z-propagating thin film lithium niobate strip multimode waveguides is numerically studied and a mathematical relation between structural parameters leading to hybrid modes is formulated. Dependence of hybrid modes on waveguide dimensions, sidewall angles and wavelength is also analyzed. The results obtained are used to design lithium niobate on insulator (LNOI) taper for converting fundamental TM mode to higher order TE mode, and an optimum length for achieving a high conversion efficiency of 99.5% is evaluated. Birefringent Y-propagating LN and isotropic Z-propagating LN tapers are compared in terms of length, figures of merit, and fabrication tolerance. Tapers exhibit a broad bandwidth of 200 nm with an extinction ratio less than − 18 dB. The results of mode hybridization analysis are useful in design optimization of adiabatic tapers, tunable time delays, optical interconnects, mode converters and demultiplexers for mode division multiplexing (MDM) applications.