bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the Effects of Two Mindful Eating Exercises on Chocolate	Consumption
Authors: Mantzios Michael , Skillett Kirby , Egan Helen
Published: March 2020

Abstract. The present study aimed to investigate and compare the impact of the Mindful Construal Diary (MCD) and the Mindful Raisin Exercise on the sensory tasting experience of chocolate and participants’ chocolate consumption. Participants were randomly allocated into three conditions (MCD, mindful raisin exercise, and mindless control), and engaged with either the MCD, the mindful raisin exercise, or, were asked to read a news article, respectively, while they ate a piece of chocolate. They then rated their satisfaction and desire to consume more chocolate on a 10-point Likert scale, and filled in a state mindful eating scale. Afterward, participants were informed that the study had ended and were asked to wait while the experimenter recorded some information, and any extra chocolate consumption during this time was recorded. Participants in both mindfulness conditions consumed significantly less chocolate after the exercise than participants in the control condition. No significant differences were found between the three conditions on ratings of satisfaction and desire to consume more chocolate. Both the MCD and the raisin exercise can be used to successfully moderate the intake of calorific foods, while the MCD can be utilized as an alternative practice to the typical meditation-based interventions.
Evolution of Elastic and Mechanical Properties During Fault Shear: The Roles of Clay Content, Fabric Development, and Porosity
Authors: Kenigsberg Abby R. , Rivière Jacques , Marone Chris , Saffer Demian M.
Published: March 2020

Phyllosilicates weaken faults due to the formation of shear fabrics. Although the impacts of clay abundance and fabric on frictional strength, sliding stability, and porosity of faults are well studied, their influence on elastic properties is less known, though they are key factors for fault stiffness. We document the role that fabric and consolidation play in elastic properties and show that smectite content is the most important factor determining whether fabric or porosity controls the elastic response of faults. We conducted a suite of shear experiments on synthetic smectite‐quartz fault gouges (10–100 wt% smectite) and sediment incoming to the Sumatra subduction zone. We monitored Vp, Vs, friction, porosity, shear and bulk moduli. We find that mechanical and elastic properties for gouges with abundant smectite are almost entirely controlled by fabric formation (decreasing mechanical and elastic properties with shear). Though fabrics control the elastic response of smectite‐poor gouges over intermediate shear strains, porosity is the primary control throughout the majority of shearing. Elastic properties vary systematically with smectite content: High smectite gouges have values of Vp ~ 1,300–1,800 m/s, Vs ~ 900–1,100 m/s, K ~ 1–4 GPa, and G ~ 1–2 GPa, and low smectite gouges have values of Vp ~ 2,300–2,500 m/s, Vs ~ 1,200–1,300 m/s, K ~ 5–8 GPa, and G ~ 2.5–3 GPa. We find that, even in smectite‐poor gouges, shear fabric also affects stiffness and elastic moduli, implying that while smectite abundance plays a clear role in controlling gouge properties, other fine‐grained and platy clay minerals may produce similar behavior through their control on the development of fabrics and thin shear surfaces.
Depth‐Resolved Photochemical Lability of Dissolved Organic Matter in the Western Tropical Pacific Ocean
Authors: Yang Fangming , Song Guisheng , Massicotte Philippe , Wei Hao , Xie Huixiang
Published: March 2020

Water samples collected from various depths of the offshore South China and Philippine Seas were exposed to solar‐simulated radiation. Photomineralization of dissolved organic carbon (DOC) and photobleaching of chromophoric dissolved organic matter (CDOM) and its humic‐like fluorescent constituent (FDOM) were observed in all samples. Protein‐like FDOM was, however, either photo‐decomposed or photo‐produced, depending on the sample's depth. The photobleaching of CDOM and humic‐like FDOM was much faster in deep than in shallow water samples while photomineralization displayed a weaker vertical zonation. Prior‐irradiated deep water inoculated with surface‐water bacteria showed enhanced microbial DOC removal but CDOM production. Results from this study suggest that deep‐ocean CDOM and FDOM can barely survive photobleaching during one ocean mixing cycle, but photochemical turnover of the bio‐refractory deep DOC is considerably longer than its average radiocarbon age. Coupled photochemical‐microbial processes can not only remove part of the bio‐refractory deep DOM but also regenerate part of it during ocean overturning circulation.
An epidermal sEMG tattoo-like patch as a new human–machine interface for patients with loss of voice
Authors: Liu Huicong , Dong Wei , Li Yunfei , Li Fanqi , Geng Jiangjun , Zhu Minglu , Chen Tao , Zhang Hongmiao , Sun Lining , Lee Chengkuo
Published: March 2020

Throat cancer treatment involves surgical removal of the tumor, leaving patients with facial disfigurement as well as temporary or permanent loss of voice. Surface electromyography (sEMG) generated from the jaw contains lots of voice information. However, it is difficult to record because of not only the weakness of the signals but also the steep skin curvature. This paper demonstrates the design of an imperceptible, flexible epidermal sEMG tattoo-like patch with the thickness of less than 10 μm and peeling strength of larger than 1 N cm−1 that exhibits large adhesiveness to complex biological surfaces and is thus capable of sEMG recording for silent speech recognition. When a tester speaks silently, the patch shows excellent performance in recording the sEMG signals from three muscle channels and recognizing those frequently used instructions with high accuracy by using the wavelet decomposition and pattern recognization. The average accuracy of action instructions can reach up to 89.04%, and the average accuracy of emotion instructions is as high as 92.33%. To demonstrate the functionality of tattoo-like patches as a new human–machine interface (HMI) for patients with loss of voice, the intelligent silent speech recognition, voice synthesis, and virtual interaction have been implemented, which are of great importance in helping these patients communicate with people and make life more enjoyable.
Transcription co-activator P300 activates Elk1-aPKC-ι signaling mediated epithelial-to-mesenchymal transition and malignancy in hepatocellular carcinoma
Authors: Ma Chaoqun , Huang Shuhong , Xu Lei , Tian Li , Yang Yan , Wang Jianming
Published: March 2020

Epithelial-to-mesenchymal transition (EMT) plays an important role in invasion and metastasis of hepatocellular carcinoma (HCC). Our previous study found that atypical protein kinase C-ι (aPKC-ι) promoted the EMT process in HCC. However, how the aPKC-ι signaling pathway is regulated in HCC has not been elucidated. In this study, vector transfection was utilized to study the invasion of HCC cells, and the mechanism between P300 and aPKC-ι signaling pathways in regulating the EMT process of HCC was further elucidated in vitro and in vivo. We found both P300 and aPKC-ι were highly expressed in HCC and they were correlated with tumor progression and poor survival in HCC patients. P300 knockdown inhibited EMT, invasion and other malignant events of HCC cells but promoted cell apoptosis and cycle arrest. However, the effects mediated by P300 knockdown were abolished by aPKC-ι overexpression. Further studies showed that P300 upregulates aPKC-ι expression through increasing the transcription of Elk1, a transcriptional activator of aPKC-ι, and stabilizing Elk1 protein and its phosphorylation. In conclusion, our work uncovered the molecular mechanism by which oncogenic aPKC-ι is upregulated in HCC and suggests that P300, like aPKC-ι, may be used as a prognostic biomarker and therapeutic target in patients with HCC.
Intrinsic origin of interfacial second-order magnetic anisotropy in ferromagnet/normal metal heterostructures
Authors: Gweon Hyung Keun , Park Hyeon-Jong , Kim Kyoung-Whan , Lee Kyung-Jin , Lim Sang Ho
Published: March 2020

Interfacial perpendicular magnetic anisotropy, which is characterized by first-order (K1) and second-order (K2) anisotropy, is the core phenomenon for nonvolatile magnetic devices. A sizable K2 satisfying a specific condition stabilizes the easy-cone state, where equilibrium magnetization forms at an angle from the film normal. The easy-cone state offers intriguing possibilities for advanced spintronic devices and unique spin textures, such as spin superfluids and easy-cone domain walls. Experimental realization of the easy-cone state requires understanding the origin of K2, thereby enhancing K2. However, the previously proposed origins of K2 cannot fully account for the experimental results. Here, we experimentally show that K2 scales almost linearly with the work function difference between the Co and X layers in Pt/Co/X heterostructures (X = Pd, Cu, Pt, Mo, Ru, W, and Ta), suggesting the central role of the inversion asymmetry in K2. Our result provides a guideline for enhancing K2 and realizing magnetic applications based on the easy-cone state.
An analytical theory of balanced cellular growth
Authors: Dourado Hugo , Lercher Martin J.
Published: March 2020

The biological fitness of microbes is largely determined by the rate with which they replicate their biomass composition. Mathematical models that maximize this balanced growth rate while accounting for mass conservation, reaction kinetics, and limits on dry mass per volume are inevitably non-linear. Here, we develop a general theory for such models, termed Growth Balance Analysis (GBA), which provides explicit expressions for protein concentrations, fluxes, and growth rates. These variables are functions of the concentrations of cellular components, for which we calculate marginal fitness costs and benefits that are related to metabolic control coefficients. At maximal growth rate, the net benefits of all concentrations are equal. Based solely on physicochemical constraints, GBA unveils fundamental quantitative principles of cellular resource allocation and growth; it accurately predicts the relationship between growth rates and ribosome concentrations inE. coliand yeast and between growth rate and dry mass density inE. coli.
Internal control beliefs shape positive affect and associated neural dynamics during outcome valuation
Authors: Stolz David S. , Müller-Pinzler Laura , Krach Sören , Paulus Frieder M.
Published: March 2020

Experiencing events as controllable is essential for human well-being. Based on classic psychological theory, we test how internal control beliefs impact the affective valuation of task outcomes, neural dynamics and ensuing behavioral preferences. In three consecutive studies we show that dynamics in positive affect increase, with a qualitative shift towards self-evaluative pride, when agents believe they caused a given outcome. We demonstrate that these outcomes engage brain networks processing self-referential information in the cortical midline. Here, activity in the ventromedial prefrontal cortex tracks outcome valence regarding both success as well as internal control, and covaries with positive affect in response to outcomes. These affective dynamics also relate to increased functional coupling between the ventral striatum and cortical midline structures. Finally, we show that pride predicts preferences for control, even at monetary costs. Our investigations extend recent models of positive affect and well-being, and emphasize that control beliefs drive intrinsic motivation.
Virtual-freezing fluorescence imaging flow cytometry
Authors: Mikami Hideharu , Kawaguchi Makoto , Huang Chun-Jung , Matsumura Hiroki , Sugimura Takeaki , Huang Kangrui , Lei Cheng , Ueno Shunnosuke , Miura Taichi , Ito Takuro , Nagasawa Kazumichi , Maeno Takanori , Watarai Hiroshi , Yamagishi Mai , Uemura Sotaro , Ohnuki Shinsuke , Ohya Yoshikazu , Kurokawa Hiromi , Matsusaka Satoshi , Sun Chia-Wei , Ozeki Yasuyuki , Goda Keisuke
Published: March 2020

By virtue of the combined merits of flow cytometry and fluorescence microscopy, imaging flow cytometry (IFC) has become an established tool for cell analysis in diverse biomedical fields such as cancer biology, microbiology, immunology, hematology, and stem cell biology. However, the performance and utility of IFC are severely limited by the fundamental trade-off between throughput, sensitivity, and spatial resolution. Here we present an optomechanical imaging method that overcomes the trade-off by virtually freezing the motion of flowing cells on the image sensor to effectively achieve 1000 times longer exposure time for microscopy-grade fluorescence image acquisition. Consequently, it enables high-throughput IFC of single cells at >10,000 cells s−1 without sacrificing sensitivity and spatial resolution. The availability of numerous information-rich fluorescence cell images allows high-dimensional statistical analysis and accurate classification with deep learning, as evidenced by our demonstration of unique applications in hematology and microbiology.
Maltotriose-based probes for fluorescence and photoacoustic imaging of bacterial infections
Authors: Zlitni Aimen , Gowrishankar Gayatri , Steinberg Idan , Haywood Tom , Sam Gambhir Sanjiv
Published: March 2020

Currently, there are no non-invasive tools to accurately diagnose wound and surgical site infections before they become systemic or cause significant anatomical damage. Fluorescence and photoacoustic imaging are cost-effective imaging modalities that can be used to noninvasively diagnose bacterial infections when paired with a molecularly targeted infection imaging agent. Here, we develop a fluorescent derivative of maltotriose (Cy7-1-maltotriose), which is shown to be taken up in a variety of gram-positive and gram-negative bacterial strains in vitro. In vivo fluorescence and photoacoustic imaging studies highlight the ability of this probe to detect infection, assess infection burden, and visualize the effectiveness of antibiotic treatment in E. coli-induced myositis and a clinically relevant S. aureus wound infection murine model. In addition, we show that maltotriose is an ideal scaffold for infection imaging agents encompassing better pharmacokinetic properties and in vivo stability than other maltodextrins (e.g. maltohexose).
Olfactory memory representations are stored in the anterior olfactory nucleus
Authors: Aqrabawi Afif J. , Kim Jun Chul
Published: March 2020

The anterior olfactory nucleus (AON) is the initial recipient of odour information from the olfactory bulb, and the target of dense innervation conveying spatiotemporal cues from the hippocampus. We hypothesized that the AON detects the coincidence of these inputs, generating patterns of activity reflective of episodic odour engrams. Using activity-dependent tagging combined with neural manipulation techniques, we reveal that contextually-relevant odour engrams are stored within the AON and that their activity is necessary and sufficient for the behavioural expression of odour memory. Our findings offer a new model for studying the mechanisms underlying memory representations.
Intensive care for human hearts in pluripotent stem cell models
Authors: Golforoush Pelin , Schneider Michael D.
Published: March 2020

Successful drug discovery is ultimately contingent on the availability of workable, relevant, predictive model systems. Conversely, for cardiac muscle, the lack of human preclinical models to inform target validation and compound development has likely contributed to the perennial problem of clinical trial failures, despite encouraging non-human results. By contrast, human cardiomyocytes produced from pluripotent stem cell models have recently been applied to safety pharmacology, phenotypic screening, target validation and high-throughput assays, facilitating cardiac drug discovery. Here, we review the impact of human pluripotent stem cell models in cardiac drug discovery, discussing the range of applications, readouts, and disease models employed, along with the challenges and prospects to advance this fruitful mode of research further.
Replacing fishmeal with plant protein in Atlantic salmon (Salmo salar) diets by supplementation with fish protein hydrolysate
Authors: Egerton S. , Wan A. , Murphy K. , Collins F. , Ahern G. , Sugrue I. , Busca K. , Egan F. , Muller N. , Whooley J. , McGinnity P. , Culloty S. , Ross R. P. , Stanton C.
Published: March 2020

The effects of feeding an 80% plant protein diet, with and without fish protein hydrolysate (FPH) supplementation, on the growth and gut health of Atlantic salmon were investigated. Fish were fed either (A) a control diet containing 35% fishmeal, (B) an 80% plant protein diet with 15% fishmeal, (C) an 80% plant protein diet with 5% fishmeal and 10% partly hydrolysed protein, or (D) an 80% plant protein diet with 5% fishmeal and 10% soluble protein hydrolysate. Fish on the 80% plant- 15% fishmeal diet were significantly smaller than fish in the other dietary groups. However, partly-hydrolysed protein supplementation allowed fish to grow as well as fish fed the control 35% fishmeal diet. Fish fed the FPH diets (diets C and D) had significantly higher levels of amino acids in their blood, including 48% and 27% more branched chain amino acids compared to fish on the 35% fishmeal diet, respectively. Plant protein significantly altered gut microbial composition, significantly decreasing α-diversity. Spirochaetes and the familiesMoritellaceae, Psychromonadaceae, HelicobacteraceaeandBacteroidaceaewere all found at significantly lower abundances in the groups fed 80% plant protein diets compared to the control fishmeal diet.
Suppression of antibiotic resistance evolution by single-gene deletion
Authors: Horinouchi Takaaki , Maeda Tomoya , Kotani Hazuki , Furusawa Chikara
Published: March 2020

Antibiotic treatment generally results in the selection of resistant bacterial strains, and the dynamics of resistance evolution is dependent on complex interactions between cellular components. To better characterize the mechanisms of antibiotic resistance and evaluate its dependence on gene regulatory networks, we performed systematic laboratory evolution of Escherichia coli strains with single-gene deletions of 173 transcription factors under three different antibiotics. This resulted in the identification of several genes whose deletion significantly suppressed resistance evolution, including arcA and gutM. Analysis of double-gene deletion strains suggested that the suppression of resistance evolution caused by arcA and gutM deletion was not caused by epistatic interactions with mutations known to confer drug resistance. These results provide a methodological basis for combinatorial drug treatments that may help to suppress the emergence of resistant pathogens by inhibiting resistance evolution.
The Role of Transthyretin in Oligodendrocyte Development
Authors: Alshehri Bandar , Pagnin Maurice , Lee Jae Young , Petratos Steven , Richardson Samantha J.
Published: March 2020

Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs) in blood and cerebrospinal fluid. Previously, two reports identified TTR null mice as hypothyroid in the central nervous system (CNS). This prompted our investigations into developmentally regulated TH-dependent processes in brains of wildtype and TTR null mice. Despite logical expectations of a hypomyelinating phenotype in the CNS of TTR null mice, we observed a hypermyelination phenotype, synchronous with an increase in the density of oligodendrocytes in the corpus callosum and anterior commissure of TTR null mice during postnatal development. Furthermore, absence of TTR enhanced proliferation and migration of OPCs with decreased apoptosis. Neural stem cells (NSCs) isolated from the subventricular zone of TTR null mice at P21 revealed that the absence of TTR promoted NSC differentiation toward a glial lineage. Importantly, we identified TTR synthesis in OPCs, suggestive of an alternate biological function in these cells that may extend beyond an extracellular TH-distributor protein. The hypermyelination mechanism may involve increased pAKT (involved in oligodendrocyte maturation) in TTR null mice. Elucidating the regulatory role of TTR in NSC and OPC biology could lead to potential therapeutic strategies for the treatment of acquired demyelinating diseases.
The interplay between bone healing and remodeling around dental implants
Authors: Irandoust Soroush , Müftü Sinan
Published: March 2020

Long-term bone healing/adaptation after a dental implant treatment starts with diffusion of mesenchymal stem cells to the wounded region and their subsequent differentiation. The healing phase is followed by the bone-remodeling phase. In this work, a mechano-regulatory cellular differentiation model was used to simulate tissue healing around an immediately loaded dental implant. All tissue types were modeled as poroelastic in the healing phase. Material properties of the healing region were updated after each loading cycle for 30 cycles (days). The tissue distribution in the healed state was then used as the initial condition for the remodeling phase during which regions healed into bone adapt their apparent density with respect to a homeostatic remodeling stimulus. The short- (bone healing) and long-term (bone remodeling) effects of initial implant micromotion during the healing phase were studied. Development of soft tissue was observed both in the coronal region due to high fluid velocity, and on the vertical sides of the healing-gap due to high shear stress. In cases with small implant micromotion, tissue between the implant threads differentiated into bone during the healing phase but resorbed during remodeling. In cases with large implant micromotion, higher percentage of the healing region differentiated into soft tissue resulting in smaller volume of bone tissue available for remodeling. However, the remaining bone region developed higher density bone tissue. It was concluded that an optimal range of initial implant micromotion could be designed for a specific patient in order to achieve the desired long-term functional properties.
Modulation of oculomotor control during reading of mirrored and inverted texts
Authors: Chandra Johan , Krügel André , Engbert Ralf
Published: March 2020

The interplay between cognitive and oculomotor processes during reading can be explored when the spatial layout of text deviates from the typical display. In this study, we investigate various eye-movement measures during reading of text with experimentally manipulated layout (word-wise and letter-wise mirrored-reversed text as well as inverted and scrambled text). While typical findings (e.g., longer mean fixation times, shorter mean saccades lengths) in reading manipulated texts compared to normal texts were reported in earlier work, little is known about changes of oculomotor targeting observed in within-word landing positions under the above text layouts. Here we carry out precise analyses of landing positions and find substantial changes in the so-called launch-site effect in addition to the expected overall slow-down of reading performance. Specifically, during reading of our manipulated text conditions with reversed letter order (against overall reading direction), we find a reduced launch-site effect, while in all other manipulated text conditions, we observe an increased launch-site effect. Our results clearly indicate that the oculomotor system is highly adaptive when confronted with unusual reading conditions.
Evidence of Cosmic Impact at Abu Hureyra, Syria at the Younger Dryas Onset (~12.8 ka): High-temperature melting at >2200 °C
Authors: Moore Andrew M. T. , Kennett James P. , Napier William M. , Bunch Ted E. , Weaver James C. , LeCompte Malcolm , Adedeji A. Victor , Hackley Paul , Kletetschka Gunther , Hermes Robert E. , Wittke James H. , Razink Joshua J. , Gaultois Michael W. , West Allen
Published: March 2020

At Abu Hureyra (AH), Syria, the 12,800-year-old Younger Dryas boundary layer (YDB) contains peak abundances in meltglass, nanodiamonds, microspherules, and charcoal. AH meltglass comprises 1.6 wt.% of bulk sediment, and crossed polarizers indicate that the meltglass is isotropic. High YDB concentrations of iridium, platinum, nickel, and cobalt suggest mixing of melted local sediment with small quantities of meteoritic material. Approximately 40% of AH glass display carbon-infused, siliceous plant imprints that laboratory experiments show formed at a minimum of 1200°–1300 °C; however, reflectance-inferred temperatures for the encapsulated carbon were lower by up to 1000 °C. Alternately, melted grains of quartz, chromferide, and magnetite in AH glass suggest exposure to minimum temperatures of 1720 °C ranging to >2200 °C. This argues against formation of AH meltglass in thatched hut fires at 1100°–1200 °C, and low values of remanent magnetism indicate the meltglass was not created by lightning. Low meltglass water content (0.02–0.05% H2O) is consistent with a formation process similar to that of tektites and inconsistent with volcanism and anthropogenesis. The wide range of evidence supports the hypothesis that a cosmic event occurred at Abu Hureyra ~12,800 years ago, coeval with impacts that deposited high-temperature meltglass, melted microspherules, and/or platinum at other YDB sites on four continents.
Comparative analysis of HER2 copy number between plasma and tissue samples in gastric cancer using droplet digital PCR
Authors: Kim Boram , Nam Soo Kyung , Seo Soo Hyun , Park Kyoung Un , Ahn Sang-Hoon , Park Do Joong , Kim Hyung-Ho , Kim Woo Ho , Lee Hye Seung
Published: March 2020

In this study, we measured the human epidermal growth factor receptor 2 (HER2) copy number in both tissue and plasma samples of gastric cancer patients by using droplet digital polymerase chain reaction (ddPCR) method. Eighty gastric cancer patients were enrolled and both formalin-fixed and paraffin-embedded tissue and preoperative plasma samples were collected. HER2 status was determined by HER2 immunohistochemistry (IHC)/silver in situ hybridization (SISH) in tissue samples and ddPCR of the target gene HER2 and the reference gene eukaryotic translation initiation factor 2C, 1 in both tissue and plasma. The concordance rate of tissue HER2 status determined by IHC/SISH and HER2 ddPCR was 90.0% (72/80), and the sensitivity and specificity of tissue ddPCR were 85.0% and 95.0%, respectively. The concordance rate of plasma ddPCR and IHC/SISH was 63.8% (51/80). The sensitivity, specificity, positive predictive value, and negative predictive value of plasma HER2 ddPCR were 37.5%, 90.0%, 79.0%, and 59.0%, respectively. As HER2 measurement by tissue ddPCR showed a high concordance rate with HER2 status by IHC/SISH, it could replace tissue IHC/SISH testing in gastric cancer. These findings may contribute to the development of tissue and plasma HER2 testing that would be useful in daily practice.
Author Correction: Characterization of metal binding of bifunctional kinase/phosphatase AceK and implication in activity modulation
Authors: Zhang Xiaoying , Shen Qingya , Lei Zhen , Wang Qianyi , Zheng Jimin , Jia Zongchao
Published: March 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Pancreatic islets seeded in a novel bioscaffold forms an organoid to rescue insulin production and reverse hyperglycemia in models of type 1 diabetes
Authors: Elizondo Diana M. , Brandy Nailah Z. D. , da Silva Ricardo L. L. , de Moura Tatiana R. , Ali Jamel , Yang Dazhi , Lipscomb Michael W.
Published: March 2020

Therapeutic approaches to combat type 1 diabetes (T1D) include donor pancreas transplantation, exogenous insulin administration and immunosuppressive therapies. However, these clinical applications are limited due to insufficient tissue compatible donors, side effects of exogenous insulin administration and/or increased onset of opportunistic infections attributable to induced global immunosuppression. An alternative approach to alleviate disease states is to utilize insulin-producing pancreatic islets seeded in a bioscaffold for implantation into diabetic recipients. The present studies now report that a newly developed cationic polymer biomaterial serves as an efficient bioscaffold for delivery of donor syngeneic pancreatic islet cells to reverse hyperglycemia in murine streptozotocin induced- or non-obese diabetic mouse models of T1D. Intraperitoneal implantation of pancreatic islets seeded within the copolymer bioscaffold supports long-term cell viability, response to extracellular signaling cues and ability to produce soluble factors into the microenvironment. Elevated insulin levels were measured in recipient diabetic mice upon implantation of the islet-seeded biomaterial coupled with reduced blood glucose levels, collectively resulting in increased survival and stabilization of metabolic indices. Importantly, the implanted islet-seeded biomaterial assembled into a solid organoid substructure that reorganized the extracellular matrix compartment and recruited endothelial progenitors for neovascularization. This allowed survival of the graft long-termin vivoand access to the blood for monitoring glucose levels. These results highlight the novelty, simplicity and effectiveness of this biomaterial for tissue regeneration andin vivorestoration of organ functions.
Transcriptomic and computational analysis identified LPA metabolism, KLHL14 and KCNE3 as novel regulators of Epithelial-Mesenchymal Transition
Authors: Di Lollo V. , Canciello A. , Orsini M. , Bernabò N. , Ancora M. , Di Federico M. , Curini V. , Mattioli M. , Russo V. , Mauro A. , Cammà C. , Barboni B.
Published: March 2020

Epithelial-mesenchymal transition (EMT) is a complex biological program between physiology and pathology. Here, amniotic epithelial cells (AEC) were used as in vitro model of transiently inducible EMT in order to evaluate the transcriptional insights underlying this process. Therefore, RNA-seq was used to identify the differentially expressed genes and enrichment analyses were carried out to assess the intracellular pathways involved. As a result, molecules exclusively expressed in AEC that experienced EMT (GSTA1-1 and GSTM3) or when this process is inhibited (KLHL14 and KCNE3) were identified. Lastly, the network theory was used to obtain a computational model able to recognize putative controller genes involved in the induction and in the prevention of EMT. The results suggested an opposite role of lysophosphatidic acid (LPA) synthesis and degradation enzymes in the regulation of EMT process. In conclusion, these molecules may represent novel EMT regulators and also targets for developing new therapeutic strategies.
Transcriptomic and metabolomic analyses of Lycium ruthenicum and Lycium barbarum fruits during ripening
Authors: Zhao Jianhua , Li Haoxia , Yin Yue , An Wei , Qin Xiaoya , Wang Yajun , Li Yanlong , Fan Yunfang , Cao Youlong
Published: March 2020

Red wolfberry (or goji berry,Lycium barbarum; LB) is an important agricultural product with a high content of pharmacologically important secondary metabolites such as phenylpropanoids. A close relative, black wolfberry (L. ruthenicum; LR), endemic to the salinized deserts of northwestern China, is used only locally. The two fruits exhibit many morphological and phytochemical differences, but genetic mechanisms underlying them remain poorly explored. In order to identify the genes of interest for further studies, we studied transcriptomic (Illumina HiSeq) and metabolomic (LC-MS) profiles of the two fruits during five developmental stages (young to ripe). As expected, we identified much higher numbers of significantly differentially regulated genes (DEGs) than metabolites. The highest numbers were identified in pairwise comparisons including the first stage for both species, but total numbers were consistently somewhat lower for the LR. The number of differentially regulated metabolites in pairwise comparisons of developmental stages varied from 66 (stages 3 vs 4) to 133 (stages 2 vs 5) in both species. We identified a number of genes (e.g.AAT1,metE,pip) and metabolites (e.g. rutin, raffinose, galactinol, trehalose, citrulline and DL-arginine) that may be of interest to future functional studies of stress adaptation in plants. As LB is also highly suitable for combating soil desertification and alleviating soil salinity/alkalinity/pollution, its potential for human use may be much wider than its current, highly localized, relevance.
Selective Binding of HSC70 and its Co-Chaperones to Structural Hotspots on CFTR
Authors: Baaklini Imad , Gonçalves Conrado de Campos , Lukacs Gergely L. , Young Jason C.
Published: March 2020

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel cause cystic fibrosis. Chaperones, including HSC70, DNAJA1 and DNAJA2, play key roles in both the folding and degradation of wild-type and mutant CFTR at multiple cellular locations. DNAJA1 and HSC70 promote the folding of newly synthesized CFTR at the endoplasmic reticulum (ER), but are required for the rapid turnover of misfolded channel at the plasma membrane (PM). DNAJA2 and HSC70 are also involved in the ER-associated degradation (ERAD) of misfolded CFTR, while they assist the refolding of destabilized channel at the PM. These outcomes may depend on the binding of chaperones to specific sites within CFTR, which would be exposed in non-native states. A CFTR peptide library was used to identify binding sites for HSC70, DNAJA1 and DNAJA2, validated by competition and functional assays. Each chaperone had a distinct binding pattern, and sites were distributed between the surfaces of the CFTR cytosolic domains, and domain interfaces known to be important for channel assembly. The accessibility of sites to chaperones will depend on the degree of CFTR folding or unfolding. Different folded states may be recognized by unique combinations of HSC70, DNAJA1 and DNAJA2, leading to divergent biological effects.
A Novel System for Functional Determination of Variants of Uncertain Significance using Deep Convolutional Neural Networks
Authors: Zimmerman Lior , Zelichov Ori , Aizenmann Arie , Barbash Zohar , Vidne Michael , Tarcic Gabi
Published: March 2020

Many drugs are developed for commonly occurring, well studied cancer drivers such as vemurafenib for BRAF V600E and erlotinib for EGFR exon 19 mutations. However, most tumors also harbor mutations which have an uncertain role in disease formation, commonly called Variants of Uncertain Significance (VUS), which are not studied or characterized and could play a significant role in drug resistance and relapse. Therefore, the determination of the functional significance of VUS and their response to Molecularly Targeted Agents (MTA) is essential for developing new drugs and predicting response of patients. Here we present a multi-scale deep convolutional neural network (DCNN) architecture combined with an in-vitro functional assay to investigate the functional role of VUS and their response to MTA’s. Our method achieved high accuracy and precision on a hold-out set of examples (0.98 mean AUC for all tested genes) and was used to predict the oncogenicity of 195 VUS in 6 genes. 63 (32%) of the assayed VUS’s were classified as pathway activating, many of them to a similar extent as known driver mutations. Finally, we show that responses of various mutations to FDA approved MTAs are accurately predicted by our platform in a dose dependent manner. Taken together this novel system can uncover the treatable mutational landscape of a drug and be a useful tool in drug development.
Gene-flow from steppe individuals into Cucuteni-Trypillia associated populations indicates long-standing contacts and gradual admixture
Authors: Immel Alexander , Țerna Stanislav , Simalcsik Angela , Susat Julian , Šarov Oleg , Sîrbu Ghenadie , Hofmann Robert , Müller Johannes , Nebel Almut , Krause-Kyora Ben
Published: March 2020

The Cucuteni-Trypillia complex (CTC) flourished in eastern Europe for over two millennia (5100–2800 BCE) from the end of the Neolithic to the Early Bronze Age. Its vast distribution area encompassed modern-day eastern Romania, Moldova and western/central Ukraine. Due to a lack of existing burials throughout most of this time, only little is known about the people associated with this complex and their genetic composition. Here, we present genome-wide data generated from the skeletal remains of four females that were excavated from two Late CTC sites in Moldova (3500–3100 BCE). All individuals carried a large Neolithic-derived ancestry component and were genetically more closely related to Linear Pottery than to Anatolian farmers. Three of the specimens also showed considerable amounts of steppe-related ancestry, suggesting influx into the CTC gene-pool from people affiliated with, for instance, the Ukraine Mesolithic. The latter scenario is supported by archaeological evidence. Taken together, our results confirm that the steppe component arrived in eastern Europe farming communities maybe as early as 3500 BCE. In addition, they are in agreement with the hypothesis of ongoing contacts and gradual admixture between incoming steppe and local western populations.
Diet influences the functions of the human intestinal microbiome
Authors: De Angelis Maria , Ferrocino Ilario , Calabrese Francesco Maria , De Filippis Francesca , Cavallo Noemi , Siragusa Sonya , Rampelli Simone , Di Cagno Raffaella , Rantsiou Kalliopi , Vannini Lucia , Pellegrini Nicoletta , Lazzi Camilla , Turroni Silvia , Lorusso Nicola , Ventura Mario , Chieppa Marcello , Neviani Erasmo , Brigidi Patrizia , O’Toole Paul W. , Ercolini Danilo , Gobbetti Marco , Cocolin Luca
Published: March 2020

Gut microbes programme their metabolism to suit intestinal conditions and convert dietary components into a panel of small molecules that ultimately affect host physiology. To unveil what is behind the effects of key dietary components on microbial functions and the way they modulate host–microbe interaction, we used for the first time a multi-omic approach that goes behind the mere gut phylogenetic composition and provides an overall picture of the functional repertoire in 27 fecal samples from omnivorous, vegan and vegetarian volunteers. Based on our data, vegan and vegetarian diets were associated to the highest abundance of microbial genes/proteins responsible for cell motility, carbohydrate- and protein-hydrolyzing enzymes, transport systems and the synthesis of essential amino acids and vitamins. A positive correlation was observed when intake of fiber and the relative fecal abundance of flagellin were compared. Microbial cells and flagellin extracted from fecal samples of 61 healthy donors modulated the viability of the human (HT29) colon carcinoma cells and the host response through the stimulation of the expression of Toll-like receptor 5, lectin RegIIIα and three interleukins (IL-8, IL-22 and IL-23). Our findings concretize a further and relevant milestone on how the diet may prevent/mitigate disease risk.
Socio-ecological connectivity differs in magnitude and direction across urban landscapes
Authors: Egerer Monika , Fouch Nakisha , Anderson Elsa C. , Clarke Mysha
Published: March 2020

Connectivity of social-ecological systems promotes resilience across urban landscapes. Community gardens are social-ecological systems that support food production, social interactions, and biodiversity conservation. We investigate how these hubs of ecosystem services facilitate socio-ecological connectivity and service flows as a network across complex urban landscapes. In three US cities (Baltimore, Chicago, New York City), we use community garden networks as a model system to demonstrate how biophysical and social features of urban landscapes control the pattern and magnitude of ecosystem service flows through these systems. We show that community gardens within a city are connected through biological and social mechanisms, and connectivity levels and spatial arrangement differ across cities. We found that biophysical connectivity was higher than social connectivity in one case study, while they were nearly equal in the other two. This higher social connectivity can be attributed to clustered distributions of gardens within neighborhoods (network modularity), which promotes neighborhood-scale connectivity hotspots, but produces landscape-scale connectivity coldspots. The particular patterns illustrate how urban form and social amenities largely shape ecosystem service flows among garden networks. Such socio-ecological analyses can be applied to enhance and stabilize landscape connectedness to improve life and resilience in cities.
Rapid Pyrazinamide Drug Susceptibility Testing using a Closed-Tube PCR Assay of the Entire pncA gene
Authors: Whitfield Michael G. , Marras Salvatore A. E. , Warren Rob M. , Van Rie Annelies , Rice John , Wangh Lawrence J. , Kreiswirth Barry N.
Published: March 2020

The continued use of pyrazinamide in the treatment of tuberculosis in the absence of a rapid, accurate and standardized pyrazinamide drug susceptibility assays is of great concern. While whole genome sequencing holds promise, it is not yet feasible option in low resource settings as it requires expensive instruments and bioinformatic analysis. We investigated the diagnostic performance of a closed-tube Linear-After-The-Exponential (LATE)-PCR assay for pyrazinamide susceptibility in Mycobacterium tuberculosis. Based on a set of 654 clinical Mycobacterium tuberculosis culture isolates with known mutations throughout the pncA gene as determined by Sanger sequencing, the assay displays excellent sensitivity of 96.9% (95% CI: 95.2–98.6) and specificity of 97.9% (95% CI: 96.1–99.7). In a subset of 384 isolates with phenotypic drug susceptibility testing, we also observed high sensitivity of 98.9% (95% CI: 97.5–100) but lower specificity of 91.8% (95% CI: 87.9–95.8) when compared to phenotypic drug susceptibility testing. We conclude that the LATE PCR assay offers both a rapid and accurate prediction of pyrazinamide susceptibility.
Author Correction: High-throughput format for the phenotyping of fungi on solid substrates
Authors: Cánovas David , Studt Lena , Marcos Ana T. , Strauss Joseph
Published: March 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESTORE: Robust intEnSiTy nORmalization mEthod for multiplexed imaging
Authors: Chang Young Hwan , Chin Koei , Thibault Guillaume , Eng Jennifer , Burlingame Erik , Gray Joe W.
Published: March 2020

Recent advances in multiplexed imaging technologies promise to improve the understanding of the functional states of individual cells and the interactions between the cells in tissues. This often requires compilation of results from multiple samples. However, quantitative integration of information between samples is complicated by variations in staining intensity and background fluorescence that obscure biological variations. Failure to remove these unwanted artifacts will complicate downstream analysis and diminish the value of multiplexed imaging for clinical applications. Here, to compensate for unwanted variations, we automatically identify negative control cells for each marker within the same tissue and use their expression levels to infer background signal level. The intensity profile is normalized by the inferred level of the negative control cells to remove between-sample variation. Using a tissue microarray data and a pair of longitudinal biopsy samples, we demonstrated that the proposed approach can remove unwanted variations effectively and shows robust performance.
Pathway-specific enzymes from bamboo and crop leaves biosynthesize anti-nociceptive C-glycosylated flavones
Authors: Sun Yuwei , Chen Zhuo , Yang Jingya , Mutanda Ishmael , Li Shiyi , Zhang Qian , Zhang Ying , Zhang Yulian , Wang Yong
Published: March 2020

C-glycosylated flavones (CGFs) are promising candidates as anti-nociceptive compounds. The leaves of bamboo and related crops in the grass family are a largely unexploited bioresource with a wide array of CGFs. We report here pathway-specific enzymes includingC-glycosyltransferases (CGTs) and P450 hydroxylases from cereal crops and bamboo species accumulating abundant CGFs. Mining of CGTs and engineering of P450s that decorate the flavonoid skeleton allowed the production of desired CGFs (with yield of 20–40 mg/L) in anEscherichia colicell factory. We further explored the antinociceptive activity of major CGFs in mice models and identified isoorientin as the most potent, with both neuroanalgesic and anti-inflammatory effects superior to clinical drugs such as rotundine and aspirin. Our discovery of the pain-alleviating flavonoids elicited from bamboo and crop leaves establishes this previously underutilized source, and sheds light on the pathway and pharmacological mechanisms of the compounds.
Growth and rapid succession of methanotrophs effectively limit methane release during lake overturn
Authors: Mayr Magdalena J. , Zimmermann Matthias , Dey Jason , Brand Andreas , Wehrli Bernhard , Bürgmann Helmut
Published: March 2020

Lakes and reservoirs contribute substantially to atmospheric concentrations of the potent greenhouse gas methane. Lake sediments produce large amounts of methane, which accumulate in the oxygen-depleted bottom waters of stratified lakes. Climate change and eutrophication may increase the number of lakes with methane storage in the future. Whether stored methane escapes to the atmosphere during annual lake overturn is a matter of controversy and depends critically on the response of the methanotroph assemblage. Here we show, by combining 16S rRNA gene and pmoA mRNA amplicon sequencing, qPCR, CARD-FISH and potential methane-oxidation rate measurements, that the methanotroph assemblage in a mixing lake underwent both a substantial bloom and ecological succession. As a result, methane oxidation kept pace with the methane supplied from methane-rich bottom water and most methane was oxidized. This aspect of freshwater methanotroph ecology represents an effective mechanism limiting methane transfer from lakes to the atmosphere.
Applying deep learning to single-trial EEG data provides evidence for complementary theories on action control
Authors: Vahid Amirali , Mückschel Moritz , Stober Sebastian , Stock Ann-Kathrin , Beste Christian
Published: March 2020

Efficient action control is indispensable for goal-directed behaviour. Different theories have stressed the importance of either attention or response selection sub-processes for action control. Yet, it is unclear to what extent these processes can be identified in the dynamics of neurophysiological (EEG) processes at the single-trial level and be used to predict the presence of conflicts in a given moment. Applying deep learning, which was blind to cognitive theory, on single-trial EEG data allowed to predict the presence of conflict in ~95% of subjects ~33% above chance level. Neurophysiological features related to attentional and motor response selection processes in the occipital cortex and the superior frontal gyrus contributed most to prediction accuracy. Importantly, deep learning was able to identify predictive neurophysiological processes in single-trial neural dynamics. Hence, mathematical (artificial intelligence) approaches may be used to foster the validation and development of links between cognitive theory and neurophysiology of human behavior.
Publisher Correction: Tailoring of an unusual oxidation state in a lanthanum tantalum(IV) oxynitride via precursor microstructure design
Authors: Bubeck Cora , Widenmeyer Marc , Richter Gunther , Coduri Mauro , Goering Eberhard , Yoon Songhak , Weidenkaff Anke
Published: March 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.