bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of biomarkers in adult Fontan patients with decompensated heart failure
Authors: Nguyen Vidang P. , Li Song , Dolgner Stephen J. , Steinberg Zachary L. , Buber Jonathan
Published: June 2020

Background:

The incidence of heart failure is increasing within the Fontan population. The use of serological markers, including B-type natriuretic peptide, has been limited in this patient population.

Methods:

This was a single-centre retrospective study of Fontan patients in acute decompensated heart failure. Fontan patients underwent a 1:2 match with non-Fontan patients for each heart failure hospitalisation for comparative analysis. A univariate logistic regression model was used to assess associations between laboratory and echocardiographic markers and a prolonged length of stay of 7 days or greater.

Results:

B-type natriuretic peptide levels were significantly lower in Fontan patients admitted for heart failure than that in non-Fontan patients [390.9 (±378.7) pg/ml versus 1245.6 (±1160.7) pg/ml, respectively, p < 0.0001] and were higher in Fontan patients with systemic ventricular systolic or diastolic dysfunction than that in Fontan patients with normal systemic ventricular function [833.6 (±1547.2) pg/ml versus 138.6 (±134.0) pg/ml, p = 0.017]. The change from the last known outpatient value was smaller in Fontan patients in comparison with non-Fontan patients [65.7 (±185.7) pg/ml versus 1638.0 (±1444.7) pg/ml, respectively, p < 0.0001]. Low haemoglobin and high blood urea nitrogen levels were associated with a prolonged length of stay.

Conclusion:

B-type natriuretic peptide levels do not accurately reflect decompensated heart failure in Fontan patients when compared to non-Fontan heart failure patients and should, therefore, be used with caution in this patient population.
REJECTED! ANTITRUST ECONOMISTS AS EXPERT WITNESSES IN THE POST-DAUBERTWORLD
Authors: Giocoli Nicola
Published: June 2020

Economists regularly appear as expert witnesses in antitrust litigations. This paper analyzes how their models and methodologies have performed vis-à-vis the standards of relevance and reliability affirmed by the US Supreme Court inDaubertand its progeny. Some explanations for the economists’ troubles when facing aDaubertchallenge in antitrust cases are provided.
Revisiting Modern Moral Philosophy
Authors: Frey Jennifer A.
Published: June 2020

This essay revisits Elizabeth Anscombe's ‘Modern Moral Philosophy' with two goals in mind. The first is to recover and reclaim its radical vision, by setting forth a unified account of its three guiding theses. On the interpretation advanced here, Anscombe's three theses are not independently intelligible; their underlying unity is the perceived necessity of absolute prohibitions for any sound account of practical reason. The second goal is to show that Anscombe allows for a thoroughly unmodern sense of ‘moral' that applies to human actions; the paper concludes with some reasons to think that this unmodern sense of ‘moral' is worthy of further philosophical attention and defense.
Love and Unselfing in Iris Murdoch
Authors: Driver Julia
Published: June 2020

Iris Murdoch believes that unselfing is required for virtue, as it takes us out of our egoistic preoccupations, and connects us to the Good in the world. Love is a form of unselfing, illustrating how close attention to another, and the way they really are, again, takes us out of a narrow focus on the self. Though this view of love runs counter to a view that those in love often overlook flaws in their loved ones, or at least down-play them, I argue that it is compatible with Murdoch's view that love can overlook some flaws, ones that do not speak to the loved one's true self. Unselfing requires that we don't engage in selfish delusion, but a softer view of our loved ones is permitted.
Progress towards eliminating industrially produced trans-fatty acids in the Canadian marketplace, 2013–2017
Authors: Franco-Arellano Beatriz , Arcand JoAnne , Kim Min Ah , Schermel Alyssa , L’Abbé Mary R
Published: June 2020

Objective:

To assess the prevalence of partially hydrogenated oils (PHO), hydrogenated oils (HO) and/or both in Canadian packaged foods in 2013 and 2017 and to determine the mean trans-fatty acid (TFA) content of products declaring such oils.

Design:

Repeated cross-sectional study of the Food Label Information Program.

Setting:

Food labels (n 32 875) were collected from top Canadian grocery retailers in 2013 and 2017. Proportions of products declaring PHO, HO and/or both in the Ingredients List were calculated by year and food category. The percentage contribution of TFA (g) to total fat (g) was calculated and compared against the voluntary TFA limits, defined as <2 % of total fat content for fats and oils, and <5 % for all other foods. Foods exceeding limits were identified. The mean TFA content (in g/serving and per 100 g) was calculated for products with these oils.

Results:

The use of PHO, HO and/or both significantly decreased in Canadian foods from 2013 to 2017 (0·8 to 0·2 %, 5 to 2·4 % and 5·7 to 2·6 %, respectively, for PHO, HO and/or both). The mean TFA content of products containing PHO increased (0·34 to 0·57 g TFA/serving); although it was not statistically significant, it is still concerning that TFA content increased. The TFA content significantly decreased in foods with HO (0·24 to 0·16 g TFA/serving, P < 0·05) during 2013–2017.

Conclusions:

Products with PHO continue to be present in the Canadian marketplace, despite voluntary efforts to eliminate them. Products with HO should also be monitored, as they can also contribute to TFA content in foods.
Association between serum vitamin D and depressive symptoms in apparently healthy male adults undergoing routine health check-ups at a single centre
Authors: Kim Sung Hoon , Lee Hae Jeong , Chae Chang Ho , Park Seung Hyun , Son Jun Seok
Published: June 2020

Objective:

To determine the level of vitamin D and to identify the association between vitamin D and depressive symptoms in apparently healthy Korean male adults.

Design:

A retrospective study design. Among 43 513 participants between 1 March and 30 November 2018, after eliminating participants with a history of depression or vitamin D deficiency, 9058 were included. To determine the level of vitamin D, serum 25-hydroxyvitamin D [25(OH)D] was measured. To assess the level of depression, the Korean version of the Center for Epidemiologic Studies Depression Scale (CES-D) was used.

Setting:

South Korea.

Participants:

Male adults who underwent routine health check-ups.

Results:

The average vitamin D level was 22·31 ± 7·09 ng/ml as 25(OH)D, while the number of subjects in the vitamin D insufficiency group with a finding of <20 ng/ml was 3783 (41·8 %). The mean CES-D score in all subjects was 8·31 ± 5·97 points, and the proportion of the depressive symptoms group with a score of ≥16 was 8·71 %. The OR of patients in the depressive symptoms group also being in the insufficiency group was found to be 1·49 (95 % CI 1·12, 2·00).

Conclusions:

A total of 41·8 % of apparently healthy male adults had vitamin D levels <20 ng/ml. We identified an association between vitamin D insufficiency and depressive symptoms in apparently healthy Korean male adults.
A compact flexible textile artificial magnetic conductor-based wearable monopole antenna for low specific absorption rate wrist applications
Authors: El Atrash Mohamed , Abdalla Mahmoud A. , Elhennawy Hadia M.
Published: June 2020

A compact monopole antenna backed with a 1 × 2 textile-based artificial magnetic conductor (AMC) array is proposed. Textile was mainly selected for the AMC materials according to an investigation that took place between different AMC substrate materials, where it was settled that the textile one displayed the highest antenna gain and efficiency. The monopole antenna and the AMC, distanced apart by 5 mm, combined form the integrated design. It operates at 2.4 GHz, which was particularly selected as the resonant frequency for wirelessly sending the subject's symptoms data via Wi-Fi, with realized gain and total efficiency of 6.76 dBi and 88.4%, respectively, in free space. Separated by 3 mm from the specific anthropomorphic mannequin human hand model, it displays a realized gain and total efficiency of 4.06 dBi and 44.39%, respectively, in a flat condition. Furthermore, it exhibits a specific absorption rate (SAR) of 1.8 W/kg averaged over 10 g of tissue. When bent over the human hand model, it performs well and exhibits a maximum SAR of 0.521 and 0.406 W/kg, averaged over 1 and 10 g of tissues, respectively. As a result of such outcomes, the proposed integrated design can be nominated for wearable hand/wrist and Wi-Fi applications.
Soybean density and Palmer amaranth (Amaranthus palmeri) establishment time: effects on weed biology, crop yield, and economic returns
Authors: Korres Nicholas E. , Norsworthy Jason K. , Mauromoustakos Andy , Williams Martin M.
Published: June 2020

Knowledge of crop–weed interference effects on weed biology along with yield penalties can be used for the development of integrated weed management (IWM) tactics. Nevertheless, little is known about the beneficial effects of soybean [Glycine max (L.) Merr.] density, an important aspect of IWM, on late Palmer amaranth (Amaranthus palmeri S. Watson) establishment time. Two field experiments were conducted in 2014 and 2015 to investigate how various soybean densities and A. palmeri establishment timings in weeks after crop emergence (WAE) affect height, biomass, and seed production of the weed but also crop yield in drill-seeded soybean. Soybean density had a significant impact on dry weight and seed production of A. palmeri that established within the first 2 wk of crop emergence, but not for establishment timings of the weed 4 wk and later in relation to crop emergence. Differential performance of A. palmeri gender was observed, regarding greater biomass production of female than male plants under crop presence, and merits further investigation. Grain yield reductions were recorded at earlier A. palmeri establishment timings (i.e., 0 and 1 WAE) compared with 8 WAE establishment timing in 2014 and 2015. High soybean densities resulted in greater soybean yields compared with low soybean density, but no grain yield benefits were observed between medium and high soybean densities. Crop budget analysis revealed the benefits of moderate seeding rate (i.e., 250, 000 seeds ha−1) increases in comparison to lower (i.e., 125,000 seeds ha−1) or high (i.e., 400,000 seeds ha−1) on crop revenue, net income returns, and breakeven price. Earlier A. palmeri establishment timings (i.e., 0, 1, and 2 WAE) resulted in lower crop revenue and net income returns compared with later establishment timings of the weed.
Phenotypic diversity of weedy rice (Oryza sativaf.spontanea) biotypes found in California and implications for management
Authors: Karn Elizabeth , De Leon Teresa , Espino Luis , Al-Khatib Kassim , Brim-DeForest Whitney
Published: June 2020

Weedy rice (Oryza sativaf.spontaneaRosh.) is an emerging weed of California rice (Oryza sativaL.) that has potential to cause large yield losses. Early detection of weedy rice in the field is ideal to effectively control and prevent the spread of this weed. However, it is difficult to differentiate weedy rice from cultivated rice during early growth stages due to the close genetic and phenotypic relatedness of cultivated rice and weedy rice. The objective of this study is to examine phenotypic variation in weedy rice biotypes from California and to identify traits that could be used to visually identify weedy rice infestations at early growth stages for effective management. Greenhouse experiments were conducted in 2017 and 2018 using five phenotypically distinct biotypes of weedy rice found in California, along with diverse cultivated, weedy, and wild rice types in a randomized complete block design. We measured variation for 13 phenotypic traits associated with weedy rice and conducted principal component analysis and factor analysis to identify important weedy traits. Most weedy rice individuals within a biotype clustered together by phenotypic similarity. Pericarp color, hull color, chlorophyll content, grain length, plant height, leaf pubescence, collar color, and leaf sheath color account for most of the observed variation. California weedy rice biotypes are phenotypically distinct from wild rice and from weedy rice from the southern United States in their combinations of seed phenotypes and vegetative characteristics. In comparison with the locally grown temperatejaponicacultivars, California weedy rice tends to be taller, with lower chlorophyll content and a red pericarp. Weedy rice biotypes vary in seed shattering and seed dormancy. For weedy rice management, plant height and chlorophyll content are distinct traits that could be used to differentiate weedy rice from the majority of cultivated rice varieties in California during vegetative stages of rice growth.
Upper Plate Controls on the Formation of Broken Foreland Basins in the Andean Retroarc Between 26°S and 28°S: From Cretaceous Rifting to Paleogene and Miocene Broken Foreland Basins
Authors: Zapata S. , Sobel E. R. , Del Papa C. , Glodny J.
Published: June 2020

Marked along‐strike changes in stratigraphy, mountain belt morphology, basement exhumation, and deformation styles characterize the Andean retroarc; these changes have previously been related to spatiotemporal variations in the subduction angle. We modeled new apatite fission track and apatite (U‐Th‐Sm)/He data from nine ranges located between 26°S and 28°S. Using new and previously published data, we constructed a Cretaceous to Pliocene paleogeographic model that delineates a four‐stage tectonic evolution: extensional tectonics during the Cretaceous (120–75 Ma), the formation of a broken foreland basin between 55 and 30 Ma, reheating due to burial beneath sedimentary rocks (18–13 Ma), and deformation, exhumation, and surface uplift during the Late Miocene and the Pliocene (13–3 Ma). Our model highlights how preexisting upper plate structures control the deformation patterns of broken foreland basins. Because retroarc deformation predates flat‐slab subduction, we propose that slab anchoring may have been the precursor of Eocene–Oligocene compression in the Andean retroarc. Our model challenges models which consider broken foreland basins and retroarc deformation in the NW Argentinian Andes to be directly related to Miocene flat subduction.
An Evaluation of the Large‐Scale Atmospheric Circulation and Its Variability in CESM2 and Other CMIP Models
Authors: Simpson Isla R. , Bacmeister Julio , Neale Richard B. , Hannay Cecile , Gettelman Andrew , Garcia Rolando R. , Lauritzen Peter H. , Marsh Daniel R. , Mills Michael J. , Medeiros Brian , Richter Jadwiga H.
Published: June 2020

The Community Earth System Model 2 (CESM2) is the latest Earth System Model developed by the National Center for Atmospheric Research in collaboration with the university community and is significantly advanced in most components compared to its predecessor (CESM1). Here, CESM2's representation of the large‐scale atmospheric circulation and its variability is assessed. Further context is providedthrough comparison to the CESM1 large ensemble and other models from the Coupled Model Intercomparison Project (CMIP5 and CMIP6). This includes an assessment of the representation of jet streams and storm tracks, stationary waves, the global divergent circulation, the annular modes, the North Atlantic Oscillation, and blocking. Compared to CESM1, CESM2 is substantially improved in the representation of the storm tracks, Northern Hemisphere (NH) stationary waves, NH winter blocking and the global divergent circulation. It ranks within the top 10% of CMIP class models in many of these features. Some features of the Southern Hemisphere (SH) circulation have degraded, such as the SH jet strength, stationary waves, and blocking, although the SH jet stream is placed at approximately the correct location. This analysis also highlights systematic deficiencies in these features across the new CMIP6 archive, such as the continued tendency for the SH jet stream to be placed too far equatorward, the North Atlantic westerlies to be too strong over Europe, the storm tracks as measured by low‐level meridional wind variance to be too weak and a lack of blocking in the North Atlantic sector.
Common-path interferometric label-free protein sensing with resonant dielectric nanostructures
Authors: Barth Isabel , Conteduca Donato , Reardon Christopher , Johnson Steven , Krauss Thomas F.
Published: June 2020

Research toward photonic biosensors for point-of-care applications and personalized medicine is driven by the need for high-sensitivity, low-cost, and reliable technology. Among the most sensitive modalities, interferometry offers particularly high performance, but typically lacks the required operational simplicity and robustness. Here, we introduce a common-path interferometric sensor based on guided-mode resonances to combine high performance with inherent stability. The sensor exploits the simultaneous excitation of two orthogonally polarized modes, and detects the relative phase change caused by biomolecular binding on the sensor surface. The wide dynamic range of the sensor, which is essential for fabrication and angle tolerance, as well as versatility, is controlled by integrating multiple, tuned structures in the field of view. This approach circumvents the trade-off between sensitivity and dynamic range, typical of other phase-sensitive modalities, without increasing complexity. Our sensor enables the challenging label-free detection of procalcitonin, a small protein (13 kDa) and biomarker for infection, at the clinically relevant concentration of 1 pg mL−1, with a signal-to-noise ratio of 35. This result indicates the utility for an exemplary application in antibiotic guidance, and opens possibilities for detecting further clinically or environmentally relevant small molecules with an intrinsically simple and robust sensing modality.
Dendritic cells-derived interferon-λ1 ameliorated inflammatory bone destruction through inhibiting osteoclastogenesis
Authors: Chen Yueqi , Wang Yiran , Tang Ruohui , Yang Jing , Dou Ce , Dong Yutong , Sun Dong , Zhang Chengmin , Zhang Lincheng , Tang Yong , Dai Qijie , Luo Fei , Xu Jianzhong , Dong Shiwu
Published: June 2020

Bone infection contributing to inflammatory osteolysis is common in orthopedic surgery. The dynamic balance between bone formation and bone resorption is destroyed due to excessive osteoclast fusion and differentiation, which results in severe bone matrix loss. Many therapeutic approaches that restrain osteoclast formation and function act as efficient ways to prevent inflammatory bone erosion. We have demonstrated for the first time that dendritic cells-derived interferon-λ1 (IFN-λ1) inhibited inflammatory bone destruction in vivo and explored its underlying mechanisms on osteoclast formation in vitro. We found that IFN-λ1 was highly expressed in infectious bone tissue compared with that of non-infectious bone tissue. Additionally, dendritic cells marker genes such as CD80, CD86, and CD1a were higher expressed in infectious bone tissue than that of non-infectious bone tissue. Dendritic cells that were pretreated with LPS showed high expression of IFN-λ1. Moreover, conditioned medium of LPS-pretreated dendritic cells significantly inhibited osteoclast differentiation, as determined by TRAP staining assay. This suppressive effect was reversed by adding an IFN-λ1 monoclonal antibody. It was also investigated whether exogenous IFN-λ1 restrained osteoclastogenesis, bone resorption, F-actin ring formation, osteoclast-specific gene expression, release of pro-inflammatory cytokines, and translocation of p65 and NFATc1 by preventing the NF-κB signaling pathway and NLRP3 inflammasome formation, as well as by inducing the JAK-STAT signaling pathways in vitro. In vivo study indicated that IFN-λ1 prevents lipopolysaccharide (LPS)-induced inflammatory bone destruction by inhibiting excessive osteoclast fusion and bone resorption activity. In conclusion, our findings confirmed that dendritic cells-derived IFN-λ1 could attenuate osteoclast formation and bone resorptive activity in vitro and in vivo. These novel findings pave the way for the use of exogenous IFN-λ1 as a potential therapeutic treatment for excessive osteoclast-related diseases, such as inflammatory osteolysis, by regulating osteoclastogenesis to maintain the dynamic balance between bone formation and bone resorption.
Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells
Authors: Cheteh Emarndeena H. , Sarne Victoria , Ceder Sophia , Bianchi Julie , Augsten Martin , Rundqvist Helene , Egevad Lars , Östman Arne , Wiman Klas G.
Published: June 2020

Cancer-associated fibroblasts (CAFs) promote tumor growth and progression, and increase drug resistance through several mechanisms. We have investigated the effect of CAFs on the p53 response to doxorubicin in prostate cancer cells. We show that CAFs produce interleukin-6 (IL-6), and that IL-6 attenuates p53 induction and upregulation of the pro-apoptotic p53 target Bax upon treatment with doxorubicin. This is associated with increased levels of MDM2 mRNA, Mdm2 protein bound to p53, and ubiquitinated p53. IL-6 also inhibited doxorubicin-induced cell death. Inhibition of JAK or STAT3 alleviated this effect, indicating that IL-6 attenuates p53 via the JAK/STAT signaling pathway. These results suggest that CAF-derived IL-6 plays an important role in protecting cancer cells from chemotherapy and that inhibition of IL-6 could have significant therapeutic value.
Molecule-based nonlinear optical switch with highly tunable on-off temperature using a dual solid solution approach
Authors: Zhang Shi-Yong , Shu Xia , Zeng Ying , Liu Qing-Yan , Du Zi-Yi , He Chun-Ting , Zhang Wei-Xiong , Chen Xiao-Ming
Published: June 2020

Nonlinear optical switches that reversibly convert between on/off states by thermal stimuli are promising for applications in the fields of photoelectronics and photonics. Currently one main drawback for practical application lies in the control of their switch temperature, especially for the temperature range near room temperature. By mixed melting treatment, here we describe an alloy-like nonlinear optical switch with tunable switch temperature via a dual solid solution approach within the coordination polymer system. We initially prepare a coordination polymer (i-PrNHMe2)[Cd(SCN)3], which functions as a high-contrast thermoresponsive nonlinear optical switch originating from a phase transition at around 328 K. Furthermore, by taking advantage of a synergistic dual solid solution effect, the melt mixing of it with its analogue (MeNHEt2)[Cd(SCN)3], which features an unequal anionic chain templated by an isomeric ammonium, can afford coordination polymer solid solutions with switch temperatures that are tunable in a range of 273–328 K merely by varying the component ratio.
Human beige adipocytes for drug discovery and cell therapy in metabolic diseases
Authors: Singh Amar M. , Zhang Liang , Avery John , Yin Amelia , Du Yuhong , Wang Hui , Li Zibo , Fu Haian , Yin Hang , Dalton Stephen
Published: June 2020

Human beige adipocytes (BAs) have potential utility for the development of therapeutics to treat diabetes and obesity-associated diseases. Although several reports have described the generation of beige adipocytes in vitro, their potential utility in cell therapy and drug discovery has not been reported. Here, we describe the generation of BAs from human adipose-derived stem/stromal cells (ADSCs) in serum-free medium with efficiencies >90%. Molecular profiling of beige adipocytes shows them to be similar to primary BAs isolated from human tissue. In vitro, beige adipocytes exhibit uncoupled mitochondrial respiration and cAMP-induced lipolytic activity. Following transplantation, BAs increase whole-body energy expenditure and oxygen consumption, while reducing body-weight in recipient mice. Finally, we show the therapeutic utility of BAs in a platform for high-throughput drug screening (HTS). These findings demonstrate the potential utility of BAs as a cell therapeutic and as a tool for the identification of drugs to treat metabolic diseases.
Direct transfer of tri- and di-fluoroethanol units enabled by radical activation of organosilicon reagents
Authors: Chen Xiang , Gong Xingxing , Li Zhengyu , Zhou Gang , Zhu Zhihong , Zhang Weilu , Liu Shanshan , Shen Xiao
Published: June 2020

Trifluoroethanol and difluoroethanol units are important motifs in bioactive molecules, but the methods to direct incorporate these units are limited. Herein, we report two organosilicon reagents for the transfer of trifluoroethanol and difluoroethanol units into molecules. Through intramolecular C-Si bond activation by alkoxyl radicals, these reagents were applied in allylation, alkylation and alkenylation reactions, enabling efficient synthesis of various tri(di)fluoromethyl group substituted alcohols. The broad applicability and general utility of the approach are highlighted by late-stage introduction of these fluoroalkyl groups to complex molecules, and the synthesis of antitumor agent Z and its difluoromethyl analog Z′.
Low-dose phase retrieval of biological specimens using cryo-electron ptychography
Authors: Zhou Liqi , Song Jingdong , Kim Judy S. , Pei Xudong , Huang Chen , Boyce Mark , Mendonça Luiza , Clare Daniel , Siebert Alistair , Allen Christopher S. , Liberti Emanuela , Stuart David , Pan Xiaoqing , Nellist Peter D. , Zhang Peijun , Kirkland Angus I. , Wang Peng
Published: June 2020

Cryo-electron microscopy is an essential tool for high-resolution structural studies of biological systems. This method relies on the use of phase contrast imaging at high defocus to improve information transfer at low spatial frequencies at the expense of higher spatial frequencies. Here we demonstrate that electron ptychography can recover the phase of the specimen with continuous information transfer across a wide range of the spatial frequency spectrum, with improved transfer at lower spatial frequencies, and as such is more efficient for phase recovery than conventional phase contrast imaging. We further show that the method can be used to study frozen-hydrated specimens of rotavirus double-layered particles and HIV-1 virus-like particles under low-dose conditions (5.7 e/Å2) and heterogeneous objects in an Adenovirus-infected cell over large fields of view (1.14 × 1.14 μm), thus making it suitable for studies of many biologically important structures.
Human norovirus targets enteroendocrine epithelial cells in the small intestine
Authors: Green Kim Y. , Kaufman Stuart S. , Nagata Bianca M. , Chaimongkol Natthawan , Kim Daniel Y. , Levenson Eric A. , Tin Christine M. , Yardley Allison Behrle , Johnson Jordan A. , Barletta Ana Beatriz F. , Khan Khalid M. , Yazigi Nada A. , Subramanian Sukanya , Moturi Sangeetha R. , Fishbein Thomas M. , Moore Ian N. , Sosnovtsev Stanislav V.
Published: June 2020

Human noroviruses are a major cause of diarrheal illness, but pathogenesis is poorly understood. Here, we investigate the cellular tropism of norovirus in specimens from four immunocompromised patients. Abundant norovirus antigen and RNA are detected throughout the small intestinal tract in jejunal and ileal tissue from one pediatric intestinal transplant recipient with severe gastroenteritis. Negative-sense viral RNA, a marker of active viral replication, is found predominantly in intestinal epithelial cells, with chromogranin A-positive enteroendocrine cells (EECs) identified as a permissive cell type in this patient. These findings are consistent with the detection of norovirus-positive EECs in the other three immunocompromised patients. Investigation of the signaling pathways induced in EECs that mediate communication between the gut and brain may clarify mechanisms of pathogenesis and lead to the development of in vitro model systems in which to evaluate norovirus vaccines and treatment.
A nanomaterials discovery robot for the Darwinian evolution of shape programmable gold nanoparticles
Authors: Salley Daniel , Keenan Graham , Grizou Jonathan , Sharma Abhishek , Martín Sergio , Cronin Leroy
Published: June 2020

The fabrication of nanomaterials from the top-down gives precise structures but it is costly, whereas bottom-up assembly methods are found by trial and error. Nature evolves materials discovery by refining and transmitting the blueprints using DNA mutations autonomously. Genetically inspired optimisation has been used in a range of applications, from catalysis to light emitting materials, but these are not autonomous, and do not use physical mutations. Here we present an autonomously driven materials-evolution robotic platform that can reliably optimise the conditions to produce gold-nanoparticles over many cycles, discovering new synthetic conditions for known nanoparticle shapes using the opto-electronic properties as a driver. Not only can we reliably discover a method, encoded digitally to synthesise these materials, we can seed in materials from preceding generations to engineer more sophisticated architectures. Over three independent cycles of evolution we show our autonomous system can produce spherical nanoparticles, rods, and finally octahedral nanoparticles by using our optimized rods as seeds.
AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2
Authors: Yang Acong , Shao Tie-Juan , Bofill-De Ros Xavier , Lian Chuanjiang , Villanueva Patricia , Dai Lisheng , Gu Shuo
Published: June 2020

MicroRNAs (miRNAs) associated with Argonaute proteins (AGOs) regulate gene expression in mammals. miRNA 3’ ends are subject to frequent sequence modifications, which have been proposed to affect miRNA stability. However, the underlying mechanism is not well understood. Here, by genetic and biochemical studies as well as deep sequencing analyses, we find that AGO mutations disrupting miRNA 3’ binding are sufficient to trigger extensive miRNA 3’ modifications in HEK293T cells and in cancer patients. Comparing these modifications in TUT4, TUT7 and DIS3L2 knockout cells, we find that TUT7 is more robust than TUT4 in oligouridylating mature miRNAs, which in turn leads to their degradation by the DIS3L2 exonuclease. Our findings indicate a decay machinery removing AGO-associated miRNAs with an exposed 3’ end. A set of endogenous miRNAs including miR-7, miR-222 and miR-769 are targeted by this machinery presumably due to target-directed miRNA degradation.
A supramolecular system that strictly follows the binding mechanism of conformational selection
Authors: Yang Liu-Pan , Zhang Li , Quan Mao , Ward Jas S. , Ma Yan-Long , Zhou Hang , Rissanen Kari , Jiang Wei
Published: June 2020

Induced fit and conformational selection are two dominant binding mechanisms in biology. Although induced fit has been widely accepted by supramolecular chemists, conformational selection is rarely studied with synthetic systems. In the present research, we report a macrocyclic host whose binding mechanism is unambiguously assigned to conformational selection. The kinetic and thermodynamic aspects of this system are studied in great detail. It reveals that the kinetic equation commonly used for conformational selection is strictly followed here. In addition, two mathematical models are developed to determine the association constants of the same guest to the two host conformations. A “conformational selectivity factor” is defined to quantify the fidelity of conformational selection. Many details about the kinetic and thermodynamic aspects of conformational selection are revealed by this synthetic system. The conclusion and the mathematical models reported here should be helpful in understanding complex molecular recognition in both biological and synthetic systems.
The impact of climate and antigenic evolution on seasonal influenza virus epidemics in Australia
Authors: Lam Edward K. S. , Morris Dylan H. , Hurt Aeron C. , Barr Ian G. , Russell Colin A.
Published: June 2020

Although seasonal influenza viruses circulate globally, prevention and treatment occur at the level of regions, cities, and communities. At these scales, the timing, duration and magnitude of epidemics vary substantially, but the underlying causes of this variation are poorly understood. Here, based on analyses of a 15-year city-level dataset of 18,250 laboratory-confirmed and antigenically-characterised influenza virus infections from Australia, we investigate the effects of previously hypothesised environmental and virological drivers of influenza epidemics. We find that anomalous fluctuations in temperature and humidity do not predict local epidemic onset timings. We also find that virus antigenic change has no consistent effect on epidemic size. In contrast, epidemic onset time and heterosubtypic competition have substantial effects on epidemic size and composition. Our findings suggest that the relationship between influenza population immunity and epidemiology is more complex than previously supposed and that the strong influence of short-term processes may hinder long-term epidemiological forecasts.
Quantifying CDK inhibitor selectivity in live cells
Authors: Wells Carrow I. , Vasta James D. , Corona Cesear R. , Wilkinson Jennifer , Zimprich Chad A. , Ingold Morgan R. , Pickett Julie E. , Drewry David H. , Pugh Kathryn M. , Schwinn Marie K. , Hwang Byounghoon , Zegzouti Hicham , Huber Kilian V. M. , Cong Mei , Meisenheimer Poncho L. , Willson Timothy M. , Robers Matthew B.
Published: June 2020

Concerted multidisciplinary efforts have led to the development of Cyclin-Dependent Kinase inhibitors (CDKi’s) as small molecule drugs and chemical probes of intracellular CDK function. However, conflicting data has been reported on the inhibitory potency of CDKi’s and a systematic characterization of affinity and selectivity against intracellular CDKs is lacking. We have developed a panel of cell-permeable energy transfer probes to quantify target occupancy for all 21 human CDKs in live cells, and present a comprehensive evaluation of intracellular isozyme potency and selectivity for a collection of 46 clinically-advanced CDKi’s and tool molecules. We observed unexpected intracellular activity profiles for a number of CDKi’s, offering avenues for repurposing of highly potent molecules as probes for previously unreported targets. Overall, we provide a broadly applicable method for evaluating the selectivity of CDK inhibitors in living cells, and present a refined set of tool molecules to study CDK function.
Multistable and dynamic CRISPRi-based synthetic circuits
Authors: Santos-Moreno Javier , Tasiudi Eve , Stelling Joerg , Schaerli Yolanda
Published: June 2020

Gene expression control based on CRISPRi (clustered regularly interspaced short palindromic repeats interference) has emerged as a powerful tool for creating synthetic gene circuits, both in prokaryotes and in eukaryotes; yet, its lack of cooperativity has been pointed out as a potential obstacle for dynamic or multistable synthetic circuit construction. Here we use CRISPRi to build a synthetic oscillator (“CRISPRlator”), bistable network (toggle switch) and stripe pattern-forming incoherent feed-forward loop (IFFL). Our circuit designs, conceived to feature high predictability and orthogonality, as well as low metabolic burden and context-dependency, allow us to achieve robust circuit behaviors in Escherichia coli populations. Mathematical modeling suggests that unspecific binding in CRISPRi is essential to establish multistability. Our work demonstrates the wide applicability of CRISPRi in synthetic circuits and paves the way for future efforts towards engineering more complex synthetic networks, boosted by the advantages of CRISPR technology.
Core functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy
Authors: Li Mengbo , Parker Benjamin L. , Pearson Evangeline , Hunter Benjamin , Cao Jacob , Koay Yen Chin , Guneratne Oneka , James David E. , Yang Jean , Lal Sean , O’Sullivan John F.
Published: June 2020

Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.
Modeling mitigation of influenza epidemics by baloxavir
Authors: Du Zhanwei , Nugent Ciara , Galvani Alison P. , Krug Robert M. , Meyers Lauren Ancel
Published: June 2020

Influenza viruses annually kill 290,000–650,000 people worldwide. Antivirals can reduce death tolls. Baloxavir, the recently approved influenza antiviral, inhibits initiation of viral mRNA synthesis, whereas oseltamivir, an older drug, inhibits release of virus progeny. Baloxavir blocks virus replication more rapidly and completely than oseltamivir, reducing the duration of infectiousness. Hence, early baloxavir treatment may indirectly prevent transmission. Here, we estimate impacts of ramping up and accelerating baloxavir treatment on population-level incidence using a new model that links viral load dynamics from clinical trial data to between-host transmission. We estimate that ~22 million infections and >6,000 deaths would have been averted in the 2017–2018 epidemic season by administering baloxavir to 30% of infected cases within 48 h after symptom onset. Treatment within 24 h would almost double the impact. Consequently, scaling up early baloxavir treatment would substantially reduce influenza morbidity and mortality every year. The development of antivirals against the SARS-CoV2 virus that function like baloxavir might similarly curtail transmission and save lives.
Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition
Authors: Stopfer Lauren E. , Mesfin Joshua M. , Joughin Brian A. , Lauffenburger Douglas A. , White Forest M.
Published: June 2020

Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoire’s response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking normalization controls. We describe an experimental platform that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input. HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma cell lines to profile the immunopeptidome response to CDK4/6 inhibition and interferon-γ — known modulators of antigen presentation — uncovers treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.
Durable and controlled depletion of neutrophils in mice
Authors: Boivin Gael , Faget Julien , Ancey Pierre-Benoit , Gkasti Aspasia , Mussard Julie , Engblom Camilla , Pfirschke Christina , Contat Caroline , Pascual Justine , Vazquez Jessica , Bendriss-Vermare Nathalie , Caux Christophe , Vozenin Marie-Catherine , Pittet Mikael J. , Gunzer Matthias , Meylan Etienne
Published: June 2020

Neutrophils are an essential part of the innate immune system. To study their importance, experimental studies often aim to deplete these cells, generally by injecting anti-Ly6G or anti-Gr1 antibodies. However, these approaches are only partially effective, transient or lack specificity. Here we report that neutrophils remaining after anti-Ly6G treatment are newly derived from the bone marrow, instead of depletion escapees. Mechanistically, newly generated, circulating neutrophils have lower Ly6G membrane expression, and consequently reduced targets for anti-Ly6G-mediated depletion. To overcome this limitation, we develop a double antibody-based depletion strategy that enhances neutrophil elimination by anti-Ly6G treatment. This approach achieves specific, durable and controlled reduction of neutrophils in vivo, and may be suitable for studying neutrophil function in experimental models.
Stable isotopes show that earthquakes enhance permeability and release water from mountains
Authors: Hosono Takahiro , Yamada Chisato , Manga Michael , Wang Chi-Yuen , Tanimizu Masaharu
Published: June 2020

Hydrogeological properties can change in response to large crustal earthquakes. In particular, permeability can increase leading to coseismic changes in groundwater level and flow. These processes, however, have not been well-characterized at regional scales because of the lack of datasets to describe water provenances before and after earthquakes. Here we use a large data set of water stable isotope ratios (n = 1150) to show that newly formed rupture systems crosscut surrounding mountain aquifers, leading to water release that causes groundwater levels to rise (~11 m) in down-gradient aquifers after the 2016 Mw 7.0 Kumamoto earthquake. Neither vertical infiltration of soil water nor the upwelling of deep fluids was the major cause of the observed water level rise. As the Kumamoto setting is representative of volcanic aquifer systems at convergent margins where seismotectonic activity is common, our observations and proposed model should apply more broadly.
A new viewpoint on antlers reveals the evolutionary history of deer (Cervidae, Mammalia)
Authors: Samejima Yuusuke , Matsuoka Hiroshige
Published: June 2020

Recent molecular phylogeny of deer revealed that the characters of antlers previously focused on are homoplasious, and antlers tend to be considered problematic for classification. However, we think antlers are important tools and reconsidered and analysed the characters and structures to use them for classification. This study developed a method to describe the branching structure of antlers by using antler grooves, which are formed on the antlers by growth, and then projecting the position of the branching directions of tines on the burr circumference. By making diagrams, comparing the branching structure interspecifically, homologous elements (tines, beams, and processes) of the antlers of 25 species of 16 genera were determined. Subsequently, ancestral state reconstruction was performed on the fixed molecular phylogenetic tree. It was revealed that Capreolinae and Cervini gained respective three-pointed antlers independently, and their subclades gained synapomorphous tines. We found new homologous and synapomorphous characters, as the antler of Eld’s deer, which has been classified in Rucervus, is structurally close to that of Elaphurus rather than that of Rucervus, consistent with molecular phylogeny. The methods of this study will contribute to the understanding of the branching structure and phylogeny of fossil species and uncover the evolutionary history of Cervidae.
When Lone Wolf Defectors Undermine the Power of the Opt-Out Default
Authors: Ferguson Eamonn , Shichman Ruslan , Tan Jonathan H. W.
Published: June 2020

High levels of cooperation are a central feature of human society, and conditional cooperation has been proposed as one proximal mechanism to support this. The counterforce of free-riding can, however, undermine cooperation and as such a number of external mechanisms have been proposed to ameliorate the effects of free-riding. One such mechanism is setting cooperation as the default (i.e., an opt-out default). We posit, however, that in dynamic settings where people can observe and condition their actions on others’ behaviour, ‘lone wolf’ defectors undermine initial cooperation encouraged by an opt-out default, while ‘good shepherds’ defeat the free-riding encouraged by an opt-in default. Thus, we examine the dynamic emergence of conditional cooperation under different default settings. Specifically, we develop a game theoretical model to analyse cooperation under defaults for cooperation (opt-out) and defection (opt-in). The model predicts that the ‘lone wolf’ effect is stronger than the ‘good shepherd’ effect, which – if anticipated by players – should strategically deter free-riding under opt-out and cooperation under opt-in. Our experimental games confirm the existence of both ‘lone wolf’ defectors and ‘good shepherd’ cooperators, and that the ‘lone wolf’effect is stronger in the context of organ donation registration behaviour. We thus show a potential ‘dark side’ to conditional cooperation (‘lone wolf effect’) and draw implications for the adoption of an opt-out organ donation policy.
Constitutive expression of Asparaginase in Gossypium hirsutum triggers insecticidal activity against Bemisia tabaci
Authors: Gul Ambreen , Hussain Ghulam , Iqbal Adnan , Rao Abdul Qayyum , Din Salah ud , Yasmeen Aneela , Shahid Naila , Ahad Ammara , Latif Ayesha , Azam Saira , Samiullah Tahir Rehman , Hassan Samina , Shahid Ahmad Ali , Husnain Tayyab
Published: June 2020

Whitefly infestation of cotton crop imparts enormous damage to cotton yield by severely affecting plant health, vigour and transmittingCottonLeafCurlVirus (CLCuV). Genetic modification of cotton helps to overcome both the direct whitefly infestation as well as CLCuV based cotton yield losses. We have constitutively overexpressed asparaginase (ZmASN) gene inGossypium hirsutumto overcome the cotton yield losses imparted by whitefly infestation. We achieved 2.54% transformation efficiency in CIM-482 byAgrobacterium-mediated shoot apex transformation method. The relative qRT-PCR revealed 40-fold higher transcripts ofasparaginasein transgenic cotton line vs. non-transgenic cotton lines. Metabolic analysis showed higher contents of aspartic acid and glutamic acid in seeds and phloem sap of the transgenic cotton lines. Phenotypically, the transgenic cotton lines showed vigorous growth and height, greater number of bolls, and yield. Among six representative transgenic cotton lines, line 14 had higher photosynthetic rate, stomatal conductance, smooth fiber surface, increased fiber convolutions (SEM analysis) and 95% whitefly mortality as compared to non-transgenic cotton line. The gene integration analysis by fluorescencein situhybridization showed single copy gene integration at chromosome number 1. Collectively, asparaginase gene demonstrated potential to control whitefly infestation, post-infestation damages and improve cotton plant health and yield: a pre-requisite for farmer’s community.