bluuebunny/crossref_metadata_2025 huggingface dataset:
A Unified Breaking Onset Criterion for Surface Gravity Water Waves in Arbitrary Depth
Authors: Derakhti Morteza , Kirby James T. , Banner Michael L. , Grilli Stephan T. , Thomson Jim
Published: May 2020

We investigate the validity and robustness of the Barthelemy et al. (2018, https://doi.org/10.1017/jfm.2018.93) wave‐breaking onset prediction framework for surface gravity water waves in arbitrary water depth, including shallow water breaking over varying bathymetry. We show that the Barthelemy et al. (2018) breaking onset criterion, which they validated for deep and intermediate water depths, also segregates breaking crests from nonbreaking crests in shallow water, with subsequent breaking always following the exceedance of their proposed generic breaking threshold. We consider a number of representative wave types, including regular, irregular, solitary, and focused waves, shoaling over idealized bed topographies including an idealized bar geometry and a mildly to steeply sloping planar beach. Our results show that the new breaking onset criterion is capable of detecting single and multiple breaking events in time and space in arbitrary water depth. Further, we show that the new generic criterion provides improved skill for signaling imminent breaking onset, relative to the available kinematic or geometric breaking onset criteria in the literature. In particular, the new criterion is suitable for use in wave‐resolving models that cannot intrinsically detect the onset of wave breaking.
Polar Phasing and Cross‐Equatorial Heat Transfer Following a Simulated Abrupt NH Warming of a Glacial Climate
Authors: Moreno‐Chamarro E. , Ferreira D. , Marshall J.
Published: May 2020

A 150‐ to 220‐year lag between abrupt Greenland warming and maximum Antarctic warming characterizes past glacial Dansgaard‐Oeschger events. In a modeling study, we investigate how the cross‐equatorial oceanic heat transport (COHT) might drive this phasing during an abrupt Northern Hemisphere (NH) warming. We use the MITgcm in an idealized continental configuration with two ocean basins, one wider, one narrower, under glacial‐like conditions with sea ice reaching midlatitudes. An exaggerated eccentricity‐related solar radiation anomaly is imposed over 100 years to trigger an abrupt NH warming and sea‐ice melting. The Hadley circulation shifts northward in response, weakening the NH trade winds, subtropical cells, and COHT in both ocean basins. This induces heat convergence in the Southern Hemisphere (SH) ocean subsurface, from where upward heat release melts sea ice and warms SH high latitudes. Although the small‐basin meridional overturning circulation also weakens, driven by NH ice melting, it contributes at most one‐third to the total COHT anomaly, hence playing a subsidiary role in the SH and NH initial warming. Switching off the forcing cools the NH; yet heat release continues from the SH ocean subsurface via isopycnal advection‐diffusion and vertical mixing, driving further sea ice melting and high latitude warming for ~50–70 more years. A phasing in polar temperatures resembling reconstructions thus emerges, linked to changes in the subtropical cells’ COHT, and SH ocean heat storage and surface fluxes. Our results highlight the potential role of the atmosphere circulation and wind‐driven global ocean circulation in the NH–SH phasing seen in DO events.
Understanding Preservation of Primary Signatures in Apatite by Comparing Matrix and Zircon‐Hosted Crystals From the Eoarchean Acasta Gneiss Complex (Canada)
Authors: Antoine C. , Bruand E. , Guitreau M. , Devidal J.‐L.
Published: May 2020

A novel way to investigate the petrogenesis of ancient polymetamorphosed terranes is to study zircon‐hosted mineral inclusions, which are sensitive to melt evolution such as apatite. Recent contributions on such inclusions in unmetamorphosed granitoids can provide valuable petrogenetic information and, in turn, represent a way to circumvent effects of metamorphism. Yet the impact of metamorphism on apatite inclusion has never been studied in detail. To address the issue of chemical and isotopic preservation of primary signals in apatite crystals both in the matrix and armored within zircons, we have studied apatite crystals from four 3.6–4.0 Ga TTG granitoids from the Acasta Gneiss Complex (Canada). Our results demonstrate that U‐Th‐Pb isotope systematics in matrix apatite crystals were reset at 1.8–1.7 Ga (Wopmay orogen) whereas primary REE signatures were preserved in many crystals. In contrast, zircon‐hosted apatite inclusions all preserved primary REE signatures despite variable ages between 1.7 and 4.0 Ga. We interpret reset ages to be a consequence of metamorphism that managed to affect U‐Th‐Pb systematics because of advanced radiation damage accumulation in host‐zircon lattices. Only the most pristine zircon crystal has an apatite inclusion with a concordant age consistent with the magmatic age of the zircon (4.0 Ga). In addition, our results show that apatite crystals from TTG have distinct REE composition from post‐Archean granitoids apatites, that is preserved even in some apatites with reset ages. This capacity to retain primary information and discriminate granitoid types makes apatite a very valuable tool for reconstructing the nature and evolution of ancient crustal rocks through the use of detrital minerals.
Hydrological Model Calibration for Dammed Basins Using Satellite Altimetry Information
Authors: Zhong Ruida , Zhao Tongtiegang , Chen Xiaohong
Published: May 2020

Downstream stakeholders are often hindered when performing water management decision making based on effective hydrological modeling and streamflow anticipation, due to alterations of river flow caused by upstream damming. Meanwhile, spaceborne altimeters and imagers can provide valuable data for the upper data‐limited reservoirs by monitoring their operations. This study proposes a novel modeling approach that incorporates reservoir levels from satellite altimetry into hydrological model calibration. Doing so enables model parameter determination and retrieval of upper reservoir inflow for dammed basins, when only the altered downstream flow observations are available. Case studies are performed for two large reservoirs in the Dongjiang basin, a typical dam‐affected area in South China. Two settings for determining the stage‐volume (S‐V) curve are tested: (1) The curves are prefitted by satellite information and (2) the curves are optimized by calibration in conjunction with the model parameters. Results show that the proposed approach is effective in identifying the hydrological model parameters and retrieving the upper reservoir inflow of data‐limited dammed basins. Our analyses also show that the error in satellite altimetry has significant influences and can impede reasonable determination of the model parameters, and the fitted S‐V curves perform more reasonably and robustly than calibrated S‐V curves with respect to retrieving reservoir inflow, and thus, the fitted S‐V curve is more highly recommended. Overall, our approach provides an effective solution for aiding downstream stakeholders and researchers in understanding the upper reservoir operation and analyzing the hydrology of dammed basins, when knowledge about the upstream area is limited.
Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis
Authors: Dimopoulos Meletios A. , Leleu Xavier , Moreau Philippe , Richardson Paul G. , Liberati Anna Marina , Harrison Simon J. , Miles Prince H. , Ocio Enrique M. , Assadourian Sylvie , Campana Frank , Malinge Laure , Sémiond Dorothée , van de Velde Helgi , Yong Kwee
Published: May 2020

The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ≥2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30–0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38–0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ≥60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates.
Diverse coral reef invertebrates exhibit patterns of phylosymbiosis
Authors: O’Brien Paul A , Tan Shangjin , Yang Chentao , Frade Pedro R , Andreakis Nikos , Smith Hillary A , Miller David J , Webster Nicole S , Zhang Guojie , Bourne David G
Published: May 2020

Microbiome assemblages of plants and animals often show a degree of correlation with host phylogeny; an eco-evolutionary pattern known as phylosymbiosis. Using 16S rRNA gene sequencing to profile the microbiome, paired with COI, 18S rRNA and ITS1 host phylogenies, phylosymbiosis was investigated in four groups of coral reef invertebrates (scleractinian corals, octocorals, sponges and ascidians). We tested three commonly used metrics to evaluate the extent of phylosymbiosis: (a) intraspecific versus interspecific microbiome variation, (b) topological comparisons between host phylogeny and hierarchical clustering (dendrogram) of host-associated microbial communities, and (c) correlation of host phylogenetic distance with microbial community dissimilarity. In all instances, intraspecific variation in microbiome composition was significantly lower than interspecific variation. Similarly, topological congruency between host phylogeny and the associated microbial dendrogram was more significant than would be expected by chance across all groups, except when using unweighted UniFrac distance (compared with weighted UniFrac and Bray–Curtis dissimilarity). Interestingly, all but the ascidians showed a significant positive correlation between host phylogenetic distance and associated microbial dissimilarity. Our findings provide new perspectives on the diverse nature of marine phylosymbioses and the complex roles of the microbiome in the evolution of marine invertebrates.
Drought and plant litter chemistry alter microbial gene expression and metabolite production
Authors: Malik Ashish A , Swenson Tami , Weihe Claudia , Morrison Eric W , Martiny Jennifer B H , Brodie Eoin L , Northen Trent R , Allison Steven D
Published: May 2020

Drought represents a significant stress to microorganisms and is known to reduce microbial activity and organic matter decomposition in Mediterranean ecosystems. However, we lack a detailed understanding of the drought stress response of microbial decomposers. Here we present metatranscriptomic and metabolomic data on the physiological response of in situ microbial communities on plant litter to long-term drought in Californian grass and shrub ecosystems. We hypothesised that drought causes greater microbial allocation to stress tolerance relative to growth pathways. In grass litter, communities from the decade-long ambient and reduced precipitation treatments had distinct taxonomic and functional profiles. The most discernable physiological signatures of drought were production or uptake of compatible solutes to maintain cellular osmotic balance, and synthesis of capsular and extracellular polymeric substances as a mechanism to retain water. The results show a clear functional response to drought in grass litter communities with greater allocation to survival relative to growth that could affect decomposition under drought. In contrast, communities on chemically more diverse and complex shrub litter had smaller physiological differences in response to long-term drought but higher investment in resource acquisition traits across precipitation treatments, suggesting that the functional response to drought is constrained by substrate quality. Our findings suggest, for the first time in a field setting, a trade off between microbial drought stress tolerance, resource acquisition and growth traits in plant litter microbial communities.
Combining gene expression profiling and machine learning to diagnose B-cell non-Hodgkin lymphoma
Authors: Bobée Victor , Drieux Fanny , Marchand Vinciane , Sater Vincent , Veresezan Liana , Picquenot Jean-Michel , Viailly Pierre-Julien , Lanic Marie-Delphine , Viennot Mathieu , Bohers Elodie , Oberic Lucie , Copie-Bergman Christiane , Molina Thierry Jo , Gaulard Philippe , Haioun Corinne , Salles Gilles , Tilly Hervé , Jardin Fabrice , Ruminy Philippe
Published: May 2020

Non-Hodgkin B-cell lymphomas (B-NHLs) are a highly heterogeneous group of mature B-cell malignancies. Their classification thus requires skillful evaluation by expert hematopathologists, but the risk of error remains higher in these tumors than in many other areas of pathology. To facilitate diagnosis, we have thus developed a gene expression assay able to discriminate the seven most frequent B-cell NHL categories. This assay relies on the combination of ligation-dependent RT-PCR and next-generation sequencing, and addresses the expression of more than 130 genetic markers. It was designed to retrieve the main gene expression signatures of B-NHL cells and their microenvironment. The classification is handled by a random forest algorithm which we trained and validated on a large cohort of more than 400 annotated cases of different histology. Its clinical relevance was verified through its capacity to prevent important misclassification in low grade lymphomas and to retrieve clinically important characteristics in high grade lymphomas including the cell-of-origin signatures and the MYC and BCL2 expression levels. This accurate pan-B-NHL predictor, which allows a systematic evaluation of numerous diagnostic and prognostic markers, could thus be proposed as a complement to conventional histology to guide the management of patients and facilitate their stratification into clinical trials.
Osteogenesis imperfecta mutations in plastin 3 lead to impaired calcium regulation of actin bundling
Authors: Schwebach Christopher L. , Kudryashova Elena , Zheng Weili , Orchard Matthew , Smith Harper , Runyan Lucas A. , Egelman Edward H. , Kudryashov Dmitri S.
Published: May 2020

Mutations in actin-bundling protein plastin 3 (PLS3) emerged as a cause of congenital osteoporosis, but neither the role of PLS3 in bone development nor the mechanisms underlying PLS3-dependent osteoporosis are understood. Of the over 20 identified osteoporosis-linked PLS3 mutations, we investigated all five that are expected to produce full-length protein. One of the mutations distorted an actin-binding loop in the second actin-binding domain of PLS3 and abolished F-actin bundling as revealed by cryo-EM reconstruction and protein interaction assays. Surprisingly, the remaining four mutants fully retained F-actin bundling ability. However, they displayed defects in Ca2+ sensitivity: two of the mutants lost the ability to be inhibited by Ca2+, while the other two became hypersensitive to Ca2+. Each group of the mutants with similar biochemical properties showed highly characteristic cellular behavior. Wild-type PLS3 was distributed between lamellipodia and focal adhesions. In striking contrast, the Ca2+-hyposensitive mutants were not found at the leading edge but localized exclusively at focal adhesions/stress fibers, which displayed reinforced morphology. Consistently, the Ca2+-hypersensitive PLS3 mutants were restricted to lamellipodia, while chelation of Ca2+ caused their redistribution to focal adhesions. Finally, the bundling-deficient mutant failed to co-localize with any F-actin structures in cells despite a preserved F-actin binding through a non-mutation-bearing actin-binding domain. Our findings revealed that severe osteoporosis can be caused by a mutational disruption of the Ca2+-controlled PLS3’s cycling between adhesion complexes and the leading edge. Integration of the structural, biochemical, and cell biology insights enabled us to propose a molecular mechanism of plastin activity regulation by Ca2+.
Loss of Spry1 reduces growth of BRAFV600-mutant cutaneous melanoma and improves response to targeted therapy
Authors: Montico Barbara , Colizzi Francesca , Giurato Giorgio , Rizzo Aurora , Salvati Annamaria , Baboci Lorena , Benedetti Dania , Pivetta Eliana , Covre Alessia , Bo Michele Dal , Weisz Alessandro , Steffan Agostino , Maio Michele , Sigalotti Luca , Fratta Elisabetta
Published: May 2020

Mitogen-activated protein kinase (MAPK) pathway activation is a central step in BRAFV600-mutant cutaneous melanoma (CM) pathogenesis. In the last years, Spry1 has been frequently described as an upstream regulator of MAPK signaling pathway. However, its specific role in BRAFV600-mutant CM is still poorly defined. Here, we report that Spry1 knockdown (Spry1KO) in three BRAFV600-mutant CM cell lines markedly induced cell cycle arrest and apoptosis, repressed cell proliferation in vitro, and impaired tumor growth in vivo. Furthermore, our findings indicated that Spry1KOreduced the expression of several markers of epithelial–mesenchymal transition, such as MMP-2 both in vitro and in vivo. These effects were associated with a sustained and deleterious phosphorylation of ERK1/2. In addition, p38 activation along with an increase in basal ROS levels were found in Spry1KOclones compared to parental CM cell lines, suggesting that BRAFV600-mutant CM may restrain the activity of Spry1 to avoid oncogenic stress and to enable tumor growth. Consistent with this hypothesis, treatment with the BRAF inhibitor (BRAFi) vemurafenib down-regulated Spry1 levels in parental CM cell lines, indicating that Spry1 expression is sustained by the MAPK/ERK signaling pathway in a positive feedback loop that safeguards cells from the potentially toxic effects of ERK1/2 hyperactivation. Disruption of this feedback loop rendered Spry1KOcells more susceptible to apoptosis and markedly improved response to BRAFi both in vitro and in vivo, as a consequence of the detrimental effect of ERK1/2 hyperactivation observed upon Spry1 abrogation. Therefore, targeting Spry1 might offer a treatment strategy for BRAFV600-mutant CM by inducing the toxic effects of ERK-mediated signaling.
BBMRI-ERIC’s contributions to research and knowledge exchange on COVID-19
Authors:   on behalf of the BBMRI-ERIC community, Holub Petr , Kozera Lukasz , Florindi Francesco , van Enckevort Esther , Swertz Morris , Reihs Robert , Wutte Andrea , Valík Dalibor , Mayrhofer Michaela Th.
Published: May 2020

During the COVID-19 pandemic, the European biobanking infrastructure is in a unique position to preserve valuable biological material complemented with detailed data for future research purposes. Biobanks can be either integrated into healthcare, where preservation of the biological material is a fork in clinical routine diagnostics and medical treatment processes or they can also host prospective cohorts or material related to clinical trials. The paper discussed objectives of BBMRI-ERIC, the European research infrastructure established to facilitate access to quality-defined biological materials and data for research purposes, with respect to the COVID-19 crisis: (a) to collect information on available European as well as non-European COVID-19-relevant biobanking resources in BBMRI-ERIC Directory and to facilitate access to these via BBMRI-ERIC Negotiator platform; (b) to help harmonizing guidelines on how data and biological material is to be collected to maximize utility for future research, including large-scale data processing in artificial intelligence, by participating in activities such as COVID-19 Host Genetics Initiative; (c) to minimize risks for all involved parties dealing with (potentially) infectious material by developing recommendations and guidelines; (d) to provide a European-wide platform of exchange in relation to ethical, legal, and societal issues (ELSI) specific to the collection of biological material and data during the COVID-19 pandemic.
Correction: Use of biomaterials for sustained delivery for anti-VEGF to treat retinal diseases
Authors: Seah Ivan , Zhao Xinxin , Lin Qianyu , Liu Zengping , Su Steven Zheng Zhe , Yuen Yew Sen , Hunziker Walter , Lingam Gopal , Loh Xian Jun , Su Xinyi
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
A mechanistic explanation of the transition to simple multicellularity in fungi
Authors: Heaton Luke L. M. , Jones Nick S. , Fricker Mark D.
Published: May 2020

Development of multicellularity was one of the major transitions in evolution and occurred independently multiple times in algae, plants, animals, and fungi. However recent comparative genome analyses suggest that fungi followed a different route to other eukaryotic lineages. To understand the driving forces behind the transition from unicellular fungi to hyphal forms of growth, we develop a comparative model of osmotrophic resource acquisition. This predicts that whenever the local resource is immobile, hard-to-digest, and nutrient poor, hyphal osmotrophs outcompete motile or autolytic unicellular osmotrophs. This hyphal advantage arises because transporting nutrients via a contiguous cytoplasm enables continued exploitation of remaining resources after local depletion of essential nutrients, and more efficient use of costly exoenzymes. The model provides a mechanistic explanation for the origins of multicellular hyphal organisms, and explains why fungi, rather than unicellular bacteria, evolved to dominate decay of recalcitrant, nutrient poor substrates such as leaf litter or wood.
Using publicly available satellite imagery and deep learning to understand economic well-being in Africa
Authors: Yeh Christopher , Perez Anthony , Driscoll Anne , Azzari George , Tang Zhongyi , Lobell David , Ermon Stefano , Burke Marshall
Published: May 2020

Accurate and comprehensive measurements of economic well-being are fundamental inputs into both research and policy, but such measures are unavailable at a local level in many parts of the world. Here we train deep learning models to predict survey-based estimates of asset wealth across ~ 20,000 African villages from publicly-available multispectral satellite imagery. Models can explain 70% of the variation in ground-measured village wealth in countries where the model was not trained, outperforming previous benchmarks from high-resolution imagery, and comparison with independent wealth measurements from censuses suggests that errors in satellite estimates are comparable to errors in existing ground data. Satellite-based estimates can also explain up to 50% of the variation in district-aggregated changes in wealth over time, with daytime imagery particularly useful in this task. We demonstrate the utility of satellite-based estimates for research and policy, and demonstrate their scalability by creating a wealth map for Africa’s most populous country.
Colossal flexoresistance in dielectrics
Authors: Park Sung Min , Wang Bo , Paudel Tula , Park Se Young , Das Saikat , Kim Jeong Rae , Ko Eun Kyo , Lee Han Gyeol , Park Nahee , Tao Lingling , Suh Dongseok , Tsymbal Evgeny Y. , Chen Long-Qing , Noh Tae Won , Lee Daesu
Published: May 2020

Dielectrics have long been considered as unsuitable for pure electrical switches; under weak electric fields, they show extremely low conductivity, whereas under strong fields, they suffer from irreversible damage. Here, we show that flexoelectricity enables damage-free exposure of dielectrics to strong electric fields, leading to reversible switching between electrical states—insulating and conducting. Applying strain gradients with an atomic force microscope tip polarizes an ultrathin film of an archetypal dielectric SrTiO3 via flexoelectricity, which in turn generates non-destructive, strong electrostatic fields. When the applied strain gradient exceeds a certain value, SrTiO3 suddenly becomes highly conductive, yielding at least around a 108-fold decrease in room-temperature resistivity. We explain this phenomenon, which we call the colossal flexoresistance, based on the abrupt increase in the tunneling conductance of ultrathin SrTiO3 under strain gradients. Our work extends the scope of electrical control in solids, and inspires further exploration of dielectric responses to strong electromechanical fields.
Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion
Authors: Ke Wenfan , Saba James A. , Yao Cong-Hui , Hilzendeger Michael A. , Drangowska-Way Anna , Joshi Chintan , Mony Vinod K. , Benjamin Shawna B. , Zhang Sisi , Locasale Jason , Patti Gary J. , Lewis Nathan , O’Rourke Eyleen J.
Published: May 2020

The gut microbiota metabolizes drugs and alters their efficacy and toxicity. Diet alters drugs, the metabolism of the microbiota, and the host. However, whether diet-triggered metabolic changes in the microbiota can alter drug responses in the host has been largely unexplored. Here we show that dietary thymidine and serine enhance 5-fluoro 2′deoxyuridine (FUdR) toxicity in C. elegans through different microbial mechanisms. Thymidine promotes microbial conversion of the prodrug FUdR into toxic 5-fluorouridine-5′-monophosphate (FUMP), leading to enhanced host death associated with mitochondrial RNA and DNA depletion, and lethal activation of autophagy. By contrast, serine does not alter FUdR metabolism. Instead, serine alters E. coli’s 1C-metabolism, reduces the provision of nucleotides to the host, and exacerbates DNA toxicity and host death without mitochondrial RNA or DNA depletion; moreover, autophagy promotes survival in this condition. This work implies that diet-microbe interactions can alter the host response to drugs without altering the drug or the host.
An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells
Authors: Colli Maikel L. , Ramos-Rodríguez Mireia , Nakayasu Ernesto S. , Alvelos Maria I. , Lopes Miguel , Hill Jessica L. E. , Turatsinze Jean-Valery , Coomans de Brachène Alexandra , Russell Mark A. , Raurell-Vila Helena , Castela Angela , Juan-Mateu Jonàs , Webb-Robertson Bobbie-Jo M. , Krogvold Lars , Dahl-Jorgensen Knut , Marselli Lorella , Marchetti Piero , Richardson Sarah J. , Morgan Noel G. , Metz Thomas O. , Pasquali Lorenzo , Eizirik Décio L.
Published: May 2020

Interferon-α (IFNα), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFNα by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFNα induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFNα effects on human beta cells.
Kinesin-14 motors drive a right-handed helical motion of antiparallel microtubules around each other
Authors: Mitra Aniruddha , Meißner Laura , Gandhimathi Rojapriyadharshini , Renger Roman , Ruhnow Felix , Diez Stefan
Published: May 2020

Within the mitotic spindle, kinesin motors cross-link and slide overlapping microtubules. Some of these motors exhibit off-axis power strokes, but their impact on motility and force generation in microtubule overlaps has not been investigated. Here, we develop and utilize a three-dimensional in vitro motility assay to explore kinesin-14, Ncd, driven sliding of cross-linked microtubules. We observe that free microtubules, sliding on suspended microtubules, not only rotate around their own axis but also move around the suspended microtubules with right-handed helical trajectories. Importantly, the associated torque is large enough to cause microtubule twisting and coiling. Further, our technique allows us to measure the in situ spatial extension of the motors between cross-linked microtubules to be about 20 nm. We argue that the capability of microtubule-crosslinking kinesins to cause helical motion of overlapping microtubules around each other allows for flexible filament organization, roadblock circumvention and torque generation in the mitotic spindle.
Vesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster
Authors: Chen Po-Lin , Huang Kai-Ting , Cheng Chu-Ya , Li Jian-Chiuan , Chan Hsiao-Yen , Lin Tzu-Yang , Su Matthew P. , Yang Wei-Yuan , Chang Henry C. , Wang Horng-Dar , Chen Chun-Hong
Published: May 2020

Mitochondrial aging, which results in mitochondrial dysfunction, is strongly linked to many age-related diseases. Aging is associated with mitochondrial enlargement and transport of cytosolic proteins into mitochondria. The underlying homeostatic mechanisms that regulate mitochondrial morphology and function, and their breakdown during aging, remain unclear. Here, we identify a mitochondrial protein trafficking pathway in Drosophila melanogaster involving the mitochondria-associated protein Dosmit. Dosmit induces mitochondrial enlargement and the formation of double-membraned vesicles containing cytosolic protein within mitochondria. The rate of vesicle formation increases with age. Vesicles originate from the outer mitochondrial membrane as observed by tracking Tom20 localization, and the process is mediated by the mitochondria-associated Rab32 protein. Dosmit expression level is closely linked to the rate of ubiquitinated protein aggregation, which are themselves associated with age-related diseases. The mitochondrial protein trafficking route mediated by Dosmit offers a promising target for future age-related mitochondrial disease therapies.
Gestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring
Authors: Cuzon Carlson Verginia C. , Gremel Christina M. , Lovinger David M.
Published: May 2020

Fetal alcohol exposure (FAE) is the leading preventable developmental cause of cognitive dysfunction. Even in the absence of binge drinking, alcohol consumption during pregnancy can leave offspring deficient. However, the mechanisms underlying these deficiencies are unknown. Using a mouse model of gestational ethanol exposure (GEE), we show increased instrumental lever-pressing and disruption of efficient habitual actions in adults, indicative of disrupted cognitive function. In vivo electrophysiology reveals disrupted action encoding in dorsolateral striatum (DLS) associated with altered habit learning. GEE mice exhibit decreased GABAergic transmission onto DLS projection neurons, including inputs from parvalbumin interneurons, and increased endocannabinoid tone. Chemogenetic activation of DLS parvalbumin interneurons reduces the elevated lever pressing of GEE mice. Pharmacologically increasing endocannabinoid tone mimics GEE effects on cognition and synaptic transmission. These findings show GEE induces long-lasting deficits in cognitive function that may contribute to human FAE, and identify potential mechanisms for future therapeutic targeting.
Methylation of a CGATA element inhibits binding and regulation by GATA-1
Authors: Yang Lu , Chen Zhiliang , Stout Elizabeth S. , Delerue Fabien , Ittner Lars M. , Wilkins Marc R. , Quinlan Kate G. R. , Crossley Merlin
Published: May 2020

Alterations in DNA methylation occur during development, but the mechanisms by which they influence gene expression remain uncertain. There are few examples where modification of a single CpG dinucleotide directly affects transcription factor binding and regulation of a target gene in vivo. Here, we show that the erythroid transcription factor GATA-1 — that typically binds T/AGATA sites — can also recognise CGATA elements, but only if the CpG dinucleotide is unmethylated. We focus on a single CGATA site in the c-Kit gene which progressively becomes unmethylated during haematopoiesis. We observe that methylation attenuates GATA-1 binding and gene regulation in cell lines. In mice, converting the CGATA element to a TGATA site that cannot be methylated leads to accumulation of megakaryocyte-erythroid progenitors. Thus, the CpG dinucleotide is essential for normal erythropoiesis and this study illustrates how a single methylated CpG can directly affect transcription factor binding and cellular regulation.
Mott gap collapse in lightly hole-doped Sr2−xKxIrO4
Authors: Nelson J. N. , Parzyck C. T. , Faeth B. D. , Kawasaki J. K. , Schlom D. G. , Shen K. M.
Published: May 2020

The evolution of Sr2IrO4 upon carrier doping has been a subject of intense interest, due to its similarities to the parent cuprates, yet the intrinsic behaviour of Sr2IrO4 upon hole doping remains enigmatic. Here, we synthesize and investigate hole-doped Sr2−xKxIrO4 utilizing a combination of reactive oxide molecular-beam epitaxy, substitutional diffusion and in-situ angle-resolved photoemission spectroscopy. Upon hole doping, we observe the formation of a coherent, two-band Fermi surface, consisting of both hole pockets centred at (π, 0) and electron pockets centred at (π/2, π/2). In particular, the strong similarities between the Fermi surface topology and quasiparticle band structure of hole- and electron-doped Sr2IrO4 are striking given the different internal structure of doped electrons versus holes.
Selective C-H trifluoromethoxylation of (hetero)arenes as limiting reagent
Authors: Deng Zhijie , Zhao Mingxin , Wang Feng , Tang Pingping
Published: May 2020

Methods for direct C-H trifluoromethoxylation of arenes and heteroarenes are rare, despite the importance of trifluoromethoxylated compounds for pharmaceuticals, agrochemicals, and material sciences. Especially selective C-H trifluoromethoxylation of pyridines remains a formidable challenge. Here we show a general late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagent with trifluoromethoxide anion. The reaction is mediated by silver salts under mild reaction conditions, exhibiting broad substrate scope and wide functional-group compatibility. In addition, ortho-position selective C-H trifluoromethoxylation of pyridines is observed. The method is not only applicable to the gram-scale synthesis of trifluoromethoxylated products but also allows efficient late-stage C-H trifluoromethoxylation of marketed small-molecule drugs, common pharmacophores and natural products.
Activation of allylic esters in an intramolecular vinylogous kinetic resolution reaction with synergistic magnesium catalysts
Authors: Li Dan , Yang Yuling , Zhang Minmin , Wang Linqing , Xu Yingfan , Yang Dongxu , Wang Rui
Published: May 2020

Kinetic resolution (KR) of racemic starting materials is a powerful and practical alternative to prepare valuable enantiomerically enriched compounds. A magnesium-catalyzed kinetic resolution based on a designed intramolecular vinylogous Michael reaction is disclosed. Here we show a synergistic catalytic strategy based on the development of chiral ligands. Substrates containing linear allylic ester structures are designed and synthesized to construct key [6.6.5]-tricyclic chiral skeletons via this kinetic resolution process. Detailed mechanistic studies reveal a rational mechanism for the current intramolecular vinylogous KR reaction. The desired direct intramolecular asymmetric vinylogous Michael reaction of linear allylic esters is realized in high efficiency and enantioselectivity with the synergistic catalytic system.
Continuous monitoring of suspended sediment concentrations using image analytics and deriving inherent correlations by machine learning
Authors: Ghorbani Mohammad Ali , Khatibi Rahman , Singh Vijay P. , Kahya Ercan , Ruskeepää Heikki , Saggi Mandeep Kaur , Sivakumar Bellie , Kim Sungwon , Salmasi Farzin , Hasanpour Kashani Mahsa , Samadianfard Saeed , Shahabi Mahmood , Jani Rasoul
Published: May 2020

The barriers for the development of continuous monitoring of Suspended Sediment Concentration (SSC) in channels/rivers include costs and technological gaps but this paper shows that a solution is feasible by: (i) using readily available high-resolution images; (ii) transforming the images into image analytics to form a modelling dataset; and (iii) constructing predictive models by learning inherent correlation between observed SSC values and their image analytics. High-resolution images were taken of water containing a series of SSC values using an exploratory flume. Machine learning is processed by dividing the dataset into training and testing sets and the paper uses the following models: Generalized Linear Machine (GLM) and Distributed Random Forest (DRF). Results show that each model is capable of reliable predictions but the errors at higher SSC are not fully explained by modelling alone. Here we offer sufficient evidence for the feasibility of a continuous SSC monitoring capability in channels before the next phase of the study with the goal of producing practice guidelines.
Fleeting Perceptual Experience and the Possibility of Recalling Without Seeing
Authors: Jones William , Pincham Hannah , Gootjes-Dreesbach Ellis Luise , Bowman Howard
Published: May 2020

We explore an intensely debated problem in neuroscience, psychology and philosophy: the degree to which the “phenomenological consciousness” of the experience of a stimulus is separable from the “access consciousness” of its reportability. Specifically, it has been proposed that these two measures are dissociated from one another in one, or both directions. However, even if it was agreed that reportability and experience were doubly dissociated, the limits of dissociation logic mean we would not be able to conclusively separate the cognitive processes underlying the two. We take advantage of computational modelling and recent advances in state-trace analysis to assess this dissociation in an attentional/experiential blink paradigm. These advances in state-trace analysis make use of Bayesian statistics to quantify the evidence for and against a dissociation. Further evidence is obtained by linking our finding to a prominent model of the attentional blink – the Simultaneous Type/Serial Token model. Our results show evidence for a dissociation between experience and reportability, whereby participants appear able to encode stimuli into working memory with little, if any, conscious experience of them. This raises the possibility of a phenomenon that might be called sight-blind recall, which we discuss in the context of the current experience/reportability debate.
Expression of genes of the Pho regulon is altered in Streptomyces coelicolor
Authors: Millan-Oropeza Aaron , Henry Céline , Lejeune Clara , David Michelle , Virolle Marie-Joelle
Published: May 2020

Most currently used antibiotics originate from Streptomycetes and phosphate limitation is an important trigger of their biosynthesis. Understanding the molecular processes underpinning such regulation is of crucial importance to exploit the great metabolic diversity of these bacteria and get a better understanding of the role of these molecules in the physiology of the producing bacteria. To contribute to this field, a comparative proteomic analysis of two closely related model strains,Streptomyces lividansandStreptomyces coelicolorwas carried out. These strains possess identical biosynthetic pathways directing the synthesis of three well-characterized antibiotics (CDA, RED and ACT) but onlyS. coelicolorexpresses them at a high level. Previous studies established that the antibiotic producer,S. coelicolor, is characterized by an oxidative metabolism and a reduced triacylglycerol content compared to the none producer,S. lividans, characterized by a glycolytic metabolism. Our proteomic data support these findings and reveal that these drastically different metabolic features could, at least in part, due to the weaker abundance of proteins of the two component system PhoR/PhoP inS. coelicolorcompared toS. lividans. In condition of phosphate limitation, PhoR/PhoP is known to control positively and negatively, respectively, phosphate and nitrogen assimilation and our study revealed that it might also control the expression of some genes of central carbon metabolism. The tuning down of the regulatory role of PhoR/PhoP inS. coelicoloris thus expected to be correlated with low and high phosphate and nitrogen availability, respectively and with changes in central carbon metabolic features. These changes are likely to be responsible for the observed differences betweenS. coelicolorandS. lividansconcerning energetic metabolism, triacylglycerol biosynthesis and antibiotic production. Furthermore, a novel view of the contribution of the bio-active molecules produced in this context, to the regulation of the energetic metabolism of the producing bacteria, is proposed and discussed.
First evidence of a palaeo-nursery area of the great white shark
Authors: Villafaña Jaime A. , Hernandez Sebastian , Alvarado Alonso , Shimada Kenshu , Pimiento Catalina , Rivadeneira Marcelo M. , Kriwet Jürgen
Published: May 2020

Shark nurseries are essential habitats for shark survival. Notwithstanding the rich fossil record of the modern great white shark (Carcharodon carcharias, GWS), its use of nursery areas in the fossil record has never been assessed before. Here, we analysed the fossil record of the GWS from three South American Pliocene localities, assessed body size distributions and applied previously established criteria to identify palaeo-nurseries. We found that juveniles dominate the Coquimbo locality (Chile), whereas subadults and adults characterize Pisco (Peru) and Caldera (Chile), respectively. These results, summed to the paleontological and paleoenvironmental record of the region, suggest that Coquimbo represents the first nursery area for the GWS in the fossil record. Our findings demonstrate that one of the top predators in today’s oceans has used nursery areas for millions of years, highlighting their importance as essential habitats for shark survival in deep time.
A new approach to prevent cervical stenosis in postmenopausal women after loop electrosurgical excision procedure: a randomized controlled trial
Authors: Lin Jing , Meng Yu , Chen Yi , Li Zhunan , Xu Ying , Wu Dan
Published: May 2020

To determine whether regular cervical dilatation is effective for preventing cervical stenosis, and to identify the associated risk factors, in postmenopausal women after LEEP. This was a prospective randomized clinical trial in postmenopausal women who underwent LEEP at our hospital between August 2018 and May 2019. Patients who met the study criteria were randomly allocated to three groups: control group (without any intervention), intervention group A (underwent cervical dilatation at the 3rd, 5th, and 8th week after LEEP) and intervention group B (underwent cervical dilatation at the 4th, 8th, and 12th week after LEEP). A colposcopic follow-up examination was conducted at 6 months after LEEP to determine the incidence of cervical stenosis. A total of 404 postmenopausal women were found to be finally eligible for the study. The rate of cervical stenosis in the control group was significantly higher than that in the intervention group, and the rate in group A was significantly lower than that in group B. We found regular dilatation after LEEP in postmenopausal women can prevent cervical stenosis. Further, the 3rd, 5th, and 8th weeks after LEEP are optimal time points. Finally, LEEP frequency and resection depth are significant risk factors and can be used to screen postmenopausal women at risk for cervical stenosis after LEEP.
Non-mantle-plume process caused the initial spreading of the South China Sea
Authors: Yu Xun , Liu Zhifei
Published: May 2020

The mantle plume process is thought to be the prevailing dynamic mechanism for the South China Sea opening, but controversy persists due to the lack of critical evidence of magma in the initial seafloor spreading. International Ocean Discovery Program (IODP) Expedition 367 successfully recovered at Site U1500 the mid-ocean ridge basalt (MORB) representing the magma activity of the initial spreading of the South China Sea during the earliest Oligocene. Here we present the whole-rock and olivine phenocryst geochemistry of the basalts to constrain the potential influence of the Hainan mantle plume on the evolution of the South China Sea. Major and trace elemental compositions indicate that the basalts were mainly influenced by fractional crystallization of olivine and formed by melting of a spinel peridotite source without any pyroxenite in mantle source. The calculated mantle potential temperature of those most primitive basalts is much lower than plume-related MORB of Iceland, but similar to normal MORB elsewhere. Both lithological composition and mantle potential temperature clearly contradict with the mantle plume model, signifying that the mantle plume didn’t exist at the earliest Oligocene. Therefore, the initial spreading of the South China Sea should be caused by non-plume processes, most likely by the westward subduction of the Pacific Plate.
Influence of garlic and pepper powder on physicochemical and sensory qualities of flavoured rice noodle
Authors: Utama-ang Niramon , Cheewinworasak Thosaphon , Simawonthamgul Natthawut , Samakradhamrongthai Rajnibhas Sukeaw
Published: May 2020

This research aimed to investigate the effect of dried garlic powder (DGP) and dried white pepper powder (DWPP) on physicochemical and sensory properties and to develop a garlic-pepper flavoured purple rice noodle (GPFRD). The garlic-pepper powder (GPP) aroma found to be comprised of pine, garlic, onion, citrus and woody characteristic. The 78 g of DGP and 20 g of DWPP provided high sensory rating score of pepper aroma (5.9 ± 0.1) and overall aroma (5.6 ± 0.2) with a high content of beta-caryophyllene (0.101 ± 0.04 mg/g powder), limonene (0.069 ± 0.02 mg/g powder), allicin (10.48 ± 0.18 mg/g powder) and piperine (0.71 ± 0.11 mg/g powder). The cooked GPFRD mixed with garlic-pepper at 2% possessed the good quality of physical and chemical properties with sensory rating score. The GPFRD using 2% of GPP provided preference rating score in the range of 6.0–6.7 with consumer acceptance at 82.0% and purchase intention at 74.0%. Consequently, the optimum ratio of DGP and DWPP provided a better spice mix for aroma, flavour, with some bioactive compound aspects. A suitable amount of GPP can provide the preferable properties of flavoured purple rice noodles.