bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unoccupied aerial system enabled functional modeling of maize (Zea mays L.) height reveals dynamic expression of loci associated to temporal growth
Authors: Anderson Steven L. , Murray Seth C. , Chen Yuanyuan , Malambo Lonesome , Chang Anjin , Popescu Sorin , Cope Dale , Jung Jinha 
Published: November 2019

AbstractUnoccupied aerial systems (UAS) were used to phenotype growth trajectories of inbred maize populations under field conditions. Three recombinant inbred line populations were surveyed on a weekly basis collecting RGB images across two irrigation regimens (irrigated and non-irrigated/rain fed). Plant height, estimated by the 95th percentile (P95) height from UAS generated 3D point clouds, exceeded 70% correlation to manual ground truth measurements and 51% of experimental variance was explained by genetics. The Weibull sigmoidal function accurately modeled plant growth (R2: >99%; RMSE: < 4 cm) from P95 genetic means. The mean asymptote was strongly correlated (r2=0.66-0.77) with terminal plant height. Maximum absolute growth rates (mm d-1) were weakly correlated to height and flowering time. The average inflection point ranged from 57 to 60 days after sowing (DAS) and was correlated with flowering time (r2=0.45-0.68). Functional growth parameters (asymptote, inflection point, growth rate) alone identified 34 genetic loci, each explaining 3 to 15% of total genetic variation. Plant height was estimated at one-day intervals to 85 DAS, identifying 58 unique temporal quantitative trait loci (QTL) locations. Genomic hotspots on chromosome 1 and 3 indicated chromosomal regions associated with functional growth trajectories influencing flowering time, growth rate, and terminal growth. Temporal QTL demonstrated unique dynamic expression patterns not observable previously, no QTL were significantly expressed throughout the entire growing season. UAS technologies improved phenotypic selection accuracy and permitted monitoring traits on a temporal scale previously infeasible using manual measurements, furthering understanding of crop development and biological trajectories.Author summaryUnoccupied aerial systems (UAS) now can provide high throughput phenotyping to functionally model plant growth and explore genetic loci underlying temporal expression of dynamic phenotypes, specifically plant height. Efficient integration of temporal phenotyping via UAS, will improve the scientific understanding of dynamic, quantitative traits and developmental trajectories of important agronomic crops, leading to new understanding of plant biology. Here we present, for the first time, the dynamic nature of quantitative trait loci (QTL) over time under field conditions. To our knowledge, this is first empirical study to expand beyond selective developmental time points, evaluating functional and temporal QTL expression in maize (Zea mays L.) throughout a growing season within a field-based environment.
Native Hydrogen/Deuterium Exchange Mass Spectrometry of Structured DNA Oligonucleotides
Authors: Largy Eric , Gabelica Valérie 
Published: November 2019

ABSTRACTAlthough solution hydrogen-deuterium exchange mass spectrometry (HDX/MS) is well-established for the analysis of the structure and dynamics of proteins, it is currently not exploited for nucleic acids. Here we used DNA G-quadruplex structures as model systems to demonstrate that DNA oligonucleotides are amenable to in-solution HDX/MS in native conditions. In trimethylammonium acetate solutions and in soft source conditions, the protonated phosphate groups are fully back-exchanged in the source, while the exchanged nucleobases remain labeled without detectable back-exchange. As a result, the exchange rates depend strongly on the secondary structure (hydrogen bonding status) of the oligonucleotides, but neither on their charge state nor on the presence of non-specific adducts. We show that native mass spectrometry methods can measure these exchange rates on the second to the day time scale with high precision. Such combination of HDX with native MS opens promising avenues for the analysis of the structural and biophysical properties of oligonucleotides and their complexes.
Ubiquitin transfer by a RING E3 ligase occurs from a closed E2~Ub conformation
Authors: Branigan Emma , Penedo J. Carlos , Hay Ronald T. 
Published: November 2019

AbstractUbiquitination is a eukaryotic post-translational modification that modulates a host of cellular processes1. Modification is mediated by an E1 activating enzyme (E1), an E2 conjugating enzyme (E2) and an E3 ligase (E3). The E1 catalyses formation of a highly reactive thioester linked conjugate between ubiquitin and E2 (E2~Ub)2. The largest class of ubiquitin E3 ligases, which is represented by RING E3s, bind both substrate and E2~Ub and facilitate transfer of ubiquitin from the E2 to substrate. Based on extensive structural analysis3–5 it has been proposed that RING E3s prime the E2~Ub conjugate for catalysis by locking it into a “closed” conformation where ubiquitin is folded back onto the E2 exposing the restrained thioester bond to attack by a substrate nucleophile. However the proposal that the RING dependent closed conformation of E2~Ub represents the active form that mediates ubiquitin transfer is a model that has yet to be experimentally tested. Here we use single molecule Förster Resonance Energy Transfer (smFRET) to test this hypothesis and demonstrate that ubiquitin is transferred from the closed conformation during an E3 catalysed reaction. Using Ubc13 as an E2, we designed a FRET labelled E2~Ub conjugate, which distinguishes between closed and alternative conformations. Firstly, we defined the high FRET state as the closed conformation using a stable isopeptide linked E2~Ub conjugate, while the low FRET state represents more open conformations. Secondly, we developed a real-time smFRET assay to monitor RING E3 catalysed ubiquitination with a thioester linked E2~Ub conjugate and determined the catalytically active conformation. Our results demonstrate that the reaction proceeds from the high FRET or closed conformation and confirm the hypothesis that the closed conformation is the active form of the conjugate. These findings are not only relevant to RING E3 catalysed ubiquitination but are also broadly applicable to E3 mediated ligation of other ubiquitin-like proteins (Ubls) to substrates.
Developmental trajectory of pre-hematopoietic stem cell formation from endothelium
Authors: Zhu Qin , Gao Peng , Tober Joanna , Bennett Laura , Chen Changya , Uzun Yasin , Li Yan , Mumau Melanie , Yu Wenbao , He Bing , Speck Nancy A. , Tan Kai 
Published: November 2019

SummaryHematopoietic stem and progenitor cells (HSPCs) differentiate from hemogenic endothelial (HE) cells through an endothelial to hematopoietic cell transition (EHT). Newly formed HSPCs accumulate in intra-arterial clusters (IACs) before colonizing the fetal liver. To examine the cell and molecular transitions during the EHT, and the heterogeneity of HSPCs within IACs, we profiled ∼37,000 cells from the caudal arteries of embryonic day 9.5 (E9.5) to E11.5 mouse embryos by single-cell transcriptome and chromatin accessibility sequencing. We identified an intermediate developmental stage prior to HE that we termed pre-HE, characterized by increased accessibility of chromatin enriched for SOX, FOX, GATA, and SMAD motifs. A developmental bottleneck separates pre-HE from HE, with RUNX1 dosage regulating the efficiency of the pre-HE to HE transition. Distinct developmental trajectories within IAC cells result in two populations of CD45+HSPCs; an initial wave of lympho-myeloid-biased progenitors, followed by precursors of hematopoietic stem cells (pre-HSCs).
Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling
Authors: You Inchul , Erickson Emily C. , Donovan Katherine A. , Eleuteri Nicholas A. , Fischer Eric S. , Gray Nathanael S. , Toker Alex 
Published: November 2019

SUMMARYThe PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Our findings indicate that AKT degradation may confer prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.
MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity
Authors: Whitlock Nichelle C. , Trostel Shana Y. , Wilkinson Scott , Terrigino Nicholas T. , Hennigan S. Thomas , Lake Ross , Carrabba Nicole V. , Atway Rayann , Walton Elizabeth D. , Gryder Berkley E. , Capaldo Brian J. , Ye Huihui , Sowalsky Adam G. 
Published: November 2019

ABSTRACTLocalized prostate cancer develops very slowly in most men, with the androgen receptor (AR) and MYC transcription factors amongst the most well-characterized drivers of prostate tumorigenesis. Canonically, MYC up-regulation in luminal prostate cancer cells functions to oppose the terminally differentiating effects of AR. However, the effects of MYC up-regulation are pleiotropic and inconsistent with a poorly proliferative phenotype. Here we show that increased MYC expression and activity are associated with the down-regulation ofMEIS1, a HOX-family transcription factor. Using RNA-seq to profile a series of human prostate cancer specimens laser capture microdissected on the basis of MYC immunohistochemistry, MYC activity andMEIS1expression were inversely correlated. Knockdown ofMYCexpression in prostate cancer cells increased expression ofMEIS1and increased occupancy of MYC at theMEIS1locus. Finally, we show in laser capture microdissected human prostate cancer samples and the prostate TCGA cohort thatMEIS1expression is inversely proportional to AR activity as well asHOXB13, a known interacting protein of both AR and MEIS1. Collectively, our data demonstrate that elevated MYC in a subset of primary prostate cancers functions in a negative role in regulatingMEIS1expression, and that this down-regulation may contribute to MYC-driven development and progression.
Targeting RNA Polymerase I transcription synergises with TOP1 inhibition in potentiating the DNA damage response in high-grade serous ovarian cancer
Authors: Yan Shunfei , Madhamshettiwar Piyush B. , Simpson Kaylene J. , Ellis Sarah , Kang Jian , Cullinane Carleen , Sheppard Karen E. , Hannan Katherine M. , Hannan Ross D. , Sanij Elaine , Pearson Richard B. , Chan Keefe T. 
Published: November 2019

AbstractLimited effective therapeutic options are available for patients with recurrent high-grade serous carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. We have shown efficacy in poly-ADP ribose polymerase (PARP) inhibitor-resistant HGSC for the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 through its ability to activate a nucleolar-associated DNA damage response (DDR). Here, we screen the protein-coding genome to identify potential targets whose inhibition enhances the efficacy of CX-5461. We identify a network of cooperating inhibitory interactions, including components of homologous recombination (HR) DNA repair and DNA topoisomerase 1 (TOP1). We highlight that CX-5461 combined with topotecan, a TOP1 inhibitor used as salvage therapy in HGSC, induces robust cell cycle arrest and cell death in a panel of HR-proficient HGSC cell lines. The combination potentiates a nucleolar-associated DDR via recruitment of phosphorylated replication protein A (RPA) and ataxia telangiectasia and Rad3 related protein (ATR). CX-5461 plus low-dose topotecan cooperate to potently inhibit xenograft tumour growth, indicating the potential for this strategy to improve salvage therapeutic regimens to treat HGSC.
An early warning system to identify house price bubbles
Authors: Hagemann Daniel , Wohlmann Monika 
Published: November 2019

PurposeThe global financial and economic crisis resulting from the US housing crisis has shown that house prices can have far-reaching consequences for the real economy. For macroprudential supervision, it is, therefore, necessary to identify house price bubbles at an early stage to counteract speculative price developments and to ensure financial market stability. This paper aims to develop an early warning system to signal speculative price bubbles.Design/methodology/approachThe results of explosivity tests are used to identify periods of excessive price increases in 18 industrialized countries. The early warning system is then based on a logit and an ordered logit regression, in which monetary, macroeconomic, regulatory, demographic and private factors are used as explanatory variables.FindingsThe empirical results show that monetary developments have the highest explanatory power for the existence of house price bubbles. Further, the study reveals currently emerging house price bubbles in Norway, Sweden and Switzerland.Practical implicationsThe results implicate a new global housing boom, particularly in those countries that did not experience a major price correction during the global financial crisis.Originality/valueThe ordered logit model is an advanced approach that offers the advantage of being able to differentiate between different phases of a house price bubble, thereby allowing a multi-level assessment of the risk of speculative excesses in the housing market.
The search and matching process in the housing market
Authors: Lisi Gaetano 
Published: November 2019

PurposeThis paper aims to study the relationship between the rental and selling prices, a very important topic that forms the fundamentals of real estate markets.Design/methodology/approachThis theoretical paper makes use of a search and matching model of the housing market. The search and matching models are the benchmark models of the “matching” markets, such as the labour market and the housing market, where trade is a decentralised, uncoordinated and time-consuming economic activity.FindingsUnlike the previous related literature, where this relation is usually analysed in the context of the present value equation, this paper shows the existence of a “dual” relation between rental and selling prices as follows: one in the homeownership market and another one in the rental market. This “dual” relation connects the rental and homeownership markets and allows to get equilibrium in both markets with positive house prices.Research limitations/implicationsSeveral topics could be deepened for making the paper richer and more interesting, although at the cost of much more mathematics. First of all, the introduction of specific functional forms for both the rent function and the sale price function, so as to calculate both the elasticity of rent with respect to sale price and the elasticity of sale price with respect to rent. In this way, it would be possible to understand how each market (rental and homeownership) reacts to shock and policies that affect the other market.Practical implicationsIn general, this framework could help policymakers to design housing policy reforms that take into consideration the effects on both markets. Indeed, some policies could have positive effects on rental markets but perverse effects on homeownership markets and vice versa.Originality/valueNone of the existing and related works of research have considered how to take advantage of the search and matching approach to derive both a “rent function” and a “sale price function” that connect closely the rental and homeownership markets.
Sharp Force Homicide in Denmark 1992–2016
Authors: Thomsen Asser H. , Hougen Hans Petter , Villesen Palle , Brink Ole , Leth Peter M. 
Published: November 2019

AbstractSharp force trauma is a common homicide method. The weapon is typically a knife, which is easily accessible and does not require special skills. We have analyzed all 471 sharp force homicides in Denmark during 1992–2016 with special focus on aspects that are relevant to forensic pathologists, including the distribution of wounds and organ injuries. Most homicides were committed inside with a kitchen knife. The front left thorax was the most common area to be affected by sharp force trauma. In 18.9% of the victims, there was only one sharp injury, the majority on the thorax. The most common trajectory for stab wounds was directly posterior with no deviation to the sides or up/down followed by directly anterior. The heart (including pericardium) and lungs (including hemo‐ and pneumothorax) had injuries in more than 75% of the victims. 67% of victims were males. Female victims had more sharp force injuries and defense wounds than male victims. Most females were killed in domestic homicides (73.7%), most commonly in partner killings (56.4%). In contrast, many male victims were killed in a setting of nightlife/intoxication (34.0%) most by a friend/acquaintance delivering a few stab wounds. The results clearly show strong sex differences in both victims and offenders. This could be useful for shaping policies and public opinion, and as a route for understanding the developments in interpersonal violence. In the narrow setting of death investigation, our results will provide an evidence‐based approach to understanding the injury patterns in sharp force homicide.
The formation of hybrid complexes between isoenzymes of glyceraldehyde‐3‐phosphate dehydrogenase regulates its aggregation state, the glycolytic activity and sphingolipid status in Saccharomyces cerevisiae
Authors: Randez‐Gil Francisca , Sánchez‐Adriá Isabel E. , Estruch Francisco , Prieto Jose A. 
Published: November 2019

SummaryThe glycolytic enzyme glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) has been traditionally considered a housekeeping protein involved in energy generation. However, evidence indicates that GAPDHs from different origins are tightly regulated and that this regulation may be on the basis of glycolysis‐related and glycolysis‐unrelated functions. In Saccharomyces cerevisiae, Tdh3 is the main GAPDH, although two other isoenzymes encoded by TDH1 and TDH2 have been identified. Like other GAPDHs, Tdh3 exists predominantly as a tetramer, although dimeric and monomeric forms have also been isolated. Mechanisms of Tdh3 regulation may thus imply changes in its oligomeric state or be based in its ability to interact with Tdh1 and/or Tdh2 to form hybrid complexes. However, no direct evidence of the existence of these interactions has been provided and the exact function of Tdh1,2 is unknown. Here, we show that Tdh1,2 immunopurified with a GFP‐tagged version of Tdh3 and that lack of this interaction stimulates the Tdh3’s aggregation. Furthermore, we found that the combined knockout of TDH1 and TDH2 promotes the loss of cell’s viability and increases the growing rate, glucose consumption and CO2 production, suggesting a higher glycolytic flux in the mutant cells. Consistent with this, the tdh3 strain, which displays impaired in vitro GAPDH activity, exhibited the opposite phenotypes. Quite remarkably, tdh1 tdh2 mutant cells show increased sensitivity to aureobasidin A, an inhibitor of the inositolphosphoryl ceramide synthase, while cells lacking Tdh3 showed improved tolerance. The results are in agreement with a link between glycolysis and sphingolipid (SLs) metabolism. Engineering Tdh activity could be thus exploited to alter the SLs status with consequences in different aspects of yeast biotechnology.
Estimating Potential Climate Change Effects on the Upper Neuse Watershed Water Balance Using the SWAT Model
Authors: Ercan Mehmet B. , Maghami Iman , Bowes Benjamin D. , Morsy Mohamed M. , Goodall Jonathan L. 
Published: November 2019

AbstractClimate change poses water resource challenges for many already water stressed watersheds throughout the world. One such watershed is the Upper Neuse Watershed in North Carolina, which serves as a water source for the large and growing Research Triangle Park region. The aim of this study was to quantify possible changes in the watershed’s water balance due to climate change. To do this, we used the Soil and Water Assessment Tool (SWAT) model forced with different climate scenarios for baseline, mid‐century, and end‐century time periods using five different downscaled General Circulation Models. Before running these scenarios, the SWAT model was calibrated and validated using daily streamflow records within the watershed. The study results suggest that, even under a mitigation scenario, precipitation will increase by 7.7% from the baseline to mid‐century time period and by 9.8% between the baseline and end‐century time period. Over the same periods, evapotranspiration (ET) would decrease by 5.5 and 7.6%, water yield would increase by 25.1% and 33.2%, and soil water would increase by 1.4% and 1.9%. Perhaps most importantly, the model results show, under a high emission scenario, large seasonal differences with ET estimated to decrease by up to 42% and water yield to increase by up to 157% in late summer and fall. Planning for the wetter predicted future and corresponding seasonal changes will be critical for mitigating the impacts of climate change on water resources.
Cross‐reactivities of non‐homologous allergens
Authors: Bublin Merima , Breiteneder Heimo 
Published: November 2019

AbstractAllergen cross‐reactivities occur when IgE antibodies, originally raised against a specific allergen, bind to identical or highly similar surface areas of another related allergen. It is a commonly held view that cross‐reactivity requires more than 70% sequence identity, while proteins that share <50% sequence identity are rarely cross‐reactive. This also implies that cross‐reactive proteins have a similar 3D fold and belong to the same protein family. At first, the existence of cross‐reactivity between non‐homologous allergens was not expected because it was contrary to the above described concepts. Now, several lines of evidence demonstrate that IgE cross‐reactivity also exists between unrelated allergens. In this Editorial, we aim to summarize the existing literature on IgE cross‐reactivity between non‐homologous allergens.