bluuebunny/crossref_metadata_2025_split huggingface dataset:
A combined human in silico and CRISPR/Cas9-mediated in vivo zebrafish based approach for supporting gene target validation in early drug discovery
Authors: Winter Matthew J. , Ono Yosuke , Ball Jonathan S. , Walentinsson Anna , Michaelsson Erik , Tochwin Anna , Scholpp Steffen , Tyler Charles R. , Rees Steve , Hetheridge Malcolm J , Bohlooly-Y Mohammad 
Published: September 2021

AbstractThe clinical heterogeneity of heart failure has challenged our understanding of the underlying genetic mechanisms of this disease. In this respect, large-scale patient DNA sequencing studies have become an invaluable strategy for identifying potential genetic contributing factors. The complex aetiology of heart failure, however, also means that in vivo models are vital to understand the links between genetic perturbations and functional impacts. Traditional approaches (e.g. genetically-modified mice) are optimal for assessing small numbers of proposed target genes, but less practical when multiple targets are identified. The zebrafish, in contrast, offers great potential for higher throughput in vivo gene functional assessment to aid target prioritisation and support definitive studies undertaken in mice. Here we used whole-exome sequencing and bioinformatics on human patient data to identify 3 genes (API5, HSPB7, and LMO2) suggestively associated with heart failure that were also predicted to play a broader role in disease aetiology. The role of these genes in cardiovascular system development and function was then further investigated using in vivo CRISPR/Cas9-mediated gene mutation analysis in zebrafish. We observed multiple impacts in F0 knockout zebrafish embryos (crispants) following effective somatic mutation, including reductions in ventricle size, pericardial oedema, and chamber malformation. In the case of lmo2, there was also a significant impact on cardiovascular function as well as an expected reduction in erythropoiesis. The data generated from both the human in silico and zebrafish in vivo assessments undertaken supports roles for API5, HSPB7, and LMO2 in human cardiovascular disease and identifies them as potential drug targets for further investigation. The data presented also supports the use of human in silico genetic variant analysis, in combination with zebrafish crispant phenotyping, as a powerful approach for assessing gene function as part of an integrated multi-level drug target validation strategy.
Global mapping of the energetic and allosteric landscapes of protein binding domains
Authors: Faure Andre J. , Domingo Júlia , Schmiedel Jörn M. , Hidalgo-Carcedo Cristina , Diss Guillaume , Lehner Ben 
Published: September 2021

AbstractAllosteric communication between distant sites in proteins is central to nearly all biological regulation but still poorly characterised for most proteins, limiting conceptual understanding, biological engineering and allosteric drug development. Typically only a few allosteric sites are known in model proteins, but theoretical, evolutionary and some experimental studies suggest they may be much more widely distributed. An important reason why allostery remains poorly characterised is the lack of methods to systematically quantify long-range communication in diverse proteins. Here we address this shortcoming by developing a method that uses deep mutational scanning to comprehensively map the allosteric landscapes of protein interaction domains. The key concept of the approach is the use of ‘multidimensional mutagenesis’: mutational effects are quantified for multiple molecular phenotypes—here binding and protein abundance—and in multiple genetic backgrounds. This is an efficient experimental design that allows the underlying causal biophysical effects of mutations to be accurately inferred en masse by fitting thermodynamic models using neural networks. We apply the approach to two of the most common human protein interaction domains, an SH3 domain and a PDZ domain, to produce the first global atlases of allosteric mutations for any proteins. Allosteric mutations are widely dispersed with extensive long-range tuning of binding affinity and a large mutational target space of network-altering ‘edgetic’ variants. Mutations are more likely to be allosteric closer to binding interfaces, at Glycines in secondary structure elements and at particular sites including a chain of residues connecting to an opposite surface in the PDZ domain. This general approach of quantifying mutational effects for multiple molecular phenotypes and in multiple genetic backgrounds should allow the energetic and allosteric landscapes of many proteins to be rapidly and comprehensively mapped.
Interaction between BID and VDAC1 is required for mitochondrial demise and cell death in neurons
Authors: Oppermann Sina , Mertins Barbara , Meissner Lilja , Krasel Cornelius , Psakis Georgios , Reiß Philipp , Dolga Amalia M. , Plesnila Nikolaus , Bünemann Moritz , Essen Lars-Oliver , Culmsee Carsten 
Published: September 2021

AbstractMitochondrial damage is a key feature of regulated cell death in neurons. In particular, mitochondrial outer membrane permeabilization (MOMP) has been proposed as a starting point for mitochondrial demise upon cellular stress. Potential mechanisms for MOMP presented in the literature include membrane pore formation by Bcl2-family proteins such as BID and BAX, oligomerization of voltage-dependent anion channels (VDACs) and hetero-oligomer formation of these proteins. In our study, we demonstrate a direct interaction between the voltage-dependent anion channel VDAC1 and the pro-apoptotic protein BID in dying neurons both in vitro and in vivo. Binding of BID to VDAC1 affects anion conductance through VDAC1 and is associated with glutamate-induced cell death in cultured neurons and ischemic brain injury. In cultured neurons, reducing VDAC1 expression significantly attenuates BID-induced hallmarks of mitochondrial damage such as mitochondrial fission, declined mitochondrial respiration, increased ROS production, and mitochondrial membrane potential breakdown. Our data highlight a critical role for VDAC1 as a mitochondrial receptor for activated BID, thereby serving as a key decision point between life and death in neurons.One Sentence SummaryVDAC1 interacts with BID to mediate mitochondrial membrane permeabilization and neuronal cell death.
The impact of genetic relationship between training and validation populations on genomic prediction accuracy in Atlantic salmon
Authors: Fraslin Clémence , Yáñez José M. , Robledo Diego , Houston Ross D. 
Published: September 2021

AbstractThe potential of genomic selection to improve production traits has been widely demonstrated in many aquaculture species. Atlantic salmon breeding programmes typically consist of sibling testing schemes, where traits that cannot be measured on the selection candidates are measured on the candidates’ siblings (such as disease resistance traits). While annual testing on close relatives is effective, it is expensive due to high genotyping and phenotyping costs. Therefore, accurate prediction of breeding values in distant relatives could significantly reduce the cost of genomic selection. The aims of this study were (i) to evaluate the impact of decreasing the genomic relationship between the training and validation populations on the accuracy of genomic prediction for two key target traits; body weight and resistance to sea lice; and (ii) to assess the interaction of genetic relationship with SNP density, a major determinant of genotyping costs. Phenotype and genotype data from two year classes of a commercial breeding population of Atlantic salmon were used. The accuracy of genomic predictions obtained within a year class was similar to that obtained combining the data from the two year classes for sea lice count (0.49 - 0.48) and body weight (0.63 - 0.61), but prediction accuracy was close to zero when the prediction was performed across year groups. Systematically reducing the relatedness between the training and validation populations within a year class resulted in decreasing accuracy of genomic prediction; when the training and validation populations were set up to contain no relatives with genomic relationships >0.3, the accuracies fell from 0.48 to 0.27 for sea lice count and from 0.63 to 0.29 for body weight. Lower relatedness between training and validation populations also tended to result in highly biased predictions. No clear interaction between decreasing SNP density and relatedness between training and validation population was found. These results confirm the importance of genetic relationships between training and selection candidate populations in salmon breeding programmes, and suggests that prediction across generations using existing approaches would severely compromise the efficacy of genomic selection.
Activation of endoplasmic reticulum stress via clustering of the inner nuclear membrane protein SUN2
Authors: Vidak Sandra , Serebryannyy Leonid A. , Pegoraro Gianluca , Misteli Tom 
Published: September 2021

SUMMARYOne of the major cellular mechanisms to ensure protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is typically triggered by accumulation of misfolded proteins in the ER lumen. Here we describe activation of ER stress via protein aggregation in the cell nucleus. We find in the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) activation of ER stress due to the aggregation of the diseases-causing progerin protein at the nuclear envelope. The presence of nucleoplasmic protein aggregates is sensed and signaled to the ER lumen via immobilization and clustering of the inner nuclear membrane protein SUN2, leading to activation of the Unfolded Protein Response (UPR). These results identify a nuclear trigger of ER stress and they provide insight into the molecular disease mechanisms of HGPS.
Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14 and Sic1 for origin licensing inS. cerevisiae
Authors: Philip Jasmin , Örd Mihkel , Silva Andriele , Singh Shaneen , Diffley John F. X. , Remus Dirk , Loog Mart , Ikui Amy 
Published: September 2021

AbstractCdc6, a subunit of the pre-replicative complex, contains multiple regulatory Cdk1 consensus sites, SP or TP motifs. InS. cerevisiae, Cdk1 phosphorylates Cdc6-T7 to recruit Cks1, the Cdk1 phospho-adaptor in S-phase, for subsequent multisite phosphorylation and protein degradation. Cdc6 accumulates in mitosis and is tightly bound by Clb2 through N-terminal phosphorylation in order to prevent premature origin licensing and degradation. It has been extensively studied how Cdc6 phosphorylation is regulated by the Cyclin-Cdk1 complex. However, a detailed mechanism on how Cdc6 phosphorylation is reversed by phosphatases has not been elucidated. Here, we show that PP2ACdc55dephosphorylates Cdc6 N-terminal sites to release Clb2. Cdc14 dephosphorylates the C-terminal phospho-degron, leading to Cdc6 stabilization in mitosis. In addition, the Cdk1 inhibitor, Sic1, releases Clb2·Cdk1·Cks1 from Cdc6 to load Mcm2-7 on the chromatin upon mitotic exit. Thus, pre-RC assembly and origin licensing is promoted by the attenuation of distinct CDK-dependent Cdc6 inhibitory mechanisms.
Towards precision ecology: Relationships of multiple sampling methods quantifying abundance for comparisons among studies
Authors: Hoffmann Benjamin D. , Pettit Magen 
Published: September 2021

ABSTRACTBecause different sampling techniques will provide different abundance values, it is currently difficult to compare results among many studies to form holistic understandings of how abundance influences ant ecology. Using three sampling methods in the same location we found pitfall traps best confirmed A. gracilipes presence recording the fewest zero values (9.1%), card counts were the least reliable (67.1%), and tuna lures were intermediate (30.1%). The abundance of A. gracilipes from card counts ranged from 0 to 20, in pitfall traps from 0 to 325, and the full range of tuna lure abundance scores (0-7) were sampled. We then determined the relationships between these three standard ant sampling techniques for the abundance of yellow crazy ant Anoplolepis gracilipes. Irrespective of the data transformation method, the strongest relationship was between pitfall traps and tuna lures, and the least strong was between pitfall traps and card counts. We then demonstrate the utility of this knowledge by analysing A. gracilipes abundance reported within published literature to show where the populations in those studies sit on an abundance spectrum. We also comment on insights into the relative utility of the three methods we used to determine A. gracilipes abundance among populations of varying abundance. Pitfall traps was the most reliable method to determine if the species was present at the sample level. Tuna lures were predominantly reliable for quantifying the presence of workers, but were limited by the number of workers that can gather around a spoonful of tuna. Card counts were the quickest method, but were seemingly only useful when A. gracilipes abundance is not low. Finally we discuss how environmental and biological variation needs to be accounted for in future studies to better standardise sampling protocols to help progress ecology as a precision science.
Improved prediction of protein-protein interactions using AlphaFold2
Authors: Bryant P. , Pozzati G. , Elofsson A. 
Published: September 2021

AbstractPredicting the structure of interacting protein chains is a fundamental step towards understanding protein function. Unfortunately, no computational method can produce accurate structures of protein complexes. AlphaFold2, has shown unprecedented levels of accuracy in modelling single chain protein structures. Here, we apply AlphaFold2 for the prediction of heterodimeric protein complexes. We find that the AlphaFold2 protocol together with optimized multiple sequence alignments, generate models with acceptable quality (DockQ≥0.23) for 63% of the dimers. From the predicted interfaces we create a simple function to predict the DockQ score which distinguishes acceptable from incorrect models as well as interacting from non-interacting proteins with state-of-art accuracy. We find that, using the predicted DockQ scores, we can identify 51% of all interacting pairs at 1% FPR. The protocol can be found at: https://gitlab.com/ElofssonLab/FoldDock.
Measuring liquidity in agricultural land markets
Authors: Kionka Marlene , Odening Martin , Plogmann Jana , Ritter Matthias 
Published: September 2021

PurposeLiquidity is an important aspect of market efficiency. The purpose of this paper is threefold: first, this paper aims to discuss indicators that provide information about liquidity in agricultural land markets. Second, this paper aims to reflect on determinants of market liquidity and analyze the relationship with land prices. Third, this paper aims to conduct an empirical analysis for Germany that illustrates these concepts and allows hypothesis testing.Design/methodology/approachThis study reviews liquidity dimensions and measurement in financial markets and derives indicators applicable to farmland markets. In an empirical analysis, this study exhibits the spatial and temporal variability of land market liquidity in Lower Saxony, a German federal state with the highest agricultural production value. This study uses a rich dataset that includes 72,547 sale transactions of arable land between 1990 and 2018. The research focuses on volume-based (number of transactions, volume and turnover) and time-based (trading frequency and durations) measures. A panel vector autoregression and Granger causality tests are applied to investigate the relation between land turnover and land prices.FindingsThe paper confirms the thinness of farmland markets but also reveals regional and temporal heterogeneity of land market liquidity. This study finds that the relation between market liquidity and prices is ambiguous. This study concludes that a high demand from expanding farms absorbs supply shocks regardless of the current price level in agricultural land markets.Originality/valueEven though the relevance of agricultural land markets’ thinness is widely acknowledged in the literature, this paper is one of the first attempts to measure liquidity in agricultural land markets and to explain its relationship with land prices.
Maize storage losses and its main determinants in China
Authors: Zhang Meiyi , Luo Yi , Huang Dong , Miao Haimin , Wu Laping , Zhu Junfeng 
Published: September 2021

PurposeThe purpose of this study was to estimate on-farm maize storage losses and to empirically analyse the main determinants of maize storage losses in China.Design/methodology/approachBased on a nationwide survey of 1,196 households in 23 provinces (autonomous regions and municipalities) in China, the authors estimated on-farm maize storage losses and used a fractional logit model to analyse the main determinants of maize storage losses in China.FindingsThe results showed that, first, 1.78% of maize was lost during the storage stage in China and that storage loss experienced by smallholders varied across regions. Second, the empirical analysis showed that storage quantities have significant and negative effects on storage losses and that an economy of scale in household storage may exist; the percentage of maize stored for consumption and feed has significant and positive effects on storage losses, which may be related to market requirements and management activities. Third, compared to traditional facilities, silos and warehouses cause lower storage losses, while spraying chemicals and re-drying maize in the storage stage incur higher losses, possibly because to save costs, smallholders conduct loss-reduction activities only when they suffer serious losses, and when taking measures, farmers may sort grains, which also increases losses. Fourth, harvesting maize when it matures is significantly associated with lower storage losses.Research limitations/implicationsTo reduce storage losses, first, farmers' awareness of food saving and loss reduction must be increased. This could be achieved through agricultural training and education regarding food-saving practices. Second, the government could provide subsidies or low-interest credits to encourage farmers to use advanced facilities and promote land transfers to realize economies of scale. Finally, the government should accelerate the construction of smart agriculture systems and the timely monitoring of crop growth to suggest farmers to harvest at the appropriate time.Originality/valueReducing post-harvest loss (PHL) has become an important means of increasing the food supply and reducing resources use in China. This study provides a complete introduction to household maize storage losses and can therefore help characterize the current state of PHL in China, which is of vital importance to food security and food policy.
Barriers to radical innovation in research institutions in China
Authors: Yang Jianhua , Al-Sayed Rafif 
Published: September 2021

PurposeThis study aims to develop a better understanding of radical innovation performance and proposes a comprehensive and theoretical model of the barriers impeding radical innovation from the perspective of researchers working in research institutions in China. Both quantitative and qualitative techniques were used to test the hypotheses regarding barriers to radical innovation and the model proposed in this research.Design/methodology/approachThe data was collected through questionnaires and semi-structured interviews with researchers from different research institutions across several cities in China. Next, the data was analyzed by deploying the structural equation modeling technique and calculating the statistical significance of correlations, regression and path coefficients among the latent variables.FindingsThe results indicated the major barriers impeding radical innovation in Chinese research institutes. Based on these findings, suggested policies, regulations and business models are put forward that can promote radical innovation in these institutes through increasing research freedom, enhancing organizational flexibility, attracting talented researchers and expanding research collaboration.Originality/valueThe research proposes a comprehensive and theoretical model of the barriers impeding radical innovation from the perspective of researchers working in research institutions in China.
Maslow’s theory for preventive healthcare in India – a content analysis approach
Authors: Chopra Komal 
Published: September 2021

Purpose
The purpose of the study was to apply Maslow’s hierarchy of needs to understand consumer motivation for preventive health care in India using content analysis.

Design/methodology/approach
Content analysis approach which is a qualitative-based approach was adopted. The responses were collected through semi-structured interviews using purposeful sampling method, and the responses were analyzed using content analysis approach. Sub themes and main themes were derived from the data which related to concepts in Maslow’s theory.

Findings
The results indicate the following: healthy food, healthy diet and health supplements are the basic need; sustainability of health and fitness and health security relate to safety and security need; feeling of pride in being fit, being a role model of fitness for others and influence of electronic media relate to social and self-esteem need; freedom from disease and peace of mind fulfill the need for self-actualization.

Research limitations/implications
To strengthen the external validity, a mix of alternate research methodologies adopting qualitative and quantitative approach need to be adopted.

Practical implications
This study will help to better understand motivation for preventive health care. It will enable health-care companies to design health-care marketing programs based on Maslow’s theory to motivate individuals to purchase health products. The public health-care departments can issue guidelines based on Maslow’s theory to motivate citizens toward preventive health care.

Originality/value
Maslow’s theory was applied in the context of preventive health care.
Mechanisms of the copper third body as an interfacial media on copper matrix friction materials with different compositions
Authors: Du Xiangyu , Yang Junying , Gao Fei , Han Xiaoming , Su Linlin 
Published: September 2021

Purpose
This paper aims to reveal the effects of the copper third body on different copper matrix friction materials with a novel experimental way called “exogenous powder.”

Design/methodology/approach
An accurate adding device of exogenous copper powder was designed to control the flow rate. The tribological properties with and without exogenous copper powder were investigated by a pin-on-disc tribometer during dry sliding.

Findings
Experimental results indicate that the Cu addition tends to increase the friction coefficient. For pure Cu material, the exogenous copper third body exhibits poor fluidity on the friction surface, causing serious adhesive wear on the friction interface. For the Cu 90% + 10% Gr material, the plasticity of exogenous copper powder may intensify the deformation of the third body of the surface, presenting layered accumulation distribution. For the pure Cu and Cu 95% + 5% SiO2 material, the Cu addition makes the composition and density of the third body uneven in the direction of depth.

Originality/value
The role of the copper component on different materials is revealed from a new perspective, and the relationship between the third body structure and the friction properties is explored.