bluuebunny/crossref_metadata_2025 huggingface dataset:
The genome of C57BL/6J “Eve”, the mother of the laboratory mouse genome reference strain
Authors: Sarsani Vishal Kumar , Raghupathy Narayanan , Fiddes Ian T. , Armstrong Joel , Thibaud-Nissen Francoise , Zinder Oraya , Bolisetty Mohan , Howe Kerstin , Hinerfeld Doug , Ruan Xiaoan , Rowe Lucy , Barter Mary , Ananda Guruprasad , Paten Benedict , Weinstock George M. , Churchill Gary A. , Wiles Michael V. , Schneider Valerie A. , Srivastava Anuj , Reinholdt Laura G.
Published: January 2019

Isogenic laboratory mouse strains are used to enhance reproducibility as individuals within a strain are essentially genetically identical. For the most widely used isogenic strain, C57BL/6, there is also a wealth of genetic, phenotypic, and genomic data, including one of the highest quality reference genomes (GRCm38.p6). However, laboratory mouse strains are living reagents and hence genetic drift occurs and is an unavoidable source of accumulating genetic variability that can have an impact on reproducibility over time. Nearly 20 years after the first release of the mouse reference genome, individuals from the strain it represents (C57BL/6J) are at least 26 inbreeding generations removed from the individuals used to generate the mouse reference genome. Moreover, C57BL/6J is now maintained through the periodic reintroduction of mice from cryopreserved embryo stocks that are derived from a single breeder pair, aptly named C57BL/6J Adam and Eve. To more accurately represent the genome of today’s C57BL/6J mice, we have generated ade novoassembly of the C57BL/6J Eve genome (B6Eve) using high coverage, long-read sequencing, optical mapping, and short-read data. Using these data, we addressed recurring variants observed in previous mouse studies. We have also identified structural variations that impact coding sequences, closed gaps in the mouse reference assembly, some of which are in genes, and we have identified previously unannotated coding sequences through long read sequencing of cDNAs. This B6Eve assembly explains discrepant observations that have been associated with GRCm38-based analyses, and has provided data towards a reference genome that is more representative of the C57BL/6J mice that are in use today.
Noninvasive sleep monitoring in large-scale screening of knock-out mice reveals novel sleep-related genes
Authors: Joshi Shreyas S. , Sethi Mansi , Striz Martin , Cole Neil , Denegre James M. , Ryan Jennifer , Lhamon Michael E. , Agarwal Anuj , Murray Steve , Braun Robert E. , Fardo David W. , Kumar Vivek , Donohue Kevin D. , Sunderam Sridhar , Chesler Elissa J. , Svenson Karen L. , O’Hara Bruce F.
Published: January 2019

Sleep is a critical process that is well-conserved across mammalian species, and perhaps most animals, yet its functions and underlying mechanisms remain poorly understood. Identification of genes and pathways that can influence sleep may shed new light on these functions. Genomic screens enable the detection of previously unsuspected molecular processes that influence sleep. In this study, we report results from a large-scale phenotyping study of sleep-wake parameters for a population of single-gene knockout mice. Sleep-wake parameters were measured using a high throughput, non-invasive piezoelectric system called PiezoSleep. Knockout mice generated on a C57BL6/N (B6N) background were monitored for sleep and wake parameters for five days. By analyzing data from over 6000 mice representing 343 single gene knockout lines, we identified 122 genes influencing traits like sleep duration and bout length that have not been previously implicated in sleep, including those that affect sleep only during a specific circadian phase. PiezoSleep also allows assessment of breath rates during sleep and this was integrated as a supplemental tool in identifying aberrant physiology in these knockout lines. Sex differences were evident in both normal and altered sleep behavior. Through a combination of genetic and phenotypic associations, and known QTLs for sleep, we propose a set of candidate genes playing specific roles in sleep. The high “hit rate” demonstrates that many genes can alter normal sleep behaviors through a variety of mechanisms. Further investigation of these genes may provide insight into the pathways regulating sleep, functional aspects of sleep, or indirect potentially pathological processes that alter normal sleep.
Gene activation by a CRISPR-assistant trans enhancer
Authors: Xu Xin Hui , Dai Wei , Wang Dan Yang , Wu Jian , Wang Jin Ke
Published: January 2019

Gene activation is essential to the basic biological research and biomedicine. Therefore, various gene activators such as activation domain-ZNF, TALE and CRISPR proteins have been developed for this end, in which the CRISPR protein dead Cas9 (dCas9) is now most widely used. However, the current gene activators are still limited by their inefficient gene activation activity. In this study, we developed a new strategy, CRISPR-assistant trans enhancer, for activating gene expression in high efficiency by combining dCas9-VP64/sgRNA with a widely used strong enhancer, the CMV enhancer. In this strategy, a trans CMV enhancer DNA was recruited to target gene by dCas9-VP64/sgRNA via annealing between 3’ end of sgRNA and CMV enhancer. The trans enhancer activates gene transcription as the natural looped cis enhancer. The trans enhancer could activate both exogenous reporter gene and variant endogenous genes in various cells, with much higher activation efficiency than the current dCas9 activators.
Augmented Intelligence with Natural Language Processing Applied to Electronic Health Records is Useful for Identifying Patients with Non-Alcoholic Fatty Liver Disease at Risk for Disease Progression
Authors: Van Vleck Tielman T. , Chan Lili , Coca Steven G. , Craven Catherine K. , Do Ron , Ellis Stephen B. , Kannry Joseph L. , Loos Ruth J.F. , Bonis Peter A. , Cho Judy , Nadkarni Girish N.
Published: January 2019

Objective

Electronic health record (EHR) systems contain structured data and unstructured documentation. Clinical insights can be derived from analyzing both but optimal methods for this have not been studied extensively. We compared various approaches to analyzing EHR data for non-alcoholic fatty liver disease (NAFLD).

Materials and Methods

We compared analysis of structured and unstructured EHR data using natural language processing (NLP), free-text search, and diagnostic codes against expert adjudication as the reference standard.

Results

Out of 38,575 patients, we identified 2,281 patients with NAFLD. From the remainder, 10,653 patients with similar data density were selected as a control group. NLP was more sensitive than ICD and text search (NLP 0.93 vs. ICD 0.28 vs. text search 0.81) with higher a F2 score (NLP 0.92 vs. ICD 0.34 vs. text search 0.81). 619 patients had suspected NAFLD documented in radiology notes not acknowledged in other forms of clinical documentation. Of these, 232 (37.5%) were found to have more advanced liver disease after a median of 1,057 days.

Discussion

NLP-based approaches have superior accuracy in identifying NAFLD within the EHR compared to ICD/text search-based approaches. Suspected NAFLD on imaging is often not acknowledged in subsequent clinical documentation. Many such patients are later found to have more advanced liver disease.

Conclusion

For identification of NAFLD, NLP performed better than alternative selection modalities and facilitated follow-on analysis of information flow. If accuracy can be proven to persist across clinical domains, NLP can identify patient phenotypes for biomedical research in an accurate and high-throughput manner.
The Isolation and Identification of Fungi Gathered from Districts in Bangkok, Thailand Where Dengue Fever Is at Epidemic Levels
Authors: Wasinpiyamongkol Ladawan , Kanchanaphum Panan
Published: January 2019

Background

The Aedes mosquito is a major vector of many important diseases such as dengue, chikungunya, Zika, and yellow fever. Biological methods of controlling mosquitos are desirable because they are ecologically friendlier, safer, and more cost effective than chemical and physical methods of controlling mosquitos.

Methods

Water samples in the mosquitoes’ breeding containers from districts in Bangkok were collected from the mosquitoes breeding containers situated in seven districts of Bangkok, Thailand. The DNA was extracted from each sample of the isolated fungi. Purified DNA specimens were amplified in a PCR reaction with universal primers of ITS1 and ITS4. All the PCR product was sequencing, alignment and comparing the homologous sequence in GenBank database.

Results

Fourteen strains of fungi were isolated. The most commonly found strain was Penicillium citrinum, which was discovered in six of the 30 isolated fungi samples.

Conclusion

Biological control strategies for the mosquito population should be further investigated because they are considered to be ecologically friendlier, safer, and more cost effective than chemical insecticides.
Happy you, happy me: expressive changes on a stranger’s voice recruit faster implicit processes than self-produced expressions
Authors: Rachman Laura , Dubal Stéphanie , Aucouturier Jean-Julien
Published: January 2019

In social interactions, people have to pay attention both to thewhatandwho. In particular, expressive changes heard on speech signals have to be integrated with speaker identity, differentiating e.g. self- and other-produced signals. While previous research has shown that self-related visual information processing is facilitated compared to non-self stimuli, evidence in the auditory modality remains mixed. Here, we compared electroencephalography (EEG) responses to expressive changes in sequence of self- or other-produced speech sounds, using a mismatch negativity (MMN) passive oddball paradigm. Critically, to control for speaker differences, we used programmable acoustic transformations to create voice deviants which differed from standards in exactly the same manner, making EEG responses to such deviations comparable between sequences. Our results indicate that expressive changes on a stranger’s voice are highly prioritized in auditory processing compared to identical changes on the self-voice. Other-voice deviants generate earlier MMN onset responses and involve stronger cortical activations in a left motor and somatosensory network suggestive of an increased recruitment of resources for less internally predictable, and therefore perhaps more socially relevant, signals.
Topoisomerase 2β-dependent nuclear DNA damage shapes extracellular growth factor responses through AKT phosphorylation dynamics to control virus latency
Authors: Hu Hui-Lan , Shiflett Lora A. , Kobayashi Mariko , Chao Moses V. , Wilson Angus C. , Mohr Ian , Huang Tony T.
Published: January 2019

The mTOR pathway integrates both extracellular and intracellular signals and serves as a central regulator of cell metabolism, growth, survival and stress responses. Neurotropic viruses, such as herpes simplex virus-1 (HSV-1), also rely on cellular AKT-mTORC1 signaling to achieve viral latency. Here, we define a novel genotoxic response whereby spatially separated signals initiated by extracellular neurotrophic factors and nuclear DNA damage are integrated by the AKT-mTORC1 pathway. We demonstrate that endogenous DNA double-strand breaks (DSBs) mediated by Topoisomerase 2β-DNA cleavage complex (TOP2βcc) intermediates are required to achieve AKT-mTORC1 signaling and maintain HSV-1 latency in neurons. Suppression of host DNA repair pathways that remove TOP2βcc trigger HSV-1 reactivation. Moreover, perturbation of AKT phosphorylation dynamics by downregulating the PHLPP1 phosphatase led to AKT mis-localization and disruption of DSB-induced HSV-1 reactivation. Thus, the cellular genome integrity and environmental inputs are consolidated and co-opted by a latent virus to balance lifelong infection with transmission.
The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells
Authors: Kabir Shaheen , Cidado Justin , Andersen Courtney , Dick Cortni , Lin Pei-Chun , Mitros Therese , Ma Hong , Baik Ron , Belmonte Matthew , Drew Lisa , Corn Jacob
Published: January 2019

Overexpression of anti-apoptotic proteins MCL1 and Bcl-xL is a frequent event in blood and solid cancers. Inhibitors targeting MCL1 are in clinical development, however many cancer models are intrinsically resistant to this approach. To discover mechanisms underlying resistance to MCL1 inhibition, we performed multiple flow-cytometry based genome-wide CRISPR screens that interrogate two drugs directly or indirectly targeting MCL1. Remarkably, both screens identified three components (CUL5, RNF7 and UBE2F) of a cullin-RING ubiquitin ligase complex (CRL5) that resensitized cells to MCL1 inhibition. We find that levels of the BH3-only pro-apoptotic proteins Bim and Noxa are proteasomally regulated by the CRL5 complex. Accumulation of Noxa caused by depletion of CRL5 components particularly skewed the balance in favor of apoptosis when cells were challenged with an MCL1 inhibitor. Discovery of a novel role of CRL5 in apoptosis and resistance to MCL1 inhibitors exposes new drug targets and the potential to improve combination treatments.
Molecular evolution across developmental time reveals rapid divergence in early embryogenesis
Authors: Cutter Asher D. , Garrett Rose H. , Mark Stephanie , Wang Wei , Sun Lei
Published: January 2019

Ontogenetic development hinges on the changes in gene expression in time and space within an organism, suggesting that the demands of ontogenetic growth can impose or reveal predictable pattern in the molecular evolution of genes expressed dynamically across development. Here we characterize co-expression modules of the C. elegans transcriptome, using a time series of 30 points from early-embryo to adult. By capturing the functional form of expression profiles with quantitative metrics, we find fastest evolution in the distinctive set of genes with transcript abundance that declines through development from a peak in young embryos. These genes are highly enriched for oogenic function (maternal provisioning), are non-randomly distributed in the genome, and correspond to a life stage especially prone to inviability in inter-species hybrids. These observations conflict with the “early conservation model” for the evolution of development, though expression-weighted sequence divergence analysis provides some support for the “hourglass model.” Genes in co-expression modules that peak toward adulthood also evolve fast, being hyper-enriched for roles in spermatogenesis, implicating a history of sexual selection and relaxation of selection on sperm as key factors driving rapid change to ontogenetically distinguishable co-expression modules of genes. We propose that these predictable trends of molecular evolution for dynamically-expressed genes across ontogeny predispose particular life stages, early embryogenesis in particular, to hybrid dysfunction in the speciation process.

Impact Summary

The development of an organism from a single-celled embryo to a reproductive adult depends on dynamic gene expression over developmental time, with natural selection capable of shaping the molecular evolution of those differentially-expressed genes in distinct ways. We quantitatively analyzed the dynamic transcriptome profiles across 30 timepoints in development for the nematode C. elegans. In addition to rapid evolution of adult-expressed genes with functional roles in sperm, we uncovered the unexpected result that the distinctive set of genes that evolve fastest are those with peak expression in young embryos, conflicting with some models of the evolution of development. The rapid molecular evolution of genes in early embryogenesis contrasts with the exceptional conservation of embryonic cell lineages between species, and corresponds to a developmental period that is especially sensitive to inviability in inter-species hybrid embryos. We propose that these predictable trends of molecular evolution for dynamically-expressed genes across development predispose particular life stages, early embryogenesis in particular, to hybrid dysfunction in the speciation process.
Post-hoc modification of linear models: combining machine learning with domain information to make solid inferences from noisy data
Authors: van Vliet Marijn , Salmelin Riitta
Published: January 2019

Linear machine learning models “learn” a data transformation by being exposed to examples of input with the desired output, forming the basis for a variety of powerful techniques for analyzing neuroimaging data. However, their ability to learn the desired transformation is limited by the quality and size of the example dataset, which in neuroimaging studies is often notoriously noisy and small. In these cases, it is desirable to fine-tune the learned linear model using domain information beyond the example dataset. To this end, we present a framework that decomposes the weight matrix of a fitted linear model into three subcomponents: the data covariance, the identified signal of interest, and a normalizer. Inspecting these subcomponents in isolation provides an intuitive way to inspect the inner workings of the model and assess its strengths and weaknesses. Furthermore, the three subcomponents may be altered, which provides a straightforward way to inject prior information and impose additional constraints. We refer to this process as “post-hoc modification” of a model and demonstrate how it can be used to achieve precise control over which aspects of the model are fitted to the data through machine learning and which are determined through domain information. As an example use case, we decode the associative strength between words from electroencephalography (EEG) reading data. Our results show how the decoding accuracy of two example linear models (ridge regression and logistic regression) can be boosted by incorporating information about the spatio-temporal nature of the data, domain information about the N400 evoked potential and data from other participants.

Highlights

We present a framework to decompose any linear model into three subcomponents that are straightforward to interpret.

By modifying the subcomponents before re-assembling them into a linear model, prior information and further constraints may be injected into the model.

As an example, we boost the performance of a linear regressor and classifier by injecting knowledge about the spatio-temporal nature of the data, the N400 evoked potential and data from other participants.
zGrad: A nanobody-based degron system to inactivate proteins in zebrafish
Authors: Yamaguchi Naoya , Colak-Champollion Tugba , Knaut Holger
Published: January 2019

The analysis of protein function is essential to modern biology. While protein function has mostly been studied through gene or RNA interference, more recent approaches to degrade proteins directly have been developed. Here, we adapted the anti-GFP nanobody-based system deGradFP from flies to zebrafish. We named this system zGrad and show that zGrad efficiently degrades transmembrane, cytosolic and nuclear GFP-tagged proteins in zebrafish in an inducible and reversible manner. Using tissue-specific and inducible promoters in combination with functional GFP-fusion proteins, we demonstrate that zGrad can inactivate transmembrane, cytosolic and nuclear proteins globally, locally and temporally with different consequences. Global protein depletion results in phenotypes similar to loss of gene activity while local and temporal protein inactivation yields more restricted and novel phenotypes. Thus, zGrad is a versatile tool to study the spatial and temporal requirement of proteins in zebrafish.
Oxytocin reduces top-down control of attention by increasing bottom-up attention allocation to social but not non-social stimuli
Authors: Xu Xiaolei , Li Jialin , Chen Zhuo , Kendrick Keith M. , Becker Benjamin
Published: January 2019

The neuropeptide oxytocin (OXT) may facilitate attention to social stimuli by influencing early stage bottom-up processing although findings in relation to different emotional expressions are inconsistent and its influence on top-down cognitive processing mechanisms unclear. In the current double-blind, placebo (PLC) controlled, between subject design study we therefore recruited 71 male subjects to investigate the effects of intranasal OXT (24IU) on both bottom-up attention allocation and top-down attention inhibition using a visual antisaccade paradigm with concurrent eye movement acquisition. Our results show that OXT increased antisaccade errors for social stimuli (all types of emotional faces), but not shapes. This effect of OXT was modulated by trait behavioral inhibition and there was also evidence for reduced state anxiety after OXT treatment. Antisaccades are under volitional control and therefore this indicates that OXT treatment produced reduced top-down inhibition. However, the overall findings are consistent with OXT acting to reduce top-down control of attention as a result of increasing bottom-up early attentional processing of social, but not non-social, stimuli in situations where the two systems are in potential conflict. This effect of OXT is also modulated by individual levels of trait behavioral inhibition possibly as a result of an anxiolytic action.
Killer whale genomes reveal a complex history of recurrent admixture and vicariance
Authors: Foote Andrew D. , Martin Michael D. , Louis Marie , Pacheco George , Robertson Kelly M. , Sinding Mikkel-Holger S. , Amaral Ana R. , Baird Robin W. , Baker C. Scott , Ballance Lisa , Barlow Jay , Brownlow Andrew , Collins Tim , Constantine Rochelle , Dabin Willy , Dalla Rosa Luciano , Davison Nicholas J. , Durban John W. , Esteban Ruth , Ferguson Steven H. , Gerrodette Tim , Guinet Christophe , Bradley Hanson M. , Hoggard Wayne , Matthews Cory J. D. , Samarra Filipa I. P. , de Stephanis Renaud , Tavares Sara B. , Tixier Paul , Totterdell John A. , Wade Paul , Gilbert M. Thomas P. , Wolf Jochen B.W. , Morin Phillip A.
Published: January 2019

Reconstruction of the demographic and evolutionary history of populations assuming a consensus tree-like relationship can mask more complex scenarios, which are prevalent in nature. An emerging genomic toolset, which has been most comprehensively harnessed in the reconstruction of human evolutionary history, enables molecular ecologists to elucidate complex population histories. Killer whales have limited extrinsic barriers to dispersal and have radiated globally, and are therefore a good candidate model for the application of such tools. Here, we analyse a global dataset of killer whale genomes in a rare attempt to elucidate global population structure in a non-human species. We identify a pattern of genetic homogenisation at lower latitudes and the greatest differentiation at high latitudes, even between currently sympatric lineages. The processes underlying the major axis of structure include high drift at the edge of species’ range, likely associated with founder effects and allelic surfing during post-glacial range expansion. Divergence between Antarctic and non-Antarctic lineages is further driven by ancestry segments with up to four-fold older coalescence time than the genome-wide average; relicts of a previous vicariance during an earlier glacial cycle. Our study further underpins that episodic gene flow is ubiquitous in natural populations, and can occur across great distances and after substantial periods of isolation between populations. Thus, understanding the evolutionary history of a species requires comprehensive geographic sampling and genome-wide data to sample the variation in ancestry within individuals.
NMDAR-activated PP1 dephosphorylates GluN2B to modulate NMDAR synaptic content
Authors: Chiu Andrew M. , Wang Jiejie , Fiske Michael P. , Hubalkova Pavla , Barse Levi , Gray John A. , Sanz-Clemente Antonio
Published: January 2019

In mature neurons, postsynaptic NMDARs are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing Protein Phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission.

HIGHLIGHTS

Phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (GluN2B-pS1480) maintains NMDARs at extrasynaptic sites.

Extrasynaptic NMDARs form a stable protein complex containing PP1.

Global NMDAR activation increases NMDAR synaptic content by promoting PP1-mediated dephosphorylation of GluN2B-pS1480.

GluN2B-pS1480 dephosphorylation is mediated by a PP1 subpopulation not involved in LTD and is enhanced by age.
High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes
Authors: Marjaneh Mahdi Moradi , Sivakumaran Haran , Hillman Kristine M , Kaufmann Susanne , Hussein Nehal , Lima Luize G , Ham Sunyoung , Kar Siddhartha , Beesley Jonathan , Fachal Laura , Easton Douglas F , Dunning Alison M , Möller Andreas , Chenevix-Trench Georgia , Edwards Stacey L , French Juliet D
Published: January 2019

Fine-mapping of breast cancer GWAS regions has identified 195 high confidence signals containing more than 5,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements and thus may confer the risk by altering gene expression in cis. We analyzed allelic expression imbalance (AEI) of genes surrounding known breast cancer signals, using normal breast and breast tumor transcriptome data and imputed genotypes. Fourteen genes, including NTN4, were identified whose expression was associated with CCV genotype. We showed that CCVs at this signal were located within an enhancer that physically interacts with the NTN4 promoter. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. Here, we present the most comprehensive AEI analysis of breast cancer CCVs resulting in identification of new candidate risk genes.
GuiltyTargets: Prioritization of Novel Therapeutic Targets with Deep Network Representation Learning
Authors: Muslu Özlem , Hoyt Charles Tapley , Hofmann-Apitius Martin , Fröhlich Holger
Published: January 2019

The majority of clinical trial failures are caused by low efficacy of investigated drugs, often due to a poor choice of target protein. Computational prioritization approaches aim to support target selection by ranking candidate targets in the context of a given disease. We propose a novel target prioritization approach, GuiltyTargets, which relies on deep network representation learning of a genome-wide protein-protein interaction network annotated with disease-specific differential gene expression and uses positive-unlabeled machine learning for candidate ranking. We evaluated our approach on six diseases of different types (cancer, metabolic, neurodegenerative) within a 10 times repeated 5-fold stratified cross-validation and achieved AUROC values between 0.92 - 0.94, significantly outperforming a previous approach, which relies on manually engineered topological features. Moreover, we showed that GuiltyTargets allows for target repositioning across related disease areas. Applying GuiltyTargets to Alzheimer’s disease resulted into a number of highly ranked candidates that are currently discussed as targets in the literature. Interestingly, one (COMT) is also the target of an approved drug (Tolcapone) for Parkinson’s disease, highlighting the potential for target repositioning of our method.

Availability

The GuiltyTargets Python package is available on PyPI and all code used for analysis can be found under the MIT License at https://github.com/GuiltyTargets.

Author summary

Many drug candidates fail in clinical trials due to low efficacy. One of the reasons is the choice of the wrong target protein, i.e. perturbation of the protein does not effectively modulate the disease phenotype on a molecular level. In consequence many patients do not demonstrate a clear response to the drug candidate. Traditionally, targets are selected based on evidence from the literature and follow-up experiments. However, this process is very labor intensive and often biased by subjective choices. Computational tools could help a more rational and unbiased choice of target proteins and thus increase the chance of drug discovery programs. In this work we propose a novel machine learning based method for target candidate ranking. The method (GuiltyTargets) captures properties of known targets to learn a ranking of candidates. GuiltyTargets compares favorably against existing machine learning based target prioritization methods and allowed us to propose novel targets for Alzheimer’s disease.
ICA512 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitor
Authors: Toledo Pamela L , Torkko Juha M , Müller Andreas , Wegbrod Carolin , Sönmez Anke , Solimena Michele , Ermácora Mario R
Published: January 2019

Type 1 diabetes islet cell autoantigen 512 (ICA512) is a tyrosine phosphatase-like intrinsic membrane protein involved in the biogenesis and turnover of insulin secretory granules (SGs) in pancreatic islet β-cells. Whereas its membrane proximal and cytoplasmic domains have been functionally and structurally characterized, the role of ICA512 N-terminal segment named regulated endocrine-specific protein 18 homology domain (RESP18HD), which encompasses residues 35-131, remains largely unknown. Here we show that ICA512 RESP18HD residues 91-131 encode for an intrinsically disordered region (IDR), which in vitro acts as a condensing factor for the reversible aggregation of insulin and other β-cell proteins in a pH and Zn2+ regulated fashion. At variance with what has been shown for other granule cargoes with aggregating properties, the condensing activity of ICA512 RESP18HD is displayed at pH close to neutral, i.e. in the pH range found in the early secretory pathway, while it is resolved at acidic pH and Zn2+ concentrations resembling those present in mature SGs. Moreover, we show that ICA512 RESP18HD residues 35-90, preceding the IDR, inhibit insulin fibrillation in vitro. Finally, we found that glucose-stimulated secretion of RESP18HD upon exocytosis of SGs from insulinoma INS-1 cells is associated with cleavage of its IDR, conceivably to prevent its aggregation upon exposure to neutral pH in the extracellular milieu. Taken together, these findings point to ICA512 RESP18HD being a condensing factor for protein sorting and granulogenesis early in the secretory pathway, and for prevention of amyloidogenesis.
Highly efficient homology-directed repair using transient CRISPR/Cpf1-geminiviral replicon in tomato
Authors: Vu Tien Van , Sivankalyani Velu , Kim Eun-Jung , Doan Duong Thi Hai , Tran Mil Thi , Kim Jihae , Sung Yeon Woo , Park Minwoo , Kang Yang Jae , Kim Jae-Yean
Published: January 2019

Genome editing via the homology-directed repair (HDR) pathway in somatic plant cells is very inefficient compared to error-prone repair by nonhomologous end joining (NHEJ). Here, we increased HDR-based genome editing efficiency approximately 3-fold compared to a Cas9-based single-replicon system via the use of de novo multi-replicon systems equipped with CRISPR/LbCpf1 in tomato and obtained replicon-free but stable HDR alleles. The efficiency of CRISPR/LbCpf1-based HDR was significantly modulated by physical culture conditions such as temperature and light. Ten days of incubation at 31°C under a light/dark cycle after Agrobacterium-mediated transformation resulted in the best performance among the tested conditions. Furthermore, we developed our single-replicon system into a multi-replicon system that effectively increased HDR efficiency. Although this approach is still challenging, we showed the feasibility of HDR-based genome editing of a salt-tolerant SlHKT1;2 allele without genomic integration of antibiotic markers or any phenotypic selection. Self-pollinated offspring plants carrying the HKT1;2 HDR allele showed stable inheritance and germination tolerance in the presence of 100 mM NaCl. Our work may pave the way for transgene-free editing of alleles of interest in asexually as well as sexually reproducing plants.
Molecular recognition of M1-linked ubiquitin chains by native and phosphorylated UBAN domains
Authors: Herhaus Lina , Bedem Henry van den , Tang Sean , Wakatsuki Soichi , Dikic Ivan , Rahighi Simin
Published: January 2019

Although the Ub-binding domain in ABIN proteins and NEMO (UBAN) is highly conserved, UBAN-containing proteins exhibit different Ub-binding properties, resulting in their diverse biological roles. Post-translational modifications further control UBAN domain specificity for poly-Ub chains. However, precisely, how the UBAN domain structurally confers such functional diversity remains poorly understood. Here we report crystal structures of ABIN-1 alone and in complex with one or two M1-linked di-Ub chains. ABIN-1 UBAN forms a homo-dimer that provides two symmetrical Ub-binding sites on either side of the coiled-coil structure. Moreover, crystal structures of ABIN1 UBAN in complex with di-Ub chains reveal a concentration-dependency of UBAN/di-Ub binding stoichiometry. Analysis of UBAN/M1-linked di-Ub binding characteristics indicates that phosphorylated S473 in OPTN and its corresponding phospho-mimetic residue in ABIN-1 (E484) are essential for high affinity interactions with M1-linked Ub chains. Also, a phospho-mimetic mutation of A303 in NEMO, corresponding to S473 of OPTN, increases binding affinity for M1-linked Ub chains. These findings are in line with the diverse physiological roles of UBAN domains, as phosphorylation of OPTN UBAN is required to enhance its binding to Ub during mitophagy.
A mechanism for ligand gated strand displacement in ZTP riboswitch transcription regulation
Authors: Strobel Eric J. , Cheng Luyi , Berman Katherine E. , Carlson Paul D. , Lucks Julius B.
Published: January 2019

Cotranscriptional folding is an obligate step of RNA biogenesis that can guide RNA structure and function by forming transient intermediate folds. This is especially true for transcriptional riboswitches in the which the formation of ligand-dependent structures during transcription regulates downstream gene expression. However, the intermediate structures that comprise cotranscriptional RNA folding pathways and the mechanisms that enable transit between them remain largely unknown. Here we determine the series of cotranscriptional folds and rearrangements that mediate antitermination by the Clostridium beijerinckii pfl riboswitch in response to the purine biosynthetic intermediate ZMP. We uncover sequence and structural determinants that modulate a regulatory RNA strand displacement reaction and identify biases within natural ZTP riboswitch sequences that promote on-pathway folding. Our findings establish a mechanism for ZTP riboswitch antitermination and suggest general strategies by which nascent RNA molecules can navigate cotranscriptional folding pathways efficiently.
Fibril formation rewires interactome of the Alzheimer protein Tau by π-stacking
Authors: Ferrari Luca , Stucchi Riccardo , Konstantoulea Aikaterini , Kamp Gerarda van de , Kos Renate , Geerts Willie J.C. , Förster Friedrich G. , Altelaar Maarten A.F. , Hoogenraad Casper C. , Rüdiger Stefan G.D.
Published: January 2019

Aggregation of the Tau protein defines progression of neurodegenerative diseases, including Alzheimer’s Disease. Tau assembles into oligomers and fibrils. The molecular basis of their toxicity is poorly understood. Here we show that π-stacking by Arginine side chains rewires the interactome of Tau upon aggregation. Oligomeric nano-aggregates scavenge the COPI complex, fibrils attract proteins involved in microtubule binding, RNA binding and phosphorylation. The aberrant interactors have disordered regions with unusual sequence features. Arginines are crucial to initiate such aberrant interactions. Remarkably, substitution of Arginines by Lysines abolishes scavenging, which indicates a key role for the pi-stacking of the Arginine side chain. The molecular chaperone Hsp90 tames such re-arrangements, which suggests that the natural protein quality control system can suppress aberrant interactions. Together, our data present a molecular mode of action for derailment of protein-protein interaction in neurodegeneration.

HIGHLIGHTS

Tau fibrils act as fishing net for proteins.

Tau fibrils attract specific protein families associated with Alzheimer.

π-stacking by Arginines key for aberrant binding to Tau fibrils

The Hsp90 chaperone stalls fibril growth and alters interactome
The role of trait anxiety in associative learning during and after an aversive event
Authors: Ilse Arne , Prameswari Virginia , Kahl Evelyn , Fendt Markus
Published: January 2019

Trait anxiety is considered to be a risk factor for anxiety disorders. The aim of the present study was to investigate how trait anxiety affects associative learning during and after an aversive event in laboratory rats. For this, rats were first submitted to a light–dark box test, followed by relief, safety, and fear learning. Our data demonstrate that all types of learning were affected by trait anxiety, both on a group and on an individual level. Whereas high levels of anxiety impaired relief and safety learning, fear learning was more pronounced. These findings help to show how trait anxiety might be involved in the etiology of anxiety disorders and pathological sensation- and risk-seeking.
Noradrenergic stabilization of heterosynaptic LTP requires activation of Epac in the hippocampus
Authors: Brandwein Nathan J. , Nguyen Peter V.
Published: January 2019

Beta-adrenergic receptor (β-AR) activation by norepinephrine (NE) enhances memory and stabilizes long-term potentiation (LTP), a form of synaptic plasticity believed to underlie some forms of hippocampal memory. LTP can occur at multiple synaptic pathways as a result of strong stimulation to one pathway preceding milder stimulation of an adjacent, independent pathway. Synaptic tagging allows LTP to be transferred, or captured, at heterosynaptic pathways. Previous research has shown that β-AR activation promotes heterosynaptic LTP by engaging various signaling cascades. In particular, cyclic adenosine monophosphate (cAMP) activates cAMP-dependent protein kinase A (PKA) and guanine nucleotide exchange protein activated by cAMP (Epac), to enhance LTP. Epac activation can occlude subsequent induction of stable homosynaptic LTP after β-AR activation, but it is unclear whether Epac activation is required for heterosynaptic LTP following pairing of the natural transmitter, NE, with one 100 Hz train of stimulation (“NE-LTP”). Using electrophysiologic recordings of CA1 field excitatory postsynaptic potentials during stimulation of two independent synaptic pathways in murine hippocampal slices, we show that distinct inhibitors of Epac blocked stabilization of homo- and heterosynaptic NE-LTP. PKA inhibition also attenuated heterosynaptic transfer of NE-LTP, but only when a PKA inhibitor was applied during tetanization of a second, heterosynaptic pathway that was not treated with NE. Our data suggest that NE, paired with 100 Hz, activates Epac to stabilize homo- and heterosynaptic LTP. Epac may regulate the production of plasticity-related proteins and subsequent synaptic capture of NE-LTP at a heterosynaptic pathway. Epac activation under these conditions may enable behavioral experiences that engage noradrenergic inputs to hippocampal circuits to be transformed into stable long-term memories.
The resin-flowing model in prepreg lamination of print circuit board
Authors: Liu Shitao , Cui Rong , Cao Hongwei , Qiu Jinhong
Published: January 2019

Purpose

This paper aims to show a resin-flowing model based on Darcy’s law to display the flowing properties of prepreg during lamination. The conformity between the model and experimental results demonstrates that it can provide a guideline on print circuit board (PCB) lamination.

Design/methodology/approach

Based on the theoretical derivations of Darcy’s law, this paper made an analysis on the flow of prepreg in the pressing process, according to which a theoretical model, namely, resin-flowing model was further formulated.

Findings

This paper establishes a resin-flowing model, according to which two experiment-verified conclusions can be drawn: first, the resin-flowing properties of material A and B can be improved when the heating rate is between 1.5 and 2.5 min/°C; second, increased pressure gradient can add the amount of flowing resin, mainly featured by increasing pressure and reducing filled thickness of prepreg.

Originality/value

This model provides guidance on setting lamination parameters for most kinds of prepregs and decreasing starvation risk for PCB production.
Immigrant–native wage gap in Europe: the role of cognitive skills and their use at work
Authors: Tverdostup Maryna , Paas Tiiu
Published: January 2019

Purpose

The purpose of this paper is to address the role of cognitive skills and extent of skill use at work in explaining the immigrant–native wage gap in Europe. The study targets immigrant–native disparities in literacy and numeracy cognitive skills, as important, yet not exhaustive factor behind immigrants’ wage penalty.

Design/methodology/approach

The research relies on the Program of International Assessment of Adult Competencies data for 15 European countries. The empirical analysis employs multivariate regression analysis and incorporates the full set of plausible values for each skill domain, to correctly measure cognitive skills. To estimate standard errors, the authors employ Jackknife replication methodology with 80 replication weights and final population weight.

Findings

The authors document that, on average, immigrants achieve substantially worse scores in literacy and numeracy test domains. Only highly educated immigrants tend to improve their skills over time in host countries. The results of wage gap analysis indicate that having cognitive skills, demographic profile and occupation category comparable to natives does not yield comparable wage rate. The remaining wage gap results from the systematic differences in skills application at work, as immigrants use their skills to lower extent, relative to natives.

Originality/value

The research employs a novel measure of productive human capital, which accounts for cognitive skills in literacy and numeracy domains, and frequencies of skill use at work. It allows to more precisely evaluate the immigrant–native disparity in human capital application and its reflection on the wage rate.
Can pay gaps between gay men and lesbians shed light on male–female pay gaps?
Authors: Wang Jing , Gunderson Morley
Published: January 2019

Purpose

The purpose of this paper is to estimate the relative importance of gender discrimination and differences in household responsibilities as determinants of the male–female pay gap.

Design/methodology/approach

It parses out the relative importance of those two factors by using the pay between gay men vs lesbian women as a comparison group that should reflect only gender discrimination. Subtracting the pay gap between gay men and lesbians (reflecting only gender discrimination) from the male–female pay gap for their heterosexual counterparts (reflecting both gender discrimination and household responsibilities) provides evidence of the relative importance of gender discrimination and household responsibilities in explaining the male–female pay gap.

Findings

The results show that essentially all of the male–female pay gap is attributed to differences in household responsibilities.

Originality/value

This paper advances the literature of gender wage gap by using a novel comparison group – gay men vs lesbian women – to estimate the relative importance of gender discrimination and differences in household responsibilities as determinants of the male–female pay gap.
Does foreign aid help alleviate income inequality? New evidence from African countries
Authors: Younsi Moheddine , Khemili Hasna , Bechtini Marwa
Published: January 2019

Purpose

The purpose of this paper is to examine the relationship between foreign aid and income inequality (IIQ) reduction for 16 African countries using unbalanced panel data covering the period 1990–2011. This paper attempts to answer the critical question: does foreign aid lead to IIQ reduction?

Design/methodology/approach

To examine the effect of foreign aid on IIQ, this paper uses an RE model with robust OLS regression and system-GMM estimator, which are useful in dealing with the endogeneity problems.

Findings

Results of RE model indicate that foreign aid, foreign direct investment, trade openness as well as corruption have a positive and statistically significant effect on IIQ. Government spending and inflation have a negative and statistically significant effect on IIQ, while GDP per capita growth has a negative but statistically insignificant relationship with IIQ. The results are robust by using system-GMM dynamic panel model which confirms that the coefficients of all considered variables remain same sign and significance.

Research limitations/implications

This study implies that an increase in foreign aid is associated with an increase in IIQ. As an effective strategy to foreign aid, this paper suggests that improving of financial sector development, and institutional quality and policies can reduce income inequalities and stimulate economic growth.

Originality/value

This paper is the first of its kind to empirically explore the relationship between IIQ and foreign aid measured here by net aid transfers as a share of GDP in African countries, using modern econometric techniques, time period and a variety of control variables.