bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of non-additive genetic associations on age-related complex diseases
Authors: Guindo-Martínez Marta , Amela Ramon , Bonàs-Guarch Silvia , Puiggròs Montserrat , Salvoro Cecilia , Miguel-Escalada Irene , Carey Caitlin E , Cole Joanne B. , Rüeger Sina , Atkinson Elizabeth , Leong Aaron , Sanchez Friman , Ramon-Cortes Cristian , Ejarque Jorge , Palmer Duncan S , Kurki Mitja ,   FinnGen Consortium, Aragam Krishna , Florez Jose C , Badia Rosa M. , Mercader Josep M. , Torrents David
Published: May 2020

Genome-wide association studies (GWAS) are not fully comprehensive as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implemented an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels, includes the analysis of the X chromosome and non-additive models to test for association. We applied this methodology to 62,281 subjects across 22 age-related diseases and identified 94 genome-wide associated loci, including 26 previously unreported. We observed that 27.6% of the 94 loci would be missed if we only used standard imputation strategies and only tested the additive model. Among the new findings, we identified three novel low-frequency recessive variants with odds ratios larger than 4, which would need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases.
Determination and correction of aberrations in full field OCT using phase gradient autofocus by maximizing the likelihood function
Authors: Matkivsky Vasily , Moiseev Alexander , Shilyagin Pavel , Rodionov Alexander , Spahr Hendrik , Pfäffle Clara , Hüttmann Gereon , Hillmann Dierck , Gelikonov Grigory
Published: May 2020

A method for numerical estimation and correction of aberrations of the eye in fundus imaging with optical coherence tomography (OCT) is presented. Aberrations are determined statistically by using the estimate based on likelihood function maximization. The method can be considered as an extension of the phase gradient autofocusing algorithm in synthetic aperture radar imaging to 2D optical aberrations correction. The efficiency of the proposed method has been demonstrated in OCT fundus imaging with 6λ aberrations. After correction, single photoreceptors were resolved. It is also shown that wavefront distortions with high spatial frequencies can be determined and corrected.

Graphical Abstract for Table of Contents

[Text.This work is dedicated to development a method for numerical estimation and correction of aberrations of the eye in fundus imaging with OCT. Aberration evaluation is performed statistically by using estimate based on likelihood function maximization. The efficiency of the proposed method has been demonstrated in OCT fundus imaging with 6λ aberrations. It has been shown that spatial high-frequency wavefront distortions can be determined]
Antisense oligonucleotide-mediated correction ofCFTRsplicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells
Authors: Michaels Wren E. , Bridges Robert J. , Hastings Michelle L.
Published: May 2020

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in more than 15% of CF cases. One commonCFTRsplicing mutation isCFTRc.3718-2477C>T (3849+10kbC>T), which creates a new 5’ splice site, resulting in splicing to a cryptic exon with a premature termination codon. Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting theCFTRc.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance. We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients. Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.
GroEL/ES buffers entropic traps in folding pathway during evolution of a model substrate
Authors: Sadat Anwar , Tiwari Satyam , Verma Kanika , Ray Arjun , Ali Mudassar , Upadhyay Vaibhav , Singh Anupam , Chaphalkar Aseem , Ghosh Asmita , Chakraborty Rahul , Chakraborty Kausik , Mapa Koyeli
Published: May 2020

The folding landscape of proteins can change during evolution with the accumulation of mutations that may introduce entropic or enthalpic barriers in the protein folding pathway, making it a possible substrate of molecular chaperonesin vivo. Can the nature of such physical barriers of folding dictate the feasibility of chaperone-assistance? To address this, we have simulated the evolutionary step to chaperone-dependence keeping GroEL/ES as the target chaperone and GFP as a model protein in an unbiased screen. We find that the mutation conferring GroEL/ES dependencein vivoandin vitroencode an entropic trap in the folding pathway rescued by the chaperonin. Additionally, GroEL/ES can edit the formation of non-native contacts similar to DnaK/J/E machinery. However, this capability is not utilized by the substratesin vivo. As a consequence, GroEL/ES caters to buffer mutations that predominantly cause entropic traps, despite possessing the capacity to edit both enthalpic and entropic traps in the folding pathway of the substrate protein.
Modeling the dynamics of antibody–target binding in living tumors
Authors: Tang Yu , Cao Yanguang
Published: May 2020

Antibodies have become an attractive class of therapeutic agents for solid tumors, mainly because of their high target selectivity and affinity. The target binding properties of antibodies are critical for their efficacy and toxicity. Our lab has developed a bioluminescence resonance energy transfer (BRET) imaging approach that directly supports measurement of the binding dynamics between antibodies and their targets in the native tumor environment. In the present study, we have developed a spatially resolved computational model to analyze the longitudinal BRET imaging of antibody–target binding and to explore the mechanisms of biphasic binding dynamics between cetuximab and its target, the epidermal growth factor receptor (EGFR). The model suggested that cetuximab bound differently to EGFR in the stroma-rich area than in stroma-poor regions, and this difference was confirmed by immunofluorescence staining. Compared to the binding in vitro, cetuximab bound to EGFR to a “slower-but-tighter” degree in the living tumors. These findings have provided spatially resolved characterizations of antibody–target binding in living tumors and have yielded many mechanistic insights into the factors that affect antibody interactions with its targets.
Sphingolipids mediate polar sorting of PIN2 through phosphoinositide consumption at thetrans-Golgi Network
Authors: Ito Yoko , Esnay Nicolas , Platre Matthieu Pierre , Noack Lise C. , Menzel Wilhelm , Claverol Stephane , Moreau Patrick , Jaillais Yvon , Boutté Yohann
Published: May 2020

The lipid composition of organelles acts as a landmark to define membrane identity and specify subcellular function. Phosphoinositides are anionic lipids acting in protein sorting and trafficking at thetrans-Golgi network (TGN). In animal cells, sphingolipids are known to control the turnover of phosphoinositides through lipid exchange mechanisms at endoplasmic reticulum/TGN contact sites. In this study, we discovered a completely new mechanism acting on sphingolipid-mediated phosphoinositides homeostasis at the TGN in plant cells. We used multi-approaches to show that a reduction of the acyl-chain length of sphingolipid results in increased level of phosphatidylinositol-4-phosphate (PI4P) at the TGN, independently from either lipid exchange induced by sphingolipid synthetic flux, or local PI4P synthesis. Instead, we found that sphingolipids mediate the consumption of PI4P through phosphoinositide-specific phospholipase C (PI-PLC) and this process impacts the sorting of the auxin efflux carrier PIN2 at the TGN. Together, our data identify a new mode of action of sphingolipids in lipid interplay at the TGN during protein sorting.
Time-limited alterations in cortical activity of a Knock-in mice model ofKCNQ2-related Developmental and Epileptic Encephalopathy
Authors: Biba Najoua , Becq Hélène , Kurz Marie , Pallesi Emilie , Villard Laurent , Milh Mathieu , Santini Pierre-Pascal Lenck , Aniksztejn Laurent
Published: May 2020

De novomissense variants in theKCNQ2gene encoding the Kv7.2 subunit of the voltage-gated potassium Kv7/M channel are the main cause of Developmental and Epileptic Encephalopathy (DEE).KCNQ2related-DEE is characterized by pharmaco-resistant neonatal seizures associated with a developmental delay. While seizures usually resolve some weeks or months after birth, cognitive/behavioral deficits persist. To better understand the cellular mechanisms underlyingKCNQ2-associatednetwork dysfunction and their progression over time, we investigatedin vivo,using local field potential recordings of freely moving animals, andex-vivoin layers II/III and V of motor cortical slices, using patch-clamp recordings, the electrophysiological properties of pyramidal cells from a heterozygous knock-in (KI) mouse model carrying the p.T274M pathogenic variant during neonatal, post-weaning and juvenile developmental stages. We found that KI mice displayed spontaneous seizures preferentially at post-weaning rather than at juvenile stages. At the cellular level, the variant led to a reduction in M current density/chord conductance and to an increase in neuronal excitability. These alterations were observed already during the neonatal period in pyramidal cells of layers II / III and during post-weaning stage in pyramidal cells of layer V. Moreover there was an increase in the frequency of spontaneous network driven events mediated by GABA receptors in the layers II/III suggesting that the excitability of some interneurons was also increased. However, all these alterations were time limited and no more observed in layers II/III and V of juvenile mice. At this stage, M-current density and neuronal excitability were not different from the measurements made in juvenile wild-type mice. Thus our data indicate that the action of the variant on neuronal activity is developmentally regulated and that some cellular mechanisms leading to the recovery of Kv7/M channels function took place during brain maturation of KI mice. These results raise the possibility that the age related seizure remission observed inKCNQ2-related DEE patient results also from a time limited alteration of Kv7 channels activity and neuronal excitability.
Designed Anchoring Geometries Determine Lifetimes of Biotin-Streptavidin Bonds under Constant Load and Enable Ultra-Stable Coupling
Authors: Gruber Sophia , Löf Achim , Sedlak Steffen M. , Benoit Martin , Gaub Hermann E. , Lipfert Jan
Published: May 2020

The small molecule biotin and the homotetrameric protein streptavidin (SA) form a stable and robust complex that plays a pivotal role in many biotechnological and medical applications. In particular, the biotin-streptavidin linkage is frequently used in single molecule force spectroscopy (SMFS) experiments. Recent data suggest that biotin-streptavidin bonds show strong directional dependence and a broad range of multi-exponential lifetimes under load. Here, we investigate engineered SA variants with different valencies and a unique tethering point under constant forces using a magnetic tweezer assay. We observed two orders-of-magnitude differences in the lifetimes, which we attribute to the distinct force loading geometries in the different SA variants. We identified an especially long-lived tethering geometry that will facilitate ultra-stable SMFS experiments and pave the way for new biotechnological applications.
Engineering and optimization of the 2-phenylethylglucosinolate production inNicotiana benthamianaby combining biosynthetic genes fromBarbarea vulgarisandArabidopsis thaliana
Authors: Wang Cuiwei , Crocoll Christoph , Agerbirk Niels , Halkier Barbara Ann
Published: May 2020

Among the glucosinolate (GLS) defense compounds characteristic of the Brassicales order, several have been shown to promote human health. This includes 2-phenylethylglucosinolate (2PE) derived from homophenylalanine (HPhe). In this study, we used transient expression inNicotiana benthamianato validate and characterize previously predicted key genes in the 2PE biosynthetic pathway fromBarbarea vulgarisand demonstrate the feasibility of engineering 2PE production. We used genes fromB. vulgarisandArabidopsis thaliana, in which the biosynthesis of GLSs is predominantly derived from HPhe and dihomomethionine, respectively. The resulting GLS profiles partially mirrored GLS profiles in the gene donor plant, but in both cases the profiles inN. benthamianawere wider than in the native plants. We found thatBvBCAT4 is a more efficient entry enzyme for biosynthesis of both HPhe and dihomomethionine and that MAM1 enzymes determine the chain-elongated profile. Co-expression of the chain elongation pathway andCYP79F6fromB. vulgariswith the remaining aliphatic GLS core pathway genes fromA. thaliana, demonstrated the feasibility of engineering production of 2PE inN. benthamiana. Noticeably, the HPhe-converting enzymeBvCYP79F6 in the core GLS pathway belongs to the CYP79F subfamily, a family believed to have substrate specificity towards chain-elongated methionine derivatives. Replacing theB. vulgarischain elongation pathway with a chimeric pathway consisting ofBvBCAT4,BvMAM1,AtIPMI andAtIPMDH1 resulted in an additional 2-fold increase in 2PE production, demonstrating that chimeric pathway with genes from different species can increase flux and boost production in an engineered pathway. Our study provides a novel approach to produce the important HPhe and 2PE in a heterologous host. Chimeric engineering of a complex biosynthetic pathway enabled detailed understanding of catalytic properties of individual enzymes - a prerequisite for understanding biochemical evolution - and with biotechnological and plant breeding potentials of new-to-nature gene combinations.
Partial endoreplication stimulates diversification in the species-richest lineage of orchids
Authors: Chumová Zuzana , Záveská Eliška , Ponert Jan , Schmidt Philipp-André , Trávníček Pavel
Published: May 2020

Some of the most burning questions in biology in recent years concern differential diversification along the tree of life and its causes. Among others, it could be triggered by the evolution of novel phenotypes accelerating diversification in lineages that bear them. In the Pleurothallidinae, the most species-rich subtribe of plants on Earth with 46 genera and ∼5,500 species, we constructed a completely new phylogeny and mapped on to it the type of endoreplication intending to trace how the phenomenon of partial endoreplication, which is unique to orchids, affects the differential diversification of lineages.

We have used NGS based target enrichment HybSeq approach for the reconstruction of the phylogeny and the flow cytometry to estimate the type of endoreplication. The BAMM and BiSSE analyses have been used to assess diversification rates and to trace the phenotype changes.

We have found that three of six changes in diversification rates are associated with changes in the endoreplication type and the clades bearing taxa with partial endoreplication showed higher net diversification rates. Our results demonstrate that multiple evolution of partial endoreplication within the subtribe considerably shapes the patterns of diversity and that partial endoreplication is a trait with an evolutionary significance.
Individual differences in (dis)honesty are represented in the brain’s functional connectivity: Robust out-of-sample prediction of cheating behavior
Authors: Speer Sebastian P.H. , Smidts Ale , Boksem Maarten A.S.
Published: May 2020

Many of the economically most costly forms of unethical behavior such as tax evasion, stock manipulations or movie and music piracy relate to the moral domain of (dis)honesty, in which unethical behavior is not targeted at a clearly identifiable victim. While large individual differences in (dis)honesty are evident, the neurocognitive determinants of this heterogeneity remain elusive. We combined connectome-based predictive modelling (CPM) on resting state functional connectivity patterns with a novel experimental task, which measures spontaneous and voluntary cheating inconspicuously, to investigate how these task-independent neural patterns shape our (dis)honest choices. Our analyses revealed that functional connectivity in a network of regions, including the dorsolateral prefrontal cortex and the inferior frontal gyrus, commonly linked to cognitive control processes, but also the medial prefrontal cortex and temporal pole, associated with self-referential thinking, and the caudate nucleus, linked to reward processing, are of central importance in promoting honesty. In a leave-one-out cross-validation analysis, we show that this neural model can reliably and accurately predict how much an unseen participant will cheat on our task. Participants who cheated the most, also scored highest on several impulsivity measures, which highlights the ecological validity of our task. Notably, when comparing neural and self-report measures, the neural measures were found to be significantly more important in predicting cheating. Our findings suggest that a person’s dis(honest) decisions depend on how well the self-referential thinking network is functionally connected to the control and reward networks.
Single-cell analysis supports a luminal-neuroendocrine trans-differentiation in human prostate cancer
Authors: Dong Baijun , Miao Juju , Wang Yanqing , Luo Wenqin , Ji Zhongzhong , Lai Huadong , Zhang Man , Cheng Xiaomu , Wang Jinming , Fang Yuxiang , Zhu Helen He , Chua Chee Wai , Fan Liancheng , Zhu Yinjie , Pan Jiahua , Wang Jia , Xue Wei , Gao Wei-Qiang
Published: May 2020

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore novel intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.
TAZ inhibits GR and coordinates hepatic glucose homeostasis in normal physiologic states
Authors: Xu Simiao , Liu Yangyang , Hu Ruixiang , Wang Min , Stöhr Oliver , Xiong Yibo , Chen Liang , Kang Hong , Zheng Lingyun , Cai Songjie , He Li , Wang Cunchuan , Copps Kyle D. , White Morris F. , Miao Ji
Published: May 2020

The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiologic and pathologic states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ interactsviaits WW domain with the ligand-binding domain of GR to limit the binding of GR to gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate distinct roles of the hippo pathway effector proteins yes-associated protein 1 (YAP) and TAZ in liver physiology: while deletion of hepatic YAP has little effect on glucose homeostasis, hepatic TAZ protein expression decreases upon fasting and coordinates gluconeogenesis in response to physiologic fasting and feeding.
Restricting visual exploration directly impedes neural activity, functional connectivity, and memory
Authors: Liu Zhong-Xu , Rosenbaum R. Shayna , Ryan Jennifer D.
Published: May 2020

We move our eyes to explore the visual world, extract information, and create memories. The number of gaze fixations – the stops that the eyes make – has been shown to correlate with activity in the hippocampus, a region critical for memory, and with later recognition memory. Here, we combined eyetracking with fMRI to provide direct evidence for the relationships between gaze fixations, neural activity, and memory during scene viewing. Compared to free viewing, fixating a single location reduced: 1) subsequent memory, 2) neural activity along the ventral visual stream into the hippocampus, 3) neural similarity between effects of subsequent memory and visual exploration, and 4) functional connectivity among the hippocampus, parahippocampal place area, and other cortical regions. Gaze fixations were uniquely related to hippocampal activity, even after controlling for neural effects due to subsequent memory. Individual gaze fixations may provide the basic unit of information on which memory binding processes operate.
A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic β-cells
Authors: Li Mark , Shao Fan , Qian Qingwen , Yu Wenjie , Zhang Zeyuan , Chen Biyi , Su Dan , Guo Yuwei , Phan An-Vi , Song Long-sheng , Stephens Samuel B. , Sebag Julien , Imai Yumi , Yang Ling , Cao Huojun
Published: May 2020

Micropeptides (microproteins) encoded by transcripts previously annotated as long noncoding RNA (IncRNAs) are emerging as important mediators of fundamental biological processes in health and disease. Here we applied two computational tools to identify putative micropeptides encoded by lncRNAs that are expressed in the human pancreas. We experimentally verified one such micropeptide encoded by a β-cell- and neural cell-enriched lncRNATUNAR(also known as TUNA, HI-LNC78 or LINC00617). We named this highly conserved 48-amino-acid micropeptideBeta cell- andNeural cell-regulin(BNLN). BNLN contains a single-pass transmembrane domain and localized at the endoplasmic reticulum in pancreatic β-cells. Overexpression of BNLN lowered ER calcium levels, increased cytosolic calcium levels, and maintained ER homeostasis in response to high glucose challenge. To determine the physiological and pathological roles of BNLN, we assessed the BNLN expression in islets from mice fed with a high-fat diet and a regular diet, and found thatBNLNis suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN elevated glucose-stimulated insulin secretion in INS-1 cells. Lastly, BNLN overexpression enhanced insulin secretion in islets from lean and obese mice as well as from humans. Taken together, our study provides the first evidence that lncRNA-encoded micropeptides play a critical role in pancreatic β-cell function and provides a foundation for future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes.
Reactivation of latent infections with migration shapes population-level disease dynamics
Authors: Becker Daniel J. , Ketterson Ellen D. , Hall Richard J.
Published: May 2020

Annual migration is common across animal taxa and can dramatically shape the spatial and temporal patterns of infectious disease. Although migration can decrease infection prevalence in some contexts, these energetically costly long-distance movements can also have immunosuppressive effects that may interact with transmission processes in complex ways. Here we develop a mechanistic model for the reactivation of latent infections driven by physiological changes or energetic costs associated with migration (i.e., “migratory relapse”) and its effects on disease dynamics. We determine conditions under which migratory relapse can amplify or reduce infection prevalence across pathogen and host traits (e.g., infectious periods, virulence, overwinter survival, timing of relapse) and transmission phenologies. We show that relapse at either the start or end of migration can dramatically increase prevalence across the annual cycle and may be crucial for maintaining pathogens with low transmissibility and short infectious periods in migratory populations. Conversely, relapse at the start of migration can reduce the prevalence of highly virulent pathogens by amplifying culling of infected hosts during costly migration, especially for highly transmissible pathogens and those transmitted during migration or the breeding season. Our study provides a mechanistic foundation for understanding the spatiotemporal patterns of relapsing infections in migratory hosts, with implications for zoonotic surveillance and understanding how infection patterns will respond to shifts in migratory propensity associated with environmental change. Further, our work suggests incorporating within-host processes into population-level models of pathogen transmission may be crucial for reconciling the range of migration–infection relationships observed across migratory species.
The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates
Authors: Abdel-Nour Mena , Ramaglia Valeria , Bianchi Athanasia A. , Tsalikis Jessica , Chau Hien N. , Kalia Suneil K. , Kalia Lorraine V. , Chen Jane-Jane , Arnoult Damien , Gommerman Jennifer L. , Philpott Dana J. , Girardin Stephen E.
Published: May 2020

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Here we show that the eIF2α kinase HRI potentiates the autophagic clearance of cytosolic protein aggregates when the UPS is inhibited. In cells silenced for HRI, proteasome inhibition resulted in accumulation of aggresomes and ubiquitinated proteins, as well as cytotoxicity. Moreover, silencing of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month oldHri-/-mice as compared toHri+/+littermates. Moreover, agedHri-/-mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans where it may contribute to impaired micturition and/or constipation. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response (cUPR) that could be leveraged to bolster the clearance of cytotoxic protein aggregates.
Personalized anti-cancer drug combination prediction by an Integrated Multi-level Network
Authors: Feng Fangyoumin , Zhang Zhengtao , Ding Guohui , Hui Lijian , Li Yixue , Li Hong
Published: May 2020

Anti-cancer drug combination is an effective solution to improve treatment efficacy and overcome resistance. Here we propose a network-based method (DComboNet) to prioritize the candidate drug combinations. The level one model is to predict generalized anti-cancer drug combination effectiveness and level two model is to predict personalized drug combinations. By integrating drugs, genes, pathways and their associations, DComboNet achieves better performance than previous methods, with high AUC value of around 0.8. The level two model performs better than level one model by introducing cancer sample specific transcriptome data into network construction. DComboNet is further applied on finding combinable drugs for sorafenib in hepatocellular cancer, and the results are verified with literatures and cell line experiments. More importantly, three potential mechanism modes of combinations were inferred based on network analysis. In summary, DComboNet is valuable for prioritizing drug combination and the network model may facilitate the understanding of the combination mechanisms.
Resolution of subcomponents of synaptic release from post-synaptic currents in rat hair-cell/auditory-nerve fiber synapses
Authors: Young Eric D. , Wu Jingjing Sherry , Niwa Mamiko , Glowatzki Elisabeth
Published: May 2020

The synapse between inner hair cells and auditory nerve fiber dendrites shows large EPSCs, which are either monophasic or multiphasic. Multiquantal or uniquantal flickering release have been proposed to underlie the unusual multiphasic waveforms. Here the nature of multiphasic waveforms is analyzed using EPSCs recordedin vitroin rat afferent dendrites. Spontaneous EPSCs were deconvolved into a sum of presumed release events with monophasic EPSC waveforms. Results include: first, the charge of EPSCs is about the same for multiphasic versus monophasic EPSCs. Second, EPSC amplitudes decline with the number of release events per EPSC. Third, there is no evidence of a mini-EPSC. Most results can be accounted for by versions of either uniquantal or multiquantal release. However, serial neurotransmitter release in multiphasic EPSCs shows properties that are not fully explained by either model, especially that the amplitudes of individual release events is established at the beginning of a multiphasic EPSC, constraining possible models of vesicle release.
Unraveling the interaction between doxorubicin and DNA origami nanostructures for customizable chemotherapeutic drug release
Authors: Ijäs Heini , Shen Boxuan , Heuer-Jungemann Amelie , Keller Adrian , Kostiainen Mauri A. , Liedl Tim , Ihalainen Janne A. , Linko Veikko
Published: May 2020

Doxorubicin (DOX) is a common drug in cancer chemotherapy, and its high DNA-binding affinity can be harnessed in preparing DOX-loaded DNA nanostructures for targeted delivery and therapeutics. Although DOX has been widely studied, the existing literature of DOX-loaded DNA-carriers remains limited and incoherent. Here, based on an in-depth spectroscopic analysis, we characterize and optimize the DOX loading into different 2D and 3D scaffolded DNA origami nanostructures (DONs). In our experimental conditions, all DONs show similar DOX binding capacities (one DOX molecule per two to three base pairs), and the binding equilibrium is reached within seconds, remarkably faster than previously acknowledged. To characterize drug release profiles, DON degradation and DOX release from the complexes upon DNase I digestion was studied. For the employed DONs, the relative doses (DOX molecules released per unit time) may vary by two orders of magnitude depending on the DON superstructure. In addition, we identify DOX aggregation mechanisms and spectral changes linked to pH, magnesium, and DOX concentration. These features have been largely ignored in experimenting with DNA nanostructures, but are probably the major sources of the incoherence of the experimental results so far. Therefore, we believe this work can act as a guide to tailoring the release profiles and developing better drug delivery systems based on DNA-carriers.
The Evolution and Fate of Diversity Under Hard and Soft Selection
Authors: Chen Patrick J. , Kassen Rees
Published: May 2020

How genetic variation arises and persists over evolutionary time despite the depleting effects of natural selection remains a long-standing question. Here, we investigate the impacts of two extreme forms of population regulation – at the level of the total, mixed population (hard selection) and at the level of local, spatially distinct patches (soft selection) – on the emergence and fate of diversity under strong divergent selection. We find that while the form of population regulation has little effect on rates of diversification it can modulate the long-term fate of genetic variation, diversity being more readily maintained under soft selection compared to hard selection. The mechanism responsible for coexistence is negative frequency dependent selection which, while present initially under both forms of population regulation, persists over the long-term only under soft selection. Importantly, coexistence is robust to continued evolution of niche specialist types under soft selection but not hard selection. These results suggest that soft selection could be a general mechanism for the maintenance of ecological diversity over evolutionary time scales.
Contrast-FEL – a test for differences in selective pressures at individual sites among clades and sets of branches
Authors: Kosakovsky Pond Sergei L. , Wisotsky Sadie R , Escalante Ananias , Magalis Brittany Rife , Weaver Steven
Published: May 2020

A number of evolutionary hypotheses can be tested by comparing selective pressures among sets of branches in a phylogenetic tree. When the question of interest is to identify specific sites within genes that may be evolving differently, a common approach is to perform separate analyses on subsets of sequences, and compare parameter estimates in apost hocfashion. This approach is statistically suboptimal, and not always applicable. Here, we develop a simple extension of a popular fixed effects likelihood method in the context of codon-based evolutionary phylogenetic maximum likelihood testing, Contrast-FEL. It is suitable for identifying individual alignment sites where any among theK ≥2 sets of branches in a phylogenetic tree have detectably differentdN/dSratios, indicative of different selective regimes. Using extensive simulations, we show that Contrast-FEL delivers good power, exceeding 90% for sufficiently large differences, while maintaining tight control over false positive rates. We conclude by applying Contrast-FEL to data from five previously published studies spanning a diverse range of organisms and focusing on different evolutionary questions.
Predation Has Small, Short-Term, and in Certain Conditions Random Effect on the Evolution of Aging
Authors: Lenart Peter , Bienertová-Vašků Julie , Berec Luděk
Published: May 2020

The pace of aging varies considerably in nature. Historically, scientists focused mostly on why and how has aging evolved, while only a few studies explored mechanisms driving evolution of specific rates of aging. Here we develop an agent-based model simulating evolution of aging in prey subject to predation. Our results suggest that predation affects the pace of aging in prey only if young, vivid animals are not much more likely to escape predators than the old ones. However, even this effect slowly vanishes when the predator diet composition evolves, too. Furthermore, evolution of a specific aging rate, in our model, is driven mainly by a single parameter, the strength of a trade-off between aging and fecundity. Indeed, in absence of this trade-off the evolutionary impacts of predation on the prey aging rate appear random. Our model produces several testable predictions which may be useful for other areas of aging research.
Novel ACE2-Independent Carbohydrate-Binding of SARS-CoV-2 Spike Protein to Host Lectins and Lung Microbiota
Authors: Chiodo Fabrizio , Bruijns Sven C.M. , Rodriguez Ernesto , Li R.J. Eveline , Molinaro Antonio , Silipo Alba , Di Lorenzo Flaviana , Garcia-Rivera Dagmar , Valdes-Balbin Yury , Verez-Bencomo Vicente , van Kooyk Yvette
Published: May 2020

The immediate call for translational research in the field of coronavirus disease (COVID-19) pandemic, needs new and unexplored angles to support and contribute to this important worldwide health problem. The aim of this study is to better understand the pathogenic mechanisms underlying COVID-19, deciphering the carbohydrate-mediated interactions of the SARS-CoV-2 spike protein. We studied the carbohydrate-binding receptors that could be important for viral entry and for immune-modulatory responses, and we studied the interactions of the spike protein with the host lung microbiota. Exploring solid-phase immunoassays, we evaluated the interactions between the SARS-CoV-2 spike protein and a library of 12 different human carbohydrate-binding proteins (C-type lectins and Siglecs) involved in binding, triggering and modulation of innate and adaptive immune-responses. We revealed a specific binding of the SARS-CoV-2 spike protein to the receptors DC-SIGN, MGL, Siglec-9 and Siglec-10 that are all expressed on myeloid immune cells. In addition, because the lung microbiota can promote or modulate viral infection, we studied the interactions between the SARS-CoV-2 spike protein and a library ofStreptococcus pneumoniaecapsular polysaccharides, as well as other bacterial glyco-conjugates. We show specific binding of the spike protein to differentS. pneumoniaecapsular polysaccharides (serotypes 19F and 23F but not to serotype 14). Moreover we demonstrated a specific binding of SARS-CoV-2 spike protein to the lipopolysaccharide from the opportunistic human pathogenPseudomonas aeruginosa, one of the leading cause of acute nosocomial infections and pneumonia. Interestingly, we identified rhamnosylated epitopes as one of the discriminating structures in lung microbiota to bind SARS-CoV-2 spike protein. In conclusion, we revealed novel ACE2-independent carbohydrate-mediated interactions with immune modulating lectins expressed on myeloid cells, as well as host lung microbiota glyco-conjugates. Our results identified new molecular pathways using host lectins and signalling, that may contribute to viral infection and subsequent immune exacerbation. Moreover we identified specific rhamnosylated epitopes in lung microbiota to bind SARS-CoV-2, providing a hypothetical link between the presence of specific lung microbiota and SARS-CoV-2 infection and severity.
Novel method for the prediction of drug-drug Interaction based on Gene Expression profiles
Authors: Taguchi Yh. , Turki Turki
Published: May 2020

The accurate prediction of new interactions between drugs is important for avoiding unknown (mild or severe) adverse reactions to drug combinations. The development of effectivein silicomethods for evaluating drug interactions based on gene expression data requires an understanding of how various drugs alter gene expression. Current computational methods for the prediction of drug-drug interactions (DDIs) utilize data for known DDIs to predict unknown interactions. However, these methods are limited in the absence of known predictive DDIs. To improve DDIs’ interpretation, a recent study has demonstrated strong non-linear (i.e., dosedependent) effects of DDIs. In this study, we present a new unsupervised learning approach involving tensor decomposition (TD)-based unsupervised feature extraction (FE) in 3D. We utilize our approach to reanalyze available gene expression profiles forSaccharomyces cerevisiae. We found that non-linearity is possible, even for single drugs. Thus, non-linear dose-dependence cannot always be attributed to DDIs. Our analysis provides a basis for the design of effective methods for evaluating DDIs.
Shifts from pulled to pushed range expansions caused by reduction of landscape connectivity
Authors: Dahirel Maxime , Bertin Aline , Haond Marjorie , Blin Aurélie , Lombaert Eric , Calcagno Vincent , Fellous Simon , Mailleret Ludovic , Malausa Thibaut , Vercken Elodie
Published: May 2020

Abstract

Range expansions are key processes shaping the distribution of species; their ecological and evolutionary dynamics have become especially relevant today, as human influence reshapes ecosystems worldwide. Many attempts to explain and predict range expansions assume, explicitly or implicitly, so-called “pulled” expansion dynamics, in which the low-density edge populations provide most of the “fuel” for the species advance. Some expansions, however, exhibit very different dynamics, with high-density populations behind the front “pushing” the expansion forward. These two types of expansions are predicted to have different effects on e.g. genetic diversity and habitat quality sensitivity. However, empirical studies are lacking due to the challenge of generating reliably pushed vs. pulled expansions in the laboratory, or discriminating them in the field. We here propose that manipulating the degree of connectivity among populations may prove a more generalizable way to create pushed expansions. We demonstrate this with individual-based simulations as well as replicated experimental range expansions (using the parasitoid waspTrichogramma brassicaeas model). By analyzing expansion velocities and neutral genetic diversity, we showed that reducing connectivity led to pushed dynamics. Low connectivity alone, i.e. without density-dependent dispersal, can only lead to “weakly pushed” expansions, where invasion speed conforms to pushed expectations, but the decline in genetic diversity does not. In empirical expansions however, low connectivity may in some cases also lead to adjustments to the dispersal-density function, recreating “classical” pushed expansions. In the current context of habitat loss and fragmentation, we need to better account for this relationship between connectivity and expansion regimes to successfully predict the ecological and evolutionary consequences of range expansions.
A framework for designing miRNA-based distributed cell classifier circuits
Authors: Nowicka Melania , Siebert Heike
Published: May 2020

Motivation

Cell classifiers are synthetic bio-devices performing type-specificin vivoclassification. The circuits identify a cell state based on its molecular fingerprint. In particular, the classifiers may be designed to recognize cancerous cells and trigger their apoptosis, shaping a novel therapy for cancer patients. Recently, we introduced a new theoretical design of such devices employing distributed classifiers. Here, a group of single-circuit classifiers decides collectively according to a pre-defined threshold function whether a cell is cancerous. The multi-circuit architecture has shown the potential to predict the cell condition with high accuracy. However, lack of far-reaching machinery to design and evaluate distributed cell classifiers, in particular, assessing their robustness to noise and novel information, makes their application limited.

Results

In this study, we present a comprehensive framework for designing and evaluating miRNA-based distributed cell classifiers comprising data simulation, pre-processing, and an extensive testing scheme. We develop optimization criteria that allow increasing the accuracy and robustness of classifiers to noise and novel information as shown in simulated and real-world data studies. The evaluation performed on cancer data demonstrates that distributed classifiers outperform single-circuit designs in terms of prediction accuracy. Our classifiers include relevant miRNAs previously described in the literature, as well as more complex regulation patterns included in the data.

Availability

The code and data are available at:https://github.com/MelaniaNowicka/RAccoon.

Contact

m.nowicka@fu-berlin.de
RBFOX2 is Critical for Maintaining Alternative Polyadenylation Patterns and Mitochondrial Health in Rat Myoblasts
Authors: Cao Jun , Verma Sunil K. , Jaworski Elizabeth , Mohan Stephanie , Nagasawa Chloe K. , Rayavara Kempaiah , Sooter Amanda , Miller Sierra N. , Holcomb Richard J. , Ji Ping , Elrod Nathan D. , Yildirim Eda , Wagner Eric J. , Popov Vsevolod , Garg Nisha J. , Routh Andrew L. , Kuyumcu-Martinez Muge N.
Published: May 2020

RBFOX2, which has a well-established role in alternative splicing, is linked to heart diseases. However, it is unclear whether RBFOX2 has other roles in RNA processing that can influence gene expression/function in muscle cells, contributing to disease pathology. Here, we employed both 3’-end and nanopore cDNA sequencing to reveal a previously unrecognized role for RBFOX2 in maintaining alternative polyadenylation (APA) signatures in myoblasts. We found that RBFOX2-mediated APA modulates both mRNA levels and isoform expression of a collection of genes including contractile and mitochondrial genes. We identified the key muscle-specific contractile gene,Tropomyosin 1and essential mitochondrial gene,Slc25a4as APA targets of RBFOX2. Unexpectedly, depletion of RBFOX2 adversely affected mitochondrial health in myoblasts that is in part mediated by disrupted APA of mitochondrial geneSlc25a4. Mechanistically, we found that RBFOX2 regulation ofSlc25a4APA is mediated through consensus RBFOX2 binding motifs near the distal polyadenylation site enforcing the use of the proximal polyadenylation site. In sum, our results unveiled a new role for RBFOX2 in fine tuning expression levels of mitochondrial and contractile genes via APA in myoblasts relevant to heart diseases.
CCR4-NOT complex nuclease Caf1 is a novel shuttle factor involved in the degradation of ubiquitin-modified proteins by 26S proteasome
Authors: Kandasamy Ganapathi , Pradhan Ashis Kumar , Palanimurugan R
Published: May 2020

Protein degradation by ubiquitin proteasome system (UPS) is the major selective proteolytic pathway responsible for the degradation of short lived proteins ranging from regulatory proteins to abnormal proteins. Many diseases are associated with abnormal protein degradation; occasionally such dysregulated protein degradation is compensated by various transcriptional and translational control mechanisms in the cell. Among those pathways CCR4-NOT protein complex is responsible for transcriptional and transitional control of various gene expressions. Furthermore, CCR4-NOT complex also has a RING type ubiquitin ligase (E3) which is required for the degradation of several proteins. Here we report a novel function that the CCR4-NOT complex 3’-5’ exonuclease Caf1 is involved in ubiquitindependent degradation of short lived proteins by the 26S proteasome in yeastSaccharomyces cerevisiae. caf1deletion results in stabilization of R-Ura3 (N-end rule) and Ub-V76-Ura3 (Ubiquitin fusion degradation) substrates from proteasomal degradation. Additionally,caf1deletion accumulates ubiquitin-modified Ub-V76-Ura3 proteins and Caf1 binds to poly-ubiquitin conjugates and linear tetra ubiquitin chains. Surprisingly, Caf1 interacts with 19S regulatory particle complex of the 26S proteasome. Therefore, we conclude that Caf1 has an exciting novel function as an ubiquitin shuttle factor in which Caf1 targets ubiquitin-modified proteins to 26S proteasome for efficient degradation.