bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTThe 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

AbstractAntibodies 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

AbstractThe 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

AbstractDe 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

AbstractThe 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

AbstractAmong 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

AbstractSome 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

AbstractMany 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

AbstractNeuroendocrine 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

AbstractThe 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

AbstractWe 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

ABSTRACTMicropeptides (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

AbstractAnnual 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

ABSTRACTLarge 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.