bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct mechanoreceptor pezo-1 isoforms modulate food intake in the nematode Caenorhabditis elegans
Authors: Hughes K , Shah A , Bai X , Adams J , Bauer R , Jackson J , Harris E , Ficca A , Freebairn P , Mohammed S , Fernández EM , Bainbridge C , Brocco MA , Stein W , Vidal-Gadea AG 
Published: May 2021

AbstractTwo PIEZO mechanosensitive cation channels, PIEZO1 and PIEZO2, have been identified in mammals, where they are involved in numerous sensory processes. While structurally similar, PIEZO channels are expressed in distinct tissues and exhibit unique properties. How different PIEZOs transduce force, how their transduction mechanism varies, and how their unique properties match the functional needs of the tissues they are expressed in remain all-important unanswered questions. The nematode Caenorhabditis elegans has a single PIEZO ortholog (pezo-1) predicted to have twelve isoforms. These isoforms share many transmembrane domains but differ in those that distinguish PIEZO1 and PIEZO2 in mammals. We used transcriptional and translational reporters to show that putative promoter sequences immediately upstream of the start codon of long pezo-1 isoforms predominantly drive GFP expression in mesodermally derived tissues (such as muscle and glands). In contrast, sequences upstream of shorter pezo-1 isoforms resulted in GFP expression primarily in neurons. Putative promoters upstream of different isoforms drove GFP expression in different cells of the same organs of the digestive system. The observed unique pattern of complementary expression suggests that different isoforms could possess distinct functions within these organs. We used mutant analysis to show that pharyngeal muscles and glands require long pezo-1 isoforms to respond appropriately to the presence of food. The number of pezo-1 isoforms in C. elegans, their putative differential pattern of expression, and roles in experimentally tractable processes make this an attractive system to investigate the molecular basis for functional differences between members of the PIEZO family of mechanoreceptors.
CuAAC stabilization of an NMR mixed labeled dimer
Authors: Sapienza Paul J. , Currie Michelle M. , Li Kelin , Aubé Jeffrey , Lee Andrew L. 
Published: May 2021

AbstractHomo dimers are the most abundant type of enzyme in cells and as such, they represent the archetypal system for studying the remarkable phenomenon of allostery. In these systems, in which the allosteric features are manifest by the effect of the first binding event on the similar event at the second site, the most informative state is the asymmetric single bound (lig1) form, yet it tends to be elusive thermodynamically. Here we take significant steps towards obtaining milligram quantities of pure lig1 of the allosteric homodimer, chorismate mutase, in the form of a mixed isotopically labeled dimer stabilized by Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) between the subunits. Below, we outline several critical steps required to generate high yields of both types of unnatural amino acid-containing proteins, and overcome multiple pitfalls intrinsic to CuAAC to obtain high yields of pure, fully intact, and active mixed labeled dimer. These data not only will make possible NMR-based investigations of allostery envisioned by us, but should also facilitate other structural applications where specific linkage of proteins is helpful.
CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women
Authors: Abou-Fadel Johnathan , Grajeda Brian , Jiang Xiaoting , Cailing-De La O Alyssa-Marie D. , Flores Esmeralda , Padarti Akhil , Bhalli Muaz , Le Alexander , Zhang Jun 
Published: May 2021

AbstractBreast cancer is the most commonly diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW); and new evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) is capable of exerting its cellular effects through either its classic, non-classic or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs), warranting both pathways an equally important status in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 proteins can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+/-) cell type. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCM proteins under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using multi-omics approaches, which helped us understand key factors within the CmP network, and identify 21 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs.
Genomic Selection for End-Use Quality and Processing Traits in Soft White Winter Wheat Breeding Program with Machine and Deep Learning Models
Authors: Sandhu Karansher S. , Aoun Meriem , Morris Craig , Carter Arron H. 
Published: May 2021

AbstractBreeding for grain yield, biotic and abiotic stress resistance, and end-use quality are important goals of wheat breeding programs. Screening for end-use quality traits is usually secondary to grain yield due to high labor needs, cost of testing, and large seed requirements for phenotyping. Hence, testing is delayed until later stages in the breeding program. Delayed phenotyping results in advancement of inferior end-use quality lines into the program. Genomic selection provides an alternative to predict performance using genome-wide markers. Due to large datasets in breeding programs, we explored the potential of the machine and deep learning models to predict fourteen end-use quality traits in a winter wheat breeding program. The population used consisted of 666 wheat genotypes screened for five years (2015-19) at two locations (Pullman and Lind, WA, USA). Nine different models, including two machine learning (random forest and support vector machine) and two deep learning models (convolutional neural network and multilayer perceptron), were explored for cross-validation, forward, and across locations predictions. The prediction accuracies for different traits varied from 0.45-0.81, 0.29-0.55, and 0.27-0.50 under cross-validation, forward, and across location predictions. In general, forward prediction accuracies kept increasing over time due to increments in training data size and was more evident for machine and deep learning models. Deep learning models performed superior over the traditional ridge regression best linear unbiased prediction (RRBLUP) and Bayesian models under all prediction scenarios. The high accuracy observed for end-use quality traits in this study support predicting them in early generations, leading to the advancement of superior genotypes to more extensive grain yield trailing. Furthermore, the superior performance of machine and deep learning models strengthen the idea to include them in large scale breeding programs for predicting complex traits.
GraFT: Graph Filtered Temporal Dictionary Learning for Functional Neural Imaging
Authors: Charles Adam S. , Cermak Nathan , Affan Rifqi , Scott Ben , Schiller Jackie , Mishne Gal 
Published: May 2021

AbstractOptical imaging of calcium signals in the brain has enabled researchers to observe the activity of hundreds-to-thousands of individual neurons simultaneously. Current methods predominantly focus on matrix factorization and aim at detecting neurons in the imaged field-of-view, and then inferring the corresponding time-traces. The explicit locality constraints on the cell shapes additionally limits the applicability to optical imaging at different scales (i.e., dendritic or widefield data). Here we present a new method that frames the problem of isolating independent fluorescing components as a dictionary learning problem. Specifically, we focus on the time-traces, which are the main quantity used in scientific discovery, and learn the dictionary of time traces with the spatial maps acting as the presence coefficients encoding which pixels the time traces are active in. Furthermore, we present a novel graph filtering model which redefines connectivity between pixels in terms of their shared temporal activity, rather than spatial proximity. This model greatly eases the ability of our method to handle data with complex non-local spatial structure, such as dendritic imaging. We demonstrate important properties of our method, such as robustness to initialization, implicitly inferring number of neurons and simultaneously detecting different neuronal types, on both synthetic data and real data examples. Specifically, we demonstrate applications of our method to calcium imaging both at the dendritic, somatic, and widefield scales.
Identification of multiple TAR DNA Binding Protein retropseudogene lineages during the evolution of primates
Authors: Opazo Juan C. , Zavala Kattina , Vargas-Chacoff Luis , Morera Francisco J. , Mardones Gonzalo A. 
Published: May 2021

AbstractThe TAR DNA Binding Protein (TARDBP) gene has gained attention in biomedicine after the discovery of several pathogenic mutations. The lack of knowledge about its evolutionary history contrasts with a large number of studies in the biomedical area. This study aimed to investigate the retrotransposition evolutionary dynamics associated with this gene in primates. We identified retropseudogenes that originated in the ancestors of anthropoids, catarrhines, and lemuriformes, i.e. the strepsirrhine clade that inhabit Madagascar. We also found species-specific retropseudogenes in the philippine tarsier, Bolivian squirrel monkey, capuchin monkey and vervet. Although retropseudogenes are not able to produce a functional protein, we can not rule out that they may represent genetic material upon which evolution acts on, especially with regulatory functions.
Cryptic genetic variations of alanine:glyoxylate aminotransferase shape its fitness and dynamics
Authors: Dindo Mirco , Pascarelli Stefano , Chiasserini Davide , Grottelli Silvia , Costantini Claudio , Uechi Gen-Ichiro , Giardina Giorgio , Laurino Paola , Cellini Barbara 
Published: May 2021

AbstractGenetic variations expand the conformational landscape of proteins and may underlie cryptic properties that promote environmental adaptability. However, they can also represent modifying factors for disease susceptibility, by changing frustrated regions that in turn affect protein overall intracellular fitness. In this dichotomy between conservation and innovation, understanding at structural level how genetic variations keep the balance to maintain protein fitness represents an unmet need.Herein, we took advantage of known genetic variations of human alanine:glyoxylate aminotransferase (AGT1), which is present as a common major allelic form (AGT-Ma) and a minor polymorphic form (AGT-Mi) expressed in 20% of Caucasian population. By crystallographic studies and molecular dynamics simulations we showed that the polymorphic amino acid substitutions shape the conformational flexibility of AGT1 so that three surface regions that are structured in AGT-Ma become disordered in AGT-Mi, thanks to plasticity effects propagated from the mutation site(s) to the whole structure. In-depth biochemical characterisation of variants from a library encompassing the three regions correlate this plasticity to a fitness window between AGT-Ma and AGT-Mi, and suggest the existence of cryptic functions related to protein-protein interactions. These results establish that naturally-occurring genetic variations tip the balance between stability and frustration to expand the potential innovability of the protein.
Cellular heterogeneity in DNA alkylation repair as a trade-off between cell survival and genetic plasticity
Authors: Vincent Maxence S. , Uphoff Stephan 
Published: May 2021

AbstractDNA repair mechanisms fulfil a dual role, as they are essential for cell survival and genome maintenance. Here, we studied how cells regulate the interplay between DNA repair and mutation. We focused on the Escherichia coli adaptive response that increases resistance to DNA alkylation damage. Combination of single-molecule imaging and microfluidic-based single-cell microscopy showed that noise in the gene activation timing of the master regulator Ada is accurately propagated to generate a distinct subpopulation of cells in which all proteins of the adaptive response are absent. Although lack of these proteins causes extreme sensitivity to alkylation stress, cellular heterogeneity in DNA alkylation repair provides a functional benefit by increasing the evolvability of the whole population. We demonstrated this by monitoring the dynamics of nascent mutations during alkylation stress as well as the frequency of fixed mutations that are generated by the distinct subpopulations of the adaptive response. This highlighted that evolvability is a trade-off between mutability and cell survival. Stochastic modulation of DNA repair capacity by the adaptive response solves this trade-off through the generation of a viable hypermutable subpopulation of cells that acts as a source of genetic diversity in a clonal population.
Efficient Alcoholic Conversion of Glycerol by Engineered Saccharomyces cerevisiae
Authors: Khattab Sadat M. R. , Watanabe Takashi 
Published: May 2021

ABSTRACTGlycerol is an eco-friendly solvent that enhances plant biomass decomposition via glycerolysis in many pretreatment methods. Nonetheless, the lack of efficient conversion of glycerol by natural Saccharomyces cerevisiae hinders its use in these methods. Here, we have aimed to develop a complete strategy for the generation of efficient glycerol-converting yeast by modifying the oxidation of cytosolic nicotinamide adenine dinucleotide (NADH) by an O2-dependent dynamic shuttle, while abolishing both glycerol phosphorylation and biosynthesis. By following a vigorous glycerol oxidation pathway, the engineered strain increased the conversion efficiency (CE) to up to 0.49 g ethanol/g glycerol (98% of theoretical CE), with production rate > 1 g·L·h, when glycerol was supplemented in a single fed-batch fermentation in a rich medium. Furthermore, the engineered strain fermented a mixture of glycerol and glucose, producing > 86 g/L bioethanol with 92.8% CE. To our knowledge, this is the highest ever reported titer in this field. Notably, this strategy changed conventional yeast from a non-grower on minimal medium containing glycerol to a fermenting strain with productivity of 0.25−0.5 g·L·h and 84−78% CE, which converted 90% of the substrate to products. Our findings may improve the utilization of glycerol in several eco-friendly biorefinery approaches.IMPORTANCEWith the development of efficient lignocellulosic biorefineries, glycerol has attracted attention as an eco-friendly biomass-derived solvent that can enhance the dissociation of lignin and cell wall polysaccharides during the pretreatment process. Co-conversion of glycerol with the sugars released from biomass after glycerolysis increases the resources for ethanol production and lowers the burden of component separation. However, titer productivity hinders the industrial application of this process. Therefore, generation of efficient glycerol-fermenting yeast will promote the applicability of integrated biorefineries. Furthermore, glycerol is an important carbon source for the production of various chemicals. Hence, control of the metabolic flux of yeast grown on glycerol will contribute to the generation of cell factories that produce chemicals such as ethanol from glycerol, which will boost biodiesel and bioethanol industries. Additionally, the use of glycerol-fermenting yeast will reduce global warming and generation of agricultural waste, leading to the establishment of a sustainable society.
Vimentin binds to G-quadruplex repeats found at telomeres and gene promoters
Authors: Ceschi Silvia , Berselli Michele , Giantin Mery , Toppo Stefano , Spolaore Barbara , Sissi Claudia 
Published: May 2021

AbstractG-quadruplex (G4) structures that can form at guanine-rich genomic sites, including telomeres and gene promoters, are actively involved in genome maintenance, replication, and transcription, through finely tuned interactions with protein networks. In the present study, we identified the intermediate filament protein Vimentin as a binder with nanomolar affinity for those G-rich sequences that give rise to at least two adjacent G4 units, named G4 repeats. This interaction is supported by the N-terminal domains of soluble Vimentin tetramers. The selectivity of Vimentin for G4 repeats vs individual G4s provides an unprecedented result. Based on GO enrichment analysis performed on genes having putative G4 repeats within their core promoters, we suggest that Vimentin recruitment at these sites may contribute to the regulation of gene expression during cell development and migration, possibly by reshaping the local higher-order genome topology, as already reported for lamin B.Graphical abstract
INTEROCEPTIVE INFORMATION OF PHYSICAL VIGOR: OREXIN NEURONS GAUGE CIRCULATING IGF-I FOR MOTIVATIONAL MOTOR OUTPUT
Authors: Zegarra-Valdivia Jonathan A. , Fernandes Jansen , Esparza Julio , Suda Kentaro , de Sevilla Maria Estrella Fernandez , Díaz-Pacheco Sonia , Aleman Ignacio Torres 
Published: May 2021

AbstractBrain regulation of bodily functions requires interoceptive feedback signals carrying information about the periphery. As mice with low serum IGF-I levels (LID mice) show reduced spontaneous physical activity, we speculated that body vigor information might be conveyed by circulating IGF-I, a regulator of skeletal muscle and bone mass that enters the brain during physical activity. Since hypothalamic orexin neurons, that are involved in regulating physical activity, express IGF-I receptors (IGF-IR), we hypothesized that these neurons might gauge circulating IGF-I levels. Inactivation of IGF-IR in mouse orexin neurons (Firoc mice) reduced spontaneous activity. Firoc mice maintain normal physical fitness but show anxiety- and depressive-like behaviors that seems to interfere with the rewarding effects of exercise, as they were less sensitive to the rewarding actions of exercise. Further, in response to exercise, Firoc mice showed reduced activation of hypothalamic orexin neurons and ventro-tegmental area (VTA) monoaminergic neurons, as indicated by c-fos staining. Collectively, these results suggest that circulating IGF-I is gauged by orexin neurons to modulate physical activity in part by stimulation of the VTA to motivate motor output. Hence, serum IGF-I may constitute a feedback signal, informing orexin neurons to adapt physical activity to physical vigor.
Biomechanical property of limbal niche maintains stemness through YAP
Authors: Bhattacharya Swarnabh , Mukherjee Abhishek , Pisano Sabrina , Dimri Shalini , Knaane Eman , Altshuler Anna , Nasser Waseem , Dey Sunanda , Shi Lidan , Mizrahi Ido , Jokel Ophir , Amitai-Lange Aya , Kaganovsky Anna , Mimouni Michael , Socea Sergiu , Hasson Peleg , Feral Chloe , Wolfenson Haguy , Shalom-Feuerstein Ruby 
Published: May 2021

AbstractStem cells’ (SCs) decision to self-renew or differentiate largely depends on the external control of their niche. However, the complex mechanisms that underlie this crosstalk are poorly understood. To address this question, we focused on the corneal epithelial SC model in which the SC niche, known as the limbus, is spatially segregated from the differentiation compartment. We report that the unique biomechanical property of the limbus supports the nuclear localization and function of Yes-associated protein (YAP), a putative mediator of the mechanotransduction pathway. Perturbation of tissue stiffness or YAP activity affects SC function as well as tissue integrity under homeostasis and significantly inhibited the regeneration of the SC population following SC depletion. In vitro experiments revealed that substrates with the rigidity of the corneal differentiation compartment inhibit YAP localization and induce differentiation, a mechanism that is mediated by the TGFβ−SMAD2/3 pathway. Taken together, these results indicate that SC sense biomechanical niche signals and that manipulation of mechano-sensory machinery or its downstream biochemical output may bear fruits in SC expansion for regenerative therapy.HighlightsYAP is essential for limbal SC function, regeneration, and dedifferentiationLox over-expression stiffens the limbal niche, affects SC phenotype and corneal integrityCorneal rigidity represses YAP and stemness in a SMAD2/3-dependent mannerManipulation of mechanosensory or TGF-β pathway influences limbal SC expansion in vitro
nf-LO: A scalable, containerised workflow for genome-to-genome lift over
Authors: Talenti Andrea , Prendergast James 
Published: May 2021

AbstractThe increasing availability of new genome assemblies often comes with an impaired amount of associated genomic annotations, limiting the range of studies that can be performed. A common workaround is to lift over annotations from better annotated genomes. However, generating the files required to perform a liftover is computationally and labour intensive and only a limited number are currently publicly available.Here we present nf-LO (nextflow-LiftOver), a containerised and scalable Nextflow pipeline that enables liftovers within and between any species for which assemblies are available. nf-LO will consequently facilitates data interpretation across a broad range of genomic studies.