bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoplasmic reticulum stress induces a novel Ca2+signalling system initiated by Ca2+microdomains
Authors: Feliziani Constanza , Quasollo Gonzalo , Holstein Deborah , Fernandez Macarena , Paton James C , Paton Adrienne W , Lechleiter James D , Bollo Mariana 
Published: October 2020

AbstractThe accumulation of unfolded proteins within the Endoplasmic Reticulum (ER) activates a signal transduction pathway termed theunfoldedprotein response (UPR), which attempts to restore ER homeostasis. If homeostasis cannot be restored, UPR signalling ultimately induces apoptosis. Ca2+depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca2+as intracellular messenger, the precise mechanism (s) by which Ca2+release affects the UPR remains unknown. Use of a genetically encoded Ca2+indicator (GCamP6) that is tethered to the ER membrane, uncovered novel Ca2+signalling events initiated by Ca2+microdomains in human astrocytes under ER stress, as well as in a cell model deficient in all three IP3Receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons. Together, these data reveal the existence of a previously unrecognized mechanism by which stressor-mediated Ca2+release regulates ER stress.
Large-scale societal dynamics are reflected in human mood and brain
Authors: Lebedev Alexander V. , Abe Christoph , Acar Kasim , Deco Gustavo , Kringelbach Morten L. , Ingvar Martin , Petrovic Predrag 
Published: October 2020

AbstractThe stock market is a bellwether of socio-economic changes that may directly affect individual well-being. Using large-scale UK-biobank data generated over 14 years, we applied specification curve analysis to rigorously identify significant associations between the local stock market index (FTSE100) and 479,791 UK residents’ mood, as well as their alcohol intake and blood pressure adjusting the results for a large number of potential confounders, including age, sex, linear and non-linear effects of time, research site, other stock market indexes. Furthermore, we found similar associations between FTSE100 and volumetric measures of affective brain regions in a subsample (n=39,755; measurements performed over 5.5 years), which were particularly strong around phase transitions characterized by maximum volatility in the market. The main findings did not depend on applied effect-size estimation criteria (linear methods or mutual information criterion) and were replicated in two independent US-based studies (Parkinson’s Progression Markers Initiative; n=424; performed over 2,5 years and MyConnectome; n=1; 81 measurements over 1,5 years). Our results suggest that phase transitions in the society, indexed by stock market, exhibit close relationships with human mood, health and the affective brain from an individual to population level.
A novel algorithm to optimize generalized gamma distributed multiplicative noise with implications on speckle removal from OCT images
Authors: Varadarajan Divya , Magnain Caroline , Fogarty Morgan , Boas David A. , Fischl Bruce , Wang Hui 
Published: October 2020

AbstractOptical coherence tomography (OCT) images are corrupted by multiplicative generalized gamma distributed speckle noise that significantly degrades the contrast to noise ratio (CNR) of microstructural compartments in biological applications. This work proposes a novel algorithm to optimize the negative log likelihood of the spatial distribution of speckle. Specifically, the proposed method formulates a penalized negative log likelihood (P-NLL) cost function and proposes a majorize-minimize-based optimization method that removes speckle from OCT images. The optimization reduces to solving an iterative gradient descent problem. We demonstrate the usefulness of the proposed method by removing speckle in OCT images of uniform phantoms with varying scattering coefficients and human brain tissue.
A cross-species link between mTOR-related synaptic pathology and functional hyperconnectivity in autism
Authors: Pagani Marco , Bertero Alice , Trakoshis Stavros , Ulysse Laura , Locarno Andrea , Miseviciute Ieva , De Felice Alessia , Canella Carola , Supekar Kausthub , Galbusera Alberto , Menon Vinod , Tonini Raffaella , Deco Gustavo , Lombardo Michael V. , Pasqualetti Massimo , Gozzi Alessandro 
Published: October 2020

AbstractPostmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism, with a putative link to aberrant mTOR-dependent synaptic pruning. Autism is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses cause aberrant functional connectivity in autism. Using rsfMRI, electrophysiology andin silicomodelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with autism-like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic autism exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for autism-dysregulated genes interacting with mTOR or TSC2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism.SignificanceAberrant brain functional connectivity is a hallmark of autism, but the neural basis of this phenomenon remains unclear. We show that a mouse line recapitulating mTOR-dependent synaptic pruning deficits observed in postmortem autistic brains exhibits widespread functional hyperconnectivity. Importantly, pharmacological normalization of mTOR signalling completely rescues synaptic, behavioral and functional connectivity deficits. We also show that a similar connectivity fingerprint can be isolated in human fMRI scans of people with autism, where it is linked to over-expression of mTOR-related genes. Our results reveal a unifying multi-scale translational framework that mechanistically links aberrations in synaptic pruning with functional hyperconnectivity in autism.
Genetic population subdivision of Blue Swimming Crab (Portunus pelagicus) across Indonesia inferred from mitochondrial DNA: implication to sustainable fishery
Authors: Madduppa Hawis , Martaulina Rina , Zairion  , Renjani Resha Mukti , Kawaroe Mujizat , Anggraini Nurlita Putri , Subhan Beginer , Verawati Indri 
Published: October 2020

AbstractThe blue swimming crab (BSC),Portunus pelagicus(Linnaeus 1758), inhabits coastal areas of Southeast and East Asia, and is one of high fisheries commodity with export value for Indonesia and global market demand increasing annually. However, the data of genetic diversity and their spatial connectivity of populations in Indonesia are not yet known, which is important to inform unit stock management and sustainable fisheries. This study aimed to determine genetic diversity and differentiation of blue swimming crab across Indonesia populations under different Fishery Management Area, and their spatial genetic connectivity, as well as implications for sustainable fishery. A total of 297 individuals were amplified using cytochrome oxidase I mitochondrial DNA. This study shown highest value of haplotype and nucleotide diversity in the eastern part of Indonesia, where exploitation is relatively low. Significant genetic differentiation between populations (FST= 0.954;p< 0.001) and the fishery management regions (FST= 0.964;p< 0.001) were revealed. Low spatial connectivity was observed between populations in a distance of at least more than 60 kilometers. This study suggests that BSC populations in Indonesia likely have several unit stock, and preferably different fisheries management plan and action across the region thoroughly and simultaneously is effective for management and their sustainable conservation.
Integrated Use of Compost and Nitrogen Fertilizer and their Effects on the Yield and Yield Components of Wheat: A Pot Experiment
Authors: Gari Bayu Dume , Berecha Gezahegn , Mamuye Melkamu , Diriba Obsu Hirko , Nebiyu Amsalu , Nigussie Abebe , Hanč Aleš , Švehla Pavel 
Published: October 2020

AbstractThere is a research gap related to the combined effects of compost produced from coffee husks and inorganic nitrogen fertilizer (urea). The objective of this study was to evaluate the yield and yield components of wheat (Triticum aestivum L.) under the integrated application of compost and nitrogen fertilizer (urea). A pot experiment was conducted in a lath house to determine the effects of the integrated use of compost produced from coffee husks and nitrogen fertilizer (urea) on the yield and yield components of wheat. The experiment consisted of nine treatments: T1, control (untreated); T2, 5 t ha−1(8.12 g pot−1) compost; T3, 10 t ha−1(16.24 g pot−1) compost; T4, 0 t ha−1compost + 50 kg ha−1nitrogen fertilizer (NF) (0.09 g pot−1); T5, 5 t ha−1compost + 50 kg ha−1NF; T6, 10 t ha−1compost + 50 kg ha−1NF; T7, 0 t ha−1compost + 100 kg ha−1(0.18 g pot−1) NF; T8, 5 t ha−1compost + 100 kg ha−1NF; and T9, 10 t ha−1compost + 100 kg ha−1NF. The treatments were arranged in a completely randomized design (CRD) with three replications. The compost was prepared from coffee husks and applied in wet conditions. The findings showed that the addition of compost had little effect on wheat yield and yield components in the absence of nitrogen fertilizer (urea). However, the application of the highest amount of nitrogen fertilizer (urea), which is equivalent to the recommended field rate (100 kg ha−1) (equivalent to 0.18 g pot−1), and compost (5 t ha−1) (equivalent to 8.12 g pot−1) led to a significant (P≤0.05) increase in grain yield. Under this treatment, the grain yield was 26 g pot−1(equivalent to 14.741 t ha−1) which is a 66.29% increase compared with the control (8.9 g pot−1(4.969 t ha−1)); in the treatment in which only the recommended amount of nitrogen fertilizer was used (21.98 g pot−1(12.273 t ha−1)) grain yield increased by 16.74%. Spike length and dry matter yield also significantly (P≤0.05) increased with the application of integrated compost and nitrogen fertilizer (urea). The results of this experiment revealed that compost-based soil management strategies can enhance wheat production, thereby contributing positively to the viability and benefits of agricultural production systems. However, nutrient-compost interactions should receive special attention due to the great variability in the properties of compost, which may depend on the type of organic materials used.
Functional Characterization of an Electromagnetic Perceptive Protein
Authors: Mitra Sunayana , Barnaba Carlo , Schmidt Jens , Pelled Galit , Gilad Assaf A. 
Published: October 2020

AbstractMagnetoreception, the response to geomagnetic fields is a well described phenomenon in nature. However, it is likely that convergent evolution led to different mechanisms in different organisms. One intriguing example is the unique Electromagnetic Perceptive Gene (EPG) from the glass catfishKryptopterus vitreolus, that can remotely control cellular function, upon magnetic stimulation inin-vitroandin-vivo. Here, we report for the first time the cellular location and orientation of the EPG protein. We utilized a differential labelling technique to determine that the EPG protein is a membrane anchored protein with an N-terminal extracellular domain. The kinetics and diffusion dynamics of the EPG protein in response to magnetic stimulation was also elucidated using single particle imaging and tracking. Pulse chase labelling and Total Internal Reflection Fluorescence (TIRF) imaging revealed an increase in EPG kinetics post magnetic activation at a single particle level. Trajectory analysis show notably different EPG protein kinetics before and after magnetic stimulation in both 2 (free vs bound particle) and 3 state (free vs intermediate vs bound particle) tracking models. This data provides additional information to support and understand the underlying biophysical mechanisms behind EPG activation by magnetic fields and provides evidence for the basis of magnetoreception in the EPG protein that will aid in future studies that seek to further understand this novel mechanism. This study is important for understanding magnetoreception as well as developing new technologies for magnetogenetics – the utilization of electromagnetic fields to remotely control cellular function.Table of Contents Graphic
Profiling Active Enzymes for Polysorbate Degradation in Biotherapeutics by Activity-Based Protein Profiling
Authors: Li Xuanwen , Chandra Divya , Letarte Simon , Adam Gregory C. , Welch Jonathan , Yang Rong-Sheng , Bodea Smaranda , Dow Alex , Chi An , Strulson Christopher A. , Richardson Douglas D. 
Published: October 2020

AbstractPolysorbate is widely used to maintain stability of biotherapeutic proteins in formulation development. Degradation of polysorbate can lead to particle formation in drug products, which is a major quality concern and potential patient risk factor. Enzymatic activity from residual enzymes such as lipases and esterases can cause polysorbate degradation. Their high activity, even at low concentration, constitutes a major analytical challenge. In this study, we evaluated and optimized the activity-based protein profiling (ABPP) approach to identify active enzymes responsible for polysorbate degradation. Using chemical probes to enrich active serine hydrolases, more than 80 proteins were identified in harvested cell culture fluid (HCCF) from monoclonal antibodies (mAb) production. A total of 8 known lipases were identified by ABPP, while only 5 lipases were identified by a traditional abundance-based proteomics (TABP) approach. Interestingly, phospholipase B-like 2 (PLBL2), a well-known problematic HCP was not found to be active in process-intermediates from two different mAbs. In a proof-of-concept study, phospholipase A2 group VII (PLA2G7) and sialic acid acetylesterase (SIAE) were identified by ABPP as possible root causes of polysorbate-80 degradation. The established ABBP approach can fill the gap between lipase abundance and activity, which enables more meaningful polysorbate degradation investigations for biotherapeutic development.
Design to Data for mutants of β-glucosidase B from Paenibacillus polymyxa: I45K, A357S, I20A, I20V, and I20E
Authors: Luong Jennie A. , Vater Ashley , Siegel Justin B. 
Published: October 2020

ABSTRACTThe relatively small size and scope of most current datasets of biophysical mutation effects in enzymes limit the ability to develop data-driven algorithms enabling accurate generative modeling tools for designing novel enzyme function. Here, the Michaelis-Menten constants (kcat, KM, and kcat/KM) and thermal stability (TM) of five new mutations of β-glucosidase B from Paenibacillus polymyxa (BglB) are characterized. Foldit software was used to create molecular models of the mutants, for which synthetic genes were constructed and the corresponding proteins produced and purified from E. coli. It was found that mutations that disrupted pre-existing hydrogen bonds near the active site had reduced expression in contrast to mutations at the same site that did not affect native hydrogen bonding. This is consistent with previous results showing the relationship between hydrogen bonding and enzyme functionality. These mutants contribute to a growing data set of >100 mutants that have been characterized for expression, kinetic, and thermal properties
TheTrypanosoma bruceiCytoskeletal Protein KHARON Associates with Partner Proteins to Mediate Both Cytokinesis and Trafficking of Flagellar Membrane Proteins
Authors: Sanchez Marco A. , Landfear Scott M. 
Published: October 2020

ABSTRACTIn the African trypanosomeTrypanosoma brucei, the cytoskeletal proteinTbKHARON is required for trafficking of a putative Ca2+channel to the flagellar membrane, and it is essential for parasite viability in both the mammalian stage bloodstream forms and the tsetse fly procyclic forms. This protein is located at the base of the flagellum, in the pellicular cytoskeleton, and in the mitotic spindle in both life cycle forms, and it likely serves multiple functions for these parasites. To begin to deconvolve the functions of KHARON, we have investigated partners associated with this protein and their roles in parasite biology. One KHARON associated protein,TbKHAP1, is a close interaction partner that can be crosslinked to KHARON by formaldehyde and pulled down in a molecular complex, and it colocalizes withTbKHARON in the basal body at the base of the flagellum. Knockdown ofTbKHAP1mRNA has similar phenotypes to knockdown of its partnerTbKHARON, impairing trafficking of the Ca2+channel to the flagellar membrane and blocking cytokinesis, implying that theTbKHARON/TbKHAP1 complex mediates trafficking of flagellar membrane proteins. Two other KHAPs,TbKHAP2 andTbKHAP3, are in close proximity toTbKHARON, but knockdown of their mRNAs does not affect trafficking of the Ca2+channel. Two different flagellar membrane proteins, which are extruded from the flagellar membrane into extracellular vesicles, are also dependent uponTbKHARON for flagellar trafficking. These studies confirm thatTbKHARON acts in complexes with other proteins to carry out various biological functions, and that some partners are involved in the core activity of targeting membrane proteins to the flagellum.
Identification of the myogenetic oligodeoxynucleotides (myoDNs) that promote differentiation of skeletal muscle myoblasts by targeting nucleolin
Authors: Shinji Sayaka , Umezawa Koji , Nihashi Yuma , Nakamura Shunichi , Shimosato Takeshi , Takaya Tomohide 
Published: October 2020

AbstractHerein we report that the 18-base telomeric oligodeoxynucleotides (ODNs) designed from theLactobacillus rhamnosusGG genome promote differentiation of skeletal muscle myoblasts which are myogenic precursor cells. We termed these myogenetic ODNs (myoDNs). The activity of one of the myoDNs, iSN04, was independent of Toll-like receptors, but dependent on its conformational state. Molecular simulation and iSN04 mutants revealed stacking of the 13-15th guanines as a core structure for iSN04. The alkaloid berberine bound to the guanine stack and enhanced iSN04 activity, probably by stabilizing and optimizing iSN04 conformation. We further identified nucleolin as an iSN04-binding protein. Results showed that iSN04 antagonizes nucleolin, increases the levels of p53 protein translationally suppressed by nucleolin, and eventually induces myotube formation by modulating the expression of genes involved in myogenic differentiation and cell cycle arrest. This study shows that bacterial-derived myoDNs serve as aptamers and are potential nucleic acid drugs directly targeting myoblasts.
Mass spectrometry imaging of phosphatidylcholine metabolism in lungs administered with therapeutic surfactants and isotopic tracers
Authors: Ellis Shane R. , Hall Emily , Panchal Madhuriben , Flinders Bryn , Madsen Jens , Koster Grielof , Heeren Ron. M. A. , Clark Howard W. , Postle Anthony D. 
Published: October 2020

AbstractMass spectrometry imaging (MSI) visualises molecular distributions throughout tissues but is blind to dynamic metabolic processes. Here, MSI with high mass resolution together with multiple stable isotope labelling provided spatial analyses of phosphatidylcholine (PC) metabolism in mouse lungs. Dysregulated surfactant metabolism is central to many respiratory diseases. Metabolism and turnover of therapeutic pulmonary surfactants were imaged from distributions of intact and metabolic products of an added tracer, universally13C-labelled dipalmitoyl PC (U[13C]DPPC). The parenchymal distributions of newly synthesised PC species were also imaged from incorporations ofmethyl-D9-choline. This dual labelling strategy demonstrated both lack of inhibition of endogenous PC synthesis by exogenous surfactant and location of acyl chain remodelling processes acting on the U[13C]DPPC-labelled surfactant, leading to formation of polyunsaturated PC lipids. This ability to visualise discrete metabolic events will greatly enhance our understanding of lipid metabolism in diverse tissues, and has potential application to both clinical and experimental studies.
Thecis-regulatory effects of modern human-specific variants
Authors: Weiss Carly V. , Harshman Lana , Inoue Fumitaka , Fraser Hunter B. , Petrov Dmitri A. , Ahituv Nadav , Gokhman David 
Published: October 2020

AbstractThe Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1,791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.
Action detection using a neural network elucidates the genetics of mouse grooming behavior
Authors: Geuther Brian Q. , Peer Asaf , He Hao , Sabnis Gautam , Philip Vivek M. , Kumar Vivek 
Published: October 2020

AbstractAutomated detection of complex animal behaviors remains a challenging problem in neuroscience, particularly for behaviors that consist of disparate sequential motions. Grooming, a prototypical stereotyped behavior, is often used as an endophenotype in psychiatric genetics. Using mouse grooming behavior as an example, we develop a general purpose neural network architecture capable of dynamic action detection at human observer-level performance and operate across dozens of mouse strains with high visual diversity. We provide insights into the amount of human annotated training data that are needed to achieve such performance. We survey grooming behavior in the open field in 2500 mice across 62 strains, determine its heritable components, conduct GWAS to outline its genetic architecture, and perform PheWAS to link human psychiatric traits through shared underlying genetics. Our general machine learning solution that automatically classifies complex behaviors in large datasets will facilitate systematic studies of mechanisms underlying these behaviors.