bluuebunny/crossref_metadata_2025 huggingface dataset:
CopulaNet: Learning residue co-evolution directly from multiple sequence alignment for protein structure prediction
Authors: Ju Fusong , Zhu Jianwei , Shao Bin , Kong Lupeng , Liu Tie-Yan , Zheng Wei-Mou , Bu Dongbo
Published: October 2020

Protein functions are largely determined by the final details of their tertiary structures, and the structures could be accurately reconstructed based on inter-residue distances. Residue co-evolution has become the primary principle for estimating inter-residue distances since the residues in close spatial proximity tend to co-evolve. The widely-used approaches infer residue co-evolution using an indirect strategy, i.e., they first extract from the multiple sequence alignment (MSA) of query protein some handcrafted features, say, co-variance matrix, and then infer residue co-evolution using these features rather than the raw information carried by MSA. This indirect strategy always leads to considerable information loss and inaccurate estimation of inter-residue distances. Here, we report a deep neural network framework (called CopulaNet) to learn residue co-evolution directly from MSA without any handcrafted features. The CopulaNet consists of two key elements:i) an encoder to model context-specific mutation for each residue, andii) an aggregator to model correlations among residues and thereafter infer residue co-evolutions. Using the CASP13 (the 13th Critical Assessment of Protein Structure Prediction) target proteins as representatives, we demonstrated the successful application of CopulaNet for estimating inter-residue distances and further predicting protein tertiary structure with improved accuracy and efficiency. Head-to-head comparison suggested that for 24 out of the 31 free modeling CASP13 domains, ProFOLD outperformed AlphaFold, one of the state-of-the-art prediction approaches.
The price of a bit: energetic costs and the evolution of cellular signaling
Authors: Wang Teng-Long , Kuznets-Speck Benjamin , Broderick Joseph , Hinczewski Michael
Published: October 2020

Recent experiments have uncovered a fundamental information scale for cellular signaling networks: the correlation between input and output concentrations of molecules in a signaling pathway corresponds to at most 1-3 bits of mutual information. Our understanding of the physical constraints and evolutionary pressures that determine this scale remains incomplete. By focusing on a basic element of signaling pathways, the kinase-phosphatase enzymatic push-pull loop, we highlight the pivotal role played by energy resources available for signaling and their expenditure: the chemical potential energy of ATP hydrolysis, and the rate of ATP consumption. Scanning a broad range of reaction parameters based on enzymatic databases, we find that ATP chemical potentials in modern organisms are just above the threshold necessary to achieve empirical mutual information values. We also derive an analytical relation for the minimum ATP consumption required to maintain a certain signal fidelity across a range of input frequencies, where we quantify fidelity either through instantaneous or time-delayed mutual information. Attempting to increase signal fidelity beyond a few bits lowers the bandwidth, the maximum characteristic signal frequency that the network can handle at a given energy cost. The observed information scale thus represents a balancing act between fidelity and the ability to process fast-changing environmental signals. Our analytical relation defines a performance limit for kinase-phosphatase networks, and we find evidence that a component of the yeast osmotic shock pathway may be close to the optimality line. By quantifying the evolutionary pressures that operate on these networks, we argue that this is not a coincidence: natural selection on energy expenditures is capable of pushing signaling systems toward optimality, particularly in unicellular organisms. Our theoretical framework is directly verifiable using existing experimental techniques, and predicts that more examples of such optimality should exist in nature.
Temperature increases soil respiration across ecosystem types and soil development, but soil properties determine the magnitude of this effect
Authors: Dacal Marina , Delgado-Baquerizo Manuel , Barquero Jesús , Berhe Asmeret Asefaw , Gallardo Antonio , Maestre Fernando T. , García-Palacios Pablo
Published: October 2020

Soil carbon losses to the atmosphere, via soil heterotrophic respiration, are expected to increase in response to global warming, resulting in a positive carbon-climate feedback. Despite the well-known suite of abiotic and biotic factors controlling soil respiration, much less is known about how the magnitude of soil respiration responses to temperature changes over soil development and across contrasting soil properties. Here, we investigated the role of soil development stage and soil properties in driving the responses of soil heterotrophic respiration to increasing temperatures. We incubated soils from eight chronosequences ranging in soil age from hundreds to million years, and encompassing a wide range of vegetation types, climatic conditions, and chronosequences origins, at three assay temperatures (5, 15 and 25°C). We found a consistent positive effect of assay temperature on soil respiration rates across the eight chronosequences evaluated. However, soil properties such as organic carbon concentration, texture, pH, phosphorus content, and microbial biomass determined the magnitude of temperature effects on soil respiration. Finally, we observed a positive effect of soil development stage on soil respiration that did not alter the magnitude of assay temperature effects. Our work reveals that key soil properties alter the magnitude of the positive effect of temperature on soil respiration found across ecosystem types and soil development stages. This information is essential to better understand the magnitude of the carbon-climate feedback, and thus to establish accurate greenhouse gas emission targets.
Attack behaviour in naïve Gyrfalcons is modelled by the same guidance law as in Peregrines, but at a lower guidance gain
Authors: Brighton Caroline H. , Chapman Katherine E. , Fox Nicholas C. , Taylor Graham K.
Published: October 2020

The aerial hunting behaviours of birds are strongly influenced by their flight morphology and ecology, but little is known of how this variation relates to the behavioural algorithms guiding flight. Here we use onboard GPS loggers to record the attack trajectories of captive-bred Gyrfalcons (Falco rusticolus) during their maiden flights against robotic aerial targets, which we compare to existing flight data from Peregrines (Falco peregrinus) The attack trajectories of both species are modelled most economically by a proportional navigation guidance law, which commands turning in proportion to the angular rate of the line-of-sight to target, at a guidance gainN. However, Gyrfalcons operate at significantly lower values ofNthan Peregrines, producing slower turning and a longer path to intercept. Gyrfalcons are less agile and less manoeuvrable than Peregrines, but this physical constraint is insufficient to explain their lower guidance gain. On the other hand, lower values ofNpromote the tail-chasing behaviour that is typical of wild Gyrfalcons, and which apparently serves to tire their prey in a prolonged high-speed pursuit. Moreover, during close pursuit of fast evasive prey such as Ptarmigan (Lagopusspp.), proportional navigation will be less prone to being thrown off by erratic target manoeuvres ifNis low. The fact that low-gain proportional navigation successfully models the maiden attack flights of Gyrfalcons suggests that this behavioural algorithm is embedded in a hardwired guidance loop, which we hypothesise is ancestral to the clade containing Gyrfalcons and Peregrines.

SUMMARY STATEMENT

Naïve Gyrfalcons attacking aerial targets are modelled by the same proportional navigation guidance law as Peregrines, but with a lower navigation constant that promotes tail-chasing rather than efficient interception.
Phosphorylation of the mitochondrial triphosphate tunnel metalloenzyme TTM1 regulates programmed cell death in senescence
Authors: Karia Purva , Yoshioka Keiko , Moeder Wolfgang
Published: October 2020

The role of mitochondria in programmed cell death (PCD) during animal growth and development is well documented, but much less is known for plants. We previously showed that theArabidopsis thalianatriphosphate tunnel metalloenzyme (TTM) proteins TTM1 and TTM2 are tail-anchored proteins that localize in the mitochondrial outer membrane and participate in PCD during senescence and immunity, respectively. Here, we show that TTM1 is specifically involved in senescence induced by abscisic acid (ABA). Moreover, phosphorylation of TTM1 by multiple mitogen-activated protein kinases (MAPKs) regulates its function and turnover. A combination of proteomics andin vitrokinase assays revealed three major phosphorylation sites of TTM1 (S10, S437, and S490), which are phosphorylated upon perception of senescence cues such as ABA and prolonged darkness. S437 is phosphorylated by the MAP kinases MPK3 and MPK4, and S437 phosphorylation is essential for TTM1 function in senescence. These MPKs, together with three additional MAP kinases (MPK1, MPK7, and MPK6), phosphorylate S10 and S490, marking TTM1 for protein turnover, which likely prevents uncontrolled cell death. Taken together, our results show that multiple MPKs regulate the function and turnover of the mitochondrial protein TTM1 during senescence-related PCD, revealing a novel link between mitochondria and PCD.

Email addresses:purva.karia@mail.utoronto.ca
MAJORA: Continuous integration supporting decentralised sequencing for SARS-CoV-2 genomic surveillance
Authors: Nicholls Samuel M. , Poplawski Radoslaw , Bull Matthew J. , Underwood Anthony , Chapman Michael , Abu-Dahab Khalil , Taylor Ben , Jackson Ben , Rey Sara , Amato Roberto , Livett Rich , Gonçalves Sónia , Harrison Ewan M. , Peacock Sharon J. , Aanensen David M , Rambaut Andrew , Connor Thomas R. , Loman Nicholas J. ,   The COVID-19 Genomics UK (COG-UK) Consortium
Published: October 2020

Genomic epidemiology has become an increasingly common tool for epidemic response. Recent technological advances have made it possible to sequence genomes rapidly enough to inform outbreak response, and cheaply enough to justify dense sampling of even large epidemics. With increased availability of sequencing it is possible for agile networks of sequencing facilities to collaborate on the sequencing and analysis of epidemic genomic data.

In response to the ongoing SARS-CoV-2 pandemic in the United Kingdom, the COVID-19 Genomics UK (COG-UK) consortium was formed with the aim of rapidly sequencing SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies.

We describe the development and deployment of Majora, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and sample-associated metadata produced across the COG-UK network. The system was designed and implemented pragmatically to stand up capacity rapidly in a pandemic caused by a novel virus. This approach has underpinned the success of COG-UK, which has rapidly become the leading contributor of SARS-CoV-2 genomes to international databases and has generated over 60,000 sequences to date.
Evidence accumulation, not “self-control,” explains dorsolateral prefrontal activation during normative choice
Authors: Hutcherson Cendri A. , Tusche Anita
Published: October 2020

What role do cognitive control regions like the dorsolateral prefrontal cortex (dlPFC) play in normative behavior (e.g., generosity, healthy eating)? Some models suggest that dlPFC activation during normative choice reflects the use of control to overcome default hedonistic preferences. Here, we develop an alternative account, showing that anattribute-based neural drift diffusion model (anDDM)predicts trial-by-trial variation in dlPFC response across three fMRI studies and two self-control contexts (altruistic sacrifice and healthy eating). Using the anDDM to simulate a variety of self-control dilemmas generated a novel prediction: although dlPFC activity mighttypicallyincrease for norm-consistent choices, deliberate self-regulation focused on normative goals shoulddecreaseor evenreversethis pattern (i.e., greater dlPFC response for hedonic, self-interested choices). We confirmed these predictions in both altruistic and dietary choice contexts. Our results suggest that dlPFC response during normative choice may depend more on value-based evidence accumulation than inhibition of our baser instincts.
Pescoids and chimeras to probe early evo-devo in the fishAstyanax mexicanus
Authors: Torres-Paz Jorge , Rétaux Sylvie
Published: October 2020

The fish speciesAstyanax mexicanuswith its sighted and blind eco-morphotypes has become an original model to challenge vertebrate developmental evolution. Recently, we demonstrated that phenotypic evolution can be impacted by early developmental events starting from the production of oocytes in the fish ovaries.A. mexicanusoffers an amenable model to test the influence of maternal effect on cell fate decisions during early development, yet the mechanisms by which the information contained in the eggs is translated into specific developmental programs remain obscure due to the lack of specific tools in this emergent model. Here we describe methods for the generation of gastruloids from yolkless-blastoderm explants to test the influence of embryonic and extraembryonic properties on cell fate decisions, as well as the production of chimeric embryos obtained by intermorph cell transplantations to probe cell autonomous or non-autonomous processes. We show thatAstyanaxgastruloids have the potential to recapitulate the main ontogenetic events observed in intact embryos, including the internalization of mesodermal progenitors and eye development, as followed withZic:GFPreporter lines. In addition, intermorph cell grafts resulted in proper integration of exogenous cells into the embryonic tissues, with lineages becoming more restricted from mid-blastula to gastrula. The implementation of these approaches inA. mexicanuswill bring new light on the cascades of events, from the maternal pre-patterning of the early embryo to the evolution of brain regionalization.
Exploring the effects of genetic variation on gene regulation in cancer in the context of 3D genome structure
Authors: Osman Noha , Shawky Abd-El-Monsif , Brylinski Michal
Published: October 2020

Numerous genome-wide association studies (GWAS) conducted to date revealed genetic variants associated with various diseases, including breast and prostate cancers. Despite the availability of these large-scale data, relatively few variants have been functionally characterized, mainly because the majority of single-nucleotide polymorphisms (SNPs) map to the non-coding regions of the human genome. The functional characterization of these non-coding variants and the identification of their target genes remain challenging. In this communication, we explore the potential functional mechanisms of non-coding SNPs by integrating GWAS with the high-resolution chromosome conformation capture (Hi-C) data for breast and prostate cancers. We show that more genetic variants map to regulatory elements through the 3D genome structure than the 1D linear genome lacking physical chromatin interactions. Importantly, the association of enhancers, transcription factors, and their target genes with breast and prostate cancers tends to be higher when these regulatory elements are mapped to high-risk SNPs through spatial interactions compared to simply using a linear proximity. Finally, we demonstrate that topologically associating domains (TADs) carrying high-risk SNPs also contain gene regulatory elements whose association with cancer is generally higher than those belonging to control TADs containing no high-risk variants. Our results suggest that many SNPs may contribute to the cancer development by affecting the expression of certain tumor-related genes through long-range chromatin interactions with gene regulatory elements. Integrating large-scale genetic datasets with the 3D genome structure offers an attractive and unique approach to systematically investigate the functional mechanisms of genetic variants in disease risk and progression.
A global database of photosynthesis model parameters, and modelled photosynthetic responses from every major terrestrial plant clade
Authors: Rostamza Mina , McNickle Gordon G.
Published: October 2020

Plant photosynthesis is a major part of the global carbon cycle and climate system. Carbon capture by C3plants is most often modelled using the Farquhar-von-Caemmerer-Berry (FvCB) equations. We undertook a global synthesis of all parameters required to solve the FvCB model. The publicly available dataset we assembled includes 3663 observations from 336 different C3plant species among 96 taxonomic families coming from every major vascular plant clade (lycophytes, ferns, gymnosperms, magnoliids, eudicots and monocots). Geographically, the species in the database have distributions that span the majority of the globe. We used the model to predict photosynthetic rates for a hypothetical average plant in each major terrestrial plant clade and find that generally plants have dramatically increased their photosynthetic abilities through evolutionary time, with the average monocot (the youngest clade) achieving maximum rates of photosynthesis almost double that of the average lycophyte (the oldest clade). We also solved the model for different hypothetical average plant functional types (PFTs) and find that herbaceous species generally have much higher rates of photosynthesis compared to woody plants. Indeed, the maximum photosynthetic rate of graminoids is almost three times the rate of the average tree. The resulting functional responses to increasing CO2in average hypothetical PFTs would suggest that most groups are already at or near their maximum rate of photosynthesis. However, phylogenetic analysis showed that there was no evidence of niche conservatism with most variance occurring within, rather than among clades (K=0.357, p=0.001). This high within-group variability suggests that average PFTs may obscure important plant responses to increasing CO2. Indeed, when we solved the model for each of the 3663 individual observations, we found that, contrary to the predictions of hypothetical average PFTs, that most plants are predicted to be able to increase their photosynthetic rates. These results suggest that global models should seek to incorporate high within-group variability to accurately predict plant photosynthesis in response to a changing climate.
Evaluating state space discovery by persistent cohomology in the spatial representation system
Authors: Kang Louis , Xu Boyan , Morozov Dmitriy
Published: October 2020

Persistent cohomology is a powerful technique for discovering topological structure in data. Strategies for its use in neuroscience are still undergoing development. We comprehensively and rigorously assess its performance in simulated neural recordings of the brain’s spatial representation system. Grid, head direction, and conjunctive cell populations each span low-dimensional topological structures embedded in high-dimensional neural activity space. We evaluate the ability for persistent cohomology to discover these structures for different dataset dimensions, variations in spatial tuning, and forms of noise. We quantify its ability to decode simulated animal trajectories contained within these topological structures. We also identify regimes under which mixtures of populations form product topologies that can be detected. Our results reveal how dataset parameters affect the success of topological discovery and suggest principles for applying persistent cohomology, as well as persistent homology, to experimental neural recordings.
Temporal transitions in post-mitotic neurons throughout theC. elegansnervous system
Authors: Sun HaoSheng , Hobert Oliver
Published: October 2020

In most animals, the majority of the nervous system is generated and assembled into neuronal circuits during embryonic development. However, during juvenile stages, nervous systems still undergo extensive anatomical and functional changes to eventually form a fully mature nervous system by the adult stage. The molecular changes in post-mitotic neurons across post-embryonic development and the genetic programs that control these temporal transitions are not well understood. Using the model organismC. elegans, we comprehensively characterized the distinct functional states (locomotor behavior) and corresponding distinct molecular states (transcriptome) of the post-mitotic nervous system across temporal transitions from early post-embryonic periods to adulthood. We observed pervasive changes in gene expression, many of which are controlled by the developmental upregulation of the conserved heterochronic miRNAlin-4/mir-125and the subsequent promotion of a mature neuronal transcriptional program through the repression of its target, the transcription factorlin-14. The functional relevance of these molecular transitions are exemplified by a temporally regulated target gene of thelin-14transcription factor,nlp-45, a neuropeptide-encoding gene. We found thatnlp-45is required for temporal transitions in exploratory activity across larval stages, across sexual maturation, and into a diapause arrest stage. Our studies provide new insights into regulatory strategies that control neuron-type specific gene batteries to modulate distinct behaviors states across temporal, sex and environmental dimensions of post-embryonic development, and also provides a rich atlas of post-embryonic molecular changes to uncover additional regulatory mechanisms.
Production of ORF8 protein from SARS-CoV-2 using an inducible virus-mediated expression system in suspension-cultured tobacco BY-2 cells
Authors: Imamura Tomohiro , Isozumi Noriyoshi , Higashimura Yasuki , Ohki Shinya , Mori Masashi
Published: October 2020

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread worldwide in 2020, is an urgent problem to be overcome. The ORF8 of SARS-CoV-2 has been suggested to be associated with the symptoms of COVID-19, according to reports of clinical studies. However, little is known about the function of ORF8. As one of the ways to advance the functional analysis of ORF8, mass production of ORF8 with the correct three-dimensional structure is necessary. In this study, we attempted to produce ORF8 protein by chemically inducible protein production system using tobacco BY-2 cells. An ORF8-producing line was generated by the Agrobacterium method. As a result, the production of ORF8 of 8.8 ± 1.4 mg/L of culture medium was confirmed. SDS-PAGE and nuclear magnetic resonance (NMR) analysis confirmed that the ORF8 produced by this system is a dimeric form with a single structure, unlike that produced in Escherichia coli. Furthermore, it was suggested that the ORF8 produced by this system was glycosylated. Through this study, we succeeded in producing ORF8 folded into a single structure in a chemically inducible protein production system using tobacco BY-2 cells. It is expected that the functional analysis of ORF8 will be advanced using the ORF8 produced by this system and that it will greatly contribute to the development of antibodies and therapeutic agents targeting ORF8.
Evolutionary history of the Galápagos Rail revealed by ancient mitogenomes and modern samples
Authors: Chaves Jaime A. , Martinez-Torres Pedro J. , Depino Emiliano A. , Espinoza-Ulloa Sebastian , García-Loor Jefferson , Beichman Annabel , Stervander Martin
Published: October 2020

The biotas of the Galápagos Islands are probably one of the best studied island systems and have provided a broad model of insular species’ origins and evolution. Nevertheless, some Galápagos species remain poorly characterized, such as the Galápagos RailLaterallus spilonota. This bird species is one of the less explored groups of endemic vertebrates on these islands, due to its elusive behavior, cryptic plumage and restricted distribution. To date there is no genetic assessment of its origins and sister relationships to other taxa, and importantly, there is no data on its current genetic diversity. This lack of information is critical given the adverse fate of island rail species around the world in the recent past. Here we examine the genetics of Galápagos Rails using a combination of mitogenomede novoassembly with multi-locus sequencing (mtDNA+nuDNA) from both modern and historical samples. We show that the Galápagos Rail is part of the ‘American black rail clade’, sister to Black RailL. jamaicensis, with a colonization of Galápagos dated to 1.2 Mya. The separate analysis of cytb, ND2, and RAG-1 markers demonstrates shallow population structure across sampled islands, possibly due to elevated island connectivity. Additionally, birds sampled from Pinta possessed the lowest levels of genetic diversity, most likely reflecting the impact of past bottlenecks due to habitat loss caused by invasive goats grazing on sensitive habitat. The data presented here highlights the low genetic diversity in this endemic rail species and suggests the use of genetic data (both modern and historical) to guide conservation efforts.
Polo-like kinase 1 independently controls microtubule-nucleating capacity and size of the centrosome
Authors: Ohta Midori , Zhao Zhiling , Wu Di , Wang Shaohe , Harrison Jennifer L. , Gómez-Cavazos J. Sebastián , Desai Arshad , Oegema Karen
Published: October 2020

Centrosomes are composed of a centriolar core surrounded by a pericentriolar material (PCM) matrix that docks microtubule-nucleating γ-tubulin complexes. During mitotic entry, the PCM matrix increases in size and nucleating capacity in a process called centrosome maturation. Polo-like kinase 1 (PLK1) localizes to centrosomes and phosphorylates PCM matrix proteins to drive their self-assembly, which leads to PCM expansion; this expansion has been assumed to passively increase microtubule nucleation to support spindle assembly. Here, we show that PLK1 directly controls the generation of binding sites for γ-tubulin complexes on the PCM matrix, independently of PCM expansion. Selective inhibition of PLK1-dependent γ-tubulin docking leads to spindle defects and impaired chromosome segregation, without affecting PCM expansion, highlighting the importance of phospho-regulated centrosomal γ-tubulin docking sites in spindle assembly. Inhibiting both γ-tubulin docking and PCM expansion by mutating substrate target sites fully accounts for the actions of PLK-1 in transforming the centrosome during mitotic entry.

Summary Statement

Polo-like kinase 1-mediated physical expansion of centrosomes during mitotic entry is proposed to passively increase their microtubule nucleating capacity. Ohta et al. show instead that generation of microtubule-nucleating sites is directly controlled by Polo-like kinase 1, independently of centrosome size.
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

The 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

The 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

Optical 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

Postmortem 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.

Significance

Aberrant 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

The 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

There 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

Magnetoreception, 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.

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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

Polysorbate 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

The 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

In 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

Herein 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

Mass 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.