bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of site frequency spectra from low-coverage sequencing data using stochastic EM reduces overfitting, runtime, and memory usage
Authors: Rasmussen Malthe Sebro , Garcia-Erill Genís , Korneliussen Thorfinn Sand , Wiuf Carsten , Albrechtsen Anders 
Published: May 2022

AbstractThe site frequency spectrum (SFS) is an important summary statistic in population genetics used for inference on demographic history and selection. However, estimation of the SFS from called genotypes introduce bias when working with low-coverage sequencing data. Methods exist for addressing this issue, but sometimes suffer from two problems. First, they can have very high computational demands, to the point that it may not be possible to run estimation for genome-scale data. Second, existing methods are prone to overfitting, especially for multi-dimensional SFS estimation. In this article, we present a stochastic expectation-maximisation algorithm for inferring the SFS from NGS data that addresses these challenges. We show that this algorithm greatly reduces runtime and enables estimation with constant, trivial RAM usage. Further, the algorithm reduces overfitting and thereby improves downstream inference. An implementation is available at github.com/malthesr/winsfs.
Perceptual similarity judgments do not predict the distribution of errors in working memory
Authors: Tomić Ivan , Bays Paul M. 
Published: May 2022

AbstractPopulation coding models provide a quantitative account of visual working memory (VWM) retrieval errors with a plausible link to the response characteristics of sensory neurons. Recent work has provided an important new perspective linking population coding to variables of signal detection, including d-prime, and put forward a new hypothesis: that the distribution of recall errors on, e.g., a color wheel, is a consequence of the psychological similarity between points in that stimulus space, such that the exponential-like psychophysical distance scaling function can fulfil the role of population tuning and obviate the need to fit a tuning width parameter to recall data. Using four different visual feature spaces, we measured psychophysical similarity and memory errors in the same participants. Our results revealed strong evidence for a common source of variability affecting similarity judgments and recall estimates, but did not support any consistent relationship between psychophysical similarity functions and VWM errors. At the group level, the responsiveness functions obtained from the psychophysical similarity task diverged strongly from those that provided the best fit to working memory errors. At the individual level, we found convincing evidence against an association between observed and best-fitting similarity functions. Finally, our results show that the newly proposed exponential-like responsiveness function has in general no advantage over the canonical von Mises (circular normal) function assumed by previous population coding models.
Impact of bioactive molecule inclusion in lyophilized silk scaffolds varies betweenin vivoandin vitroassessments
Authors: Jameson Julie F , Pacheco Marisa O , Bender Elizabeth C , Kotta Nisha M , Black Lauren D , Kaplan David L , Grasman Jonathan M , Stoppel Whitney L 
Published: May 2022

AbstractBiomaterials can influence the coordinated efforts required to achieve tissue rehabilitation. Sponge-like silk fibroin scaffolds that include bioactive molecules have been shown to influence tissue repair. However, the mechanisms by which scaffold formulations elicit desiredin vivoresponses is unclear. Here, acellular silk scaffolds consisting of type I collagen, heparin, and/or vascular endothelial growth factor (VEGF) were used to investigate material fabrication and composition parameters that drive scaffold degradation, cell infiltration, and adipose tissue depositionin vivo. In subcutaneous implants, scaffold degradation was assessed, and results show that the percentage of cells infiltrating the scaffold increased when scaffold formulations contained bioactive molecules. To gain further insight, calculatedin vitroenzymatic degradation rates increased with higher enzyme concentrations and theoretical cleavage sites. However, the addition of type I collagen and heparin to the scaffold at relevant concentrations did not change degradation rates, compared to silk alone. Thesein vitroresults are contrary to observationsin vivo, where bioactive molecules influence local protein deposition, immune cell infiltration rates, and vascularization. Thus, quantitativein vitroandin vivoevaluations aid in determining the mechanisms by which biomaterials influence tissue repair and support intentional biomaterial design for clinical applications.Graphical AbstractThis work examines the role of scaffold fabrication and bioactive molecule inclusion on the enzymatic degradation of silk fibroin-based lyophilized sponges. Specifically, the roles of collagen I, heparin, and vascular endothelial growth factor are analyzed to determine the impact of formulation on rate of degradation. In addition, scaffolds are either pre-fabricated, where these bioactive molecules are included in the polymer solution prior to casting the scaffold or the bioactive molecules are introduced following scaffold formation through passive adsorption to the silk fibroin scaffold surface. Scaffolds are enzymatically degradedin vitro, and kinetic rate constants are calculated for the different formulations.In vivo, cellularity, adipose tissue accumulation, and scaffold area are assessed over time. Additionally, immunohistochemistry is used to visualize VEGF Receptor 2, CD 68, and α-smooth muscle actin over time.
Evolutionary trade-off and mutational bias could favor transcriptional over translational divergence within paralog pairs
Authors: Aubé Simon , Nielly-Thibault Lou , Landry Christian R. 
Published: May 2022

AbstractHow changes in the different steps of protein synthesis – transcription, translation and degradation – contribute to differences of protein abundance among genes is not fully understood. There is however accumulating evidence that transcriptional divergence might have a prominent role. Here, we show that yeast paralogous genes are more divergent in transcription than in translation. We explore two causal mechanisms for this predominance of transcriptional divergence: an evolutionary trade-off between the precision and economy of gene expression and a larger mutational target size for transcription. Performing simulations within a minimal model of post-duplication evolution, we find that both mechanisms are consistent with the observed divergence patterns. We also investigate how additional properties of the effects of mutations on gene expression, such as their asymmetry and correlation across levels of regulation, can shape the evolution of duplicates. Our results highlight the importance of fully characterizing the distributions of mutational effects on transcription and translation. They also show how general trade-offs in cellular processes and mutation bias can have far-reaching evolutionary impacts.
The Balance between Saturated and Unsaturated Fatty Acids Regulates Ovarian Cancer Cell Fate
Authors: Zhao Guangyuan , Tan Yuying , Cardenas Horacio , Vayngart David , Huang Hao , Wang Yinu , Keathley Russell , Wei Jian-Jun , Ferreira Christina R. , Cheng Ji-Xin , Matei Daniela 
Published: May 2022

AbstractFatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme highly active in cancer. Here we studied how the balance between SFAs and UFAs maintained by SCD impacts cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman spectroscopy (SRS). Further, the loss of equilibrium between UFAs and SFAs resulting from SCD knock down triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Stiff and disorganized ER membrane was visualized by electron microscopy and SRS imaging in cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and re-equilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro, translated into suppression of intraperitoneal tumor growth in xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA enriched diet, initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to new treatment strategies targeting the lipid balance.Significance StatementWe show that the balance between saturated and unsaturated fatty acids tightly regulated by the desaturase SCD impacts the survival of cancer cells; increased levels of unsaturation being protective against ER stress induced apoptosis. Decreasing fatty acid unsaturation, either through SCD depletion or through SCD inhibition coupled with a dietary intervention blocks tumor progression in vivo. Our findings support the concept of targeting the lipid balance as a new target in cancer.
Reward expectations direct learning and drive operant matching inDrosophila
Authors: Rajagopalan Adithya E. , Darshan Ran , Hibbard Karen L. , Fitzgerald James E. , Turner Glenn C. 
Published: May 2022

AbstractForaging animals must use decision-making strategies that dynamically adapt to the changing availability of rewards in the environment. A wide diversity of animals do this by distributing their choices in proportion to the rewards received from each option, Herrnstein’s operant matching law. Theoretical work suggests an elegant mechanistic explanation for this ubiquitous behavior, as operant matching follows automatically from simple synaptic plasticity rules acting within behaviorally relevant neural circuits. However, no past work has mapped operant matching onto plasticity mechanisms in the brain, leaving the biological relevance of the theory unclear. Here we discovered operant matching inDrosophilaand showed that it requires synaptic plasticity that acts in the mushroom body and incorporates the expectation of reward. We began by developing a novel behavioral paradigm to measure choices from individual flies as they learn to associate odor cues with probabilistic rewards. We then built a model of the fly mushroom body to explain each fly’s sequential choice behavior using a family of biologically-realistic synaptic plasticity rules. As predicted by past theoretical work, we found that synaptic plasticity rules could explain fly matching behavior by incorporating stimulus expectations, reward expectations, or both. However, by optogenetically bypassing the representation of reward expectation, we abolished matching behavior and showed that the plasticity rule must specifically incorporate reward expectations. Altogether, these results reveal the first synaptic level mechanisms of operant matching and provide compelling evidence for the role of reward expectation signals in the fly brain.
Common facultative endosymbionts do not influence sensitivity of cereal aphids to pyrethroids
Authors: Leybourne D J , Melloh P , Martin E A 
Published: May 2022

AbstractCereal aphids, including the bird cherry-oat aphid, Rhopalosiphum padi, and the grain aphid, Sitobion avenae, can transmit viruses that significantly reduce crop yields. To mitigate against yield losses, insecticides are routinely used to manage aphid populations.Aphids can form relationships with endosymbionts that confer fitness benefits or consequences to the aphid. Recent artificial inoculation experiments indicate that endosymbionts could increase aphid susceptibility to insecticides, but this has not been explored using aphid populations naturally infected with endosymbionts.Here, we sampled aphids from an important cereal production region in Lower Saxony, Germany. We characterised the endosymbiont profile of these aphid populations and conducted pyrethroid dose-response assays to test the hypothesis that facultative endosymbionts increase aphid susceptibility to insecticides.We find that the level of insecticide susceptibility is highly variable in S. avenae and we identify populations that are sensitive and tolerant to pyrethroids, including populations collected from the same field. For R. padi, we find evidence for decreased sensitivity to pyrethroids, representing the first report of reduced sensitivity to pyrethroids in R. padi sampled from Central Europe.We detected high endosymbiont infection frequencies in the aphid populations. 84% of aphids carry one facultative endosymbiont and 9% of aphids carry two facultative endosymbionts. We detected associations with Regiella insecticola, Fukatsia symbiotica, and Hamiltonella defensa. However, we do not identify a link between endosymbiont infection and insecticide susceptibility, indicating that other factors may govern the development of insecticide resistance and the need for alternative management strategies.
Nitric oxide is not responsible for the initial sensory-induced neurovascular coupling response in mouse cortex
Authors: Lee L , Boorman L , Glendenning E , Shen C , Berwick J , Howarth C 
Published: May 2022

AbstractNeurovascular coupling ensures that changes in neural activity are accompanied by localised changes in cerebral blood flow. While much is known about the involvement of excitatory neurons in neurovascular coupling, the role of inhibitory interneurons is unresolved. While nNOS-expressing interneurons have been shown to be capable of eliciting vasodilation, the role of nitric oxide in functional hyperemia remains a matter of debate. Therefore in the present study we applied a combination of optogenetic and pharmacological approaches, 2-dimensional optical imaging spectroscopy, and electrophysiology to investigate the role of nitric oxide in neurovascular coupling responses evoked by nNOS-expressing interneurons and whisker stimulation in mouse sensory cortex. The haemodynamic response evoked by nNOS-expressing interneurons was significantly altered in the presence of the NOS inhibitor LNAME, revealing a large initial 20-HETE-dependent vasoconstriction. In contrast, the haemodynamic response induced by sensory stimulation was largely unchanged by LNAME. Our results suggest that while nitric oxide plays a key role in neurovascular responses evoked by nNOS-expressing interneurons it does not mediate the initial sensory-induced neurovascular coupling response in mouse cortex. Thus, our results call into question the involvement of nNOS-expressing interneurons and nitric oxide in sensory-evoked functional hyperemia.
STX5’s flexibility in SNARE pairing supports Golgi functions
Authors: D’Souza Zinia , Pokrovskaya Irina , Lupashin Vladimir V. 
Published: May 2022

AbstractThe intracellular transport system is an evolutionally conserved, essential, and highly regulated network of organelles and transport vesicles that traffic protein and lipid cargoes within the cell. The events of vesicle formation, budding and fusion are orchestrated by the trafficking machinery – an elaborate set of proteins including small GTPases, vesicular coats, tethers, and SNAREs. The Golgi - the central organelle in this transport network, receives, modifies and sorts secretory and endocytic cargo. Glycosylation is one of the major modifications that occur within the Golgi, which houses enzymes and other components of glycosylation machinery. According to the current Golgi maturation model, Golgi resident proteins are constantly recycled from the late (trans) Golgi compartments to the early compartment (cis) by the evolutionary conserved vesicular trafficking machinery. The key modulator of vesicular trafficking and glycosylation at the Golgi is the Conserved Oligomeric Golgi (COG) complex – its interaction vesicular trafficking machinery particularly Golgi SNAREs (STX5, GS28 (GOSR1), GS15 (BET1L) and YKT6) that drive fusion of incoming vesicles. Since the COG complex functions upstream of SNARE-mediated vesicle fusion, we hypothesize that depletion of Golgi v-SNAREs would mirror defects observed in COG deficient cells. To test this, we created single and double knockouts (KO) of GS28 and GS15 in HEK293T cells and analyzed resulting mutants using a comprehensive set of biochemical, mass-spectrometry (MS) and microscopy approaches. Deletion of GS28 significantly affected GS15, but not the other two partners, STX5 and YKT6. Surprisingly, our analysis revealed that COG dysfunction is more deleterious for Golgi function than disrupting the canonical Golgi SNARE complex. Quantitative MS analysis of STX5-interacting SNAREs revealed unexpected flexibility of Golgi SNARE pairing in mammalian cells. We uncovered two novel non-canonical Golgi SNARE complexes – STX5/VTI1B/GS15/YKT6 and STX5/SNAP29/VAMP7 which were upregulated in GS28 KO cells. Analysis of cells co-depleted for GS28/SNAP29 or GS28/VTI1B SNAREs revealed escalated defects in Golgi glycosylation, indicating that upregulation of these complexes functionally substitutes deleted GS28. Our data points to the remarkable plasticity in the intra-Golgi membrane fusion machinery which is controlled by the COG complex.
A very long chain fatty acid responsive transcription factor, MYB93, regulates lateral root development in Arabidopsis
Authors: Uemura Yuta , Kimura Saori , Ohta Tomomichi , Suzuki Takamasa , Mase Kosuke , Kato Hiroyuki , Sakaoka Satomi , Komine Yuki , Hotta Kazuhiro , Shimizu Motoyuki , Morikami Atsushi , Tsukagoshi Hironaka 
Published: May 2022

AbstractLateral roots (LRs) are critical to rhizosphere development in plants. Although the molecular mechanisms by which auxin regulates LR development has been studied extensively, many additional regulatory systems are thought to be involved. Based on the expression analysis of LTPG1 and 2, we found that they were specifically expressed at the developing LR primordium (LRP), and the number of LRs were reduced in these mutants. Because LTPG is a protein that transports Very Long Chain Fatty Acids (VLCFAs), we hypothesized that VLCFAs regulated LR development. We revealed that late LRP development was stunted when VLCFA levels were reduced in the synthetic mutant, kcs1-5. In this study, we established a method to analyze the LRP development stages with high temporal resolution using a deep neural network. We identified a VLCFA responsible transcription factor, MYB93, from transcriptome analysis of kcs1-5. Interestingly, MYB93 showed a carbon chain length-specific expression response after treatment of VLCFA. Furthermore, myb93 transcriptome analysis suggested that MYB93 regulated the expression of cell wall organization genes. Our results indicated that VLCFA is a regulator of LRP development through transcription factor-mediated regulation of gene expression.
Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies
Authors: Ko Kuang-Ting , Lennartz Frank , Mekhaiel David , Guloglu Bora , Marini Arianna , Deuker Danielle J. , Long Carole A. , Jore Matthijs M. , Miura Kazutoyo , Biswas Sumi , Higgins Matthew K. 
Published: May 2022

AbstractAn effective malaria vaccine remains a global health priority and vaccine immunogens which prevent transmission of the parasite will have important roles in multi-component vaccines. One of the most promising candidates for inclusion in a transmission-blocking malaria vaccine is the gamete surface protein Pfs48/45, which is essential for development of the parasite in the mosquito midgut. Indeed, antibodies which bind Pfs48/45 can prevent transmission if ingested with the parasite as part of the mosquito bloodmeal. Here we present the first structure of full-length Pfs48/45, revealing its three domains to form a dynamic, planar, triangular arrangement. From this, we show where transmission-blocking and non-blocking antibodies bind on Pfs48/45. Finally, we demonstrate that antibodies which bind across this molecule can be transmission-blocking. These studies will guide the development of future Pfs48/45-based vaccine immunogens.
Parent-of-origin detection and chromosome-scale haplotyping using long-read DNA methylation sequencing and Strand-seq
Authors: Akbari Vahid , Hanlon Vincent C. T. , O’Neill Kieran , Lefebvre Louis , Schrader Kasmintan A. , Lansdorp Peter M. , Jones Steven J.M. 
Published: May 2022

AbstractHundreds of loci in human genomes have alleles that are methylated differentially according to their parent of origin. These imprinted loci generally show little variation across tissues, individuals, and populations. We show that such loci can be used to distinguish the maternal and paternal homologs for all autosomes, without the need for the parental DNA. We integrate methylation-detecting nanopore sequencing with the long-range phase information in Strand-seq data to determine the parent of origin of chromosome-length haplotypes for both DNA sequence and DNA methylation in five trios with diverse genetic backgrounds. The parent of origin was correctly inferred for all autosomes with an average mismatch error rate of 0.31% for SNVs and 1.89% for indels. Because our method can determine whether an inherited disease allele originated from the mother or the father, we predict that it will improve the diagnosis and management of many genetic diseases.
Lineage-Specific Differences and Regulatory Networks Governing Human Chondrocyte Development
Authors: Richard Daniel , Pregizer Steven , Venkatasubramanian Divya , Muthuirulan Pushpanathan , Liu Zun , Capellini Terence D. , Craft April M. 
Published: May 2022

AbstractTo address large gaps in our understanding of the molecular regulation of articular and growth plate cartilage development in humans, we used our directed differentiation approach to generate these distinct cartilage tissues from human embryonic stem cells. The resulting transcriptomic profiles of hESC-derived articular and growth plate chondrocytes were similar to fetal epiphyseal and growth plate chondrocytes, with respect to genes both known and previously unknown to cartilage biology. With the goal to characterize the regulatory landscapes accompanying these respective transcriptomes, we mapped chromatin accessibility in hESC-derived chondrocyte lineages, and mouse embryonic chondrocytes, using ATAC-sequencing. Integration of the expression dataset with the differentially accessible genomic regions revealed lineage-specific gene regulatory networks. We validated functional interactions of two transcription factors (RUNX2 in growth plate chondrocytes and RELA in articular chondrocytes) with their predicted genomic targets. The maps we provide thus represent a framework for probing regulatory interactions governing chondrocyte differentiation. This work constitutes a substantial step towards comprehensive and comparative molecular characterizations of distinct chondrogenic lineages, and sheds new light on human cartilage development and biology.