bluuebunny/crossref_metadata_2025_split huggingface dataset:
Addressing the Association Between Action Video Game Playing Experience and Visual Search in Naturalistic Multisensory scenes
Authors: Hamzeloo Mohammad , Kvasova Daria , Soto-Faraco Salvador 
Published: October 2021

AbstractPrior studies investigating the effects of routine action video game playing have demonstrated improvements in a variety of cognitive processes, including improvements in attentional tasks. However, there is little evidence indicating that the cognitive benefits of playing action video games generalize from simplified unisensory stimuli to naturalistic multisensory scenes – a fundamental characteristic of natural, everyday life environments. In particular, it is unknown whether video game experience has an impact on cross-modal congruence effects when searching through such multisensory scenes. The present pre-registered compared the performance of action video game players (AVGPs) with non-video game players (NVGPs) on a visual search task for objects embedded in video clips of realistic scenes. We run two identical online experiments with gender-balanced samples, for a total N=130. Overall, the data replicated previous findings reporting search benefits when visual targets were accompanied by semantically congruent auditory events, compared to neutral or incongruent ones. However, according to the results, AVGPs did not consistently outperform NVGPs in the search task overall, nor they exploit multisensory cues more efficiently than NVGPs. Exploratory analyses with self-reported gender as a variable revealed a potential difference in response strategy between experienced male and female AVGPs when dealing with cross-modal cues. These findings suggest that the generalization of the advantage of AVG experience to realistic, cross-modal situations should be done with caution, and considering gender-related aspects.
Nanoengineered DNA origami with repurposed TOP1 inhibitors targeting myeloid cells for the mitigation of neuroinflammation
Authors: Zhu Keying , Wang Yang , Sarlus Heela , Geng Keyi , Nutma Erik , Sun Jingxian , Kung Shin-Yu , Bay Cindy , Han Jinming , Lund Harald , Amor Sandra , Wang Jun , Zhang Xingmei , Kutter Claudia , Guerreiro Cacais André Ortlieb , Högberg Björn , Harris Robert A. 
Published: October 2021

AbstractTargeting myeloid cells, especially microglia, for the treatment of neuroinflammatory diseases such as multiple sclerosis (MS), is underappreciated. Here, we screened a library of compounds and identified the topoisomerase 1 (TOP1) inhibitor camptothecin (CPT) as a promising drug candidate for microglial modulation. CPT and its FDA-approved analog topotecan (TPT) inhibited inflammatory responses in microglia and macrophages, and ameliorated neuroinflammation in mice. Transcriptomic analysis of sorted microglia revealed an altered transcriptional phenotype following TPT treatment, with Ikzf1 identified as a potential target. Importantly, TOP1 expression was found elevated in several neuroinflammatory conditions, including human MS brains. To achieve targeted delivery to myeloid cells we designed a nanosystem using DNA origami and loaded TPT into it (TopoGami). TopoGami also significantly suppressed the inflammatory response in microglia and mitigated disease progression in MS-like mice. Our findings suggest that TOP1 inhibition represents a therapeutic strategy for neuroinflammatory diseases, and the proposed nanosystem may foster future research and drug development with a demand to target myeloid cells.
Causal evidence for a domain-specific role of left superior frontal sulcus in human perceptual decision making
Authors: Barretto García Miguel , Grueschow Marcus , Moisa Marius , Polania Rafael , Ruff Christian C. 
Published: October 2021

ABSTRACTHumans and animals can flexibly choose their actions based on different information, ranging from objective states of the environment (e.g., apples are bigger than cherries) to subjective preferences (e.g., cherries are tastier than apples). Whether the brain instantiates these different choices by recruiting either specialised or shared neural circuitry remains debated. Specifically, domain-general accounts of prefrontal cortex (PFC) function propose that prefrontal areas flexibly process either perceptual or value-based evidence depending on what is required for the present choice, whereas domain-specific theories posit that PFC sub-areas, such as the left superior frontal sulcus (SFS), selectively integrate evidence relevant for perceptual decisions. Here we comprehensively test the functional role of the left SFS for choices based on perceptual and value-based evidence, by combining fMRI with a behavioural paradigm, computational modelling, and transcranial magnetic stimulation. Confirming predictions by a sequential sampling model, we show that TMS-induced excitability reduction of the left SFS selectively changes the processing of decision-relevant perceptual information and associated neural processes. In contrast, value-based decision making and associated neural processes remain unaffected. This specificity of SFS function is evident at all levels of analysis (behavioural, computational, and neural, including functional connectivity), demonstrating that the left SFS causally contributes to evidence integration for perceptual but not value-based decisions.
A causality-inspired feature selection method for cancer imbalanced high-dimensional data
Authors: Liu Yijun , Huang Qiang , Sun Huiyan , Chang Yi 
Published: October 2021

AbstractIt is significant but challenging to explore a subset of robust biomarkers to distinguish cancer from normal samples on high-dimensional imbalanced cancer biological omics data. Although many feature selection methods addressing high dimensionality and class imbalance have been proposed, they rarely pay attention to the fact that most classes will dominate the final decision-making when the dataset is imbalanced, leading to instability when it expands downstream tasks. Because of causality invariance, causal relationship inference is considered an effective way to improve machine learning performance and stability. This paper proposes a Causality-inspired Least Angle Nonlinear Distributed (CLAND) feature selection method, consisting of two branches with a class-wised branch and a sample-wised branch representing two deconfounder strategies, respectively. We compared the performance of CLAND with other advanced feature selection methods in transcriptional data of six cancer types with different imbalance ratios. The genes selected by CLAND have superior accuracy, stability, and generalization in the downstream classification tasks, indicating potential causality for identifying cancer samples. Furthermore, these genes have also been demonstrated to play an essential role in cancer initiation and progression through reviewing the literature.Author SummarySelecting trustworthy biomarkers from high-dimensional data is an important step to help researchers and clinicians understand which genes play key roles in cancer development and progression. A large number of machine learning-based feature selection algorithms have been generated in recent years for biomarker discovery. However, these methods usually show unstable results in the face of class-imbalanced biological data, making it seem unreliable for researchers. Here we introduce the causal theory with the property of causal invariance to aid in the design of feature selection algorithms, analyze how imbalanced distributions affect feature selection methods, and propose a novel causality-based feature selection method. The method with bilateral structure adjusts the data distribution from both class-wise and sample-wise to eliminate the effect of imbalance on the results. Additionally, CLAND can simultaneously address the nonlinearity and high-dimensionality of cancer data, which broaden its application scope. We conducted extensive experiments on six real imbalance cancer datasets and obtained efficient and stable results, while the obtained biomarker has significant biological significance.
Ferroptosis assassinates tumor (FAST)
Authors: Luo Tao , Wang Yile , Wang Jinke 
Published: October 2021

AbstractIn 2020, nearly 20 million peoples got cancer and nearly 10 million peoples died of cancer, indicating the current therapies do not meet the cancer treatment and cancer remains a great threat to human health and life. New therapies are still in urgent demand. In a recent study, we developed a new effective cancer therapy, gene-interfered ferroptosis therapy (GIFT), by combining cancer cell-specific knockdown of two iron efflux genes (FPN and LCN2) with iron nanoparticles (FeNPs). GIFT shows wide antitumor activity, high cancer specificity, certain cancer eradication potential, and biosafety. To further improve the therapy, we here develop an updated GIFT named as Ferroptosis ASsassinates Tumor (FAST) by knocking down five additional ferroptosis-resistance genes (FSP1, FTH1, GPX4, SLC7A11, NRF2). As a result, we found that FAST showed more significant antitumor activity than GIFT. Especially, FAST eradicated three different types of tumors (leukemia, colon cancer and lung metastatic melanoma) from over 50 percent of cancer mice, making the mice to survive up to 250 days without tumor relapse. FAST also significantly inhibited and prevented growth of spontaneous breast cancer and improved survival in mice. Additionally, FAST showed high pan-antitumor efficacy, high cancer specificity, and in vivo safety.
μ-Theraphotoxin-Pn3a inhibition of CaV3.3 channels reveals a novel isoform-selective drug binding site
Authors: McArthur Jeffrey R. , Wen Jierong , Hung Andrew , Finol-Urdaneta Rocio K. , Adams David J. 
Published: October 2021

AbstractLow voltage-activated calcium currents are mediated by T-type calcium channels CaV3.1, CaV3.2, and CaV3.3, which modulate a variety of physiological processes including sleep, cardiac pace-making, pain, and epilepsy. CaV3 isoforms’ biophysical properties, overlapping expression and lack of subtype-selective pharmacology hinder the determination of their specific physiological roles in health and disease. Notably, CaV3.3’s contribution to normal and pathophysiological function has remained largely unexplored. We have identified Pn3a as the first subtype-selective spider venom peptide inhibitor of CaV3.3, with >100-fold lower potency against the other T-type isoforms. Pn3a modifies CaV3.3 gating through a depolarizing shift in the voltage dependence of activation thus decreasing CaV3.3-mediated currents in the normal range of activation potentials. Paddle chimeras of KV1.7 channels bearing voltage sensor sequences from all four CaV3.3 domains revealed preferential binding of Pn3a to the S3-S4 region of domain II (CaV3.3DII). This novel T-type channel pharmacological site was explored through computational docking simulations of Pn3a into all T-type channel isoforms highlighting it as subtype-specific pharmacophore with therapeutic potential. This research expands our understanding of T-type calcium channel pharmacology and supports the suitability of Pn3a as a molecular tool in the study of the physiological roles of CaV3.3 channels.
Ancient and modern geochemical signatures in the 13,500-year sedimentary record of Lake Cadagno
Authors: Berg Jasmine S. , Lepine Mathilde , Laymand Emile , Han Xingguo , Vogel Hendrik , Morlock Marina A. , Gajendra Niroshan , Gilli Adrian , Bernasconi Stefano , Schubert Carsten J. , Su Guangyi , Lever Mark A. 
Published: October 2021

ABSTRACTAlthough lake sediments are globally important organic carbon sinks and therefore important habitats for deep microbial life, the deep lacustrine biosphere has thus far been little studied compared to its marine counterpart. To investigate the impact of the underexplored deep lacustrine biosphere on the sediment geochemical environment and vice versa, we performed a comprehensive microbiological and geochemical characterization of a sedimentary sequence from Lake Cadagno covering its entire environmental history since formation following glacial retreat. We found that both geochemical gradients and microbial community shifts across the ∼13.5 kyr subsurface sedimentary record reflect redox changes in the lake, going from oxic to anoxic and sulfidic. Most microbial activity occurs within the top 40 cm of sediment, where millimolar sulfate concentrations diffusing in from the bottom water are completely consumed. In deeper sediment layers, organic carbon remineralization is much slower but microorganisms nonetheless subsist on fermentation, sulfur cycling, metal reduction, and methanogenesis. The most surprising finding was the presence of a deep, oxidizing groundwater source. This water source generates an inverse redox gradient at the bottom of the sedimentary sequence and could contribute to the remineralization of organic matter sequestered in the energy-limited deep subsurface.
Genome-wide mapping of Vibrio cholerae VpsT binding identifies a mechanism for c-di-GMP homeostasis
Authors: Guest Thomas , Haycocks James R.J. , Warren Gemma Z.L. , Grainger David C. 
Published: October 2021

ABSTRACTMany bacteria use cyclic dimeric guanosine monophosphate (c-di-GMP) to control changes in lifestyle. The molecule, synthesised by proteins having diguanylate cyclase activity, is often a signal to transition from motile to sedentary behaviour. In Vibrio cholerae, c-di-GMP can exert its effects via the transcription factors VpsT and VpsR. Together, these proteins activate genes needed for V. cholerae to form biofilms. In this work, we have mapped the genome-wide distribution of VpsT in a search for further regulatory roles. We show that VpsT binds 23 loci and recognises a degenerate DNA palindrome having the consensus 5’-W-5R-4[CG]-3Y-2W-1W+1R+2[GC]+3Y+4W+5-3’. Most genes targeted by VpsT encode functions related to motility, biofilm formation, or c-di-GMP metabolism. Most notably, VpsT activates expression of the vpvABC operon that encodes a diguanylate cyclase. This creates a positive feedback loop needed to maintain intracellular levels of c-di-GMP. Mutation of the key VpsT binding site, upstream of vpvABC, severs the loop and c-di-GMP levels fall accordingly. Hence, as well as relaying the c-di-GMP signal, VpsT impacts c-di-GMP homeostasis.
Inference of cell-type specific imprinted regulatory elements and genes during human neuronal differentiation
Authors: Liang Dan , Aygün Nil , Matoba Nana , Ideraabdullah Folami Y. , Love Michael I. , Stein Jason L. 
Published: October 2021

ABSTRACTGenomic imprinting results in gene expression biased by parental chromosome of origin and occurs in genes with important roles during human brain development. However, the cell-type and temporal specificity of imprinting during human neurogenesis is generally unknown. By detecting within-donor allelic biases in chromatin accessibility and gene expression that are unrelated to cross-donor genotype, we inferred imprinting in both primary human neural progenitor cells (phNPCs) and their differentiated neuronal progeny from up to 85 donors. We identified 43/20 putatively imprinted regulatory elements (IREs) in neurons/progenitors, and 133/79 putatively imprinted genes in neurons/progenitors. Though 10 IREs and 42 genes were shared between neurons and progenitors, most imprinting was only detected within specific cell types. In addition to well-known imprinted genes and their promoters, we inferred novel IREs and imprinted genes. We found IREs overlapped with CpG islands more than non-imprinted regulatory elements. Consistent with DNA methylation-based regulation of imprinted expression, some putatively imprinted regulatory elements also overlapped with differentially methylated regions on the maternal germline. Finally, we identified a progenitor-specific putatively imprinted gene overlap with copy number variation that is associated with uniparental disomy-like phenotypes. Our results can therefore be useful in interpreting the function of variants identified in future parent-of-origin association studies.
Regulation of Polyhomeotic condensates by intrinsically disordered sequences that affect chromatin binding
Authors: Kapur Ibani , Boulier Elodie L. , Francis Nicole J. 
Published: October 2021

ABSTRACTThe Polycomb group (PcG) complex PRC1 localizes in the nucleus in the form of condensed structures called Polycomb bodies. The PRC1 subunit Polyhomeotic (Ph) contains an oligomerizing sterile alpha motif (SAM) that is implicated in both PcG body formation and chromatin organization in Drosophila and mammalian cells. A truncated version of Ph containing the SAM (mini-Ph), forms phase separated condensates with DNA or chromatin in vitro, suggesting PcG bodies may form by SAM-driven phase separation. In cells, Ph forms multiple small condensates, while mini-Ph typically forms a single large nuclear condensate. We therefore hypothesize that sequences outside of mini-Ph, which are predicted to be intrinsically disordered, are required for proper condensate formation. We identified three distinct low complexity regions in Ph based on sequence composition. We systematically tested the role of each of these sequences in Ph condensates using live imaging of transfected Drosophila S2 cells. Each sequence uniquely affects Ph SAM-dependent condensate size, number, and morphology, but the most dramatic effects occur when the central, glutamine rich IDR is removed, which results in large Ph condensates. Like mini-Ph condensates, these condensates exclude chromatin. Chromatin fractionation experiments indicate that removal of the glutamine rich IDR reduces chromatin binding, while removal of either of the other IDRs increases chromatin binding. Our data suggest all three IDRs, and functional interactions among them, regulate Ph condensate size and number. Our results can be explained by a model in which tight chromatin binding by Ph IDRs antagonizes Ph SAM driven phase separation and highlight the complexity of regulation of biological condensates housed in single proteins.
Low Temperatures Lead to Higher Toxicity of the Fungicide Folpet to Larval Stages of Rana temporaria and Bufotes viridis
Authors: Leeb Christoph , Schuler Laura , Brühl Carsten A. , Theissinger Kathrin 
Published: October 2021

AbstractPesticides are one of the main drivers of the worldwide amphibian decline. Their actual toxicity depends on a number of factors, like the species in focus or the developmental stage of exposed individuals. As ectothermic species, the metabolism of amphibians is influenced by ambient temperature. Therefore, temperature also affects metabolic rates and thus processes that might enhance or reduce toxic effects. Studies about the interactive effect of temperature and toxicity on amphibians are rare and deliver contrasting results. To investigate the temperature-dependent pesticide sensitivity of larvae of two European species we conducted acute toxicity tests for the viticultural fungicide Folpan® 500 SC with the active ingredient folpet at different temperatures (6°C, 11°C, 16°C, 21°C, 26°C). Sensitivity of Rana temporaria and Bufotes viridis was highly affected by temperature: early larvae (Gosner stage 20) were about twice more sensitive to Folpan® 500 SC at 6°C compared to 21°C. Next to temperature, species and developmental stage of larvae had an effect on sensitivity. The most sensitive individuals (early stages of R. temporaria at 6°C) were 14.5 times more sensitive than the least sensitive ones (early stages of B. viridis at 26°C). Our results raise concerns about typical ecotoxicological studies with amphibians that are often conducted at temperatures between 15°C and 20°C. We suggest that future test designs should be performed at temperatures that reflect the temperature range amphibians are exposed to in their natural habitats. Variations in the sensitivity due to temperature should also be considered as an uncertainty factor in upcoming environmental risk assessments for amphibians.
Non-coding function for mRNAs in Focal Adhesion Architecture and Mechanotransduction
Authors: Boraas Liana , Hu Mengwei , Thornton Lauren , Vejnar Charles E. , Zhen Gang , Giraldez Antonio J. , Mayr Christine , Wang Siyuan , Nicoli Stefania 
Published: October 2021

AbstractMessenger RNA (mRNA) compartmentalization within the cytosol is well-recognized as a key mechanism of local translation-mediated regulation of protein levels, but whether such localization could be a means of exercising non-coding mRNA function is unknown. Here, we explore non-coding functions for mRNAs associated with focal adhesions (FAs), cellular structures responsible for mediating cell adhesion and response to changes in the extracellular matrix (ECM). Using high-throughput single molecule imaging and genomic profiling approaches, we find that mRNAs with distinct sequence characteristics localize to FAs in different human cell types. Notably, ∼85% of FA-mRNAs are not translationally active at steady state or under conditions of FA dissolution or activation. Untranslated mRNA sequences are anchored to FA based on their functional states by the RNA binding protein, G3BP1, forming biomolecular granules. Removing RNA or G3BP1, but not blocking new polypeptide synthesis, dramatically changes FA protein composition and organization, resulting in loss of cell contractility and cellular ability to adapt to changing ECM. We have therefor uncovered a novel, non-coding role for mRNAs as scaffolds to maintain FA structure and function, broadening our understating of noncanonical mRNA functions.
CRISPR-Cas9 induces large structural variants at on-target and off-target sitesin vivothat segregate across generations
Authors: Höijer Ida , Emmanouilidou Anastasia , Östlund Rebecka , van Schendel Robin , Bozorgpana Selma , Feuk Lars , Gyllensten Ulf , den Hoed Marcel , Ameur Adam 
Published: October 2021

AbstractTo investigate the extent and distribution of unintended mutations induced by CRISPR-Cas9in vivo,we edited the genome of fertilized zebrafish eggs and investigated DNA from >1100 larvae, juvenile and adult fish in the F0 and F1 generations. Four guide RNAs (gRNAs) were used, selected from 23 gRNAs with high on-target efficiencyin vivoin previous functional experiments. CRISPR-Cas9 outcomes were analyzed by long-read sequencing of on-target sites and off-target sites detectedin vitro.In founder larvae, on-target editing of the four gRNAs was 93-97% efficient, and three sites across two gRNAs were identified within vivooff-target editing. Seven percent of the CRISPR-Cas9 editing outcomes correspond to structural variants (SVs), i.e., insertions and deletions ≥50 bp. The adult founder fish displayed a mosaic pattern of editing events in somatic and germ cells. The F1 generation contained high levels of genome editing, with all alleles of 46 examined F1 juvenile fish affected by on-target mutations, including four cases of SVs. In addition, 26% of the juvenile F1 fish (n=12) carried off-target mutations. These CRISPR-induced off-target mutations in F1 fish were successfully validated in pooled larvae from the same founder parents. In conclusion, we demonstrate that large SVs and off-target mutations can be introducedin vivoand passed through the germline to the F1 generation. The results have important consequences for the use of CRISPR-Cas9 in clinical applications, where pre-testing for off-target activity and SVs on patient material is advisable to reduce the risk of unanticipated effects with potentially large implications.