bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ancient genomes reveal long range influence of the site and culture of Tiwanaku
Authors: Popović Danijela , Molak Martyna , Ziołkowski Mariusz , Vranich Alexei , Sobczyk Maciej , Vidaurre Delfor Ulloa , Agresti Guido , Skrzypczak Magdalena , Ginalski Krzysztof , Lamnidis Thiseas Christos , Nakatsuka Nathan , Mallick Swapan , Baca Mateusz 
Published: January 2021

AbstractTiwanaku was a civilization that flourished in the Lake Titicaca Basin (present-day Bolivia) between 500 and 1000 CE. At its apogee, Tiwanaku controlled the lake’s southern shores and influenced certain areas of the Southern Andes. There is a considerable amount of archaeological and anthropological data concerning the Tiwanaku culture; however, our understanding of the population of the site of Tiwanaku is limited. To understand the population dynamics at different stages of the Tiwanaku cultural development, we analyzed 17 low-coverage genomes from individuals dated between 300 and 1500 CE. We found that the population from the Lake Titicaca Basin remained genetically unchanged throughout more than 1200 years, indicating that significant cultural and political changes were not associated with large scale population movements. In contrast, individuals excavated from Tiwanaku’s ritual core were highly heterogeneous, some with genetic ancestry from as far away as the Amazon, supporting the proposition of foreign presence at the site. However, mixed-ancestry individuals’ presence suggests they were local descendants of incomers from afar rather than captives or visiting pilgrims. A number of human offerings from the Akapana Platform dating to ca. 950 CE mark the end of active construction and maintenance of the monumental core and the wane of Tiwanaku culture.Significance StatementTiwanaku was an important pre-Inca polity in South America and an example of primary social complexity on par with civilizations in the Indus and Nile river valley. Flourishing between 500 and 1000 CE, Tiwanaku exercised control in the south Titicaca basin and influenced a vast area in southern Peru, Bolivia, and northern Chile. Comprehensive archeological studies provided information about the rise, expansion, and fall of the Tiwanaku culture, but little is known about the monumental site’s population. To address this lacuna, we generated low coverage genomes for 17 individuals, revealing that while the Titicaca basin’s residential population was homogenous, the individuals excavated from the ritual core of Tiwanaku drew their ancestry from distant regions.
Fine-grained temporal mapping of derived high-frequency variants supports the mosaic nature of the evolution ofHomo sapiens
Authors: Andirkó Alejandro , Moriano Juan , Vitriolo Alessandro , Kuhlwilm Martin , Testa Giuseppe , Boeckx Cedric 
Published: January 2021

ABSTRACTAs our knowledge about the history of theHomo sapienslineage becomes increasingly complex, large-scale estimations of the time of emergence of derived variants become essential to be able to offer more precise answers to time-sensitive hypotheses concerning human evolution. Using an open repository of genetic variant age estimations recently made available, we offer here a temporal evaluation of various evolutionarily relevant datasets, such asHomo sapiens-specific variants, high-frequency variants found in genetic windows under positive selection, introgressed variants from extinct human species, as well as putative regulatory variants in various brain regions. We find a recurrent bimodal distribution of high-frequency variants, but also evidence for specific enrichments of gene categories in various time windows, which brings into prominence the 300-500k time slice. We also find evidence for very early mutations impacting the facial phenotype, and much more recent molecular events linked to specific brain regions such as the cerebellum or the precuneus. Additionally, we present a case study of an evolutionarily relevant gene,BAZ1B, and its targets, to emphasize the importance of applying temporal data to specific evolutionary questions. Overall, we present a unique resource that informs and complements our previous knowledge ofHomo sapiensevolution using publicly available data, and reinforce the case for the mosaic, temporally very extended nature of the evolutionary trajectory of our species.
Transcriptome variation in human tissues revealed by long-read sequencing
Authors: Glinos Dafni A , Garborcauskas Garrett , Hoffman Paul , Ehsan Nava , Jiang Lihua , Gokden Alper , Dai Xiaoguang , Aguet Francois , Brown Kathleen L. , Garimella Kiran , Bowers Tera , Costello Maura , Ardlie Kristin , Jian Ruiqi , Tucker Nathan R , Ellinor Patrick T , Harrington Eoghan D , Tang Hua , Snyder Michael , Juul Sissel , Mohammadi Pejman , MacArthur Daniel G , Lappalainen Tuuli , Cummings Beryl 
Published: January 2021

SummaryRegulation of transcript structure generates transcript diversity and plays an important role in human disease. The advent of long-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure. In this paper, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from GTEx tissues and cell lines, complementing the GTEx resource. We identified just under 100,000 new transcripts for annotated genes, and validated the protein expression of a similar proportion of novel and annotated transcripts. We developed a new computational package, LORALS, to analyze genetic effects of rare and common variants on the transcriptome via allele-specific analysis of long reads. We called allele-specific expression and transcript structure events, providing novel insights into the specific transcript alterations caused by common and rare genetic variants and highlighting the resolution gained from long-read data. We were able to perturb transcript structure upon knockdown of PTBP1, an RNA binding protein that mediates splicing, thereby finding genetic regulatory effects that are modified by the cellular environment. Finally, we use this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns.
A genetic variant alters the secondary structure of the lncRNA H19 and is associated with Dilated Cardiomyopathy
Authors: Martens Leonie , Rühle Frank , Witten Anika , Meder Benjamin , Katus Hugo A. , Arbustini Eloisa , Hasenfuß Gerd , Sinner Moritz F. , Kääb Stefan , Pankuweit Sabine , Angermann Christiane , Bornberg-Bauer Erich , Stoll Monika 
Published: January 2021

AbstractlncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNAs structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their down-stream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs we demonstrate first the significant association of a SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.
Bio-instantiated recurrent neural networks
Authors: Goulas Alexandros , Damicelli Fabrizio , Hilgetag Claus C 
Published: January 2021

AbstractBiological neuronal networks (BNNs) are a source of inspiration and analogy making for researchers that focus on artificial neuronal networks (ANNs). Moreover, neuroscientists increasingly use ANNs as a model for the brain. Despite certain similarities between these two types of networks, important differences can be discerned. First, biological neural networks are sculpted by evolution and the constraints that it entails, whereas artificial neural networks are engineered to solve particular tasks. Second, the network topology of these systems, apart from some analogies that can be drawn, exhibits pronounced differences. Here, we examine strategies to construct recurrent neural networks (RNNs) that instantiate the network topology of brains of different species. We refer to such RNNs as bio-instantiated. We investigate the performance of bio-instantiated RNNs in terms of: i) the prediction performance itself, that is, the capacity of the network to minimize the desired function at hand in test data, and ii) speed of training, that is, how fast during training the network reaches its optimal performance. We examine bio-instantiated RNNs in working memory tasks where task-relevant information must be tracked as a sequence of events unfolds in time. We highlight the strategies that can be used to construct RNNs with the network topology found in BNNs, without sacrificing performance. Despite that we observe no enhancement of performance when compared to randomly wired RNNs, our approach demonstrates how empirical neural network data can be used for constructing RNNs, thus, facilitating further experimentation with biologically realistic network topologies, in contexts where such aspect is desired.
Detection of hematopoietic stem cell transcriptome in human fetal kidneys and kidney organoids derived from human induced pluripotent stem cells (iPSC)
Authors: Hwang Jin Wook , Desterke Christophe , Loisel-Duwattez Julien , Griscelli Frank , Bennaceur-Griscelli Annelise , Turhan Ali G 
Published: January 2021

AbstractBackgroundIn mammalians, hematopoietic stem cells (HSC) arise in the dorsal aorta from the hemogenic endothelium, followed by their migration to fetal liver and to bone marrow. In zebrafish, kidney is the site of primary hematopoiesis. In humans, the presence of HSC in the fetal or adult kidney has not been established.MethodsWe analyzed the presence of HSC markers in human fetal kidneys by analysis of single-cell datasets. We then analyzed in kidney organoids derived from iPSC, the presence of hematopoietic markers using transcriptome analyses.Results12 clusters were identified of stromal, endothelial, and nephron cell type-specific markers in the two fetal stage (17 weeks) kidney datasets. Among these, expression of hematopoietic cells in Cluster 9 showed expression of primitive markers. Moreover, whole transcriptome analysis of our iPSC-derived kidney organoids revealed induction of the primitive hematopoietic transcription factor RUNX1 as found in the human fetal kidney cortex.ConclusionsThese finding support the presence of cells expressing HSC transcriptome in human kidney. The mechanisms of the appearance of the cells with the same transcriptional features during iPSC-derived kidney organoid generation requires further investigation.
Cell shape anisotropy and motility constrain self-organised feather pattern fidelity in birds
Authors: Curantz Camille , Bailleul Richard , Hidalgo Magdalena , Durande Melina , Graner François , Manceau Marie 
Published: January 2021

SummaryCellular self-organisation can emerge from stochastic fluctuations in properties of a developing tissue1–3. This mechanism explains the production of various motifs seen in nature4–7. However, events channelling its outcomes such that patterns are produced with reproducible precision key to fitness remain unexplored. Here, we compared the dynamic emergence of feather primordia arrays in poultry, finch, emu, ostrich and penguin embryos and correlated inter-species differences in pattern fidelity to the amplitude of dermal cell anisotropy in the un-patterned tissue. Using live imaging and ex vivo perturbations in these species, we showed that cell anisotropy optimises cell motility for sharp and precisely located primordia formation, and thus, proper pattern geometry. These results evidence a mechanism through which collective cellular properties of a developmental pattern system ensure stability in its self-organisation and contribute to its evolution.
Inhibition of Quorum Sensing System inPseudomonas aeruginosaby Psammaplin A and Bisaprasin Isolated from the Marine SpongeAplysinella rhax
Authors: Oluwabusola Emmanuel T. , Katermeran Nursheena Parveen , Tan Lik Tong , Diyaolu Oluwatofunmilayo , Tabudravu Jioji , Ebel Rainer , Jaspars Marcel 
Published: January 2021

AbstractNatural products isolated from marine sponges have exhibited profound bioactivity and, in some cases, serve as potent quorum sensing inhibitory agents by preventing microbial biofilm formation. In this study, the inhibitory potential of the psammaplin type compounds, psammaplin A (1) and bisaprasin (2), isolated from the marine sponge,Aplysinella rhax, was evaluated in the quorum-sensing inhibitory assay based on thePseudomonas aeruginosaPAO1lasB-gfpandP. aeruginosaPAO1rhlA-gfpbiosensor strains. The result indicated that psammaplin A (1) showed moderate inhibition againstlasB-gfpbiosensor strains but significantly inhibited the QS-gene promoters,rhlA-gfpwith IC50value at 30.69 and 2.64 μM, respectively. In contrast, bisaprasin (2) displayed significant inhibition for both biosensor strains,lasB-gfpandrhlA-gfpwith IC50values at 8.70 and 8.53 μM, respectively. To our knowledge, the antiquorum sensing activity of these marine-derived bromotyrosine compounds is described here for the first time.Significance and Impact of the StudyThe attention of the scientific community has been drawn to using marine sources to find novel quorum sensing inhibitors as antipathogenic drugs to combat antimicrobial resistance and pathogenesis caused by the proliferation of pathogenic bacteria mediated by the quorum sensing (QS) system. By blocking the QS signalling communication, the ability to assemble an organised community structure that enables drug resistance and production of virulence factors will be attenuated. The significance of this investigation is based on the discovery of bromotyrosine derivatives as potential new drug leads for the development of antipathogenic agents.
A prioritized and validated resource of mitochondrial proteins in Plasmodium identifies leads to unique biology
Authors: van Esveld Selma L. , Meerstein-Kessel Lisette , Boshoven Cas , Baaij Jochem F. , Barylyuk Konstantin , Coolen Jordy P. M. , van Strien Joeri , Duim Ronald A.J. , Dutilh Bas E. , Garza Daniel R. , Letterie Marijn , Proellochs Nicholas I. , de Ridder Michelle N. , Venkatasubramanian Prashanna Balaji , de Vries Laura E. , Waller Ross F. , Kooij Taco W.A. , Huynen Martijn A. 
Published: January 2021

AbstractPlasmodium species have a single mitochondrion that is essential for their survival and has been successfully targeted by anti-malarial drugs. Most mitochondrial proteins are imported into this organelle and our picture of the Plasmodium mitochondrial proteome remains incomplete. Many data sources contain information about mitochondrial localization, including proteome and gene expression profiles, orthology to mitochondrial proteins from other species, co-evolutionary relationships, and amino acid sequences, each with different coverage and reliability. To obtain a comprehensive, prioritized list of Plasmodium falciparum mitochondrial proteins, we rigorously analyzed and integrated eight datasets using Bayesian statistics into a predictive score per protein for mitochondrial localization. At a corrected false discovery rate of 25%, we identified 445 proteins with a sensitivity of 87% and a specificity of 97%. They include proteins that have not been identified as mitochondrial in other eukaryotes but have characterized homologs in bacteria that are involved in metabolism or translation. Mitochondrial localization of seven Plasmodium berghei orthologs was confirmed by epitope labeling and co-localization with a mitochondrial marker protein. One of these belongs to a newly identified apicomplexan mitochondrial protein family that in P. falciparum has four members. With the experimentally validated mitochondrial proteins and the complete ranked P. falciparum proteome, which we have named PlasmoMitoCarta, we present a resource to study unique proteins of Plasmodium mitochondria.
eIF4E3 Forms an Active eIF4F Complex during Stresses (eIF4FS) Targeting mTOR and Re-Programs the Translatome
Authors: Weiss B. , Allen G.E. , Kloehn J. , Abid K. , Jaquier-Gubler P. , Curran J.A. 
Published: January 2021

ABSTRACTThe eIF4E are a family of initiation factors that bind the mRNA 5’ cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not interact with 4EBP1, we demonstrate that eIF4E3 recruitment into an eIF4F complex occurs when Torin1 inhibits the mTOR pathway. Ribo-seq studies demonstrate that this complex (eIF4FS) is translationally active only during stress and that it selects specific mRNA populations based on 5’ TL (UTR) length. The interactome reveals that it associates with cellular proteins beyond the cognate initiation factors, suggesting that it may have “moon-lighting” functions. Finally, we provide evidence that cellular metabolism is altered in an eIF4E3 KO background but only upon Torin1 treatment. We propose that eIF4E3 acts as a second branch of the integrated stress response, re-programming the translatome to promote “stress resistance” and adaptation.
Quantitative coupling of cell volume and membrane tension during osmotic shocks
Authors: Roffay Chloé , Molinard Guillaume , Kim Kyoohyun , Barbarassa Victoria , Urbanska Marta , Mercier Vincent , García-Calvo José , Matile Stefan , Guck Jochen , Lenz Martin , Roux Aurélien 
Published: January 2021

ABSTRACTDuring osmotic changes of their environment, cells actively regulate their volume and plasma membrane tension that can passively change through osmosis. How tension and volume are coupled during osmotic adaptation remains unknown, as a quantitative characterization is lacking. Here, we performed dynamic membrane tension and cell volume measurements during osmotic shocks. During the first few seconds following the shock, cell volume varied to equilibrate osmotic pressures inside and outside the cell, and membrane tension dynamically followed these changes. A theoretical model based on the passive, reversible unfolding of the membrane as it detaches from the actin cortex during volume increase, quantitatively describes our data. After the initial response, tension and volume recovered from hypoosmotic shocks but not from hyperosmotic shocks. During these asymmetric recoveries, tension and volume remained coupled. Pharmacological disruption of the cytoskeleton and functional inhibition of ion channels and mTOR all affected tension and volume responses, proving that a passive mechanism is necessary and critical for the cell to adapt fast. The coupling between them was, nonetheless, maintained for a few exceptions suggesting that volume and tension regulations are independent from the regulation of their coupling.
Zinc Import Mediated by AdcABC is Critical for Colonization of the Dental Biofilm byStreptococcus mutansin an Animal Model
Authors: Ganguly Tridib , Peterson Alexandra M. , Kajfasz Jessica K. , Abranches Jacqueline , Lemos José A. 
Published: January 2021

SummaryTrace metals are essential to all domains of life but toxic when found at high concentrations. While the importance of iron in host-pathogen interactions is firmly established, contemporary studies indicate that other trace metals, including manganese and zinc, are also critical to the infectious process. In this study, we sought to identify and characterize the zinc uptake system(s) ofS. mutans, a keystone pathogen in dental caries and a causative agent of bacterial endocarditis. Different than other pathogenic bacteria, including several streptococci, that encode multiple zinc import systems, bioinformatic analysis indicated that theS. mutanscore genome encodes a single, highly conserved, zinc importer commonly known as AdcABC. Inactivation of the genes coding for the metal-binding AdcA (ΔadcA) or both AdcC ATPase and AdcB permease (ΔadcCB) severely impaired the ability ofS. mutansto grow under zinc-depleted conditions. Intracellular metal quantifications revealed that both mutants accumulated less zinc when grown in the presence of a sub-inhibitory concentration of a zinc-specific chelator. Notably, the ΔadcCBstrain displayed a severe colonization defect in a rat oral infection model. Both Δadcstrains were hypersensitive to high concentrations of manganese, showed reduced peroxide tolerance, and formed less biofilm in sucrose-containing media when cultivated in the presence of the lowest amount of zinc that support their growth, but not when zinc was supplied in excess. Collectively, this study identifies AdcABC as the lone high affinity zinc importer ofS. mutansand provides preliminary evidence that zinc is a growth-limiting factor within the dental biofilm.