bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of transcriptomics data into agent-based models of solid tumor metastasis
Authors: Retzlaff Jimmy , Lai Xin , Berking Carola , Vera Julio 
Published: January 2023

AbstractMost of the recent progress in our understanding of cancer relies in the systematic profiling of patient samples with high throughput techniques like transcriptomics. This approach has helped in finding gene signatures and networks underlying cancer aggressiveness and therapy resistance. However, -omics data alone is not sufficient to generate insights into the spatiotemporal aspects of tumor progression. Here, multi-level computational models are promising approaches, which would benefit from the possibility to integrate in their characterization the data and knowledge generated by the high throughput profiling of patient samples.We present a computational workflow to integrate transcriptomics data from tumor patients into hybrid, multi-scale models of cancer. In the method, we employ transcriptomics analysis to select key differentially regulated pathways in therapy responders and non-responders and link them to agent-based model parameters. We next utilize global and local sensitivity together with systematic model simulations to assess the relevance of variations in the selected parameters in triggering cancer progression and therapy resistance. We illustrate the methodology with ade novogenerated agent-based model accounting for the interplay between tumor and immune cells in melanoma micrometastasis. Application of the workflow identifies three different scenarios of therapy resistance.
Decoding the genetic and chemical basis of sexual attractiveness in parasitic wasps
Authors: Sun Weizhao , Lange Michelle Ina , Gadau Jürgen , Buellesbach Jan 
Published: January 2023

AbstractAttracting and securing potential mating partners is of fundamental importance for successfully initiating reproduction and thus assuring the passing of genes to the next generation. Therefore, signaling sexual attractiveness is expected to be tightly coordinated in communication systems synchronizing senders and receivers. Chemical signaling has permeated through all taxa of life as the earliest and most wide-spread form of communication and is particularly prevalent in insects. However, it has been notoriously difficult to decipher how exactly information related to sexual signaling is encoded in complex chemical profiles. Similarly, our knowledge of the genetic basis of sexual signaling is very limited and usually restricted to a few case studies with comparably simple pheromonal communication mechanisms. The present study jointly addresses these two knowledge gaps by characterizing a single gene simultaneously impacting sexual attractiveness and complex chemical surface profiles in parasitic wasps. Knocking down a fatty acid synthase gene in female wasps dramatically reduces their sexual attractiveness coinciding with a drastic decrease in male courtship and copulation behavior. Concordantly, we found a striking shift of methyl-branching patterns in the female surface pheromonal compounds, which we subsequently demonstrate to be the main cause for the greatly reduced male response. Intriguingly, this suggests a potential coding mechanism for sexual attractiveness mediated by specific methyl-branching patterns, whose genetic underpinnings are not well understood despite their high potential for encoding information. Our study sheds light on how biologically relevant information can be encoded in complex chemical profiles and on the genetic basis of sexual attractiveness.Significance StatementUnraveling the genetic basis of chemical signaling is one of the most prevalent yet challenging topics in functional genetics and animal communication studies. Here we present the characterization of a biosynthetic gene in parasitoid wasps that simultaneously impacts sexual attractiveness as well as majorly shifts complex surface pheromone compositions. The shifted pattern primarily constitutes up- and down-regulated methyl-branched compounds with very distinct branching positions. Therefore, these findings immediately suggest a potential coding mechanism for sexual attractiveness in complex chemical profiles. This advances our understanding of how genetic information can be translated into biologically relevant chemical information and reveals that sexual attractiveness can have a comparably simple genetic basis.
Phylogenomics reveals incomplete lineage sorting and ancient hybrid drove the radiation of macaques
Authors: Tan Xinxin , Qi Jiwei , Liu Zhijin , Fan Pengfei , Liu Gaoming , Zhang Liye , Shen Ying , Li Jing , Roos Christian , Zhou Xuming , Li Ming 
Published: January 2023

AbstractThe genusMacaca, with 23 species assigned into four to seven species groups, exhibits the largest geographic range and represents the most successful adaptive radiation of nonhuman primates. Here, we conducted phylogenomic analyses of 16 newly generated and eight published macaque genomes and found a strong support for the division of this genus into seven species groups. Both ancient hybrid and incomplete lineage sorting (ILS) have contributed to the radiation and evolution of macaques. Particularly, the contradicting phylogenetic positions amongsilenus/nigra, fascicularis/mulattaandarctoides/sinicalineages were likely resulted from high level of ILS and potential hybridization between the ancestors of thearctoides/sinicaandsilenus/nigralineages. Furthermore, an integrated scenario for macaque radiation is reconstructed by the help of the dated phylogenetic tree combined with documented history records. This study provides insights into ancient introgression involved in the radiation of macaques, which may help us to understand the rapid speciation of nonhuman primates.
Unique amino acid substitution in RBD region of SARS-CoV-2 Omicron XAY.2
Authors: Salsekar Lekha , Rahangdale Shefali , Tamboli Ekant , Khairnar Krishna 
Published: January 2023

ABSTRACTWe attempted to explain the rare mutation at the receptor binding domain of the spike protein in the XAY.2 variant of SARS-CoV-2 from the perspective of hydrophobic interactions. We propose that decreasing hydrophobicity at position 446 and 486 of the RBD region of the spike protein might affect the infectivity of SARS-CoV-2. We also estimated the probable mutations at the 446 and 486 position the virus may acquire, leading to a decreased hydrophobicity.
At-home, cell-free synthetic biology education modules for transcriptional regulation and environmental water quality monitoring
Authors: Jung Kirsten J. , Rasor Blake J. , Rybnicky Grant A. , Silverman Adam D. , Standeven Janet , Kuhn Robert , Granito Teresa , Ekas Holly M. , Wang Brenda M. , Karim Ashty S. , Lucks Julius B. , Jewett Michael C. 
Published: January 2023

AbstractAs the field of synthetic biology expands, the need to grow and train science, technology, engineering, and math (STEM) practitioners is essential. However, the lack of access to hands-on demonstrations has led to inequalities of opportunity and practice. In addition, there is a gap in providing content that enables students to make their own bioengineered systems. To address these challenges, we develop four shelf-stable cell-free biosensing educational modules that work by just-adding-water and DNA to freeze-dried crude extracts ofEscherichia coli. We introduce activities and supporting curricula to teach the structure and function of thelacoperon, dose-responsive behavior, considerations for biosensor outputs, and a ‘build-your-own’ activity for monitoring environmental contaminants in water. We piloted these modules with K-12 teachers and 130 high school students in their classrooms – and at home – without professional laboratory equipment or researcher oversight. This work promises to catalyze access to interactive synthetic biology education opportunities.
Imbalanced gut microbiota predicts and drives the progression of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in a fast-food diet mouse model
Authors: Fei Na , Miyoshi Sawako , Hermanson Jake B. , Miyoshi Jun , Xie Bingqing , DeLeon Orlando , Hawkins Maximilian , Charlton William , D’Souza Mark , Hart John , Sulakhe Dinanath , Martinez-Guryn Kristina B. , Chang Eugene B. , Charlton Michael R. , Leone Vanessa A. 
Published: January 2023

SummaryNonalcoholic fatty liver disease (NAFLD) is multifactorial in nature, affecting over a billion people worldwide. The gut microbiome has emerged as an associative factor in NAFLD, yet mechanistic contributions are unclear. Here, we show fast food (FF) diets containing high fat, added cholesterol, and fructose/glucose drinking water differentially impact short- vs. long-term NAFLD severity and progression in conventionally-raised, but not germ-free mice. Correlation and machine learning analyses independently demonstrate FF diets induce early and specific gut microbiota changes that are predictive of NAFLD indicators, with corresponding microbial community instability relative to control-fed mice. Shotgun metagenomics showed FF diets containing high cholesterol elevate fecal pro-inflammatory effectors over time, relating to a reshaping of host hepatic metabolic and inflammatory transcriptomes. FF diet-induced gut dysbiosis precedes onset and is highly predictive of NAFLD outcomes, providing potential insights into microbially-based pathogenesis and therapeutics.HighlightsGerm-free mice are protected from fast-food diet-induced NAFLD.Fast-food diets rapidly shift gut microbiota composition and function.Increasing dietary cholesterol exacerbates hepatic inflammation only in SPF mice.Fast-food diet-induced gut dysbiosis precedes and predicts late-stage NAFLD severity.
Profiling the bloodstream form and procyclic formTrypanosoma bruceicell cycle using single cell transcriptomics
Authors: Briggs Emma M. , Marques Catarina A. , Oldrieve Guy R. , Hu Jihua , Otto Thomas D. , Matthews Keith R. 
Published: January 2023

AbstractAfrican trypanosomes proliferate as bloodstream forms and procyclic forms in the mammal and tsetse fly midgut, respectively. This allows them to colonise the host environment upon infection and ensure life cycle progression. Yet, understanding of the mechanisms that regulate and drive the cell replication cycle of these forms is limited. Using single cell transcriptomics on unsynchronised cell populations, we have obtained high resolution cell cycle regulated transcriptomes of both procyclic and slender bloodstream formTrypanosoma bruceiwithout prior cell sorting or synchronisation. Additionally, we describe an efficient freeze-thawing protocol that allows single cell transcriptomic analysis of cryopreservedT. brucei. Computational reconstruction of the cell cycle using periodic pseudotime inference allowed the dynamic expression patterns of cycling genes to be profiled for both life cycle forms. Comparative analyses identify a core cycling transcriptome highly conserved between forms, as well as several genes where transcript levels dynamics are form-specific. Comparing transcript expression patterns with protein abundance revealed that the majority of genes with periodic cycling transcript and protein levels exhibit a relative delay between peak transcript and protein expression. This work reveals novel detail of the cell cycle regulated transcriptomes of both forms, which are available for further interrogation via an interactive webtool.
Is high-frequency activity evidence of an anterior temporal lobe network or micro-saccades?
Authors: O’Neill George C. , Mellor Stephanie , Seymour Robert A. , Alexander Nicholas , Tierney Tim M. , Timms Ryan C. , Maguire Eleanor A. , Barnes Gareth R. 
Published: January 2023

AbstractThere is renewed interest in electrical activity that extends beyond the typical electrophysiological 100 Hz bandwidth. This activity, often in the anterior temporal lobe, has been attributed to processes ranging from memory consolidation to epileptiform activity. Here, using an open-access resting state magnetoencephalography (MEG) dataset (n = 89), and a second task-based MEG dataset, we could reliably localise high-frequency power to the temporal lobes across multiple bands up to 300–400 Hz. A functional connectivity analysis of this activity revealed a robust resting state bilateral network between the temporal lobes. However, we also found robust coherence in the 100–200 and 200–300 Hz bands between source reconstructed MEG data and the electrooculography (EOG) localised to within the temporal poles. Additional denoising schemes applied to the data could reduce power localisation to the temporal poles but the topography of the functional network did not drastically alter. Whilst it is clear that this network is biological and robust to established denoising methods, we cannot definitively rule yet on whether this is of neural or myogenic origin.
Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue
Authors: Dhavale Dhruva D. , Barclay Alexander M. , Borcik Collin G. , Basore Katherine , Gordon Isabelle R. , Liu Jialu , Milchberg Moses H. , O’shea Jennifer , Rau Michael J. , Smith Zachary , Sen Soumyo , Summers Brock , Smith John , Warmuth Owen A. , Chen Qian , Fitzpatrick James A. J. , Schwieters Charles D. , Tajkhorshid Emad , Rienstra Chad M. , Kotzbauer Paul T. 
Published: January 2023

AbstractThe defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise two protofilaments with pseudo-21helical screw symmetry, very low twist and an interface formed by antiparallel beta strands of residues 85-93. The fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural landscape of LBD Asyn fibrils and inform further studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.
Force-regulated spontaneous conformational changes of integrins α5β1and αVβ3
Authors: Chen Yunfeng , Kong Fang , Li Zhenhai , Ju Lining Arnold , Zhu Cheng 
Published: January 2023

AbstractForce can modulate the properties and functions of macromolecules by inducing conformational changes, such as coiling/uncoiling, zipping/unzipping, and folding/unfolding. Here we compared force-modulated bending/unbending of two purified integrin ectodomains, α5β1and αVβ3, using single-molecule approaches. Similar to previously characterized mechano-sensitive macromolecules, the conformation of α5β1is determined by a threshold head-to-tail tension, suggesting a canonical energy landscape with a deep energy well that traps the integrin in the bent state until sufficient force tilts the energy landscape to accelerate transition to the extended state. By comparison, αVβ3exhibits bi-stability even without force and can spontaneously transition between the bent and extended conformations in a wide range of forces without energy supplies. Molecular dynamics simulations revealed consecutive formation and disruption of 7 hydrogen bonds during αVβ3bending and unbending, respectively. Accordingly, we constructed an energy landscape with hexa-stable intermediate states to break down the energy barrier separating the bent and extended states into smaller ones, making it possible for the thermal agitation energy to overcome them sequentially and to be accumulated and converted into mechanical work required for αVβ3to bend against force. Our study elucidates the different inner workings of α5β1and αVβ3at the sub-molecular level, sheds lights on how their respectively functions are facilitated by their distinctive mechano-sensitivities, helps understand their signal initiation processes, and provides critical concepts and useful design principles for engineering of protein-based biomechanical nanomachines.
Single-nucleus transcriptional profiling of GAD2-positive neurons from mouse lateral habenula reveals distinct expression of neurotransmission- and depression-related genes
Authors: Green Matthew V. , Gallegos David A. , Boua Jane-Valeriane , Bartelt Luke C. , Narayanan Arthy , West Anne E. 
Published: January 2023

ABSTRACTGlutamatergic projection neurons of the lateral habenula (LHb) drive behavioral state modulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that modulate LHb output is of interest for understanding control of motivated behaviors. A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic synthesizing enzyme GAD2, and they can inhibit nearby LHb projection neurons; however, these neurons lack markers of classic inhibitory interneurons and they co-express the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting to isolate and enrich these nuclei for single nuclear RNA sequencing (FANS-snRNAseq). Our data confirm that GAD2+/VGLUT2+ neurons intrinsic to the LHb co-express markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from either GABAergic interneurons or habenular glutamatergic neurons. We identify gene expression programs within these cells that show sex-specific differences in expression and that are implicated in major depressive disorder (MDD), which has been linked to LHb hyperactivity. Finally, we identify theNtng2gene encoding the cell adhesion protein Netrin-G2 as a marker of LHb GAD2+/VGLUT+ neurons and a gene product that may contribute to their target projections. These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of GAD2+ neurons in the LHb.
Ribonucleoprotein condensation driven by retrotransposon LINE-1 sustains RNA integrity and translation in mouse spermatocytes
Authors: Luca Chiara De , Gupta Anuj , Bortvin Alex 
Published: January 2023

SummaryTransposable elements (TE) are mobile DNA sequences whose excessive proliferation endangers the host. Although animals have evolved robust TE-targeting defenses, including Piwi-interacting (pi)RNAs, retrotransposon LINE-1 (L1) still thrives in humans and mice. To gain insights into L1 endurance, we characterized L1 Bodies (LBs) and ORF1p complexes in germ cells of piRNA-deficientMaelstromnull mice. We report that ORF1p interacts with TE RNAs, genic mRNAs, and stress granule proteins, consistent with earlier studies. We also show that ORF1p associates with the CCR4-NOT deadenylation complex and PRKRA, a Protein Kinase R factor. Despite ORF1p interactions with these negative regulators of RNA expression, the stability and translation of LB-localized mRNAs remain unchanged. To scrutinize these findings, we studied the effects of PRKRA on L1 in cultured cells and showed that it elevates ORF1p levels and L1 retrotransposition. These results suggest that ORF1p-driven condensates promote L1 propagation, without affecting the metabolism of endogenous RNAs.
Preneoplastic cells switch to Warburg metabolism from their inception exposing multiple vulnerabilities for targeted elimination
Authors: Myllymäki Henna , Kelly Lisa , Elliot Abigail M. , Carter Roderick N. , Morton Nicholas M. , Feng Yi 
Published: January 2023

SummaryOtto Warburg first described tumour cells as displaying enhanced aerobic glycolysis whilst maintaining defective oxidative phosphorylation (OXPHOS) for energy production almost 100 years ago1,2. Since then, the ‘Warburg effect’ has been widely accepted as a key feature of rapidly proliferating cancer cells3,4. Targeting cancer metabolism is now being considered as a promising precision oncology therapeutic approach5. What is not clear is how early “Warburg metabolism” initiates during cancer progression and whether changes in energy metabolism might influence tumour progressionab initio. We set out to investigate energy metabolism in HRASG12Vdriven preneoplastic cell (PNC) at inception, in a zebrafish skin PNC model; and to test how the impact of manipulating energy metabolism in the whole animal may impact PNC initiation. We find that, within 24 hours of HRASG12Vinduction, PNCs upregulate “Warburg metabolism”, and that this is required for their expansion. We show that blocking glycolysis reduces PNC proliferation, whilst increasing available glucose both enhances PNC proliferation and also reduces apoptosis. Impaired OXPHOS of PNCs might be exploited therapeutically since a mild complex I inhibitor, metformin, selectively induces apoptosis and suppresses proliferation of PNCs. In addition, we find mitochondrial fragmentation in PNCs occur prior to metabolic alteration and this is important for their survival since exposure to Drp1/Dnml1 inhibitor, mdivi, which blocks mitochondrial fragmentation leads to enhanced PNC apoptosis. Our data indicate that altered energy metabolism is one of the earliest events upon oncogene activation in somatic cells, which provide a targeted and effective tumour prevention therapy.Key findingsGlycolysis is upregulated in HRASG12Vexpressing preneoplastic cells (PNCs) in zebrafish skin, and is required for PNC proliferationOXPHOS respiration is impaired in PNCs and metformin complex I inhibition specifically eliminates PNCsPNC undergo mitochondrial fragmentation and exhibit reduced membrane potentialMdivi reverses mitochondrial fragmentation in PNCs and triggers apoptosis
Heterologous production of cyanophycin withTatumella morbiroseicyanophycin synthetase
Authors: Swain Kyle , Sharon Itai , Blackson Wyatt , Tekel Stefan , Schmeing T. Martin , Nielsen David R. , Nannenga Brent L. 
Published: January 2023

AbstractMicrobial production of biopolymers represents a promising, sustainable alternative to current approaches for plastic production. Cyanophycin synthetase 1 (CphA1) produces cyanophycin - an attractive biopolymer consisting of a poly-L-aspartic acid backbone decorated with L-arginine side groups. In this work, a series of CphA1 enzymes from different bacteria were screened for heterologous cyanophycin production in engineeredEscherichia coli, from which it was found that CphA1 fromTatumella morbirosei(TmCphA1) was especially productive.TmCphA1 was capable of supporting up to ~2-fold greater yields of insoluble cyanophycin than any other tested CphA1 enzymes, including 10.8-times more than CphA1 fromSynechocystissp. PCC6308. Finally, using a bench-scale bioreactor, cyanophycin production byTmCphA1-expressingE. colireached up to 1.9 g per liter of culture by 48 h.