bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detecting significantly recurrent genomic connections from simple and complex rearrangements in the cancer genome
Authors: Zhang Shu , Kumar Kiran H. , Shapira Ofer , Yao Xiaotong , Wala Jeremiah , Dubois Frank , Gold Rose , Haber James E. , Cherniack Andrew , Imielinski Marcin , Dalin Simona , Beroukhim Rameen 
Published: October 2023

AbstractThe detection of somatic genetic alterations that recur across cancer genomes more than expected by chance has been a major goal of cancer genomics, as these alterations are enriched for “driver” events that promote cancer. Multiple methods have been developed to detect driver point mutations and copy-number variants, but methods to detect driver rearrangements have largely not been pursued. Unlike point mutations and copy-number alterations, which can be assigned to a single genomic locus, rearrangements connect two distant genomic loci, and possibly more in the case of complex or clustered events. Here, we explore genomic features that predict the rate at which any pair of loci will be connected by rearrangements and describe two methods to detect rearrangements that recur more often than this background rate. The first, SVSig-2D, detects pairs of loci that are directly connected by a single rearrangement; the second, SVSig-2Dc also detects loci that are recurrently connected indirectly through two or more rearrangements. When applied to a pan-cancer dataset of over 2,500 cancers, these methods identified 80 significantly recurrent simple rearrangements and 29 complex rearrangements, including both known and novel events. Intriguingly, though both recurrent simple and complex rearrangements tended to be tissue-specific, this was less true for the complex events. The detection of recurrent rearrangements with methods such as these will be an essential component of cancer genomics in the whole-genome sequencing era.
High genetic diversification in a symbiotic marine annelid is driven by microgeography and glaciation
Authors: Sato Yui , Wilkins Laetitia G.E. , Gruhl Alexander , Gruber-Vodicka Harald , Dubilier Nicole 
Published: October 2023

AbstractMarine invertebrates with limited dispersal abilities exhibit high levels of genetic divergence among populations. However, the spatial extent of genetic differentiation in these species remains poorly understood because identifying natural barriers to gene flow can be challenging in the marine environment. In this study, we investigated the population genetic structure of the interstitial annelidOlavius algarvensis, a species that lays eggs in its immediate surroundings and does not have an active dispersal phase. We analyzed the mitochondrial and nuclear genome sequences of hundreds to thousands of individuals from eleven sites in the Mediterranean, spanning microgeographic scales of < 5 km to macrogeographic scales of 800 km. Comparisons of single nucleotide polymorphisms (SNPs) in mitochondrial genomes revealed a complex history of introgression events, with as many as six mitochondrial lineages co-occurring in individuals from the same site. In contrast, SNP analyses of nuclear genomes revealed clear genetic differentiation at micro- and macrographic scales, characterised by a significant isolation by distance pattern (IBD). IBD patterns further indicated the presence of a historical physical barrier to gene flow on the east coast of the island of Elba corresponding to the historical shoreline around Elba during the Last Glacial Maximum in the Late Pleistocene, and highlighting the influence of geological forces in shaping population genetic structuring in the species today. Overall, our results provide strong empirical evidence for the high genomic diversification across spatial scales in marine interstitial fauna.
Sleep stages antagonistically modulate reactivation drift
Authors: Bollmann Lars , Baracskay Peter , Stella Federico , Csicsvari Jozsef 
Published: October 2023

AbstractHippocampal reactivation of waking neuronal assemblies in sleep is a key initial step of systems consolidation. Nevertheless, it is unclear whether reactivated assemblies are static or whether they reorganize gradually over prolonged sleep. Here, we tracked reactivated CA1 assembly patterns over ∼20 hours of sleep/rest periods and related them to assemblies seen before or after in a spatial learning paradigm. We found that reactivated assembly patterns were gradually transformed and started to resemble those seen in the subsequent recall session. Periods of rapid eye movement (REM) sleep and non-REM (NREM) had antagonistic roles: while NREM accelerated the assembly drift, REM countered it. Moreover, only a subset of rate-changing pyramidal cells contributed to the drift, while stable firing rate cells maintained unaltered reactivation patterns. Our data suggest that prolonged sleep promotes the spontaneous reorganization of spatial assemblies, which can contribute to daily cognitive map changes or encoding new learning situations.
Devising reliable and accurate epigenetic predictors: choosing the optimal computational solution
Authors: Vavourakis Charlotte D. , Herzog Chiara M. , Widschwendter Martin 
Published: October 2023

AbstractIllumina DNA methylation arrays are frequently used for the discovery of methylation signatures associated with aging and disease. One of the major hurdles to overcome when training trait prediction models is the high dimensionality of the data, with the number of features (CpGs) greatly exceeding the typical number of samples assessed. In addition, most large-scale DNA methylation-based studies do not include replicate measurements for a given sample, making it impossible to estimate the degree of measurement uncertainty or the reliability of the prediction models. A recent study proposed that training penalized regression models on derived principal components (PCs) rather than on the original features (CpGs) results in more reliable age predictions, as estimated from technical replication. Moreover, the same method could be applied for predicting other phenotypes more reliably. Here, we aimed at validating the proposed PC method. We found that although dimension reduction with PCA consistently led to small improvements in the reliability of age prediction models, it severely compromised their accuracy. PC-based models needed far larger training set sizes to be similarly accurate as CpG-based models, whereas reliability did not depend on the sample size of the training set data for either approach. Finally, the PC version of a novel multiclass predictor for breast, ovarian and endometrial cancer we trained using weighted ensembles of deep-learning models also had a markedly lower predictive accuracy compared to a CpG version, suggesting limited applicability of the proposed PC method for predicting phenotypes beyond age.
Breast cancer cells can recognize and respond to different levels of progestins to achieve different phenotypic outputs
Authors: Dolan Emma L. , Safi Rachid , Chang Chingyi , Eaton Hilary E. , Krishnan Shweta , Safi Roya , Watkinson Paige , Long Henry , Xie Yingtian , Brown Myles , Murphy Susan K. , McDonnell Donald P. 
Published: October 2023

ABSTRACTThe steroid hormone progesterone, acting through its nuclear progesterone receptor (PR), has complex physiologic activities with different levels of hormones manifesting distinct and sometimes opposing phenotypic responses in target tissues. However, most of what is currently known about the transcriptional activity of PR comes from studies performed using progestins at levels that are in the high physiologic range (≥10nM), relevant only in the luteal phase of the reproductive cycle and pregnancy in humans. These studies do not consider the non-linearity of responses to progestins that exist in physiology and are not informative as to the mechanisms by which low levels of progestins, as occurs during menopause, exert their biological activities. Thus, we undertook to define the mechanisms which enable cells to recognize and respond to different levels of progestins. Using a PR expressing cell model of luminal breast cancer (T47D cells) we demonstrated that low concentration progestins (0.1-0.3nM) drive proliferation while high dose progestins (≥10nM) inhibit proliferation. Using both unbiased and targeted approaches, we found that low dose progestins facilitate cell cycle entry by enhanced expression of CCND1 and SGK1, which are both required to initiate a signaling cascade that leads to increased phospho-Rb and E2F1 transcriptional activity. CCND1 cooperates with CDK4/6 to phosphorylate Rb, while SGK1 phosphorylates p21, thereby excluding it from the nucleus and inhibiting its anti-proliferative function. Expression ofCCND1andSGK1mRNAs are primary responses to low dose progestin treatment. However, these responses occur at very low levels of receptor occupancy and in the absence of receptor phosphorylation events that have been shown to be required for nuclear translocation and transcriptional activity. These findings challenge the assumption of linearity in response to progestin dose. Further, they suggest that concentrations of progestins found in post-menopausal women (0.1-0.3nM) have the potential to exert proliferative responses in PR expressing cancers.
Five amino acid mismatches in the zinc-finger domains of CELLULOSE SYNTHASE 5 and CELLULOSE SYNTHASE 6 modulate their incorporation into cellulose synthase complexes inArabidopsis
Authors: Park Sungjin , Ding Shi-You 
Published: October 2023

AbstractMain conclusionDifferent capacities for the homodimerization of CESA5 and CESA6 are modulated by five amino acid mismatches in their zinc-finger domains and motivate discriminative incorporation of these CESAs into CSCsCellulose synthase 5 (CESA5) and CESA6 are known to share substantial functional overlap. In the zinc-finger domain of CESA5, there are five amino acid (AA) mismatches when compared to CESA6. These mismatches in CESA5 were replaced with their CESA6 counterparts one by one until all were replaced, generating nine engineered CESA5s. Each N-terminal enhanced yellow fluorescent protein-tagged engineered CESA5 was introduced toprc1-1, acesa6null mutant, and resulting mutants were subjected to phenotypic analyses. We found that five single AA-replaced CESA5 proteins partially rescue theprc1-1mutant phenotypes to different extents. Multi-AA replaced CESA5s further rescued the mutant phenotypes in an additive manner, culminating in full recovery by CESA5G43R+S49T+S54P+S80A+Y88F. Investigations in cellulose content, cellulose synthase complex (CSC) motility, and cellulose microfibril organization in the same mutants support the results of the phenotypic analyses. Bimolecular fluorescence complementation assays demonstrated that the level of homodimerization in every engineered CESA5 is substantially higher than CESA5. The mean fluorescence intensity of CSCs carrying each engineered CESA5 fluctuates with the degree to which theprc1-1mutant phenotypes are rescued by introducing a corresponding engineered CESA5, indicating that these mismatches modulate the incorporation of both CESAs into CSCs by controlling their ability to homodimerize.
Dietary restriction extends lifespan across different temperatures in the fly
Authors: Phillips Eleanor J , Simons Mirre J P 
Published: October 2023

AbstractDietary restriction (DR) has been consistently shown to extend lifespan across a range of taxa. However, it has recently been reported that DR does not extend lifespan at certain, namely lower, temperatures in flies (Drosophila melanogaster). Similar to the interpretation of other findings that appear to question DR’s universality, this finding has been interpreted as being an artefact of benign laboratory conditions. Here we re-test this hypothesis, now using a strain that shows robust lifespan extension at 25°C (across three prior experiments), and using a range of 5 diets across two temperatures, 18°C and 21°C. We found the DR longevity response to be robust, extending lifespan irrespective of temperature. We measured fecundity as a positive control for the DR phenotype, and found, as predicted, that DR reduces egg laying. It will be important for results that question DR as a phenotype to not be overinterpreted readily, as with a substantially larger sample size and a larger range of diets we were unable to replicate this prior work. Differences in experimental setup, genetic lines used and variation in the diet-lifespan reaction norm we suggest are responsible for this discrepancy. In addition, starting with a strain and conditions that show a lifespan extension by DR, as we do here, and then changing environment and/or genotype promises a more robust test of DR modulating factors.
Parkinson’s-linked LRRK2-G2019S derails AMPAR trafficking, mobility and composition in striatum with cell-type and subunit specificity
Authors: Gupta Swati , Guevara Christopher A. , Tielemans Alexander , Huntley George W. , Benson Deanna L. 
Published: October 2023

ABSTRACTParkinson’s (PD) is a multi-factorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal based cognitive function are common, appear early and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation inLrrk2also exhibit deficits in fronto-striatal-based cognitive tasks. In mice and humans, cognitive functions require dynamic adjustments in glutamatergic synapse strength through cell-surface trafficking of AMPA-type glutamate receptors (AMPARs), but it is unknown how LRRK2 mutation impacts dynamic features of AMPAR trafficking in striatal projection neurons (SPNs). Here, we usedLrrk2G2019Sknockin mice to show that surface AMPAR subunit stoichiometry is altered biochemically and functionally in mutant SPNs to favor incorporation of GluA1 over GluA2. GluA1-containing AMPARs were resistant to internalization from the cell surface, leaving an excessive accumulation of GluA1 on the surface within and outside synapses. This negatively impacted trafficking dynamics that normally support synapse strengthening, as GluA1-containing AMPARs failed to increase at synapses in response to a potentiating stimulus and showed significantly reduced surface mobility. Surface GluA2-containing AMPARs were expressed at normal levels in synapses, indicating subunit-selective impairment. Abnormal surface accumulation of GluA1 was independent of PKA activity and was limited to D1R SPNs. Since LRRK2 mutation is thought to be part of a common PD pathogenic pathway, our data suggest that sustained, striatal cell-type specific changes in AMPAR composition and trafficking contribute to cognitive or other impairments associated with PD.SIGNIFICANCE STATEMENTMutations in LRRK2 are common genetic risks for PD.Lrrk2G2019Smice fail to exhibit long-term potentiation at corticostriatal synapses and show significant deficits in frontal-striatal based cognitive tasks. While LRRK2 has been implicated generally in protein trafficking, whether G2019S derails AMPAR trafficking at synapses on striatal neurons (SPNs) is unknown. We show that surface GluA1-AMPARs fail to internalize and instead accumulate excessively within and outside synapses. This effect is selective to D1R SPNs and negatively impacts synapse strengthening as GluA1-AMPARs fail to increase at the surface in response to potentiation and show limited surface mobility. Thus, LRRK2-G2019S narrows the effective range of plasticity mechanisms, supporting the idea that cognitive symptoms reflect an imbalance in AMPAR trafficking mechanisms within cell-type specific projections.
Patterns of presence-absence variation of NLRs across populations ofSolanum chilenseare clade-dependent and mainly shaped by past demographic history
Authors: Silva-Arias Gustavo A. , Gagnon Edeline , Hembrom Surya , Fastner Alexander , Khan Muhammad Ramzan , Stam Remco , Tellier Aurélien 
Published: October 2023

AbstractUnderstanding the evolution of pathogen resistance genes (nucleotide-binding site-leucine-rich repeats, also known as NLRs) within a species requires a comprehensive examination of factors that affect gene loss and gain. We present a new reference genome ofSolanum chilense, that leads to an increased number and more accurate annotation of NLRs. Next, using a target-capture approach, we quantify the presence-absence variation (PAV) of NLRlociacross 20 populations from different habitats. We build a rigorous pipeline to validate the identification of PAV of NLRs, then show that PAV is larger within populations than between populations, suggesting that maintenance of NLR diversity is linked to population dynamics. Furthermore, the amount of PAV is not correlated with the NLR presence in gene clusters in the genome, but rather with the past demographic history of the species, with loss of NLRs in diverging populations at the distribution edges and smaller population sizes. Finally, using a redundancy analysis, we find limited evidence of PAV being linked to environmental gradients. Our results contradict the classic assumptions of the important selective role of PAV for NLRs, and suggest that NLRs PAV is driven by random processes (and weak selection) in an outcrossing plant with high nucleotide diversity.
Large-scale causal discovery using interventional data sheds light on the regulatory network architecture of blood traits
Authors: Brown Brielin C. , Morris John A. , Lappalainen Tuuli , Knowles David A. 
Published: October 2023

AbstractInference of directed biological networks is an important but notoriously challenging problem. We introduceinversesparseregression (inspre), an approach to learning causal networks that leverages large-scale intervention-response data. Applied to 788 genes from the genome-wide perturb-seq dataset,insprehelps elucidate the network architecture of blood traits.
Deconstructing the Mapper algorithm to extract richer topological and temporal features from functional neuroimaging data
Authors: Haşegan Daniel , Geniesse Caleb , Chowdhury Samir , Saggar Manish 
Published: October 2023

AbstractCapturing and tracking large-scale brain activity dynamics holds the potential to deepen our understanding of cognition. Previously, tools from Topological Data Analysis, especially Mapper, have been successfully used to mine brain activity dynamics at the highest spatiotemporal resolutions. Even though it is a relatively established tool within the field of Topological Data Analysis, Mapper results are highly impacted by parameter selection. Given that non-invasive human neuroimaging data (e.g., from fMRI) is typically fraught with artifacts and no gold standards exist regarding “true” state transitions, we argue for a thorough examination of Mapper parameter choices to better reveal their impact. Using synthetic data (with known transition structure) and real fMRI data, we explore a variety of parameter choices for each Mapper step, thereby providing guidance and heuristics for the field. We also release our parameter-exploration toolbox as a software package to make it easier for scientists to investigate and apply Mapper on any dataset.
Medicago truncatulaSOBIR1 controls specificity in the Rhizobium-legume symbiosis
Authors: Sarrette Baptiste , Luu Thi-Bich , Johansson Alexander , Fliegmann Judith , Pouzet Cécile , Le Ru Aurélie , Pichereaux Carole , Remblière Céline , Sauviac Laurent , Carles Noémie , Amblard Emilie , Guyot Valentin , Bonhomme Maxime , Cullimore Julie , Gough Clare , Jacquet Christophe , Pauly Nicolas 
Published: October 2023

SummaryMedicago truncatulaNod Factor Perception (MtNFP) is a lysin-domain Receptor-Like Kinase (LysM-RLK) that plays a key role in the Rhizobium-legume symbiosis, and is involved in plant immunity. MtNFP also has an inactive kinase domain, suggesting that the protein is involved in different receptor complexes. Using the MtNFP pseudo-kinase domain as a bait in a Yeast two Hybrid screen, we identifiedM. truncatulaSUPPRESSOR OF BIR1 (MtSOBIR1) as a new interactor of MtNFP. We showed that an interaction between the two RLKs can occurin plantaand that the kinase domain of MtSOBIR1 is active and can transphosphorylate the pseudo-kinase domain of MtNFP. Like in other plants, our data suggest a positive role of MtSOBIR1 in immunity;MtSOBIR1could functionally complement anAtsobir1mutant for defence activation, and aMtsobir1mutant was defective in pathogen-induced defence gene expression. We also showed thatMtSOBIR1has a symbiotic role withMtsobir1mutants showing a strong symbiotic phenotype in a plant genotype- and rhizobial strain-specific manner. The symbiotic role was apparent both at an early stage of rhizobial infection and in nodules. Together, these data suggest that, like MtNFP, MtSOBIR1 has a dual role, and can control immunity in both pathogenic and beneficial situations, with positive or negative roles, respectively.
The rotavirus VP5*/VP8* conformational transition permeabilizes membranes to Ca2+
Authors: De Sautu Marilina , Herrmann Tobias , Jenni Simon , Harrison Stephen C. 
Published: October 2023

ABSTRACTRotaviruses infect cells by delivering into the cytosol a transcriptionally active inner capsid particle (a "double-layer particle": DLP). Delivery is the function of a third, outer layer, which drives uptake from the cell surface into small vesicles from which the DLPs escape. In published work, we followed stages of rhesus rotavirus (RRV) entry by live-cell imaging and correlated them with structures from cryogenic electron microscopy and tomography (cryo-EM and cryo-ET). The virus appears to wrap itself in membrane, leading to complete engulfment and loss of Ca2+from the vesicle produced by the wrapping. One of the outer-layer proteins, VP7, is a Ca2+-stabilized trimer; loss of Ca2+releases both outer-layer proteins from the particle. The other outer-layer protein, VP4, activated by cleavage into VP8* and VP5*, is a trimer that undergoes a large-scale conformational rearrangement, reminiscent of the transition that viral fusion proteins undergo to penetrate a membrane. The rearrangement of VP5* thrusts a 250-residue, C-terminal segment of each of the three subunits outward, while allowing the protein to remain attached to the virus particle and to the cell being infected. We proposed that this segment inserts into the membrane of the target cell, enabling Ca2+to cross. In the work reported here, we show the validity of key aspects of this proposed sequence. By cryo-EM studies of liposome-attached virions ("triple-layer particles": TLPs) and single-particle fluorescence imaging of liposome-attached TLPs, we confirm insertion of the VP4 C-terminal segment into the membrane and ensuing generation of a Ca2+"leak". The results allow us to formulate a molecular description of early events in entry. We also discuss our observations in the context of other work on double-strand RNA virus entry.