bluuebunny/crossref_metadata_2025_split huggingface dataset:
Random,de novoand conserved proteins: How structure and disorder predictors perform differently
Authors: Middendorf Lasse , Eicholt Lars A. 
Published: July 2023

AbstractUnderstanding the emergence and structural characteristics ofde novoand random proteins is crucial for unraveling protein evolution and designing novel enzymes. However, experimental determination of their structures remains challenging. Recent advancements in protein structure prediction, particularly with AlphaFold2 (AF2), have expanded our knowledge of protein structures, but their applicability tode novoand random proteins is unclear. In this study, we investigate the structural predictions and confidence scores of AF2 and protein language model (pLM)-based predictor ESMFold forde novo, random, and conserved proteins. We find that the structural predictions forde novoand random proteins differ significantly from conserved proteins. Interestingly, a positive correlation between disorder and confidence scores (pLDDT) is observed forde novoand random proteins, in contrast to the negative correlation observed for conserved proteins. Furthermore, the performance of structure predictors forde novoand random proteins is hampered by the lack of sequence identity. We also observe varying predicted disorder among different sequence length quartiles for random proteins, suggesting an influence of sequence length on disorder predictions. In conclusion, while structure predictors provide initial insights into the structural composition ofde novoand random proteins, their accuracy and applicability to such proteins remain limited. Experimental determination of their structures is necessary for a comprehensive understanding. The positive correlation between disorder and pLDDT could imply a potential for conditional folding and transient binding interactions ofde novoand random proteins.
NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer
Authors: Li Jia J. , Vasciaveo Alessandro , Karagiannis Dimitrios , Sun Zhen , Chen Xiao , Socciarelli Fabio , Frankenstein Ziv , Zou Min , Pannellini Tania , Chen Yu , Gardner Kevin , Robinson Brian D. , de Bono Johann , Abate-Shen Cory , Rubin Mark A. , Loda Massimo , Sawyers Charles L. , Califano Andrea , Lu Chao , Shen Michael M. 
Published: July 2023

SummaryThe clinical use of potent androgen receptor (AR) inhibitors has promoted the emergence of novel subtypes of metastatic castration-resistant prostate cancer (mCRPC), including neuroendocrine prostate cancer (CRPC-NE), which is highly aggressive and lethal1. These mCRPC subtypes display increased lineage plasticity and often lack AR expression2–5. Here we show that neuroendocrine differentiation and castration-resistance in CRPC-NE are maintained by the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2)6, which catalyzes histone H3 lysine 36 dimethylation (H3K36me2). We find that organoid lines established from genetically-engineered mice7recapitulate key features of human CRPC-NE, and can display transdifferentiation to neuroendocrine states in culture. CRPC-NE organoids express elevated levels of NSD2 and H3K36me2 marks, but relatively low levels of H3K27me3, consistent with antagonism of EZH2 activity by H3K36me2. Human CRPC-NE but not primary NEPC tumors expresses high levels of NSD2, consistent with a key role for NSD2 in lineage plasticity, and high NSD2 expression in mCRPC correlates with poor survival outcomes. Notably, CRISPR/Cas9 targeting ofNSD2or expression of a dominant-negative oncohistone H3.3K36M mutant results in loss of neuroendocrine phenotypes and restores responsiveness to the AR inhibitor enzalutamide in mouse and human CRPC-NE organoids and grafts. Our findings indicate that NSD2 inhibition can reverse lineage plasticity and castration-resistance, and provide a potential new therapeutic target for CRPC-NE.
Resolving evolutionary relationships in the groundsels: phylogenomics, divergence time estimates, and biogeography ofPackera(Asteraceae: Senecioneae)
Authors: Moore-Pollard Erika R. , Mandel Jennifer R. 
Published: July 2023

AbstractThe genusPackerabelongs to the sunflower family and contains an estimated 64 species and varieties endemic to North America. SomePackeraare known to hybridize or exhibit polyploidy, making it difficult to reconstruct evolutionary relationships within the group. Previous molecular phylogenetic studies ofPackeraemploying ITS data recovered low resolution trees, providing little information on the evolutionary relationships within this complex genus. Therefore, we used next-generation sequencing data to infer nuclear and plastid phylogenies ofPackeraand related Senecioneae taxa. The nuclear phylogeny was calibrated to produce a timetree, then used to reconstruct the macroevolutionary history ofPackera,including its historical biogeography. We then compared the reconstructed evolutionary history to previously published scenarios based on phylogenetic and geohistorical data. We found that the nuclear and plastid phylogenies were highly incongruent, with the nuclear tree presenting higher resolution than the plastid tree which had an apparent lack of plastid diversity. The nuclear tree indicated that geography may have played a major role in the evolution and taxonomic diversification ofPackera. The estimated origin ofPackeraat approximately 19.2MY – 25.9MY (late Oligocene to early Miocene) is older than in most other studies. Nonetheless, it aligns well with previous geohistorical predictions, which suggest that speciation and diversification events inPackerawere driven by changes in geography and climate in North America. Moreover,Packeralikely originated in the western United States or Mexico, and subsequently diversified north and east into the rest of North America and Russia, in agreement with other studies.
Elucidation of the essentiality of lumazine synthase (RibH) forMycobacterium tuberculosissurvival and discovery of potent inhibitors for enhanced antimycobacterial therapy
Authors: Singh Monica , Dhanwal Anannya , Verma Arpita , Augustin Linus , Kumari Niti , Chakraborti Soumyananda , Agarwal Nisheeth , Sriram Dharmarajan , Dey Ruchi Jain 
Published: July 2023

AbstractTuberculosis (TB) continues to be a global health crisis, necessitating urgent interventions to address drug resistance and improve treatment efficacy. In this study, we validate the indispensable role of lumazine synthase (RibH), a vital enzyme in the riboflavin biosynthetic pathway, in the survival ofMycobacterium tuberculosis (M. tb)using a CRISPRi-based conditional gene knockdown strategy. We show that genetic and functional ablation of RibH inM. tbcannot be compensated by exogenous supply of Riboflavin, or co-factors Flavin Adenine Dinucleotide (FAD) or Flavin Mononucleotide (FMN). Capitalizing on the essentiality of RibH, we employ a high-throughput molecular docking approach to screen ∼600,000 compounds and identify inhibitors of RibH. Throughin vitroscreening of 55 shortlisted compounds, we discover 3 inhibitors that exhibit potent antimycobacterial activity. These compounds effectively also eradicate intracellularM. tbduring macrophage infection and prevent the resuscitation of the nutrient-starved persister bacteria. Moreover, these 3 compounds synergistically enhance the bactericidal effect of first-line anti-TB drugs, Isoniazid and Rifampicin. Corroborating with thein silicopredicted high docking scores along with favorable ADME and toxicity profiles, all 3 compounds demonstrate exceptional binding affinity towards purified lumazine synthase enzymein vitro, and display an acceptable safety profile in mammalian cells, with a high selective index. By providing mechanistic evidence for the essentiality of RibH inM. tbsurvival, and discovering potent RibH inhibitors with outstanding antimycobacterial activity, our study contributes to the development of superior TB treatment strategies and advances the global fight against this devastating disease.
Shared structure facilitates working memory of multiple sequences
Authors: Huang Qiaoli , Luo Huan 
Published: July 2023

AbstractDaily experiences often involve the processing of multiple sequences, yet storing them challenges the limited capacity of working memory (WM). To achieve efficient memory storage, relational structures shared by sequences would be leveraged to reorganize and compress information. Here, participants memorized a sequence of items with different colors and spatial locations and later reproduced the full color and location sequences one after another. Crucially, we manipulated the consistency between location and color sequence trajectories. First, sequences with consistent trajectories demonstrate improved memory performance and a trajectory correlation between reproduced color and location sequences. Second, sequences with consistent trajectories show neural reactivation of common trajectories, and display spontaneous replay of color sequences when recalling locations. Finally, neural reactivation correlates with WM behavior. Our findings suggest that shared common structure is leveraged for storage of multiple sequences through compressed encoding and neural replay, together facilitating efficient information organization in WM.
An allele-sharing, moment-based estimator of global, population specific and population pairsFSTunder a general model of population structure
Authors: Goudet Jérôme , Weir Bruce S. 
Published: July 2023

AbstractBeing able to properly quantify genetic differentiation is key to understanding the evolutionary potential of a species. One central parameter in this context isFST, the mean coancestry within populations relative to the mean coancestry between populations. Researchers have been estimatingFSTglobally or between pairs of populations for a long time. More recently, it has been proposed to estimate population specificFSTvalues, and between population-pair mean relative coancestry. Here, we review the several definitions and estimation methods ofFST, and stress that they provide values relative to a reference population. We show the good statistical properties of an allele sharing, method of moments based estimator ofFST(global, population specific and population pairs) under a very general model of population structure. We point to the limitation of existing likelihood and Bayesian estimators when the populations are not independent. Last, we show that recent attempts to estimate absolute, rather than relative, mean coancestry fail to do so.Author summary
Using random forests to uncover the predictive power of distance–varying cell interactions in tumor microenvironments
Authors: VanderDoes Jeremy , Marceaux Claire , Yokote Kenta , Asselin-Labat Marie-Liesse , Rice Gregory , Hywood Jack D. 
Published: July 2023

AbstractTumor microenvironments (TMEs) contain vast amounts of information on patient’s cancer through their cellular composition and the spatial distribution of tumor cells and immune cell populations. Exploring variations in TMEs among patients and cancer types, as well as determining the extent to which this information can predict variables such as patient survival or treatment success with emerging immunotherapies, is of great interest. Moreover, in the face of a large number of potential spatial cell interactions to consider, we often wish to identify specific interactions that are useful in making such predictions. We present an approach to achieve these goals based on summarizing spatial relationships in the TME using spatialKfunctions, and then applying functional data analysis and random forest models to both predict outcomes of interest and identify important spatial relationships. This approach is shown to be effective in simulation experiments. We further used the proposed approach to interrogate two real data sets of Multiplexed Ion Beam Images of TMEs in triple negative breast cancer and lung cancer patients. The methods proposed are publicly available in a companionRpackagefunkycells.Author summarySpatial data on the tumor microenvironment (TME) are becoming more prevalent. Existing methods to interrogate such data often have several deficiencies: (1) they rely on estimating the spatial relationships among cells by examining simple counts of cells within asingleradius, (2) they do not come with ways to evaluate the statistical significance of any findings, or (3) they consider multiple individual interactions resulting in overly optimistic estimates of interaction importances. Our approach, which leverages techniques in spatial statistics and uses a benchmark ensemble machine learning method addresses (1), since theKfunctions used encode the relative densities of cells over all radii up to a user-selected maximum radius, and (2) we have developed a custom approach based on permutation and cross-validation to evaluate the statistical significance of any findings of significant spatial interactions in the TME, (3) over potentially multiple interactions. Our approach is also freely available with anRimplementation calledfunkycells. In the analysis of two real data sets, we have seen that the method performs well, and gives the expected results. We think this will be a robust tool to add to the toolbox for researchers looking to interrogate, what can be sometimes unwieldy, TME data.
Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions
Authors: Yu Chen , Lad Eleonora M , Mathew Rose , Littleton Sejiro , Chen Yun , Schlepckow Kai , Degan Simone , Chew Lindsey , Amason Joshua , Kalnitsky Joan , Rickman Catherine Bowes , Proia Alan D , Colonna Marco , Haass Christian , Saban Daniel R 
Published: July 2023

AbstractDegenerative diseases of the outer retina, including age-related macular degeneration (AMD), are characterized by atrophy of photoreceptors and retinal pigment epithelium (RPE). In these blinding diseases, macrophages are known to accumulate ectopically at sites of atrophy, but their ontogeny and functional specialization within this atrophic niche remain poorly understood, especially in the human context. Here, we uncovered a transcriptionally unique profile of microglia, marked by galectin-3 upregulation, at atrophic sites in mouse models of retinal degeneration and in human AMD. Using disease models, we found that conditional deletion of galectin-3 in microglia led to defects in phagocytosis and consequent augmented photoreceptor death, RPE damage and vision loss, suggestive of a protective role.Mechanistically, Trem2 signaling orchestrated the migration of microglial cells to sites of atrophy, and there, induced galectin-3 expression. Moreover, pharmacologic Trem2 agonization led to heightened protection, but only in a galectin-3-dependent manner, further signifying the functional interdependence of these two molecules. Likewise in elderly human subjects, we identified a highly conserved population of microglia at the transcriptomic, protein and spatial levels, and this population was enriched in the macular region of postmortem AMD subjects. Collectively, our findings reveal an atrophy-associated specialization of microglia that restricts the progression of retinal degeneration in mice and further suggest that these protective microglia are conserved in AMD.One Sentence SummaryA common neuroprotective response of microglia at the site of retinal atrophy is identified in mice and humans.
Scalable and efficient DNA sequencing analysis on different compute infrastructures aiding variant discovery
Authors: Hanssen Friederike , Garcia Maxime U. , Folkersen Lasse , Pedersen Anders Sune , Lescai Francesco , Jodoin Susanne , Miller Edmund , Seybold Matthias , Wacker Oskar , Smith Nicholas ,   nf-core community, Gabernet Gisela , Nahnsen Sven 
Published: July 2023

AbstractDNA variation analysis has become indispensable in many aspects of modern biomedicine, most prominently in the comparison of normal and tumor samples. Thousands of samples are collected in local sequencing efforts and public databases requiring highly scalable, portable, and automated workflows for streamlined processing. Here, we present nf-core/sarek 3, a well-established, comprehensive variant calling and annotation pipeline for germline and somatic samples. It is suitable for any genome with a known reference. We present a full rewrite of the original pipeline showing a significant reduction of storage requirements by using the CRAM format and runtime by increasing intra-sample parallelization. Both are leading to a 70% cost reduction in commercial clouds enabling users to do large-scale and cross-platform data analysis while keeping costs and CO2emissions low. The code is available athttps://nf-co.re/sarek.
Genomic analyses capture the human-induced demographic collapse and recovery in a wide-ranging cervid
Authors: Kessler Camille , Shafer Aaron B.A. 
Published: July 2023

AbstractThe glacial cycles of the Quaternary heavily impacted species through successions of population contractions and expansions. Similarly, populations have been intensely shaped by human pressures such as unregulated hunting and land use changes. White-tailed and mule deer survived in different refugia through the Last Glacial Maximum, and their populations were severely reduced after the European colonisation. Here, we analysed 73 re-sequenced deer genomes from across their North American range to understand the consequences of climatic and anthropogenic pressures on deer demographic and adaptive history. We found a strong signal of glacial-induced vicariance and demographic decline; notably, there is a severe decline in white-tailed deer effective population size (Ne) at the end of the Last Glacial Maximum. We found robust evidence for colonial overharvest in the form of a recent and dramatic drop in Nein all analysed populations. Historical census size and restocking data show a clear parallel to historical Neestimates, and temporal Ne/Ncratio shows patterns of conservation concern for mule deer. Signatures of selection highlight genes related to temperature, including a cold receptor previously highlighted in woolly mammoth. We also detected immune-genes that we surmise reflect the changing land-use patterns in North America. Our study provides a detailed picture of anthropogenic and climatic-induced decline in deer diversity, and clues to understanding the conservation concerns of mule deer and the successful demographic recovery of white-tailed deer.
Adaptive evolution ofP. aeruginosain human airways shows phenotypic convergence despite diverse patterns of genomic changes
Authors: Espaillat Akbar , Colque Claudia Antonella , Rago Daniela , La Rosa Ruggero , Molin Søren , Johansen Helle Krogh 
Published: July 2023

AbstractSelective forces in the environment drive bacterial adaptation to novel niches, choosing the fitter variants in the population. However, in dynamic and changing environments, the evolutionary processes controlling bacterial adaptation are difficult to monitor. Here, we follow 9 cystic fibrosis patients chronically infected withPseudomonas aeruginosa, as a proxy for bacterial adaptation. We identify and describe the bacterial changes and evolution occurring between 15 and 35 years of within host evolution. We combine whole genome sequencing, RNAseq and metabolomics, and compare the evolutionary trajectories directed by the adaptation of four differentP. aeruginosalineages to the lung. Our data suggest divergent evolution at the genomic level for most of the genes, with signs of convergent evolution with respect to acquisition of mutations in regulatory genes, which drive the transcriptional and metabolomic program at late time of evolution. Metabolomics further confirmed convergent adaptive phenotypic evolution as documented by reduction of the quorum sensing molecules acyl-homoserine lactone, phenazines and rhamnolipids (except for quinolones). The modulation of the quorum sensing repertoire suggests that similar selective forces characterize at late times of evolution independent of the patient. Collectively, our data suggest that similar environments and similarP. aeruginosapopulations in the patients at prolonged time of infection are associated with an overall reduction of virulence-associated features and phenotypic convergence.SummarySelective forces in the human environment drive bacterial adaptation to novel niches, choosing the fitter variants in the population. We have investigated the evolutionary processes in 9 CF patients infected withPseudomonas aeruginosain the airways for several decades. To describe the within host evolution and trajectories of four differentP. aeruginosalineages to the lung environment we have combined whole genome sequencing, RNAseq and metabolomics. In this patient cohorte with persistent bacterial infections our data suggest that similar environments and similarP. aeruginosapopulations in the patients at prolonged time of infection are associated with an overall reduction of virulence-associated features and phenotypic convergence
Separation of evolutionary timescales in coevolving species
Authors: Buckingham Lydia J. , Ashby Ben 
Published: July 2023

AbstractMany coevolutionary processes, including host-parasite and host-symbiont interactions, involve one species or trait which evolves much faster than the other. Whether or not a coevolutionary trajectory converges depends on the relative rates of evolutionary change in the two species, and so current adaptive dynamics approaches generally either determine convergence stability by considering arbitrary (often comparable) rates of evolutionary change or else rely on necessary or sufficient conditions for convergence stability. We propose a method for determining convergence stability in the case where one species is expected to evolve much faster than the other. This requires a second separation of timescales, which assumes that the faster evolving species will reach its evolutionary equilibrium (if one exists) before a new mutation arises in the more slowly evolving species. This method, which is likely to be a reasonable approximation for many coevolving species, both provides straightforward conditions for convergence stability and is less computationally expensive than traditional analysis of coevolution models, as it reduces the trait space from a two-dimensional plane to a one-dimensional manifold. In this paper, we present the theory underlying this new separation of timescales and provide examples of how it could be used to determine coevolutionary outcomes from models.
Exploratory rearing is governed by hypothalamic MCH cells according to the locus coeruleus
Authors: Concetti Cristina , Viskaitis Paulius , Grujic Nikola , Duss Sian N. , Privitera Mattia , Bohacek Johannes , Peleg-Raibstein Daria , Burdakov Denis 
Published: July 2023

ABSTRACTExploration is essential for survival because it allows animals to gather information about their environment. Rearing is a classic exploratory behavior, during which an animal transiently stands on its hind legs to sample its environment. It is widely observed in common lab conditions as well as in the wild, yet neural signals and circuits underlying this fundamental component of innate behavior remain unclear. We examined behavioral correlates of activity in hypothalamic MCH-producing neurons (MNs) – a recently characterized but still poorly understood neural type – and found that MN activation co-occurs with exploratory rears in mice. Complementary optogenetic and pharmacological manipulations indicated that MN activity selectively promotes rearing via G-protein coupled MCHR1 receptors. Furthermore, we showin vivothat activation of the locus coeruleus noradrenergic neurons rapidly inhibits MNs and suppresses rearing through MCHR1-dependent pathways. Overall, these findings define a subcortical neural module which both tracks and controls exploratory rearing.