bluuebunny/crossref_metadata_2025_split huggingface dataset:
The evolution of fitness during range expansions in different dimensions
Authors: Yurii Kotsar , Matsuoka Hikaru , Tamiya Gen 
Published: December 2023

ABSTRACTWe develop a set of programs – the range expansions simulation kit (RESK) – to efficiently simulate range expansions of populations on a square lattice in 1D, 2D (on a strip, and on a disk) and 3D (in a cylinder, and in a sphere). In this study, we present the simulation kit to the public and present some results of using it to simulate a population of diploid individuals with finite genome regions, each containing infinite sites. Specifically, using the programs, we calculate and analyse the temporal evolution of population fitness, as well as fitness on the expansion front, in 3D for the first time. We explore the model over different conditions, compare normalisation methods for fitness, and explore the case of radial (sphere) and axial (cylinder) expansions in 3D, which might apply in the analysis of the different real-life populations, such as viruses/bacteria inside a host, marine species in ocean environments, and potentially in future space colonization planning. In 3D expansions, we find complex spatial fluctuations in deme-average fitness values, different from those in radial 2D expansions. In axial 3D (cylinder) expansions, we determine that the highest-valued deme-average fitness lies along the axis of the expansion. We also find the fluctuation patterns of fitness in 3D cylinder expansions, similar to those previously seen in radial expansions in 2D. In radial 2D (disk) expansions, we find that the fitness of a population undergoing multiple mutations shows a smooth combination of binary segregation pictures against each of those mutations. We confirm the accumulation of deleterious mutations -- a phenomenon known as expansion load -- in all scenarios above. We present the software used in the above to the public as a Julia repository, ready to use with different functions for simulating range expansions with minimal syntax.
The mutational landscape ofBacillus subtilisconditional hypermutators shows how proofreading skews DNA polymerase error rates
Authors: Tanneur Ira , Dervyn Etienne , Guérin Cyprien , Kam King Guillaume Kon , Jules Matthieu , Nicolas Pierre 
Published: December 2023

AbstractPolymerase errors during DNA replication are a major source of point mutations in genomes. The resulting rate of spontaneous mutation also depends on the counteracting activity of DNA repair mechanisms, with mutator phenotypes appearing constantly and allowing for periods of rapid evolution in nature and in the laboratory. Here, we use the Gram-positive model bacteriumBacillus subtilisto disentangle the contributions of DNA polymerase initial nucleotide selectivity, DNA polymerase proofreading, and mismatch repair (MMR) to the mutation rate. To achieve this, we constructed several conditional hypermutators with a proofreading-deficient allele ofpolCand/or a deficient allele ofmutLand performed mutation accumulation experiments. With their wide range of mutation rates and contrasting mutation profiles, these conditional hypermutators enrich theB. subtilissynthetic biology toolbox for directed evolution. Using mathematical models, we investigated how to interpret the apparent probabilities with which errors escape MMR and proofreading, highlighting the difficulties of working with counts that aggregate potentially heterogeneous mutations and with unknowns about the pathways leading to mutations in the wild-type. Aware of these difficulties, the analysis shows that proofreading prevents partial saturation of the MMR inB. subtilisand that an inherent drawback of proofreading is to skew the net polymerase error rates by amplifying intrinsic biases in nucleotide selectivity.
The ribosomal protein L22 binds theMDM4pre-mRNA and promotes exon skipping to activate p53 upon nucleolar stress
Authors: Jansen Jennifer , Bohnsack Katherine E. , Böhlken-Fascher Susanne , Bohnsack Markus T. , Dobbelstein Matthias 
Published: December 2023

ABSTRACTThe tumor suppressor p53, along with its antagonists MDM2 and MDM4, represents a central integrator of stress signaling. While DNA damage is the most widely explored trigger of a p53 response, stress arising from dysbalanced assembly of ribosomes in nucleoli is also linked to p53 induction. Deletions of the gene encoding the ribosomal protein L22 (RPL22; eL22) correlate with the presence of full-lengthMDM4mRNA in human cancer, but the mechanistic basis for this phenomenon was hitherto unknown. Here we show that L22, under conditions of ribosomal and nucleolar stress, promotes the skipping of exon 6 within theMDM4pre-mRNA. Upon L22 depletion, more full-length MDM4 is maintained, independent of treatment with nucleolar stressors, leading to diminished p53 activity and enhanced cellular proliferation. Mechanistically, L22 binds to specific RNA elements within intron 6 ofMDM4that correspond to a stem-loop consensus, leading to the skipping of exon 6. This intronic RNA overlaps with the region responsible for splice regulation by ZMAT3. Targeted deletion of these intronic elements largely abolishes L22-mediated exon skipping and re-enables cell proliferation, despite nucleolar stressors such as 5-fluorouracil. L22 also governs alternative splicing of theL22L1(RPL22L1) andUBAP2LmRNAs. Thus, L22 serves as a signaling intermediate that integrates different layers of gene expression. Defects in ribosome synthesis lead to specific alternative splicing, ultimately triggering p53-mediated transcription and arresting cell proliferation.
Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition
Authors: Satouh Yuhkoh , Tatebe Takaki , Tanida Isei , Yamaguchi Junji , Uchiyama Yasuo , Sato Ken 
Published: December 2023

AbstractMouse oocytes undergo drastic changes in organellar composition and their activities during maturation from the germinal vesicle (GV) to meiosis II (MII) stage. After fertilization, the embryo degrades parts of the maternal components via lysosomal degradation systems, including autophagy and endocytosis, as zygotic gene expression begins during embryogenesis. Here, we demonstrate that endosomal-lysosomal organelles form large spherical assembly structures, termed ELYSAs, in mouse oocytes. ELYSAs are observed in GV oocytes, attaining sizes up to 7–8 μm in diameter in MII oocytes. ELYSAs comprise tubular-vesicular structures containing endosomes and lysosomes along with cytosolic components. Most ELYSAs are also positive for an autophagy regulator, LC3. These characteristics of ELYSA resemble those of ELVA (endolysosomal vesicular assemblies) identified independently. The signals of V1-subunit of vacuolar ATPase tends to be detected on the periphery of ELYSAs in MII oocytes. After fertilization, the localization of the V1-subunit on endosomes and lysosomes increase as ELYSAs gradually disassemble at the 2-cell stage, leading to further acidification of endosomal-lysosomal organelles. These findings suggest that the ELYSA/ELVA maintain endosomal-lysosomal activity in a static state in oocytes for timely activation during early development.Summary blurbThis study describes endosomal-lysosomal organellar assembly structures in mammalian oocytes, elucidating statistical alterations in their size, distribution, and correlation with lysosomal maturation.
Objective sleep quality predicts subjective sleep ratings: a multiday observational study
Authors: Pierson-Bartel Róbert , Ujma Péter Przemyslaw 
Published: December 2023

AbstractIn both clinical and observational studies, sleep quality is usually assessed by subjective self-report. The literature is mixed about how accurately these self-reports track objectively (e.g. via polysomnography) assessed sleep quality, with frequent reports of a very low or no association. However, previous research on this question focused on between-subject designs, which may be confounded by trait-level variables. In the current study, we used the novel Budapest Sleep, Experiences and Traits Study (BSETS) dataset to investigate if within-subject differences in subjectively reported sleep quality are related to sleep macrostructure and quantitative EEG variables assessed using a mobile EEG headband. We found clear evidence that within-subject variations in sleep onset latency, wake after sleep onset, total sleep time, and sleep efficiency affect self-reported sleep quality in the morning. These effects were replicated if detailed sleep composition metrics (percentage and latency of specific vigilance states) or two alternative measures of subjective sleep quality are used instead. We found no effect of the number of awakenings or relative EEG delta and sigma power. Between-subject effects (relationships between individual mean values of sleep metrics and subjective sleep quality) were also found, highlighting that analyses focusing only on these may be erroneous. Our findings show that while previous investigations of this issue may have been confounded by between-subject effects, objective sleep quality is indeed reflected in subjective sleep ratings.
Functionally linked amygdala and prefrontal cortical regions are innervated by both single and double projecting cholinergic neurons
Authors: Barabás Bence , Reéb Zsófia , Papp Orsolya I. , Hájos Norbert 
Published: December 2023

AbstractCholinergic cells have been proposed to innervate simultaneously those cortical areas that are mutually interconnected with each other. To test this hypothesis, we investigated the cholinergic innervation of functionally linked amygdala and prefrontal cortical regions. First, using tracing experiments, we determined that cholinergic cells located in distinct basal forebrain (BF) areas projected to the different nuclei of the basolateral amygdala (BLA). Specifically, cholinergic cells in the ventral pallidum/substantia innominata (VP/SI) innervated the basal nucleus (BA), while the horizontal limb of the diagonal band of Broca (HDB) projected to its basomedial nucleus (BMA). In addition, cholinergic neurons in these two BF areas gave rise to overlapping innervation in the medial prefrontal cortex (mPFC), yet their axons segregated in the dorsal and ventral regions of the PFC. Using retrograde-anterograde viral tracing, we demonstrated that a portion of mPFC-projecting cholinergic neurons also innervated the BLA, especially the BA. By injecting retrograde tracers into the mPFC and BA, we found that 28% of retrogradely labeled cholinergic cells were double labeled, which typically located in the VP/SI. In addition, we found that vesicular glutamate transporter type 3 (VGLUT3)-expressing neurons within the VP/SI were also cholinergic and projected to the mPFC and BA, implicating that a part of the cholinergic afferents may release glutamate. In contrast, we uncovered that GABA is unlikely to be a co-transmitter molecule in HDB and VP/SI cholinergic neurons in adult mice. The dual innervation strategy, i.e., the existence of cholinergic cell populations with single as well as simultaneous projections to the BLA and mPFC, provides the possibility for both synchronous and independent control of the operation in these cortical areas, a structural arrangement that may maximize computational support for functionally linked regions. The presence of VGLUT3 in a portion of cholinergic afferents suggests more complex functional effects of cholinergic system in cortical structures.
Investigating genomic prediction strategies for grain carotenoid traits in a tropical/subtropical maize panel
Authors: LaPorte Mary-Francis , Suwarno Willy B. , Hannok Pattama , Koide Akiyoshi , Bradbury Peter , Crossa José , Palacios-Rojas Natalia , Diepenbrock Christine Helen 
Published: December 2023

AbstractVitamin A deficiency remains prevalent on a global scale, including in regions where maize constitutes a high percentage of human diets. One solution for alleviating this deficiency has been to increase grain concentrations of provitamin A carotenoids in maize (Zea maysssp.maysL.)—an example of biofortification. The International Maize and Wheat Improvement Center (CIMMYT) developed a Carotenoid Association Mapping panel of 380 inbred lines adapted to tropical and subtropical environments that have varying grain concentrations of provitamin A and other health-beneficial carotenoids. This project assesses the accuracy of several genomic prediction (GP) strategies for these traits (β-carotene, β-cryptoxanthin, provitamin A, lutein, and zeaxanthin) within and between four environments in Mexico. Methods employing Ridge Regression-Best Linear Unbiased Prediction, Elastic Net, or Reproducing Kernel Hilbert Spaces had high accuracy in predicting all tested provitamin A carotenoid traits and outperformed Least Absolute Shrinkage and Selection Operator. Furthermore, prediction accuracies were higher when using genome-wide markers rather than only the markers proximal to two previously identified carotenoid-related genes that have been used in marker-assisted selection, suggesting that GP is worthwhile for these traits, even though key genes have already been identified. Prediction accuracy was maintained for all traits (except lutein) in between-environment prediction. The TASSEL (Trait Analysis by aSSociation, Evolution, and Linkage) Genomic Selection plugin performed as well as other more computationally intensive methods for within-environment prediction. The findings observed herein indicate the utility of GP methods for these traits and could inform their resource-efficient implementation in biofortification breeding programs.
Drug promiscuity: problems and promises
Authors: VanDongen Antonius M. 
Published: December 2023

ABSTRACTTherapeutic drugs exert their effect by binding to a specific target protein (receptor) and altering its activity. However, all drugs have undesirable side effects, which likely result from the drug binding to other protein targets. Drug promiscuity refers to the ability of small molecule compounds to bind with high affinity to multiple proteins. This drug property is responsible for the problems caused by their side effects. But drug promiscuity also presents a promise: if a drug targets numerous proteins, each interaction may contribute to its therapeutic efficacy. The ability to target multiple genes is especially promising for medicines that treat systemic diseases, including neurological disorders and cancers, which result from gene network problems. Here, I will review both aspects of drug promiscuity and illustrate a potential strategy to move this forward using a computer modeling approach.
DORSSAA: Drug-target interactOmics Resource based on Stability/Solubility Alteration Assay
Authors: Zangene Ehsan , Gholizadeh Elham , Saei Amir Ata , Wilhelm Mathias , Jafari Mohieddin 
Published: December 2023

ABSTRACTAdvancements in high-throughput techniques such as Thermal Proteome Profiling (TPP) and the high-throughput Proteome Integral Solubility Alteration (PISA) assay have revolutionized our understanding of drug-protein interactions. Despite these innovations, the absence of an integrative platform for cross-study analysis of stability and solubility alteration data represents a significant bottleneck. To address this gap, we introduce DORSSAA (Drug-target interactOmics Resource based on Stability/Solubility Alteration Assay), an interactive and expandable web-based platform for the systematic analysis and visualization of proteome stability and solubility alteration assay datasets. Currently, DORSSAA features 480,456 records spanning 37 cell lines and organisms, 39 compounds, and 40,004 potential protein targets. Through its user-friendly interface, the resource supports comparative drug-protein interaction analysis and facilitates the discovery of actionable therapeutic targets. Using two case studies of the DHFR-methotrexate interaction and drug-target interaction in the case of combinatorial therapy in Leukemia cell lines, we demonstrate DORSSAA’s utility in identifying protein-drug interactions across experimental conditions. This resource empowers researchers to accelerate drug discovery and enhance our understanding of protein behavior.Abstract Figure
Protosequences in brain organoids model intrinsic brain states
Authors: van der Molen Tjitse , Spaeth Alex , Chini Mattia , Hernandez Sebastian , Kaurala Gregory A. , Schweiger Hunter E. , Duncan Cole , McKenna Sawyer , Geng Jinghui , Lim Max , Bartram Julian , Dendukuri Aditya , Zhang Zongren , Gonzalez-Ferrer Jesus , Bhaskaran-Nair Kiran , Blauvelt Lon J. , Harder Cole R.K. , Petzold Linda R. , Alam El Din Dowlette-Mary , Laird Jason , Schenke Maren , Smirnova Lena , Colquitt Bradley M. , Mostajo-Radji Mohammed A. , Hansma Paul K. , Teodorescu Mircea , Hierlemann Andreas , Hengen Keith B. , Hanganu-Opatz Ileana L. , Kosik Kenneth S. , Sharf Tal 
Published: December 2023

AbstractNeuronal firing sequences are thought to be the basic building blocks of neural coding and information broadcasting within the brain. However, when sequences emerge during neurodevelopment remains unknown. We demonstrate that structured firing sequences are present in spontaneous activity of human and murine brain organoids andex vivoneonatal brain slices from the murine somatosensory cortex. We observed a balance between temporally rigid and flexible firing patterns that are emergent phenomena in human and murine brain organoids and early postnatal murine somatosensory cortex, but not in primary dissociated cortical cultures. Our findings suggest that temporal sequences do not arise in an experience-dependent manner, but are rather constrained by an innate preconfigured architecture established during neurogenesis. These findings highlight the potential for brain organoids to further explore how exogenous inputs can be used to refine neuronal circuits and enable new studies into the genetic mechanisms that govern assembly of functional circuitry during early human brain development.
An Interpretable Model of pre-mRNA Splicing for Animal and Plant Genes
Authors: McCue Kayla , Burge Christopher B. 
Published: December 2023

AbstractPre-mRNA splicing is a fundamental step in gene expression, conserved across eukaryotes, in which the spliceosome recognizes motifs at the 3’ and 5’ splice sites (SS), excises introns and ligates exons. SS recognition and pairing is often influenced by splicing regulatory factors (SRFs) that bind to splicing regulatory elements (SREs). Several families of sequence-specific SRFs are known to be similarly ancient. Here, we describe SMsplice, a fully interpretable model of pre-mRNA splicing that combines new models of core SS motifs, SREs, and exonic and intronic length preferences. We learn models the predict SS locations with 83-86% accuracy in fish, insects and plants, and about 70% in mammals. Learned SRE motifs include both known SRF binding motifs as well as novel motifs, and both classes are supported by genetic analyses. Our comparisons across species highlight similarities between non-mammals and a greater reliance on SREs in mammalian splicing, and increased reliance on intronic SREs in plant splicing.
Hexafluoro slows retinal degeneration and improves visual function in zebrafish models of Usher syndrome 1F
Authors: Phillips Jennifer B. , Kulis Siena , Buchner Sara H. , Fox Eric J. , Wegner Jeremy , Peirce Judy , Ivanchenko Maryna V. , Corey David P. , Arbiser Jack L. , Westerfield Monte 
Published: December 2023

ABSTRACTUsher syndrome is the leading genetic cause of deafblindness, affecting hundreds of thousands of people worldwide. The deafness can be addressed with hearing aids or cochlear implants, but there is currently no treatment for the vision loss, which is due to progressive degeneration of retinal photoreceptors. Studies in animal models of Usher syndrome have shown that photoreceptor degeneration is exacerbated by exposure to bright light, and other studies have shown that light-induced photostress reduces mitochondrial function. We previously synthesized hexafluoro and showed that it is a potent Sirt3 activator that promotes mitochondrial respiration. Here we examined the efficacy of hexafluoro as a potential therapeutic for treatment of vison loss in a zebrafish model of Usher syndrome type 1F, which exhibits early and severe vision defects along with vestibular dysfunction as seen in Usher type 1 pathology. We find that hexafluoro improves visual function, reduces photoreceptor degeneration, and protects the retina against exposure to bright light in this USH1F model.
Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure
Authors: Pavelec Caitlin M. , Young Alexander P. , Luviano Hannah L. , Orrell Emily E. , Szagdaj Anna , Poudel Nabin , Wolpe Abigail G. , Thomas Samantha H. , Yeudall Scott , Upchurch Clint M. , Okusa Mark D. , Isakson Brant E. , Wolf Matthew J. , Leitinger Norbert 
Published: December 2023

AbstractPannexin 1 (PANX1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, a possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6). PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism bothin vivoandin vitro.In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knock-down of PANX1. To investigate non-ischemic heart failure and the preceding cardiac hypertrophy we administered isoproterenol, and we demonstrate that Panx1MyHC6mice were protected from systolic and diastolic left ventricle volume increases and cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+, Ly6g+), to the myocardium. Together these data demonstrate that PANX1 deficiency in cardiomyocytes impacts glycolytic metabolism and protects against cardiac hypertrophy in non-ischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.