bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural substrates of parallel devaluation-sensitive and devaluation-insensitive Pavlovian learning in humans
Authors: Pool Eva R. , Pauli Wolfgang M. , Cross Logan , O’Doherty John P. 
Published: January 2023

AbstractPavlovian learning depends on multiple and parallel associations leading to distinct classes of conditioned responses that vary in their flexibility following changes in the value of an associated outcome. Here, we aimed to differentiate brain areas involved in learning and encoding associations that are sensitive to changes in the value of an outcome from those that are not sensitive to such changes. To address this question, we combined a Pavlovian learning task with outcome devaluation, eye–tracking and functional magnetic resonance imaging. We used computational modeling to identify brain regions involved in learning stimulus-reward associations and stimulus–stimulus associations, by testing for brain areas correlating with reward–prediction errors and state-prediction errors, respectively. We found that, contrary to theoretical predictions about reward prediction errors being exclusively model–free, voxels correlating with reward prediction errors in the ventral striatum and subgenual anterior cingulate cortex were sensitive to devaluation. On the other hand, brain areas correlating with state prediction errors were found to be devaluation insensitive. In a supplementary analysis, we distinguished brain regions encoding predictions about outcome taste identity from those involved in encoding predictions about its expected spatial location. A subset of regions involved in taste identity predictions were devaluation sensitive while those involved in encoding predictions about spatial location were devaluation insensitive. These findings provide insights into the role of multiple associative mechanisms in the brain in mediating Pavlovian conditioned behavior – illustrating how distinct neural pathways can in parallel produce both devaluation sensitive and devaluation insensitive behaviors.
Excitation energy transfer between higher excited states of photosynthetic pigments: 2. Chlorophyllbis a B band energy trap
Authors: Götze Jan P. , Lokstein Heiko 
Published: January 2023

AbstractChlorophylls (Chls) are known for fast, sub-picosecond internal conversion (IC) from ultraviolet/blue absorbing (“B” or “Soret” states) to the energetically lower, red light-absorbing Q states. Consequently, excitation energy transfer (EET) in photosynthetic pigment-protein complexes involving the B states has so far not been considered. We present, for the first time, a theoretical framework for the existence of B-B EET in tightly coupled Chl aggregates, such as photosynthetic pigment-protein complexes. We show that according to a simple Förster resonance energy transport (FRET) scheme, unmodulated B-B EET likely poses an existential threat, in particular the photochemical reaction centers (RCs). This insight leads to so-far undescribed roles for carotenoids (Crts, cf. previous article in this series) and Chlb(this article) of possibly primary importance.It is demonstrated how pigments in a photosynthetic antenna pigment-protein complex (CP29) undergo FRET. Here, the focus is on the role of Chlbfor EET in the Q and B bands. Further, the initial excited pigment distribution in the B band is computed for relevant solar irradiation and wavelength-centered laser pulses. It is found that both accessory pigment classes compete efficiently with Chlaabsorption in the B band, leaving only 40% of B band excitations for Chla. B state population is preferentially relocated to Chlbafter excitation of any Chls, due to a near-perfect match of ChlbB band absorption with ChlaB state emission spectra. This results in an efficient depletion of the Chlapopulation (0.66 per IC/EET step, as compared to 0.21 in a Chla-only system). Since Chlbonly occurs in the peripheral antenna complexes, and RCs contain only Chla, this would automatically trap potentially dangerous B state population distantly from the RCs.
Genetic diversity of the eastern black rhinoceros (Diceros bicornis michaeli) in Tanzania; implications for future conservation
Authors: Mellya Ronald. V. K. , Hopcraft J. Grant C. , Eblate Ernest M. , Otiende Moses , Chuma Idrissa S. , Macha Emmanuel S. , Wambura Dickson , Kilbride Elizabeth , Mable Barbara K. 
Published: January 2023

AbstractIn the past decade, there has been a drastic decline in the number of Eastern Black rhinoceros (black rhinoceros) (Diceros bicornis michaeli), primarily because of poaching across their natural habitats, leaving few individuals in small, isolated populations that are vulnerable to demographic extinction, disease epidemics, genetic drift and inbreeding. However, genetic consequences of the demographic decline on the remaining populations have not been investigated. Using the mitochondrial control region, this study investigated how current levels of genetic diversity relate to historical patterns, quantified genetic differentiation between extant populations and assessed the impacts of previous translocations on genetic diversity across populations. A total of 74 individual eastern black rhinoceroses were sampled from five extant populations in Tanzania and one neighbouring cross-border population in the Maasai Mara in Kenya. Six maternal haplotypes were identified, with an overall haplotype diversity of h=0.7 but low overall nucleotide diversity within populations (π = 0.017) compared to historical populations from Tanzania (π = 0.021). There was extensive variation in haplotype distribution between populations, with more variation exists within (65.5 %) than among the populations (35.5%), which may indicate lack of migration between populations. Specifically, some geographically close populations with different histories of introductions didn’t share any haplotypes, suggesting that gene flow is currently restricted. The haplotypes were distributed among three east African haplogroups (CV, CE and EA) that have been described in previous studies, suggesting that multiple lineages have been preserved despite loss of haplotypes. One of the haplotypes was highly divergent and matched sequences previously classified as a subspecies that has not been recognised in recent years (D. b. ladoensis). We recommend that current levels of diversity be maintained by allowing natural movements of rhinoceroses between the populations, with the possibility of introducing additional variations by translocation of individuals between sites.
Population genomics of the mostly thelytokousDiplolepis rosae(Linnaeus, 1758) (Hymenoptera: Cynipidae) reveals population-specific selection for sex
Authors: Mozhaitseva Ksenia , Tourrain Zoé , Branca Antoine 
Published: January 2023

AbstractIn Hymenoptera, arrhenotokous parthenogenesis (arrhenotoky) is a common reproductive mode. Thelytokous parthenogenesis (thelytoky), when virgin females produce only females, is less common and is found in several taxa. In our study, we assessed the efficacy of recombination and the effect of thelytoky on the genome structure ofDiplolepis rosae, a gall wasp producing bedeguars in dog roses. We assembled a high-quality reference genome using Oxford Nanopore long-read technology and sequenced 17 samples collected in France with high-coverage Illumina reads. We found twoD.rosaeperipatric lineages that differed in the level of recombination and homozygosity. The firstD.rosaelineage showed a recombination rate that was 13.2 times higher and a per-individual heterozygosity that was 1.6 times higher. We inferred that genes under negative selection were enriched in functions related to male traits (‘sperm competition’, ‘insemination’, and ‘copulation’ gene ontology terms) in the more recombining lineage, while in the less recombining form, the same lineage genes showed traces pointing towards balancing or relaxed selection. Thus, althoughD.rosaereproduces mainly by thelytoky, selection may act to maintain sexual reproduction.SignificanceMany organisms can alternate between sexual and asexual reproduction in different ways. Sexual reproduction is essential to creating genetic diversity for adaptation to changing environments, whereas asexual reproduction is important in the short term and in stable environments. Using genomic data, we demonstrated the existence of two lineages in the rose bedeguar waspDiplolepis rosaepreviously shown to reproduce mainly by thelytokous parthenogenesis, giving almost only females. One of the lineages showed higher recombination, higher heterozygosity, and genes involved in male traits under negative selection. This could be linked to the expected advantages of maintaining sexual reproduction in natural populations.
Somatic mutation rates scale with time not growth rate in long-lived tropical trees
Authors: Satake Akiko , Imai Ryosuke , Fujino Takeshi , Tomimoto Sou , Ohta Kayoko , Na’iem Mohammad , Indrioko Sapto , Widiyatno  , Purnomo Susilo , Mollá–Morales Almudena , Nizhynska Viktoria , Tani Naoki , Suyama Yoshihisa , Sasaki Eriko , Kasahara Masahiro 
Published: January 2023

AbstractThe rates of appearance of new mutations play a central role in evolution. However, mutational processes in natural environments and their relationship with growth rates are largely unknown, particular in tropical ecosystems with high biodiversity. Here, we examined the somatic mutation landscapes of two tropical trees,Shorea laevis(slow-growing) andS. leprosula(fast-growing), in central Borneo, Indonesia. Using newly-constructed genomes, we identified a greater number of somatic mutations in tropical trees than in temperate trees. In both species, we observed a linear increase in the number of somatic mutations with physical distance between branches. However, we found that the rate of somatic mutation accumulation per meter of growth was 3.7-fold higher inS. laevisthan inS. leprosula. This difference in the somatic mutation rate was scaled with the slower growth rate ofS. laeviscompared toS. leprosula,resulting in a constant somatic mutation rate per year between the two species. We also found that somatic mutations are neutral within an individual, but those mutations transmitted to the next generation are subject to purifying selection. These findings suggest that somatic mutations accumulate with absolute time and older trees have a greater contribution towards generating genetic variation.Significance StatementThe significance of our study lies in the discovery of an absolute time-dependent accumulation of somatic mutations in long-lived tropical trees, independent of growth rate. Through a comparative analysis of somatic mutation landscapes in slow- and fast-growing species, we observed a clock-like accumulation of somatic mutations in both species, regardless of their growth rates. Although the majority of somatic mutations were restricted to a single branch, we also identified mutations present in multiple branches, likely transmitted during growth. Our findings suggest that older trees make a greater contribution towards generating genetic variation.
Environmental DNA Reveals Patterns of Biological Invasion in an Inland Sea
Authors: Duprey Joe , Gallego Ramón , Klinger Terrie , Kelly Ryan P. 
Published: January 2023

AbstractNon-native species have the potential to cause ecological and economic harm to coastal and estuarine ecosystems. Understanding which habitat types are most vulnerable to biological invasions, where invasions originate, and the vectors by which they arrive can help direct limited resources to prevent or mitigate ecological and socio-economic harm. Information about the occurrence of non-native species can help guide interventions at all stages of invasion, from first introduction, to naturalization and invasion. However, monitoring at relevant scales requires considerable investment of time, resources, and taxonomic expertise. Environmental DNA (eDNA) metabarcoding methods sample coastal ecosystems at broad spatial and temporal scales to augment established monitoring methods. We use COI mtDNA eDNA sampling to survey a diverse assemblage of species across distinct habitats in the Salish Sea in Washington State, USA, and classify each as non-native, native, or indeterminate in origin. The non-native species detected include both well-documented invaders and species not previously reported within the Salish Sea. We find a non-native assemblage dominated by shellfish and algae with native ranges in the temperate western Pacific, and find more-retentive estuarine habitats to be invaded at far higher levels than better-flushed rocky shores. Furthermore, we find an increase in invasion level with higher water temperatures in spring and summer across habitat types. This analysis contributes to a growing understanding of the biotic and abiotic factors that influence invasion level, and underscores the utility of eDNA surveys to monitor biological invasions and to better understand the factors that drive these invasions.
Species-aware DNA language models capture regulatory elements and their evolution
Authors: Karollus Alexander , Hingerl Johannes , Gankin Dennis , Grosshauser Martin , Klemon Kristian , Gagneur Julien 
Published: January 2023

AbstractThe rise of large-scale multi-species genome sequencing projects promises to shed new light on how genomes encode gene regulatory instructions. To this end, new algorithms are needed that can leverage conservation to capture regulatory elements while accounting for their evolution. Here we introduce species-aware DNA language models (LMs), which we trained on more than 800 species spanning over 500 million years of evolution. Investigating their ability to predict masked nucleotides from context, we show that DNA LMs distinguish transcription factor and RNA-binding protein motifs from background non-coding sequence. Owing to their flexibility, DNA LMs capture conserved regulatory elements over much further evolutionary distances than sequence alignment would allow. Remarkably, DNA LMs reconstruct motif instances bound in vivo better than unbound ones and account for the evolution of motif sequences and their positional constraints, showing that these models capture functional high-order sequence and evolutionary context. We further show that species-aware training yields improved sequence representations for endogenous and MPRA-based gene expression prediction, as well as motif discovery. Collectively, these results demonstrate that species-aware DNA language models are a powerful, flexible, and scalable tool to integrate information from large compendia of highly diverged genomes.
macrosyntR : Drawing automatically ordered Oxford Grids from standard genomic files in R
Authors: El Hilali Sami , Copley Richard R. 
Published: January 2023

AbstractMacrosynteny refers to the conservation of chromosomal to sub-chromosomal domains across species and its conservation can provide insight on the evolution of animal genomes. Pairwise comparison of de-novo assembled genomes based on predicted protein sequences often use a graphical visualization called an Oxford grid. We implemented an R package to draw Oxford grids from standard genomic file formats. The package can automatically order the chromosomes, to improve interpretability, and is thus helpful for both exploratory data analysis and production of publication quality graphics.
Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy
Authors: Chen Jiang , Amoozgar Zohreh , Liu Xin , Aoki Shuichi , Liu Zelong , Shin Sarah , Matsui Aya , Pu Zhangya , Lei Pin-Ji , Datta Meenal , Zhu Lingling , Ruan Zhiping , Shi Lei , Staiculescu Daniel , Inoue Koetsu , Munn Lance L. , Fukumura Dai , Huang Peigen , Bardeesy Nabeel , Ho Won Jin , Jain Rakesh. K. , Duda Dan G. 
Published: January 2023

AbstractIntrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, andin vivoT-cell depletion and CD8+T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-γ+T-cells. Depletion of CD8+but not CD4+T-cells compromised efficacy. Conversely, CD8+T-cell transfer fromCxcr3−/−versusCxcr3+/+mice intoRag1−/−immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 “priming”) with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.One Sentence SummaryImmune microenvironment reprogramming by chemotherapy and priming using CTLA-4 blockade render ICCs responsive to anti-PD-1 immunotherapy.
Decoupling of transcript and protein concentrations ensures budding yeast histone homeostasis in different nutrient conditions
Authors: Chatzitheodoridou Dimitra , Bureik Daniela , Padovani Francesco , Nadimpalli Kalyan Varma , Schmoller Kurt M. 
Published: January 2023

AbstractTo maintain protein homeostasis in changing nutrient environments, cells must precisely control the amount of their proteins, despite the accompanying changes in cell growth and biosynthetic capacity. As nutrients are major regulators of cell cycle length and progression, a particular challenge arises for the nutrient-dependent regulation of ‘cell cycle genes’, which are periodically expressed during the cell cycle. One important example are histones, which are needed at a constant histone-to-DNA stoichiometry. Here we show that budding yeast achieves histone homeostasis in different nutrients through a decoupling of transcript and protein abundance. We find that cells downregulate histone transcripts in poor nutrients to avoid toxic histone overexpression, but produce constant amounts of histone proteins through nutrient-specific regulation of translation efficiency. Our findings suggest that this allows cells to balance the need for rapid histone production under fast growth conditions with the tight regulation required to avoid toxic overexpression in poor nutrients.
Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension
Authors: van Duijvenboden Stefan , Ramírez Julia , Young William J. , Olczak Kaya J. , Ahmed Farah , Alhammadi Mohammed J.A.Y. ,   International Consortium of Blood Pressure, Bell Christopher G. , Morris Andrew P. , Munroe Patricia B. 
Published: January 2023

AbstractGenome-wide association studies of blood pressure (BP) have identified >1000 loci but the effector genes and biological pathways at these loci are mostly unknown. Using published meta-analysis summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with ≥2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, DBH) and previously unreported BP candidate genes (NRIP1, MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait withcis-eQTLs, and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, tissue expression data and literature review, we provide consolidated evidence for 394 BP candidate genes for future functional validation and identifies several new drug targets.
Acinar-ductal cell rearrangement drives pancreas branching morphogenesis in an IGF/PI3K-dependent manner
Authors: Darrigrand Jean-Francois , Salowka Anna , Spagnoli Francesca M. 
Published: January 2023

SUMMARYDuring organ formation, progenitor cells need to acquire the diversity of cell identities found in the organ as well as organize themselves into distinct structural units. How these processes are coordinated, and how tissue architecture(s) are preserved despite the dramatic cell rearrangements occurring in developing organs remain unclear. Here, we identified cellular rearrangements between acinar and ductal progenitors as a mechanism to drive branching morphogenesis in the pancreas while preserving the integrity of the acinar-ductal functional unit.Usingex vivoandin vivomouse models, we found that pancreatic ductal cells form clefts by protruding and pulling on the acinar basement membrane, which lead to acini splitting. Newly formed acini remain connected to bifurcated branches generated by ductal cell rearrangement. IGF/PI3K pathway regulates this process by controlling ductal cell fluidity. If components of the pathway are genetically or chemically dysregulated, ductal cell fluidity prevents branching and affects pancreatic cell fates. Hence, our results explain how acinar multiplication and branch bifurcation are synchronized during pancreas organogenesis.
Single fluorogen imaging reveals distinct environmental and structural features of biomolecular condensates
Authors: Wu Tingting , King Matthew R. , Qiu Yuanxin , Farag Mina , Pappu Rohit V. , Lew Matthew D. 
Published: January 2023

AbstractBiomolecular condensates are viscoelastic materials. Simulations predict that fluid-like condensations are defined by spatially inhomogeneous organization of the underlying molecules. Here, we test these predictions using single-fluorogen tracking and super-resolution imaging. Specifically, we leverage the localization and orientational preferences of freely diffusing fluorogens and the solvatochromic effect whereby specific fluorogens are turned on in response to condensate microenvironments. We deployed three different fluorogens to probe the microenvironments and molecular organization of different protein-based condensates. The spatiotemporal resolution and environmental sensitivity afforded by single-fluorogen imaging shows that the internal environments of condensates are more hydrophobic than coexisting dilute phases. Molecules within condensates are organized in a spatially inhomogeneous manner, and this gives rise to slow-moving nanoscale molecular clusters that coexist with fast-moving molecules. Fluorogens that localize preferentially to the interface help us map their distinct features. Our findings provide a structural and dynamical basis for the viscoelasticity of condensates.