bluuebunny/crossref_metadata_2025 huggingface dataset:
A theory of stochastic fluvial landscape evolution
Authors: Roberts G. G. , Wani O.
Published: February 2024

Geometries of eroding landscapes contain important information about geologic, climatic, biotic and geomorphic processes. They are also characterized by variability, which makes disentangling their origins challenging. Observations and physical models of fluvial processes, which set the pace of erosion on most continents, emphasize complexity and variability. By contrast, the spectral content of longitudinal river profiles and similarity of geometries at scales greater than approximately

 

100
 

km

highlight relatively simple emergent properties. A general challenge then, addressed in this manuscript, is development of a theory of landscape evolution that embraces such scale-dependent insights. We do so by incorporating randomness and probability into a theory of fluvial erosion. First, we explore the use of stochastic differential equations of the Langevin type, and the Fokker–Planck equation, for predicting migration of erosional fronts. Second, analytical approaches incorporating distributions of driving forces, critical thresholds and associated proxies are developed. Finally, a linear programming approach is introduced, that, at its core, treats evolution of longitudinal profiles as a Markovian stochastic problem. The theory is developed essentially from first principles and incorporates physics governing fluvial erosion. We explore predictions of this theory, including the natural growth of discontinuities and scale-dependent evolution, including local complexity and emergent simplicity.
Rapid turnover of a pea aphid superclone mediated by thermal endurance in central Chile
Authors: Martel Sebastián I. , Zamora Cristián A. , Ricote Natalia , Sepúlveda Daniela A. , Mahéo Frédérique , Simon Jean-Christophe , Figueroa Christian C. , Rezende Enrico L. , Bozinovic Francisco
Published: February 2024

Global change drivers are imposing novel conditions on Earth's ecosystems at an unprecedented rate. Among them, biological invasions and climate change are of critical concern. It is generally thought that strictly asexual populations will be more susceptible to rapid environmental alterations due to their lack of genetic variability and, thus, of adaptive responses. In this study, we evaluated the persistence of a widely distributed asexual lineage of the alfalfa race of the pea aphid,
Acyrthosiphon pisum,
along a latitudinal transect of approximately 600 km in central Chile after facing environmental change for a decade. Based on microsatellite markers, we found an almost total replacement of the original aphid superclone by a new variant. Considering the unprecedented warming that this region has experienced in recent years, we experimentally evaluated the reproductive performance of these two
A. pisum
lineages at different thermal regimes. The new variant exhibits higher rates of population increase at warmer temperatures, and computer simulations employing a representative temperature dataset suggest that it might competitively displace the original superclone. These results support the idea of a superclone turnover mediated by differential reproductive performance under changing temperatures.
Effects of past and present habitat on the gut microbiota of a wild rodent
Authors: Scholier Tiffany , Lavrinienko Anton , Kallio Eva R. , Watts Phillip C. , Mappes Tapio
Published: February 2024

The response of the gut microbiota to changes in the host environment can be influenced by both the host's past and present habitats. To quantify their contributions for two different life stages, we studied the gut microbiota of wild bank voles (
Clethrionomys glareolus
) by performing a reciprocal transfer experiment with adults and their newborn offspring between urban and rural forests in a boreal ecosystem. Here, we show that the post-transfer gut microbiota in adults did not shift to resemble the post-transfer gut microbiota of animals ‘native’ to the present habitat. Instead, their gut microbiota appear to be structured by both their past and present habitat, with some features of the adult gut microbiota still determined by the past living environment (e.g. alpha diversity, compositional turnover). By contrast, we did not find evidence of the maternal past habitat (maternal effects) affecting the post-transfer gut microbiota of the juvenile offspring, and only a weak effect of the present habitat. Our results show that both the contemporary living environment and the past environment of the host organism can structure the gut microbiota communities, especially in adult individuals. These data are relevant for decision-making in the field of conservation and wildlife translocations.
Type 1 immunity enables neonatal thymic ILC1 production
Authors: Tougaard Peter , Pérez Mario Ruiz , Steels Wolf , Huysentruyt Jelle , Verstraeten Bruno , Vetters Jessica , Divert Tatyana , Gonçalves Amanda , Roelandt Ria , Takahashi Nozomi , Janssens Sophie , Buus Terkild Brink , Taghon Tom , Leclercq Georges , Vandenabeele Peter
Published: February 2024

Thymic atrophy occurs following type 1 inflammatory conditions like viral infection and sepsis, resulting in cell death and disruption of T-cell development. However, it remains undetermined whether the thymus actively contributes to the immune response. Thus, we cultured neonatal thymusex vivowith the type 1 cytokines IL-12 plus IL-18, resulting in a rapid shift from steady-state T-cell development to the production, expansion, and thymic exit of CXCR6+CD62L-type 1 innate lymphoid cells (ILC1s). Single-cell RNA-sequencing and functional assays identified these cells as embryonic-wave-derived KLRG1+ILC1s that mainly differentiated from immature neonatal thymic ILC1s. Confocal 3D imaging confirmed neonatal thymic ILC1 expansion during MCMV infection. Furthermore, thymic grafts revealedin vivothymic ILC1 egress and type 1 inflammation-induced homing of thymus-derived KLRG1+ILC1s to the liver and peritoneal cavity. Altogether, our data reveal a novel thymic function where type 1 immunity enables the production and peripheral homing of thymic-derived ILC1s.
MAGIC matrices: freeform bioprinting materials to support complex and reproducible organoid morphogenesis
Authors: Graham Austin J. , Khoo Michelle W.L. , Srivastava Vasudha , Viragova Sara , Kim Honesty , Parekh Kavita , Hennick Kelsey M. , Bird Malia , Goldhammer Nadine , Yu Jie Zeng , Morley Cameron D. , Lebel Paul , Kumar Sanjay , Rosenbluth Jennifer M. , Nowakowski Tomasz J. , Klein Ophir , Gómez-Sjöberg Rafael , Gartner Zev J.
Published: February 2024

Organoids are powerful models of tissue physiology, yet their applications remain limited due to their relatively simple morphology and high organoid-to-organoid structural variability. To address these limitations we developed a soft, composite yield-stress extracellular matrix that supports optimal organoid morphogenesis following freeform 3D bioprinting of cell slurries at tissue-like densities. The material is designed with two temperature regimes: at 4 °C it exhibits reversible yield-stress behavior to support long printing times without compromising cell viability. When transferred to cell culture at 37 °C, the material cross-links and exhibits similar viscoelasticity and plasticity to basement membrane extracts such as Matrigel. We first characterize the rheological properties of MAGIC matrices that optimize organoid morphogenesis, including low stiffness and high stress relaxation. Next, we combine this material with a custom piezoelectric printhead that allows more reproducible and robust self-organization from uniform and spatially organized tissue “seeds.” We apply MAGIC matrix bioprinting for high-throughput generation of intestinal, mammary, vascular, salivary gland, and brain organoid arrays that are structurally similar to those grown in pure Matrigel, but exhibit dramatically improved homogeneity in organoid size, shape, maturation time, and efficiency of morphogenesis. The flexibility of this method and material enabled fabrication of fully 3D microphysiological systems, including perfusable organoid tubes that experience cyclic 3D strain in response to pressurization. Furthermore, the reproducibility of organoid structure increased the statistical power of a drug response assay by up to 8 orders-of-magnitude for a given number of comparisons. Combined, these advances lay the foundation for the efficient fabrication of complex tissue morphologies by canalizing their self-organization in both space and time.
Identification and Structural Characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3
Authors: Sim Malcolm J. W. , Hanada Ken-ichi , Stotz Zachary , Yu Zhiya , Lu Jinghua , Brennan Paul , Quastel Max , Gillespie Geraldine M. , Long Eric O. , Yang James C. , Sun Peter D.
Published: February 2024

Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that can be targeted in adoptive T cell therapy in metastatic diseases. To expand mutant KRAS specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (7VVVGAVGVGK16) using a vaccination approach with transgenic mice expressing the common HLA-I allotype, HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not Wt KRAS peptides. To investigate the molecular basis for neoantigen recognition by This TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3β and CDR1 β formed a hydrophobic pocket to interact with p6 Val of the G12V but not Wt KRAS peptide. To improve the tumor sensitivity of This TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding to HLA-A3 (G12V), but did not sufficiently improve T cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations. [203]
A covariant model of molecular and diversification patterns through time and the history of large clades
Authors: Budd Graham E. , Mann Richard P.
Published: February 2024

Abstract

Rate shifts in speciation and extinction have been recognised as important contributors to the creation of evolutionary patterns. In particular, the distribution of modern clade sizes is difficult to reconcile with models that do not include them. Although recent advances have allowed rate shifts to be integrated into evolutionary models, these have largely been for the purpose of inferring historical rate shifts across phylogenetic trees. In addition, these models have typically assumed an independence between patterns of diversification and rates of molecular and morphological evolution, despite there being mounting evidence of a connection between them. Here, we develop a new model with two principal goals: first, to explore the general patterns of diversification implied by constantly changing rates, and secondly to integrate diversification, molecular and morphological evolution into a single coherent framework. We thus develop and analyse a covariant birth-death process in which rates of all evolutionary processes (i.e. speciation, extinction and molecular and morphological change) covary continuously, both for each species and through time. We use this model to show that modern diversity is likely to be dominated by a small number of extremely large clades at any historical epoch; that these large clades are expected to be characterised by explosive early radiations accompanied by elevated rates of molecular evolution; and that extant organisms are likely to have evolved from species with unusually fast evolutionary rates. In addition, we show that under such a model, the amount of molecular change along a particular lineage is essentially independent of its height, which further weakens the molecular clock hypothesis. Finally, our model predicts the existence of “living fossil” sister groups to large clades that are both species poor and have exhibited slow rates of morphological and molecular change. Although our model is highly stochastic, it includes no special evolutionary moments or epochs. Our results thus demonstrate that the observed historical patterns of evolution can be modelled without invoking special evolutionary mechanisms or innovations that are unique to specific times or taxa, even when they are highly non-uniform: instead they could emerge from a process that is fundamentally homogeneous throughout time.
Nestling-Care Decisions by Cooperatively Breeding American Crows
Authors: Caffrey Carolee , Peterson Charles C. , Hackler Tiffany W.
Published: February 2024

During the nestling stage of breeding seasons in Stillwater, OK, pairs of American Crows (Corvus brachyrhynchos brachyrhynchos) lived alone or in groups of variable composition; auxiliaries included individuals that had delayed dispersal, immigrated into groups, or returned to natal territories after having lived elsewhere. Most, but not all, auxiliaries contributed to feeding nestlings, and their contributions varied considerably. On average, breeders fed nestlings at greater rates than did auxiliaries, and female breeders spent more time at nests than did other group members. Breeders compensated for auxiliary contributions by reducing their own; this and breeder responses to the disappearance of auxiliary feeding group members provide evidence that these long-lived, iteroparous animals were managing energy budgets so as to maximize fitness over the long term. Female breeders in larger groups spent more time at nests than did those in smaller groups, but not for expected reasons and not to any reproductive benefit. A few female auxiliaries spent increasing amounts of time at nests as nestlings aged. No other measured phenotypic characteristic of individuals was found to explain any of the wide variation in the patterns of nestling care exhibited by members of our population.
Nanopore-based DNA long-read sequencing analysis of the aged human brain
Authors: Ramirez Paulino , Sun Wenyan , Kazempour Dehkordi Shiva , Zare Habil , Fongang Bernard , Bieniek Kevin F. , Frost Bess
Published: February 2024

Aging disrupts cellular processes such as DNA repair and epigenetic control, leading to a gradual buildup of genomic alterations that can have detrimental effects in post-mitotic cells. Genomic alterations in regions of the genome that are rich in repetitive sequences, often termed “dark loci,” are difficult to resolve using traditional sequencing approaches. New long-read technologies offer promising avenues for exploration of previously inaccessible regions of the genome. Using nanopore-based long-read whole-genome sequencing of DNA extracted from aged 18 human brains, we identify previously unreported structural variants and methylation patterns within repetitive DNA, focusing on transposable elements (“jumping genes”) as crucial sources of variation, particularly in dark loci. Our analyses reveal potential somatic insertion variants and provides DNA methylation frequencies for many retrotransposon families. We further demonstrate the utility of this technology for the study of these challenging genomic regions in brains affected by Alzheimer’s disease and identify significant differences in DNA methylation in pathologically normal brains versus those affected by Alzheimer’s disease. Highlighting the power of this approach, we discover specific polymorphic retrotransposons with altered DNA methylation patterns. These retrotransposon loci have the potential to contribute to pathology, warranting further investigation in Alzheimer’s disease research. Taken together, our study provides the first long-read DNA sequencing-based analysis of retrotransposon sequences, structural variants, and DNA methylation in the aging brain affected with Alzheimer’s disease neuropathology.
Individual performance niches may buffer population responses to climate change in estuarine fishes
Authors: Bellotto Clara , Fowler Ashley M. , Booth David J.
Published: February 2024

Climate change may impact individual organisms in different ways, a consideration often overshadowed by predominant focus on population effects in studies. We examined three estuarine fish species to determine if individual fish performance, persisted across winter water temperatures. Fish performance at 16°C (current Sydney winter estuarine water temperature) and 20°C (predicted under climate change) with low and high food regimes was assessed using key physiological (growth, aerobic scope, burst speed) and behavioural parameters (foraging activity, boldness, shelter usage, predator escape response). We expected a strong positive relationship between performance at 16°C and 20°C for each parameter, and interactions with food level, however in general this was not found for any species. Relative performance was only maintained across temperatures for a few parameters, such as bite rate, boldness, and shelter response in one species (trumpeterPelates sexlineatus), with aerobic scope in silver biddyGerres subfasciatus, and boldness in fortescueCentropogon australis.

Our results suggest that individuals’ fitness (directly via changes in growth, indirectly via behaviours) will be impacted by climate warming due to differences in relative performance among individuals across water temperatures. Changes in relative performance among individuals may initially compensate for a population-level response, thereby buffering the effects of climate change.
Fluctuating salinity during development impacts fish productivity
Authors: Chung Meng-Han Joseph , Noble Daniel W. A. , Fox Rebecca J. , Harrison Lauren M. , Jennions Michael D.
Published: February 2024

Climate change is elevating salinity levels in many freshwater systems, and more erratic rainfall is increasing variation in salinity. Consequently, many species now experience more extreme developmental environments. Resultant shifts in developmental trajectories could change key life history traits that persist into adulthood. To date, however, how variation in salinity affects the life histories of freshwater species has been neglected despite its implications for fisheries. We ran a large-scale experiment with a global pest, the mosquitofish (Gambusia holbrooki), and manipulated the salinity experienced by juveniles: freshwater (0‰), stable salinity (10‰) or fluctuating salinity (0-20‰; mean = 10 ‰). Fish developing in stable, high salinity grew faster and matured earlier, albeit with a decline in male telomeres and female gut development. Stable high salinity resulted in larger adult body size in females, but not males, which increased female fecundity. Conversely, fluctuations in salinity induced fish to grow more slowly and lowered female fecundity. Crucially, several of the long-term effects of salinity fluctuations were sex-specific, more adversely affecting females than males. We highlight that environmental variability alters an organism’s vulnerability to stressors, with implications that should be considered if we wish to understand the impact of climate change on population dynamics.
Spatiotemporal profiling defines persistence and resistance dynamics during targeted treatment of melanoma
Authors: Rubinstein Jill C. , Domanskyi Sergii , Sheridan Todd B. , Sanderson Brian , Park SungHee , Kaster Jessica , Li Haiyin , Anczukow Olga , Herlyn Meenhard , Chuang Jeffrey H.
Published: February 2024

Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. Using spatial transcriptomics in patient derived xenograft models, we capture clonal lineage evolution during treatment, finding the persister state to show increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identifies intrinsic- and acquired-resistance mechanisms (e.g. dual specific phosphatases, Reticulon-4, CDK2) and suggests specific temporal windows of potential therapeutic efficacy. Using deep learning to analyze histopathological slides, we find morphological features of specific cell states, demonstrating that juxtaposition of transcriptomics and histology data enables identification of phenotypically-distinct populations using imaging data alone. In summary, we define state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones.

Statement of Significance

Tumor evolution is accelerated by application of anti-cancer therapy, resulting in clonal expansions leading to dormancy and subsequently resistance, but the dynamics of this process are incompletely understood. Tracking clonal progression during treatment, we identify conserved, global transcriptional changes and local clone-clone and spatial patterns underlying the emergence of resistance.
Does method of field preparation affect survival and growth of juvenile Chinook salmon in agricultural floodplains?
Authors: Tallman Rachelle L. , Wampler Alexandra N. , Singer Gabriel P. , Jeffres Carson A. , Cocherell Dennis E. , Colby Jordan , Fangue Nann A. , Lusardi Robert A. , Rypel Andrew L.
Published: February 2024

There is growing interest to integrate conservation initiatives into agricultural practices using a reconciliation ecology framework. In California’s Central Valley, one approach to improving crucial nursery habitat for threatened and endangered fish species is by re-creating floodplain habitats through the inundation of agricultural fields during the non-growing season. We conducted a series of field experiments in agricultural floodplains (winter-flooded rice fields that were once natural floodplains) to explore whether different field preparation methods enhanced growth and survival of floodplain-dependent fish species. Approximately 8,000 juvenile fall-run Chinook Salmon (Oncorhynchus tshawytscha) were reared for at least 28 days on eight, 0.2 ha experimental fields. Each experimental field represented one of four treatments (two replicates per treatment): addition of large wood, addition of in-field canals, addition of both large wood and in-field canals, and control-where no additional field preparations were implemented beyond standard post-growing practices: i.e., chopping rice into stubble, baling and removing excess rice straw, and discing the field with a single pass by plowing rice straw into the ground to promote decomposition. We found no significant difference in water temperature, fish growth or fish survival among habitat treatments. Across treatments, survival ranged from 50.1%-78.3% and averaged 65.75% (⁺/- 7.89% SE). These findings suggest agricultural floodplains require no additional modifications to promote fish growth and survival. Results illustrate the benefits of integrating working landscapes with conservation initiatives by creating more accessible and beneficial habitat for native fishes.
StimulatedProrocentrum donghaiensecell growth byin-situmariculture dissolved organic matter
Authors: Wang Hongwei , Wu Siyang , Ma Jian , Hong Yiting , Guo Chentao , Zhao Jing , Lin Xin
Published: February 2024

Mixotrophic dinoflagellates frequently cause harmful algal blooms (HAB) in eutrophic mariculture waters that contain diverse excreted dissolved organic matter (DOM). The phagotrophy and the utilization of single organic small molecules have been extensively investigated in the bloom-forming mixotrophic dinoflagellates. However, their ability to utilize thein-situDOM via absorbtrophy still remains unexplored. Here we examined the growth promotion effect of thein-situmariculture DOM onProrocentrum donghaiense, a representative HAB-forming species in coastal waters. Our results showed that the cell growth and photosynthesis ofP. donghaiensewere significantly promoted underin-situDOM culture conditions. Additionally, parallel cultures were set up to disclose the potential role of the bacterioplankton in the free-living community (helper), where they aid in the remineralization of thein-situDOM, and the phycosphere community (competitor), where they compete against the algal host to acquire nutrients from thein-situDOM. Meanwhile, we determined the cellular stoichiometry under different culture conditions, showing that mariculture DOM can shape cellular stoichiometry significantly. Elevated cellular N (84.96%) and P (48.3%) were observed in spring DOM groups compared with the control groups. For the first time, this study quantifies the efficient utilization of thein-situDOM via absorbtrophy, indicating the vital role in the outbreak and maintenance of HAB events.
Downscaling mutualistic networks from species to individuals reveals consistent interaction niches and roles within plant populations
Authors: Quintero Elena , Arroyo-Correa Blanca , Isla Jorge , Rodríguez-Sánchez Francisco , Jordano Pedro
Published: February 2024

Species-level networks emerge as the combination of interactions spanning multiple individuals, and their study has received considerable attention over the past 30 years. However, less is known about the structure of interaction configurations within species, even though individuals are the actual interacting units in nature.

We compiled 46 empirical, individual-based, interaction networks on plant-animal seed dispersal mutualisms, comprising 1037 plant individuals across 29 species from various regions. We compared the structure of individual-based networks to that of species-based networks and, by extending the niche concept to interaction assemblages, we explored individual plant specialization. Using a Bayesian framework to account for uncertainty derived from sampling, we examined how plant individuals “explore” the interaction niche of their populations.

Both individual-based and species-based networks exhibited high variability in network properties, lacking remarkable structural and topological differences between them. Within populations, frugivores’ interaction allocation among plant individuals was highly heterogeneous, with one to three frugivore species dominating interactions. Regardless of species or bioregion, plant individuals displayed a variety of interaction profiles across populations, with a consistently small percentage of individuals playing a central role and exhibiting high diversity in their interaction assemblage. Plant populations showed variable mid to low levels of niche specialization; and individuals’ interaction niche “breadth” accounted for 70% of the population interaction diversity, on average.

Our results highlight how downscaling from species to individual-based networks helps understanding the structuring of interactions within ecological communities and provide an empirical basis for the extension of niche theory to complex mutualistic networks.

Significance Statement

Ecological interactions in nature occur between individual partners rather than species, and their outcomes determine fitness variation. By examining among-individual variation in interaction niches, we can bridge evolutionary and ecological perspectives to understand interaction biodiversity. This study investigates individual plant variation in frugivore assemblages worldwide, exploring how plant individuals “build” their interaction profiles with animal frugivores. The structure of networks composed of individuals was surprisingly similar to networks composed of species. Within populations, only a few plants played a key role in attracting a high diversity of frugivores, making them central to the overall network structure. Individuals actually interacted with a substantial diversity of partners, with individual niche “breadth” accounting for up to 70% of total interaction diversity, on average.
Photoprotective mechanisms inElysiaspecies hostingAcetabulariachloroplasts shed light on host-donor compatibility in photosynthetic sea slugs
Authors: Morelli Luca , Havurinne Vesa , Madeira Diana , Martins Patrícia , Cartaxana Paulo , Cruz Sónia
Published: February 2024

Sacoglossa sea slugs have garnered attention due to their ability to retain intracellular functional chloroplasts from algae, while degrading other algal cell components. While protective mechanisms that limit oxidative damage under excessive light are well documented in plants and algae, the photoprotective strategies employed by these photosynthetic sea slugs remain unresolved. Species within the genusElysiaare known to retain chloroplasts from various algal sources, but the extent to which the metabolic processes from the donor algae can be sustained by the sea slugs is unclear. By comparing their responses to high light conditions through kinetic analyses, molecular techniques, and biochemical assays, this study highlights significant differences between two photosyntheticElysiaspecies with chloroplasts derived from the green algaAcetabularia acetabulum. Notably,Elysia timidadisplayed remarkable tolerance to high light stress and sophisticated photoprotective mechanisms such as an active xanthophyll cycle, efficient D1 protein recycling, accumulation of heat-shock proteins and α-tocopherol. In contrast,Elysia crispataexhibited absence or limitations in these photoprotective strategies. Our findings emphasize the intricate relationship between the host animal and the stolen chloroplasts, highlighting different capacities to protect the photosynthetic organelle from oxidative damage.
AttentionPert: Accurately Modeling Multiplexed Genetic Perturbations with Multi-scale Effects
Authors: Bai Ding , Ellington Caleb , Mo Shentong , Song Le , Xing Eric
Published: February 2024

Genetic perturbations (i.e. knockouts, variants) have laid the foundation for our understanding of many diseases, implicating pathogenic mechanisms and indicating therapeutic targets. However, experimental assays are fundamentally limited in the number of perturbation conditions they can measure. Computational methods can fill this gap by predicting perturbation effects under unseen conditions, but accurately predicting the transcriptional responses of cells to unseen perturbations remains a significant challenge. We address this by developing a novel attention-based neural network, AttentionPert, which accurately predicts gene expression under multiplexed perturbations and generalizes to unseen conditions. AttentionPert integrates global and local effects in a multi-scale model, representing both the non-uniform system-wide impact of the genetic perturbation and the localized disturbance in a network of gene-gene similarities, enhancing its ability to predict nuanced transcriptional responses to both single and multi-gene perturbations. In comprehensive experiments, AttentionPert demonstrates superior performance across multiple datasets outperforming the state-of-theart method in predicting differential gene expressions and revealing novel gene regulations. AttentionPert marks a significant improvement over current methods, particularly in handling the diversity of gene perturbations and in predicting out-of-distribution scenarios.
Lineage-resolved analysis of embryonic gene expression evolution inC. elegansandC. briggsae
Authors: Large Christopher R. L. , Khanal Rupa , Hillier LaDeana , Huynh Chau , Kubo Connor , Kim Junhyong , Waterston Robert H. , Murray John I.
Published: February 2024

What constraints govern the evolution of gene expression patterns across development remains a fundamental question of evolutionary biology. The advent of single-cell sequencing opens the possibility of learning these constraints by systematically profiling homologous cells across different organisms. The nematodeC. elegansis a well-studied model for embryonic development, and its invariant lineage that is conserved with otherCaenorhabditisspecies makes it an ideal model to directly compare gene expression between homologous progenitor and terminal cell types across evolution. We have measured the spatiotemporal divergence of gene expression across embryogenesis by collecting, annotating, and comparing the transcriptomes of homologous embryonic progenitors and terminal cell types, using a dataset comprising >200,000C. eleganscells and >190,000C. briggsaecells. We find a high level of similarity in gene expression programs between the species despite tens of millions of years of evolutionary divergence, consistent with their conserved developmental lineages. Even still, thousands of genes show divergence in their cell-type specific expression patterns, and these are enriched for categories involved in environmental response and behavior. Comparing the degree of expression conservation across cell types reveals that certain cell types such as neurons, have diverged more than others such as the intestine and body wall muscle. Taken together, this work identifies likely constraints on the evolution of developmental gene expression and provides a powerful resource for addressing diverse evolutionary questions.
XBB.1.5 monovalent booster improves antibody binding and neutralization against emerging SARS-CoV-2 Omicron variants
Authors: Jain Shilpi , Kumar Sanjeev , Lai Lilin , Linderman Susanne , Malik Ansa A. , Ellis Madison L. , Godbole Sucheta , Solis Daniel , Sahoo Malaya K. , Bechnak Kareem , Paredes Isabel , Tanios Ralph , Kazzi Bahaa , Dib Serena M. , Litvack Matthew B , Wimalasena Sonia T. , Ciric Caroline , Rostad Christina , West Richard , Teng I-Ting , Wang Danyi , Edupuganti Sri , Kwong Peter D. , Rouphael Nadine , Pinsky Benjamin A. , Douek Daniel C. , Wrammert Jens , Moreno Alberto , Suthar Mehul S.
Published: February 2024

The rapid emergence of divergent SARS-CoV-2 variants has led to an update of the COVID-19 booster vaccine to a monovalent version containing the XBB.1.5 spike. To determine the neutralization breadth following booster immunization, we collected blood samples from 24 individuals pre- and post-XBB.1.5 mRNA booster vaccination (∼1 month). The XBB.1.5 booster improved both neutralizing activity against the ancestral SARS-CoV-2 strain (WA1) and the circulating Omicron variants, including EG.5.1, HK.3, HV.1, XBB.1.5 and JN.1. Relative to the pre-boost titers, the XBB.1.5 monovalent booster induced greater total IgG and IgG subclass binding, particular IgG4, to the XBB.1.5 spike as compared to the WA1 spike. We evaluated antigen-specific memory B cells (MBCs) using either spike or receptor binding domain (RBD) probes and found that the monovalent booster largely increases non-RBD cross-reactive MBCs. These data suggest that the XBB.1.5 monovalent booster induces cross-reactive antibodies that neutralize XBB.1.5 and related Omicron variants.
Identification of differentially methylated single-nucleotide m6A sites by incorporating site-specific antibody specificity
Authors: Guo Yang , Wu Zehong , Cheng Weisheng , Ren Zhijun , Cun Yixian , Wang Jinkai
Published: February 2024

Various genome-wide and transcriptome-wide technologies are based on antibodies, however, the specificity of antibodies on different targets has not been characterized or considered in the analyses. The antibody-based MeRIP-seq is the most widely used method to determine the locations of N6-methyladenosine (m6A) on RNAs, especially for differential m6A analyses. However, the antibody specificities in different RNA regions and their resulting technical biases in differential m6A analyses have not been evaluated. Here, we evaluated the m6A antibody specificities using 100 pairs of spike-in RNAs with known m6A levels at single sites. Based on two replicates with different m6A levels on spike-in RNAs, we realized the m6A antibody specificities of the m6A sites on spike-in RNAs were greatly varied and mainly determined by the surrounding sequences of the m6A sites. Moreover, the MeRIP-seq signal fold change is the function of the real difference in m6A levels as well as the m6A antibody specificity. We then trained a machine learning model to predict the m6A antibody specificities of given sequences and predicted the m6A specificities of all RNA sequences surrounding the known m6A motif DRACH throughout the human transcriptome. Finally, we developed a Hierarchical statistic model for Differential Analysis of m6A Sites (HDAMS) by taking advantage of the predicted m6A specificities. We found that HDAMS can accurately determine the differentially methylated single-nucleotide m6A sites and the output more functionally relevant results. Our study not only provides a powerful tool for differential m6A analyses but also provides a methodological framework for other antibody-based studies to incorporate antibody specificities.
The Vps13-like protein BLTP2 is pro-survival and regulates phosphatidylethanolamine levels in the plasma membrane to maintain its fluidity and function
Authors: Banerjee Subhrajit , Daetwyler Stephan , Bai Xiaofei , Michaud Morgane , Jouhet Juliette , Madhugiri Shruthi , Johnson Emma , Wang Chao-Wen , Fiolka Reto , Toulmay Alexandre , Prinz William A.
Published: February 2024

Lipid transport proteins (LTPs) facilitate nonvesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis1. A new family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles2. One, BLTP2, is conserved across species but its function is not known. Here, we show that BLTP2 and its homolog directly regulate plasma membrane (PM) fluidity by increasing the phosphatidylethanolamine (PE) level in the PM. BLTP2 localizes to endoplasmic reticulum (ER)-PM contact sites34, 5, suggesting it transports PE from the ER to the PM. We find BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity6, 7. BLTP2 expression correlates with breast cancer aggressiveness8–10. We found BLTP2 facilitates growth of a human cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans.
The mechanism of mammalian proton-coupled peptide transporters
Authors: Lichtinger Simon M , Parker Joanne L , Newstead Simon , Biggin Philip C
Published: February 2024

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT family are conserved across all phylogenetic kingdoms and function by coupling peptide uptake to the proton electrochemical gradient. Cryo-EM structures and alphafold models have recently provided new insights into different conformational states of two mammalian POTs, SLC15A1 and SLC15A2. Nevertheless, these studies leave open important questions regarding the mechanism of proton and substrate coupling, while simultaneously providing a unique opportunity to investigate these processes using molecular dynamics (MD) simulations. Here, we employ extensive unbiased and enhanced-sampling MD to map out the full SLC15A2 conformational cycle and its thermodynamic driving forces. By computing conformational free energy landscapes in different protonation states and in the absence or presence of peptide substrate, we identify a likely sequence of intermediate protonation steps that drive inward-directed alternating access. These simulations identify key differences in the extracellular gate between mammalian and bacterial POTs, which we validate experimentally in cell-based transport assays. Our results from constant-PH MD and absolute binding free energy (ABFE) calculations also establish a mechanistic link between proton binding and peptide recognition, revealing key details underpining secondary active transport in POTs. This study provides a vital step forward in understanding proton-coupled peptide and drug transport in mammals and pave the way to integrate knowledge of solute carrier structural biology with enhanced drug design to target tissue and organ bioavailability.
Wavelet Phase Coherence of Ictal Scalp EEG-Extracted Muscle Activity (SMA) as a Biomarker for Sudden Unexpected Death in Epilepsy (SUDEP)
Authors: Gravitis Adam C. , Sivendiran Krishram , Tufa Uilki , Zukotynski Katherine , Chinvarun Yotin , Devinsky Orrin , Wennberg Richard , Carlen Peter L. , Bardakjian Berj L.
Published: February 2024

Objective

Approximately 50 million people worldwide have epilepsy and 8-17% of the deaths in patients with epilepsy are attributed to sudden unexpected death in epilepsy (SUDEP). The goal of the present work was to establish a biomarker for SUDEP so that preventive treatment can be instituted.

Approach

Seizure activity in patients with SUDEP and non-SUDEP was analyzed, specifically, the scalp EEG extracted muscle activity (SMA) and the average wavelet phase coherence (WPC) during seizures was computed for two frequency ranges (1-12 Hz, 13-30 Hz) to identify differences between the two groups.

Main results

Ictal SMA in SUDEP patients showed a statistically higher average WPC value when compared to non-SUDEP patients for both frequency ranges. Area under curve for a cross-validated logistic classifier was 81%.

Significance

Average WPC of ictal SMA is a candidate biomarker for early detection of SUDEP.
Generate Synthetic Data in R for a Hypothetical Alzheimer’s Disease Trial
Authors: Handels Ron , Jönsson Linus , Raket Lars Lau ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2024

INTRODUCTION

Representative data of recent Alzheimer’s Disease (AD) trials are difficult to obtain. We aimed to generate a synthetic version of an original real-world observational dataset, subsequently apply a plausible AD treatment effect, and make our method open-source available.

METHODS

Synthetic data was generated in the following steps: (1) Obtain real-world data from the ADNI study on demographic (age, sex, education), clinical (cognition: MMSE and ADAS; function: FAQ; composite cognition/function: CDR, ADCOMS) and biological (genetics: APOE4; cerebrospinal fluid: ABeta, Tau; imaging: PET-SUVR-centiloid) outcomes at baseline, 6, 12 and/or 18-month follow-up (35 variables), with missing data multiple-imputed to obtain 10 sets of 537 individuals. (2) Estimate (theoretical) minimum and maximum (all continuous variables) and proportions (all categorical variables). (3) Rescale to 0-1 range (continuous). (4) Estimate beta distribution shape parameters (method of moments; continuous). (5) Transform to cumulative probability distribution function (using shape parameters; continuous) and to cumulative probability (categorical). (6) Transform to a normal distribution. (7) Estimate variance-covariance matrix. (8) Generate random correlated normal data using Cholesky decomposition of variance-covariance. (9) Transform to cumulative probability distribution function. (10) Transform to beta distribution (using shape parameters; continuous). (11) Rescale to original range. (12) Keep half as control arm, and half as intervention arm, and estimate change from baseline. (13) Multiply intervention change from baseline with self-defined hypothetical relative treatment effect. We assumed correlations on normalized scale were similar to correlations on original scale. R code is available on github:https://github.com/ronhandels/synthetic-correlated-data.

RESULTS

The synthetic distribution and mean over time showed large similarity to the original data (visually assessed). The absolute difference in pairwise correlations between original and synthetic data median was 0.02 (95th percentile=0.11, max=0.18).

CONCLUSION

We judged our method sufficiently valid to generate synthetic correlated plausible hypothetical trial results.
Explainable artificial intelligence identifies an AQP4 polymorphism-based risk score associated with brain amyloid burden
Authors: Beer Simone , Elmenhorst David , Bischof Gerard N. , Ramirez Alfredo , Bauer Andreas , Drzezga Alexander ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2024

Aquaporin-4 (AQP4) is an integral component of the glymphatic system, today considered a crucial pathway for removing brain interstitial solutes like amyloid-β (Aβ). Evidence exists that genetic variation of AQP4 impacts Aβ clearance, clinical outcome in Alzheimer’s disease as well as sleep measures. We examined whether a risk score calculated from several AQP4 single-nucleotide polymorphisms (SNPs) is related to Aβ neuropathology in older cognitively unimpaired individuals. We used a machine learning approach with decision tree ensembles and explainable artificial intelligence (AI) to extract information on synergistic effects of AQP4 SNPs on brain amyloid burden from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. From this information, we formulated a sex-specific AQP4 SNP-based risk score and evaluated it on the basis of data from the screening process of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study. We found in both cohorts significant associations of the risk score with brain amyloid burden as well as amyloid positivity. The results support the hypothesis of an involvement of the glymphatic system, and particularly AQP4, in brain amyloid aggregation pathology. They suggest also that different AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden.
Improving genetic risk modeling of dementia from real-world data in underrepresented populations
Authors: Fu Mingzhou , Valiente-Banuet Leopoldo , Wadhwa Satpal S. ,   UCLA Precision Health Data Discovery Repository Working Group,   UCLA Precision Health ATLAS Working Group, Pasaniuc Bogdan , Vossel Keith , Chang Timothy S.
Published: February 2024

BACKGROUND

Genetic risk modeling for dementia offers significant benefits, but studies based on real-world data, particularly for underrepresented populations, are limited.

METHODS

We employed an Elastic Net model for dementia risk prediction using single-nucleotide polymorphisms prioritized by functional genomic data from multiple neurodegenerative disease genome-wide association studies. We compared this model withAPOEand polygenic risk score models across genetic ancestry groups, using electronic health records from UCLA Health for discovery and All of Us cohort for validation.

RESULTS

Our model significantly outperforms other models across multiple ancestries, improving the area-under-precision-recall curve by 21-61% and the area-under-the-receiver-operating characteristic by 10-21% compared to theAPOEand the polygenic risk score models. We identified shared and ancestry-specific risk genes and biological pathways, reinforcing and adding to existing knowledge.

CONCLUSIONS

Our study highlights benefits of integrating functional mapping, multiple neurodegenerative diseases, and machine learning for genetic risk models in diverse populations. Our findings hold potential for refining precision medicine strategies in dementia diagnosis.