bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serine mistranslation induces the integrated stress response without accumulation of uncharged tRNAs
Authors: Zhang Hong , Ling Jiqiang 
Published: February 2024

AbstractAminoacyl-tRNA synthetases (aaRSs) are essential enzymes that support robust and accurate protein synthesis. A rapidly expanding number of studies show that mutations in aaRSs lead to multiple human diseases, including neurological disorders and cancer. Much remains unknown about how aaRS mutations impact human health. In particular, how aminoacylation errors affect stress responses and fitness in eukaryotic cells remains poorly understood. The integrated stress response (ISR) is an adaptive mechanism in response to multiple stresses. However, chronic activation of the ISR contributes to the development of multiple diseases (e.g., neuropathies). Here we show that Ser misincorporation into Ala and Thr codons, resulting from aaRS editing defects or mutations in tRNAs, constitutively active the ISR. Such activation does not appear to depend on the accumulation of uncharged tRNAs, implicating that Ser mistranslation may lead to ribosome stalling and collision.
Comparison of six methods for stabilizing metapopulation dynamics and for their robustness against census noise
Authors: Singh Akanksha , Tung Sudipta 
Published: February 2024

AbstractNatural populations face growing extinction risks due to mismatches between traits and ecological conditions, exacerbated by habitat degradation and climate change. While several population control methods have been proposed to protect vulnerable populations, their effectiveness in spatially structured populations (metapopulations) and resilience to census inaccuracies remain unexplored. This study uses simulations to evaluate six control methods, originally designed to stabilize isolated populations, in metapopulations. We compared these methods across twelve ecological conditions based on three stability metrices and implementation costs. Without interventions, the twelve metapopulation scenarios exhibited distinct dynamics and extinction susceptibilities. Comparing the control methods against these baseline dynamics, we found that Adaptive Limiter Control consistently reduced extinction probabilities, while Lower Limiter Control effectively minimized population fluctuations in most settings, followed by Adaptive and Both Limiter Controls. These performance rankings remained robust despite simulated census errors. Our findings provide actionable insights for conservation policies aimed at stabilizing vulnerable metapopulations and offer a general framework for studying metapopulation dynamics using external interventions.
Small molecule inhibitors of hnRNPA2B1-RNA interactions reveal a predictable sorting of RNA subsets into extracellular vesicles
Authors: Corsi Jessica , Peroni Daniele , Belli Romina , Lassandro Michelangelo , Sidarovich Viktoryia , Adami Valentina , Grosskreutz Julian , Fabbiano Fabrizio , Grossmann Dajana , Hermann Andreas , Tell Gianluca , Basso Manuela , D’Agostino Vito Giuseppe 
Published: February 2024

AbstractExtracellular vesicles (EVs) are cell-secreted membranous particles contributing to intercellular communication. Coding and non-coding RNAs are widely detected EV cargo, and RNA-binding proteins (RBPs), such as hnRNPA2B1, have been circumstantially implicated in sorting vesicular RNAs. However, the contribution of competitive RBP-RNA interactions responsible for RNA-sorting outcomes still needs to be deciphered, especially for EV-RNA interference and predictability. We conducted a reverse proteomic analysis that prioritized heterogeneous nuclear ribonucleoproteins recognizing purine-rich RNA sequences representing a subset of previously identified EXO motifs. A screening campaign using a full-length human hnRNPA2B1 protein and artificial purine-rich RNA brought to small molecule inhibitors orthogonally validated through biochemical and cell-based approaches. Selected drugs effectively interfered with a post-transcriptional layer impacting secreted EV- RNAs, reducing the vesicular pro-inflammatory miR-221 while counteracting the hnRNPA2B1- or TDP43Q331K-dependent paracrine activation of NF-κB in EV-recipient cells. This study demonstrates the possibility of predicting the EV-RNA quality for developing innovative strategies targeting discrete paracrine functions.SummaryExtracellular vesicles (EVs) are cell-released, heterogeneous lipid particles conceived as vehicles for intercellular communication. RNA is a widely detected cargo, and the comprehension of EV-sorting mechanisms represents a step forward in predicting EV quality and associated paracrine effects. While it is known that specific RNA-binding proteins (RBPs) play a role in EV-RNA sorting, the quantitative contribution of competing RBP-RNA interactions and the predictability of RNA-sorting outcomes are poorly understood. Here, we show that a core of hnRNPs compete for the binding to the heterogeneous EV-RNAin vitro. Given prioritized interactions with purine-rich RNA motifs, we set up a pharmacological screen platform to find inhibitors of protein-RNA interactions. Our results suggest that selected small molecules can interfere with EV-RNA quality, altering the distribution of specific miRNA cargoes and associating with a discriminant NF-kB activation in EV-recipient cells. This work highlights the role of RBP-RNA interactions in influencing the EV-RNA quality and paracrine functions.
Backpropagation-Based Recollection of Memories: Biological Plausibility and Computational Efficiency
Authors: Ben Houidi Zied 
Published: February 2024

AbstractSince the advent of the neuron doctrine more than a century ago, information processing in the brain is widely believed to follow the forward pre to post-synaptic neurons direction. Challenging this view, we introduce thebackpropagation-based recollectionhypothesis as follows:Cue-based memory recollection occurs when backpropagated Action Potentials (APs), originating in sparse neurons that uniquely activate in response to a specific trace being recalled (e.g. image of a cat), travel backwards. The resulting transient backpropagating currents follow the available open backward and lateral pathways, guided by synaptic weights or couplings. In doing so, they stimulate the same neurons that fired during the very first perception and subsequent encoding, effectively allowing a “replay” of the experience (e.g., recalling the image of the cat).This process is pervasive, seen in tasks like cue-based attention, imagination, future episodic thinking, modality-specific language understanding, and naming.After detailing our hypothesis, we challenge it against a thorough literature review, finding compelling evidence supporting our claims. We further found that gap junctions could be a plausible medium for such currents, and that cholinergic modulation, which is known to favour backpropagated APs and is crucial for memory, is a reasonable candidate trigger for the entire process. We then leverage computer simulations to demonstrate the computational efficiency of the backpropagation-based recollection principle in (i) reconstructing an image, backwards, starting from its forward-pass sparse activations and (ii) successfully naming an object with a comparable high accuracy as a state of the art machine learning classifier. Given the converging evidence and the hypothesis’s critical role in cognition, this paradigm shift warrants broader attention: it opens the way, among others, to novel interpretations of language acquisition and understanding, the interplay between memory encoding and retrieval, as well as reconciling the apparently opposed views between sparse coding and distributed representations, crucial for developing a theory of consciousness and the mind.Significance StatementTry to mentally picture the image of a cat. In this process, the word “cat” acted as a cue, and the fragile and non-persistent retrieved mental image is a recollected memory. Similar cue-based generative activities are ubiquitous in our lives, yet the underlying neural mechanisms are still a mystery. Neuroimaging and optogenetic-based studies suggest that cue-based recollection of memories involve the reactivation of the same neural ensembles which were active during perception (encoding). However, the exact neural mechanisms that mediate such reactivation remain unknown. We elaborate a novel hypothesis explaining how this can be implemented at single neurons: we hypothesize that the very same neural pathways used for perception are used backwards for recall, thus creating similar impressions during retrieval.
The molecular basis of the anticancer effect of statins
Authors: Buccioli Giovanni , Testa Carolina , Jacchetti Emanuela , Pinoli Pietro , Carelli Stephana , Ceri Stefano , Raimondi Manuela T. 
Published: February 2024

AbstractStatins, one of the most used class of cardiovascular drugs with the primary function of reducing blood cholesterol levels, exert their effect by inhibiting the enzyme HMG-CoA reductase, the key player in cholesterol biosynthesis. While the primary indication for statins is the prevention of cardiovascular diseases, there has been growing interest in their potential anticancer effects. However, the current evidence on these effects is largely based on epidemiological observations and preclinical research, not yet substantiated by knowledge of the mechanisms behind it. Here we show that statins have an anticancer effect as they exploit the principle of Synthetic Lethality, a concept in which the combination of two non-lethal genetic or molecular events results in cell death or impairment. When either of these events occurs alone, it is not lethal, but when they happen coupled, they create a lethal condition for the cell. In this work we report that statins emerged from a computational data analysis that we performed on approximately 37,000 synthetic lethality couples. We performed this analysis to select repurposable drugs that could target genes involved in Synthetic Lethality couples with metastatic genes. We validated our discoveryin vitroby drug tests performed on cell lines derived from cancers of the breast, ovary, and cervix. Our data-driven drug repurposing strategy allowed us to understand the molecular basis of the anticancer effect of statins, a discovery which can be directly translated into practical clinical applications in oncology.
Evolutionary analysis of genome-specific duplications in flatworm genomes
Authors: Langleib Mauricio , Calvelo Javier , Costábile Alicia , Castillo Estela , Tort José F. , Hoffmann Federico G. , Protasio Anna V. , Koziol Uriel , Iriarte Andrés 
Published: February 2024

AbstractPlatyhelminthes, also known as flatworms, is a phylum of bilaterian invertebrates infamous for their parasitic representatives. The classes Cestoda, Monogenea, and Trematoda comprise parasitic helminths inhabiting multiple hosts, including fishes, humans, and livestock, and are responsible for considerable economic damage and burden on human health. As in other animals, the genomes of flatworms have a wide variety of paralogs, genes related via duplication, whose origins could be mapped throughout the evolution of the phylum. Throughin-silicoanalysis, we studied inparalogs,i.e., genome-specific duplications, focusing on their biological functions, expression changes, and evolutionary rate. These genes are assumed to be key players in the adaptation process of species to each particular niche. Our results showed that genes associated with specific functions, such as response to stress, ion binding, oxidoreductase activity, and peptidase, are overrepresented among inparalogs. This trend is conserved among species from different classes, including free-living species. Available expression data fromSchistosoma mansoni, a parasite from the trematode class, demonstrated high conservation of the expression patterns between inparalogs, but with notable exceptions, which also display evidence of rapid evolution. We discuss how natural selection may operate to maintain these genes and the particular duplication models that fit better to the observations. Our results support the critical role of gene duplication in the evolution of flatworms.
Tumor suppressor heterozygosity and homologous recombination deficiency mediate resistance to front-line therapy in breast cancer
Authors: Safonov Anton , Marra Antonio , Bandlamudi Chaitanya , O’Leary Ben , Wubbenhorst Bradley , Ferraro Emanuela , Moiso Enrico , Lee Minna , An Julia , Donoghue Mark T.A. , Will Marie , Pareja Fresia , Nizialek Emily , Lukashchuk Natalia , Sofianopoulou Eleni , Liu Yuan , Huang Xin , Ahmed Mehnaj , Mehine Miika M. , Ross Dara , Mandelker Diana , Ladanyi Marc , Schultz Nikolaus , Berger Michael F. , Scaltriti Maurizio , Reis-Filho Jorge S. , Li Bob T. , Offit Ken , Norton Larry , Shen Ronglai , Shah Sohrab , Maxwell Kara N. , Couch Fergus , Domchek Susan M. , Solit David B. , Nathanson Katherine L. , Robson Mark E. , Turner Nicholas C. , Chandarlapaty Sarat , Razavi Pedram 
Published: February 2024

ABSTRACTThe co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, but their combined biologic and clinical significance has not been evaluated. To assess the role of germline-somatic interactions on outcomes in routine practice, we developed an integrated clinicogenomic pipeline to analyze the genomes of over 4,500 patients with breast cancer. We find that germline (g)BRCA2-associated tumors are enriched forRB1loss-of-function mutations and manifest poor outcomes on standard-of-care, front-line CDK4/6 inhibitor (CDK4/6i) combinations. Amongst these tumors, gBRCA2-related homologous recombination deficiency (HRD) as well as baselineRB1LOH status promote acquisition ofRB1loss-of- function mutations under the selective pressure of CDK4/6i, causing therapy resistance. These findings suggest an alternative therapeutic strategy using sequential targeting of HRD in gBRCA-associated breast cancers through PARP inhibitorsprior toCDK4/6i therapy to intercept deleteriousRB1-loss trajectories and thus suppress the emergence of CDK4/6 inhibitor resistance. More broadly, our findings demonstrate how germline-somatic driven genomic configurations shape response to systemic therapy and can be exploited therapeutically as part of biomarker-directed clinical strategies.
Integrating Safety, Security, Sustainability and Social Responsibility Principles into the U.S Bioeconomy
Authors: Attal-Juncqua Aurelia , Getz John , Morhard Ryan , Gronvall Gigi Kwik 
Published: February 2024

AbstractBioindustrial manufacturing is undergoing rapid expansion and investment and is seen as integral to nations’ economic progress. Ensuring that bioindustrial manufacturing benefits society as the field expands is of critical, urgent importance. To better understand the industry’s ethical trajectory and to shape policy, we explored the views of biotechnology leaders on 4 aspects of ethical and social responsibility: - Safety, Security, Social Responsibility, and Sustainability, what we have termed “4S Principles”. We identified policy actions governments and other stakeholders may take to maximize societal benefits in industrial biotechnology.
Feature Reuse and Scaling: Understanding Transfer Learning with Protein Language Models
Authors: Li Francesca-Zhoufan , Amini Ava P. , Yue Yisong , Yang Kevin K. , Lu Alex X. 
Published: February 2024

AbstractLarge pretrained protein language models (PLMs) have improved protein property and structure prediction from sequences via transfer learning, in which weights and representations from PLMs are repurposed for downstream tasks. Although PLMs have shown great promise, currently there is little understanding of how the features learned by pretraining relate to and are useful for downstream tasks. We perform a systematic analysis of transfer learning using PLMs, conducting 370 experiments across a comprehensive suite of factors including different downstream tasks, architectures, model sizes, model depths, and pretraining time. We observe that while almost all down-stream tasks do benefit from pretrained models compared to naive sequence representations, for the majority of tasks performance does not scale with pretraining, and instead relies on low-level features learned early in pretraining. Our results point to a mismatch between current PLM pretraining paradigms and most applications of these models, indicating a need for better pretraining methods.
Disentangling the age-dependent causal pathways affecting multiple paternity in house sparrows
Authors: Søraker Jørgen S. , Ranke Peter Sjolte , Wright Jonathan , Ringsby Thor Harald , Sæther Bernt-Erik , Jensen Henrik , Araya-Ajoy Yimen G. 
Published: February 2024

AbstractThe causes of variation in multiple paternity (MP) in socially monogamous birds have received considerable attention. Traits like age and age-dependent morphology have been shown to be important for the distribution of MP. However, most studies fail to separate between the different processes underlying age-effects on MP, such as selective disappearance (that is, higher survival probability for certain phenotypes) versus individually plastic changes in morphology and mating behaviour with age. Using Bayesian multi-level path analysis on a long-term dataset from a house sparrow (Passer domesticus) metapopulation, we disentangle the effects of age on male and female MP, both independently from and through morphological traits. Age was a key determinant of MP for males when accounting for morphological traits, with males having MP more often as they get older (plastic component of age) and not due to disappearance of males unsuccessful to get MP (selective disappearance), challenging ‘good genes’ explanations for MP. Conversely, selective disappearance explained the higher levels of MP in older females, suggesting that higher quality females have MP more often than lower quality females. We show how an appropriate statistical decomposition of age-components and age-dependent processes provides insights to the biological drivers of MP.
Discovery of steroidal alkaloid metabolites and their accumulation in pigs after short-term tomato consumption
Authors: Sholola Maria J. , Goggans Mallory L. , Dzakovich Michael P. , Francis David M. , Jacobi Sheila K. , Cooperstone Jessica L. 
Published: February 2024

ABSTRACTScopeWhole tomato consumption has been shown to be more effective than lycopene alone against chronic disease risks, suggesting other phytochemicals play a role in the health properties of tomato-rich diets. Recently, metabolites of tomato steroidal alkaloids, an understudied class of secondary plant compounds, have been found in plasma, tissues, and urine. However, a comprehensive, targeted analysis to determine which steroidal alkaloid metabolites are present after tomato consumption is lacking. This study profiles and quantifies tomato steroidal alkaloids in blood for the first time.Methods and resultsIn a two-week parallel-arm study, piglets (n = 20) were fed diets containing 10% tomato powder or a macronutrient-matched control. Steroidal alkaloids were extracted from plasma and quantified using LC-MS. Tomatidine and alpha-tomatine were detected in plasma and confirmed with standards, while mass fragmentation spectra aided in identifying 31 additional metabolites representing 9 unique masses. Concentrations averaged to 107.7 nmol/L plasma, comprising of phase I (66%) and phase II (4.5%) metabolites.ConclusionThese results describe the profile and concentration of steroidal alkaloid metabolites in pig plasma after short-term tomato consumption. Our methodology and findings allow for future investigations of tomato steroidal alkaloid bioactivity using physiologically appropriate levels.
High-recombining genomic regions affect demography inference
Authors: Ishigohoka Jun , Liedvogel Miriam 
Published: February 2024

AbstractInference of population history of non-model species is important in evolutionary and conser- vation biology. Multiple methods of population genomics, including those to infer population history, are based on the ancestral recombination graph (ARG). These methods use observed mutations to model local genealogies changing along chromosomes. Breakpoints at which genealogies change effectively represent the positions of historical recombination events. How- ever, inference of underlying genealogies is difficult in regions with high recombination rate relative to mutation rate. This is because genealogies cover genomic intervals that are too short to accommodate sufficiently many mutations informative of the structure of the un- derlying genealogies. Despite the prevalence of high-recombining genomic regions in some non-model organisms, such as birds, its effect on ARG-based demography inference has not been well studied. Here, we use population genomics simulations to investigate the impact of high-recombining regions on ARG-based demography inference. We demonstrate that inference of effective population size and the time of population split events is systematically affected when high-recombining regions cover wide breadths of the chromosomes. We also show that excluding high-recombining genomic regions can practically mitigate this effect. Finally, we confirm the relevance of our findings in empirical analysis by contrasting demography inferences applied for a bird species, the Eurasian blackcap (Sylvia atricapilla), using different parts of the genome with high and low recombination rates. Our results suggest that demography inference using ARG-based methods should be carried out with caution when applied in species whose reference genomes contain long stretches of high-recombining regions.
Current approaches in livestock geotagging: Assessing available technologies and applications to public health research
Authors: Meisner Julianne , Bodha Boku , Stothard J. Russell , Juhasz Alexandra , Makaula Peter , Musaya Janelisa , Ngere Isaac , Gachohi John , Njenga M. Kariuki , Oketch Dismas , Muriuki Waiguru , Osoro Eric 
Published: February 2024

ABSTRACTLivestock geotrackers are increasingly used for public health research, particularly within the field of One Health, to draw inference on pathogen exposure and human risk from livestock movement data. There are many dozens, if not hundreds, of devices available to researchers, including devices purpose built for livestock such as collars, ear tags, rumen boluses, or other formats; those intended for wildlife but suitable for livestock; and devices intended for other geotracking applications which can be retrofitted for livestock. To assist other researchers in navigating the wealth of available options, we present here our experiences with six devices—four intended for livestock, one intended for wildlife, and one intended for humans— each applied to cattle, camels, sheep, goats, and donkeys. We summarize the technical specifications and features of these devices, our deployment strategies, and our experiences in terms of battery life, durability, data quality and retrieval, and acceptability by livestock owners.