bluuebunny/crossref_metadata_2025 huggingface dataset:
Disrupted cardiac bioenergetics linked to oxidized mitochondrial creatine kinase are rescued by the mitochondrial-targeting peptide SBT-20 in the D2.mdx model of Duchenne muscular dystrophy
Authors: Perry Christopher G.R. , Hughes Meghan C , Ramos Sofhia V , Brahmbhatt Aditya , Turnbull Patrick C , Polidovitch Nazari , Garibotti Madison C , Schlattner Uwe , Hawke Thomas J , Simpson Jeremy A , Backx Peter H
Published: February 2024

Mitochondrial creatine kinase (mtCK) regulates the fast export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such creatine-dependent phosphate shuttling is attenuated in several muscles, including the heart, of the D2.mdx mouse model of Duchenne muscular dystrophy at only 4 weeks of age. Here, we determined whether such attenuations occur in later stages in D2.mdx (12 months of age) in relation to mtCK thiol redox state, and whether this pathway could be preserved through administration of the mitochondrial-targeting, ROS-lowering tetrapeptide, SBT-20, in the D2.mdx mouse. In permeabilized muscle fibres prepared from cardiac left ventricles, we found that aged male D2.mdx mice have reduced creatine-dependent pyruvate oxidation and elevated complex I-supported H2O2 emission (mH2O2). Surprisingly, creatine-independent ADP-stimulated respiration was increased and mH2O2 was lowered suggesting that impairments in the faster mtCK-mediated phosphocreatine export system resulted in compensation of the alternative slower pathway of ATP export. The apparent impairments in mtCK-dependent bioenergetics occurred independent of mtCK protein content but were related to greater thiol oxidation of mtCK and a more oxidized cellular environment (lower GSH:GSSG). We then found that 12 weeks of daily treatment with SBT-20 (from day 4 to ~12 weeks of age) increased respiration and lowered mH2O2 only in the presence of creatine in D2.mdx mice without affecting calcium-induced mitochondrial permeability transition pore activity. In summary, creatine-dependent mitochondrial bioenergetics are attenuated in older D2.mdx mice in relation to mtCK thiol oxidation, which can be preserved with a ROS-lowering mitochondrial-targeting peptide. These results demonstrate a specific relationships between redox stress and metabolic reprogramming during dystrophin deficiency that can be targeted with small peptide therapeutics.
Comparison of six methods for stabilizing metapopulation dynamics and for their robustness against census noise
Authors: Singh Akanksha , Tung Sudipta
Published: February 2024

Natural 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

Extracellular 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.

Extracellular 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

Since 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 Statement

Try 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

Statins, 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

Platyhelminthes, 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

The 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

Bioindustrial 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

Large 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

The 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

Scope

Whole 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 results

In 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.

Conclusion

These 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

Inference 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

Livestock 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.
Ultra-high efficiency T cell reprogramming at multiple loci with SEED-Selection
Authors: Chang Christopher R. , Vykunta Vivasvan S. , Goodman Daniel B. , Muldoon Joseph J. , Nyberg William A. , Liu Chang , Allain Vincent , Rothrock Allison , Wang Charlotte H. , Marson Alexander , Shy Brian R. , Eyquem Justin
Published: February 2024

Multiplexed reprogramming of T cell specificity and function can generate powerful next-generation cellular therapies. However, current manufacturing methods produce heterogenous mixtures of partially engineered cells. Here, we develop a one-step process to enrich for unlabeled cells with knock-ins at multiple target loci using a family of repair templates namedSyntheticExon/Expression Disruptors (SEEDs). SEED engineering associates transgene integration with the disruption of a paired endogenous surface protein, allowing non-modified and partially edited cells to be immunomagnetically depleted (SEED-Selection). We design SEEDs to fully reprogram three critical loci encoding T cell specificity, co-receptor expression, and MHC expression, with up to 98% purity after selection for individual modifications and up to 90% purity for six simultaneous edits (three knock-ins and three knockouts). These methods are simple, compatible with existing clinical manufacturing workflows, and can be readily adapted to other loci to facilitate production of complex gene-edited cell therapies.
Epithelial folding through local degradation of an elastic basement membrane plate
Authors: Guerra Santillán K. Yanín , Jantzen Caroline , Dahmann Christian , Fischer-Friedrich Elisabeth
Published: February 2024

Epithelia are polarised layers of cells that line the outer and inner surfaces of organs. At the basal side, the epithelial cell layer is supported by a basement membrane, which is a thin polymeric layer of self-assembled extracellular matrix (ECM) that tightly adheres to the basal cell surface. Proper shaping of epithelial layers is an important prerequisite for the development of healthy organs during the morphogenesis of an organism. Experimental evidence indicates that local degradation of the basement membrane drives epithelial folding. Here, we present a coarse-grained plate theory model of the basement membrane that assumes force balance between i) cell-transduced active forces and ii) deformation-induced elastic forces. We verify key assumptions of this model through experiments in theDrosophilawing disc epithelium and demonstrate that the model can explain the emergence of outward epithelial folds upon local plate degradation. Our model accounts for local degradation of the basement membrane as a mechanism for the generation of epithelial folds in the absence of epithelial growth.
Eco-Anthropological factors explaining forest patch use by 3 species of wild Atelid monkeys co-existing with a small-scale farming community in Northeastern Costa Rica, Central America
Authors: Perea-Rodríguez Juan Pablo , Carbonero Hugo , Vargas Rocio , Chaves Claudia
Published: February 2024

The main risks for the conservation of wild non-human primates (NHP) in Costa Rica, Central America, are deforestation and the allocation of lands for agricultural activities. This is because these ecologically deleterious practices fragment continuous forests resulting in a mosaic of forest patches that differ in size and properties. Due to this, NHP, who are currently the vertebrates with the highest risk and rate of extinction, slowly adapt to this rapid environmental change, minimizing their metabolic costs to survive and reproduce. One way to balance these costs is to use forest patches depending on the benefits they provide, such as, food, shelter, or social contact. In order to understand the possible environmental factors that explain the usage of a series of 8 connected forest patches byAteles geoffroyi,Alouata paliatta, andSapajus imitatorwe collected demographic, climatological and other environmental data from 2018 until 2021. We used information-theory (i.e., AICc-based) model selection to identify the factors that best explained the presence/absence and behavior of the species of interest in the forest patches studied. Model-averaged estimates of the 2-best ranked models showed that monkey presence was highest in warmer, more humid days, especially when other groups were seen in the patch. Behavioral patterns were best explained by 4 best-ranked models and their averaged parameter estimates indicate that behavioral patterns were different in each path (0.12 ± 0.05; estimate ± SE). Furthermore, monkeys rested more often when other groups of the same species were present (0.94 ± 0.25), and foraged more during warmer (−0.06 ± 0.01), more humid days (−0.02 ± 0.001), and smaller groups (−0.14 ± 0.01). Our findings suggest that the usage of the 8 forest patches monitored by the 3 Atelid species studied depends on patch characteristics, not related to size nor the presence of a reserve, by the presence of other NHP in the patch and the meteorological conditions.
Improving the generalization of protein expression models with mechanistic sequence information
Authors: Shen Yuxin , Kudla Grzegorz , Oyarzún Diego A.
Published: February 2024

The growing demand for biological products drives many efforts to maximize expression of heterologous proteins. Advances in high-throughput sequencing can produce data suitable for building sequence-to-expression models with machine learning. The most accurate models have been trained on one-hot encodings, a mechanism-agnostic representation of nucleotide sequences. Moreover, studies have consistently shown that training on mechanistic sequence features leads to much poorer predictions, even with features that are known to correlate with expression, such as DNA sequence motifs, codon usage or mRNA secondary structures. However, despite their excellent local accuracy, current sequence-to-expression models can fail to generalize predictions far away from the training data. Through a comparative study across datasets inEscherichia coliandSaccharomyces cerevisiae, here we show that mechanistic sequence features can provide gains on model generalization, and thus improving their utility for predictive sequence design. We explore several strategies to integrate one-hot encodings and mechanistic features into a single predictive model, including feature stacking, ensemble model stacking, and geometric stacking, a novel architecture based on graph convolutional neural networks. Our work casts new light on mechanistic sequence features, underscoring the importance of domain-knowledge and feature engineering for accurate prediction of protein expression levels.
Direct Coupling Analysis and The Attention Mechanism
Authors: Caredda Francesco , Pagnani Andrea
Published: February 2024

Proteins are involved in nearly all cellular functions, encompassing roles in transport, signaling, enzymatic activity, and more. Their functionalities crucially depend on their complex three-dimensional arrangement. For this reason, being able to predict their structure from the amino acid sequence has been and still is a phenomenal computational challenge that the introduction of AlphaFold solved with unprecedented accuracy. However, the inherent complexity of AlphaFold's architectures makes it challenging to understand the rules that ultimately shape the protein's predicted structure. This study investigates a single-layer unsupervised model based on the attention mechanism. More precisely, we explore a Direct Coupling Analysis (DCA) method that mimics the attention mechanism of several popular Transformer architectures, such as AlphaFold itself. The model's parameters, notably fewer than those in standard DCA-based algorithms, can be directly used for extracting structural determinants such as the contact map of the protein family under study. Additionally, the functional form of the energy function of the model enables us to deploy a multi-family learning strategy, allowing us to effectively integrate information across multiple protein families, whereas standard DCA algorithms are typically limited to single protein families. Finally, we implemented a generative version of the model using an autoregressive architecture, capable of efficiently generating new proteins in silico. The effectiveness of our Attention-Based DCA architecture is evaluated using different families of evolutionary-related proteins, whose structural data is sourced from the Pfam database.In this study, we introduce a shallow, unsupervised model designed to understand the self-attention layer within the Evoformer block of AlphaFold. We establish a method based on Direct Coupling Analysis (DCA), wherein the interaction tensor undergoes decomposition, leveraging the same structure employed in Transformer architectures. The model's parameters, notably fewer than those in standard DCA, are interpretable through an examination of the resulting attention matrices. These matrices enable the extraction of contact information, subsequently utilized for constructing the contact map of a protein family. Additionally, the self-attention decomposition in the DCA Hamiltonian form adopted here facilitates the definition of multi-family learning architecture, enabling the inference of parameter sets shared across diverse protein families. Finally, an autoregressive generative version of the model is implemented, capable of efficiently generating new proteins in silico. This generative model reproduces the summary statistics of the original protein family while concurrently inferring direct contacts in the tertiary structure of the protein. The effectiveness of our Attention-Based DCA architecture is evaluated using Multiple Sequence Alignments (MSAs) of varying lengths and depths, with structural data sourced from the Pfam database.
Massive perturbation of sound representations by anesthesia in the auditory brainstem
Authors: Gosselin Etienne , Bagur Sophie , Bathellier Brice
Published: February 2024

Anesthesia modifies sensory representations in the thalamo-cortical circuit, but is considered to have a milder impact on peripheral sensory processing. Here, tracking the same neurons across wakefulness and isoflurane anesthesia, we show that the amplitude and sign of single neuron responses to sounds are massively modified by anesthesia in the cochlear nucleus of the brainstem, the first relay of the auditory system. The reorganization of activity is so profound that decoding of sound representation in anesthesia is not possible based on awake activity. However, population level parameters, such as average tuning strength and population decoding accuracy are weakly affected by anesthesia, explaining why its effect has previously gone unnoticed when comparing independently sampled neurons. Together, our results indicate that the functional organization of the auditory brainstem largely depends on the network state and is ill-defined under anesthesia. This demonstrates a remarkable sensitivity of an early sensory stage to anesthesia, which is bound to disrupt downstream processing.

Teaser

Anesthesia compromises the normal transmission of sensory information as early as the first relay in the auditory system.
Genetic and functional dissection of the glutamate-proline pathway reveals a shortcut for glutamate catabolism inLeishmania
Authors: Campagnaro Gustavo Daniel , Cruz Angela Kaysel
Published: February 2024

Trypanosomatids are early-divergent eukaryotes that have adapted to parasitism. During their life cycles, these parasites switch between a mammalian and an invertebrate host, and the ability to adapt their metabolism to different nutritional sources is detrimental for their success. In the invertebrate host, these protists have access to high amounts of amino acids and efficiently utilise it for energy production. Proline is a particularly efficient energy source for trypanosomes. Glutamate is also efficiently used byTrypanosoma cruzi, but it needs to be converted into proline prior to its catabolism. By employing a series of genetic modifications and functional analysis, we show here thatLeishmaniaparasites, the causative agents of leishmaniases, can utilise proline, glutamate and glutamine as energy sources, and although these parasites possess all the genes necessary for the biosynthesis of proline from glutamate, this pathway has, at best, limited function, with at least one of its components (pyrroline-5-carboxylate reductase) assuming divergent functions in different life cycle stages of the parasite. In fact, we show that the catabolism of glutamate is independent of proline biosynthesis and the former is most likely directly imported into the mitochondrion and catabolised to recover the cellular redox metabolism and increase mitochondrial membrane potential. Moreover, our data suggest a relevant role for glutamate dehydrogenase in nutritional stress response inLeishmania. These findings highlight relevant differences in amino acid metabolism betweenTrypanosomaandLeishmaniaand suggest a diversification in amino acid metabolic pathways within Trypanosomatidae.
Natural aphrodisiacs consumption by male workers in the former Katanga province, DR Congo
Authors: Obadia Paul Musa , Mulaji Gaylord Kalenda , Musambo Taty Muta , Kitenge Joseph Pyana , Kuhangana Trésor Carsi , Kayembe-Kitenge Tony , Nkulu Célestin Banza Lubaba , Nemery Benoit , Enzlin Paul
Published: February 2024

Background

In a previous cross-sectional study to determine the prevalence and determinants of erectile dysfunction (ED) among artisanal mineworkers, we found a significant association between ED and consumption of locally produced plant-derived aphrodisiacs.

Aim

We aimed to investigate the type and mode of consumption of aphrodisiacs, their possible health effects, and reasons for use among male workers in the Katanga province.

Methods

We conducted a mixed method study, first doing a survey (March 2021) among a convenience sample of 127 artisanal miners and 122 collective taxi-drivers. Participants responded to the International Index of Erectile Function (IIEF) questionnaire and had measurements of serum urea, creatinine, hepatic enzymes, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides and sexual hormones. In a second qualitative phase, 16 participants, i.e., eight miners and eight drivers were interviewed.

Results

Self-reported regular (at least once a week) consumption of aphrodisiacs was significantly more prevalent among taxi-drivers (75%) than among miners (47%). Mild-to-moderate and moderate ED were reported more frequently by aphrodisiacs consumers [20/152 (13%)] than non-consumers [6/97 (6%)]. Five types of plant-derived aphrodisiacs (Zingiber officinale, Mitragyna stipulosa, Ocimumsp, Piper nigrum, Securidaca longepedunculata) were consumed, via the oral or anal routes, sometimes together with alcohol. We found no evidence of nephrotoxicity, hepatotoxicity or disturbances in serum levels of sex hormones. Themes that emerged from interviews related to cultural perceptions about masculinity, with miners using aphrodisiacs to support failing erectile function, and taxi-drivers taking aphrodisiacs for preventing ED.

Conclusion

We found a high prevalence of plant-derived aphrodisiacs use among working men in Katanga. While no serious adverse effects were identified, more ethno-botanical studies with isolation and rigorous identification of active constituents are needed to provide the poor population with correct information and to protect them against possible unwanted toxic effects.
Whole Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families with Early Onset Complications
Authors: Mansoorshahi Sara , Yetman Anji T , Bissell Malenka M , Kim Yuli Y , Michelena Hector , Hui Dawn S , Caffarelli Anthony , Andreassi Maria G , Foffa Ilenia , Guo Dongchuan , Citro Rodolfo , De Marco Margot , Tretter Justin T , Morris Shaine A , Body Simon C , Chong Jessica X , Bamshad Michael J ,   University of Washington Center for Rare Disease Research,   BAVCon Investigators,   EBAV Investigators, Milewicz Dianna M , Prakash Siddharth K
Published: February 2024

Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation ofFBN2,MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.
Harnessing Deep Learning to Detect Bronchiolitis Obliterans Syndrome from Chest CT
Authors: Kozinski Mateusz , Oner Doruk , Gwizdala Jakub , Beigelman Catherine , Fua Pascal , Koutsokera Angela , Casutt Alessio , Palma Michele De , Aubert John-David , Bischof Horst , Garnier Christophe von , Rahi Sahand , Urschler Martin , Mansouri Nahal
Published: February 2024

Bronchiolitis Obliterans Syndrome (BOS), a fibrotic airway disease following lung transplantation, conventionally relies on pulmonary function tests (PFTs) for diagnosis due to limitations of CT images. Thus far, deep neural networks (DNNs) have not been used for BOS detection. We optimized a DNN for detection of BOS solely using CT scans by integrating an innovative co-training method for enhanced performance in low-data scenarios. The novel auxiliary task is to predict the temporal precedence of CT scans of BOS patients. We tested our method using CT scans at various stages of inspiration from 75 post-transplant patients, including 26 with BOS. The method achieved a ROC-AUC of 0.90 (95% CI: 0.840-0.953) in distinguishing BOS from non-BOS CT scans. Performance correlated with disease progression, reaching 0.88 ROC-AUC for stage I, 0.91 for stage II, and an outstanding 0.94 for stage III BOS. Importantly, performance parity existed between standard and high-resolution scans. Particularly noteworthy is the DNN’s ability to predict BOS in at-risk patients (FEV1 between 80% and 90% of best FEV1) with a robust 0.87 ROC-AUC (CI: 0.735-0.974). Using techniques for visually interpreting the results of deep neural networks, we reveal that our method is especially sensitive to hyperlucent areas compatible with air-trapping or bronchiectasis. Our approach shows the potential to improve BOS diagnosis, enabling early detection and management. Detecting BOS from low-resolution scans reduces radiation exposure and using scans at any stage of respiration makes our method more accessible. Additionally, we demonstrate that techniques that limit overfitting are essential to unlocking the power of DNNs in scenarios with scarce training data. Our method may enable clinicians to use DNNs in studies where only a modest number of patients is available.
IL-6R (trans-signaling) is a key regulator of reverse cholesterol transport in lipid-laden macrophages
Authors: Al-Rashed Fatema , AlSaeed Halemah , Almansour Nourah , Mulla Fahd Al- , Hannun Yusuf A. , Ahmad Rasheed
Published: February 2024

Background

Atherosclerosis epitomizes a multifaceted cardiovascular disorder, predominantly characterized by the accumulation of cholesterol-laden plaques within arterial walls. Despite substantial research, the precise mechanisms governing the formation of these cholesterol-rich plaques remain partially elucidated. This study delves into the complex interplay of interleukin-6 (IL-6) receptors, shedding light on their pivotal role in orchestrating cholesterol homeostasis in human macrophages.

Methods

This investigation evaluated the correlation between interleukin-6 (IL-6), its receptors (IL6R/CD126), and glycoprotein 130 (gp130), alongside established atherosclerosis biomarkers. The cohort comprised 142 subjects, balanced between lean and obese individuals (71 each). Subsequent analyses utilized THP-1-derived macrophages to discern the biochemical repercussions of inhibiting IL-6 receptors on cellular mechanisms.

Results

Data indicates a significant upsurge in IL-6 secretion correlating with atherosclerotic manifestations in the obese subset, accompanied by a concomitant diminution in IL-6 receptors IL6R/CD126 and gp130 on circulating monocytes within this group. Pharmacological obstruction of the gp130 receptor in macrophages provoked pronounced alterations in lipid metabolism, notably impacting cholesterol management. These alterations were evidenced by an escalated expression of the LDLR gene, responsible for cholesterol uptake, and a surge in de novo cholesterol synthesis, marked by the upregulation of SREBF2 and its downstream effector, mevalonate kinase (MVK). Concurrently, an increase in HMG-CoA reductase protein levels was observed. Intriguingly, a rise in intracellular cholesterol production coupled with a reduction in ABCA1 levels was noted, suggesting a potential impediment in cholesterol efflux in cells deficient in gp130. This hypothesis was further substantiated by Filipin III staining, which indicated cholesterol retention in cells subjected to gp130 inhibition. Clinical implications of these discoveries were corroborated through experiments on PBMCs from lean participants, where the gp130 inhibitor curtailed cholesterol efflux to levels comparable to those in untreated cells.

Conclusion

Collectively, our research underscores the instrumental role of gp130 in the reverse cholesterol transport pathway of macrophages. These insights pave the way for novel therapeutic strategies targeting atherosclerosis and its associated cardiovascular complications, spotlighting gp130 as a potential focal point for intervention.
Transthyretin orchestrates vitamin B12-induced stress resilience
Authors: Stein G. , Aly J.S. , Manzolillo A. , Lange L. , Riege K. , Hussain I. , Heller E.A. , Cubillos S. , Ernst T. , Hübner C.A. , Turecki G. , Hoffmann S. , Engmann O.
Published: February 2024

Chronic stress significantly contributes to mood- and anxiety disorders. Previous and current data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood. This study reveals a molecular pathway that functionally connects vitamin B12, DNA methylation (DNAme), and stress resilience. We identified Transthyretin (Ttr) as a sex-specific key target of vitamin B12 action in chronic stress. Accordingly,TTRexpression was increased postmortem in the prefrontal cortex of male, but not female, depressed patients. Virally alteredTtrin the prefrontal cortex functionally contributed to stress- and depression-related behaviors, changes in dendritic spine morphology and gene expression. In stressed mice, vitamin B12 reduced DNAme in theTtrpromoter region. Importantly, usingin vivoepigenome editing to alter DNAme in the brains of living mice for the first time, we establish a direct causal link between DNAme onTtrand stress-associated behaviors. In summary, using state-of-the-art techniques, this study uncovers a mechanistic link between cobalamin supplementation and markers of chronic stress and depression, encouraging further studies into environmental interventions for mood disorders.