bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractMultiplexed 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.
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

AbstractThe 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

AbstractThe 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.
Massive perturbation of sound representations by anesthesia in the auditory brainstem
Authors: Gosselin Etienne , Bagur Sophie , Bathellier Brice 
Published: February 2024

AbstractAnesthesia 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.TeaserAnesthesia 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

ABSTRACTTrypanosomatids 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

AbstractBackgroundIn 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.AimWe 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.MethodsWe 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.ResultsSelf-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.ConclusionWe 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

AbstractBicuspid 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

AbstractBronchiolitis 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

AbstractBackgroundAtherosclerosis 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.MethodsThis 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.ResultsData 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.ConclusionCollectively, 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

AbstractChronic 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.
Eyespots originated multiple times independently across the Lepidoptera
Authors: Hanotte Brian , Willink Beatriz , Monteiro Antónia 
Published: February 2024

AbstractEyespot colour patterns function as an effective defence against predators and have evolved numerous times independently across animals. In Nymphalid butterflies, eyespots have a single evolutionary origin close to the base of this clade, but eyespots are also present in many other lepidopteran lineages and may have multiple independent origins. Here we use phylogenetic comparative methods to investigate the evolution of eyespots across a multi-superfamily phylogeny of Lepidoptera, and to pinpoint lineages in which eyespots likely originated independently. We find a total of 30 separate origins of Discal eyespots (in the discal wing region) and 21 separate origins of Marginal eyespots (in the marginal wing region), a type of serial homologue. In four instances eyespots were preserved in most extant representatives of a subsequent species radiation. In one such instance, in the Nymphalidae, we found a Marginal eyespot common ancestor predating the origin of a Discal eyespot baring ancestor, while in the Saturniidae we observed the opposite. We conclude that eyespots do not appear to be homologous across the Lepidoptera. However, our phylogenetic inference provides a roadmap for future developmental and functional studies that can address whether discal and marginal eyespots share a homologous gene-regulatory network. This study, therefore, has implications for our understanding of the evolution of serial homologues and of convergent evolution of visual signals in insects.
Engineering an anti-CD206-synNotch receptor: insights into the development of novel synthetic receptors
Authors: Semeniuk Sofija , Qian Bin-Zhi , Cachat Elise 
Published: February 2024

AbstractImmune cells play a pivotal role in the establishment, growth and progression of tumors at primary and metastatic sites. Macrophages, in particular, play a critical role in suppressing immune responses and promoting an anti-inflammatory environment through both direct and indirect cell-cell interactions. However, our understanding of the mechanisms underlying such interactions is limited due to a lack of reliable tools for studying transient interactions between cancer cells and macrophages within the tumor microenvironment. Recent advances in mammalian synthetic biology have introduced a wide range of synthetic receptors that have been used in diverse biosensing applications. One such synthetic receptor is the synNotch receptor, which can be tailored to sense specific ligands displayed on the surface of target cells. With this study, we aimed at developing a novelαCD206-synNotch receptor, targeting CD206+macrophages, a population of macrophages that play a crucial role in promoting metastatic seeding and persistent growth. Engineered in cancer cells and used in mouse metastasis models, such tool could help monitor and understand the effects cell-cell interactions between macrophages and cancer cells have on metastasis establishment. Here, we report the development of cancer landing pad cells for versatile applications, the engineering ofαCD206-synNotch cells, report the measurements of their activity and specificity, and discuss the unexpected caveats when considering theirin vivoapplications.
Endosomal LRBA regulates the endo-lysosomal pathway
Authors: Szentgyörgyi Viktória , Lueck Leon Maximilian , Overwijn Daan , Zoeller Nadia , Hondele Maria , Spang Anne , Bakhtiar Shahrzad 
Published: February 2024

AbstractDeleterious mutations in theLRBA(Lipopolysaccharide Responsive Beige-like Anchor protein) gene cause severe childhood immune dysregulation. The clinical manifestations of LRBA deficiency syndrome are highly variable. Thus, the complexity of the symptoms involving multiple organs and the broad range of unpredictable clinical manifestations complicate the choice of therapeutic interventions. Although LRBA has been linked to Rab11-dependent trafficking of the immune checkpoint protein CTLA-4, its precise cellular role remains elusive. We show that LRBA, however, does not colocalize with Rab11. Instead, LRBA is recruited by members of the small GTPase Arf protein family to the TGN and to Rab4+endosomes, where it controls intracellular traffic. In patient-derived fibroblasts, loss of LRBA led to defects in the endosomal pathway yielding the accumulation of enlarged endolysosomes. Thus, LRBA appears to regulate flow through the endosomal system on Rab4+endosomes. Our data strongly suggest functions of LRBA beyond CTLA-4 trafficking and provide a conceptual framework to develop new therapies for LRBA deficiency.SummaryLRBA-deficient patients exhibit enlarged functional endolysosomes due to defects in recycling to the plasma membrane. LRBA localization on Rab4+endosomes depends on Arf1 and Arf3, and is essential for a functional endosomal-lysosomal pathway. Our results could inform new treatment options.