bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promoting intestinal healing by exclusive enteral nutrition with TGF-β in a mouse model of colitis
Authors: Boumessid Kawthar , Lacroix Vickie , Ovtchinnikova Ekaterina , Quaranta Nicaise Muriel , Roy Maryline , Dumay Anne , Thenet Sophie , Carriere Marie , Mas Emmanuel , Barreau Frédérick 
Published: September 2023

ABSTRACTBackground and aimsExclusive Enteral Nutrition (EEN) is the first line of treatment for pediatric Crohn’s disease (CD), but its mechanisms of action remain poorly understood. We studied EEN nutritional composition and TGF-β effect in a mouse model of colitis, as well as the role of intestinal microbiota.MethodsMice were treated with Dextran Sulfate Sodium (DSS) during 5 days to induce colitis, until the inflammatory peak (day 7) or gut restitution (day 14). After DSS treatment, some of them received EEN formula such as Modulen IBD® (DM mice) or Infatrini Peptisorb® (DINF mice), with TGF-β supplementation or neutralization, and clinical inflammation was evaluated. After sacrifice, macroscopic and microscopic inflammation were analyzed, as well as intestinal permeability (IP). The composition of mucosal colonic microbiota was analyzed and fecal microbiota transplantation was performed to evaluate its capacity to mediate anti-inflammatory and pro-regenerative effect. Colonic crypts from DSS and EEN mice were cultured as 3D organoids and cellular properties were analyzed.ResultsDSS mice developed colitis, as evidenced by the weight loss and clinical inflammation. It was accompanied by macroscopic inflammation such as colon thickness and edemas, and an elevated IP. In contrast, EEN mice with TGF-β formula present faster weight recovery and decreased inflammatory parameters, with a normalized IP, suggesting gut restitution and functionality. These functional improvements were not obtained for EEN mice without TGF-β formula. Moreover, EEN with Modulen IBD® (DM mice) modified the microbiota in comparison to DSS condition and attenuated inflammation. In addition, the organoids from DM mice colonic crypts treated had an enhanced survival, and re-epithelialization capacity.ConclusionsBoth EEN formula have anti-inflammatory properties, certainly by the nutritional composition. However, TGF-β plays a significant role in intestinal restitution and restoring barrier function. These beneficial effects are partly mediated by the microbiota to maintain gut homeostasis.
Methods for tagging an ectoparasite, the salmon louseLepeophtheirus salmonis
Authors: Folk Alexius , Mennerat Adèle 
Published: September 2023

ABSTRACTMonitoring individuals within populations is a cornerstone in evolutionary ecology, yet individual tracking of invertebrates and particularly parasitic organisms remains rare. To address this gap, we describe here a method for attaching radio frequency identification (RFID) tags to individual adult females of a marine ectoparasite, the salmon louseLepeophtheirus salmonis. Comparing two alternative types of glue, we found that one of them (2-octyl cyanoacrylate,2oc) gave a significantly higher tag retention rate than the other (ethyl 2-cyanoacrylate,e2c). This glue comparison test also resulted in a higher loss rate of adult ectoparasites from the population where tagging was done using2oc, but this included males not tagged and thus could also suggest a mere tank effect. Corroborating this, a more extensive analysis using data collected over two years showed no significant difference in mortality after repeated exposure to the2ocglue, nor did it show any significant effect of the tagging procedure on the reproduction of female salmon lice. The proportion of RFID-tagged individuals followed a negative exponential decline, with tag retention among the living female population generally high. The projected retention was found to be about 88% after 30 days or 80% after 60 days, although one of the four batches of glue used, purchased from a different supplier, appeared to give significantly lower tag retention and with greater initial loss (74% and 60% respectively). Overall, we find that RFID tagging is a simple and effective technology that enables documenting individual life histories for invertebrates of a suitable size, including marine and parasitic species, and that it can be used over long periods of study.
Motor neuron activity induces proteomic stress in the target muscle
Authors: Srivastav Saurabh , van der Graaf Kevin , Jonnalagadda Prisha C. , Thawani Maanvi , McNew James A. , Stern Michael 
Published: September 2023

AbstractSeveral lines of evidence demonstrate that increased neuronal excitability can enhance proteomic stress. For example, epilepsy can enhance the proteomic stress caused by the expression of certain aggregation-prone proteins implicated in neurodegeneration. However, unanswered questions remain concerning the mechanisms by which increased neuronal excitability accomplishes this enhancement. Here we test whether increasing neuronal excitability at a particular identified glutamatergic synapse, the Drosophila larval neuromuscular junction, can enhance the proteomic stress caused by mutations in the ER fusion geneatlastin(atl). It was previously shown that larval muscle from theatl2null mutant is defective in autophagy and accumulates protein aggregates containing ubiquitin (poly-UB aggregates). To determine if increased neuronal excitability might enhance the increased proteomic stress caused byatl2, we activated theTrpA1-encoded excitability channel within neurons. We found that TrpA1 activation had no effect on poly-UB aggregate accumulation in wildtype muscle, but significantly increased poly-UB aggregate number inatl2muscle. Previous work has shown thatatlloss from either neuron or muscle increases muscle poly-UB aggregate number. We found that neuronal TrpA1 activation enhanced poly-UB aggregate number whenatlwas removed from muscle, but not from neuron. Neuronal TrpA1 activation enhanced other phenotypes conferred by muscleatlloss, such as decreased pupal size and decreased viability. Taken together, these results indicate that the proteomic stress caused by muscleatlloss is enhanced by increasing neuronal excitability.
SpyMask Enables Combinatorial Assembly of Bispecific Binders
Authors: Driscoll Claudia L. , Keeble Anthony H. , Howarth Mark 
Published: September 2023

ABSTRACTBispecific antibodies are a successful and expanding therapeutic class, bridging two cell-types or engaging two different molecules on the same cell. Bispecifics unlock avenues towards synergy, resistance evasion, and signaling bias. Standard approaches to generate bispecifics are complicated by the need for disulfide reduction/oxidation or cloning of each binder molecule in two different formats. Here we present a modular approach to bispecifics using SpyTag/SpyCatcher spontaneous amidation, where all binders are cloned in the same format, bearing a SpyTag. Two SpyTag-fused antigen-binding modules can be precisely conjugated onto DoubleCatcher, a tandem SpyCatcher where the second Catcher is unreactive until unveiling of reactivity using site-specific protease. Assembly on DoubleCatcher is efficient in phosphate-buffered saline at 37 °C, with half-times less than 5 min for both SpyCatcher arms and over 97% bispecific homogeneity. We engineer a panel of DoubleCatchers, locked through disulfide bonds to direct binders to project in different directions from the hub. We establish a generalized methodology for one-pot assembly and purification of bispecifics in 96-well plate format. A panel of Fab, affibody or nanobody binders recognizing different sites on HER2 were coupled to DoubleCatcher, revealing unexpected combinations with anti-proliferative or pro-proliferative activity on HER2-addicted cancer cells. Bispecific activity depended sensitively on both the order of the binders within the assembly and the geometry of DoubleCatcher scaffolds. These findings support the need for straightforward assembly in different formats. SpyMask provides a simple and scalable tool to discover synergy in bispecific activity, through modulating receptor organization and geometry.
A Stochastic Programming Approach to the Antibiotics Time Machine Problem
Authors: Mesüm Oğuz , Atilgan Ali Rana , Kocuk Burak 
Published: September 2023

AbstractAntibiotics Time Machine is an important problem to understand antibiotic resistance and how it can be reversed. Mathematically, it can be modelled as follows: Consider a set of genotypes, each of which contain a set of mutated and unmutated genes. Suppose that a set of growth rate measurements of each genotype under a set of antibiotics are given. The transition probabilities of a ‘realization’ of a Markov chain associated with each arc under each antibiotic are computable via a predefined function given the growth rate realizations. The aim is to maximize the expected probability of reaching to the genotype with all unmutated genes given the initial genotype in a predetermined number of transitions, considering the following two sources of uncertainties: i) the randomness in growth rates, ii) the randomness in transition probabilities, which are functions of growth rates. We develop stochastic mixed-integer linear programming and dynamic programming approaches to solve static and dynamic versions of the Antibiotics Time Machine Problem under the aforementioned uncertainties. We adapt a Sample Average Approximation approach that exploits the special structure of the problem and provide accurate solutions that perform very well in an out-of-sample analysis.
Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner
Authors: Maddhesiya Priya , Lepko Tjasa , Steiner-Mezzardi Andrea , Schwarz Veronika , Merl-Pham Juliane , Berger Finja , Hauck Stefanie M. , Ronfani Lorenza , Bianchi Marco , Masserdotti Giacomo , Götz Magdalena , Ninkovic Jovica 
Published: September 2023

AbstractBackgroundDirect conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding the influence of the injury-induced neuroinflammatory environment and released growth factors on the direct conversion process.ResultsWe established a newin vitroculture system of postnatal astrocytes without epidermal growth factor that reflects the direct conversion rate in the injured, neuroinflammatory environmentin vivo. We demonstrated that the growth factor combination corresponding to the injured environment defines the ability of glia to be directly converted to neurons. Using this culture system, we showed that chromatin structural protein high mobility group box 2 (HMGB2) regulates the direct conversion rate downstream of the growth factor combination. We further demonstrated that Hmgb2 cooperates with neurogenic fate determinants, such as Neurog2, in opening chromatin at the loci of genes regulating neuronal maturation and synapse formation. Consequently, early chromatin rearrangements occur during direct fate conversion and are necessary for full fate conversion.ConclusionsOur data demonstrate novel growth factor-controlled regulation of gene expression during direct fate conversion. This regulation is crucial for proper maturation of induced neurons and could be targeted to improve the repair process.
Population-Level Genetic Variation Shapes Generative Brain Mechanisms
Authors: Monaghan Alicja , Akarca Danyal , Astle Duncan E. 
Published: September 2023

ABSTRACTThe structural organisation of the human brain emerges probabilistically as we develop. Due to the inherent complexity of the human brain, understanding the forces that shape this probabilistic emergence remains one of the central challenges of systems theory and neuroscience. Across 2153 children (9-11 years old) we used a computational model to simulate the formation of structural brain connectivity, conceptualised as a trade-off between the cost of new connections η and their topological value γ. We then triangulated this population-level neuroimaging and computational modelling with genomics. For each participant we assessed their genetic propensity for cognitive ability by calculating polygenic scores. Modelled parameters differed systematically for participants depending upon their genetic propensity. Those with the highest genetic propensity had a significantly weaker η term – put simply, their networks emerged with a weaker distance penalty. Strikingly, this softer distance penalty produces more stochastic, diverse, and efficient networks. Furthermore, across the sample, overlapping biological and cellular pathways between polygenic scores and each child’s optimal η-γ trade-off emerged. This application of computational modelling demonstrates a converging genomic basis for structural brain development and cognitive ability across the population, providing a mechanistic explanation of how and why characteristic network topologies emerge from children at the extreme distributions of polygenic scores, and why they might predict cognitive ability.
Multi-omic dataset of patient-derived tumor organoids of neuroendocrine neoplasms
Authors: Alcala Nicolas , Voegele Catherine , Mangiante Lise , Sexton-Oates Alexandra , Clevers Hans , Fernandez-Cuesta Lynnette , Dayton Talya L. , Foll Matthieu 
Published: September 2023

AbstractBackgroundOrganoids are three-dimensional experimental models that summarize the anatomical and functional structure of an organ. Although a promising experimental model for precision medicine, patient-derived tumor organoids (PDTOs) have currently been developed only for a fraction of tumor types.ResultsWe have generated the first multi-omic dataset (whole-genome sequencing, WGS, and RNA-sequencing, RNA-seq) of PDTOs from the rare and understudied pulmonary neuroendocrine tumors (n= 12; 6 grade 1, 6 grade 2), and provide data from other rare neuroendocrine neoplasms: small intestine (ileal) neuroendocrine tumors (n= 6; 2 grade 1 and 4 grade 2) and large-cell neuroendocrine carcinoma (n= 5; 1 pancreatic and 4 pulmonary). This dataset includes a matched sample from the parental sample (primary tumor or metastasis) for a majority of samples (21/23) and longitudinal sampling of the PDTOs (1 to 2 time-points), for a total ofn= 47 RNA-seq andn= 33 WGS. We here provide quality control for each technique, and provide the raw and processed data as well as all scripts for genomic analyses to ensure an optimal re-use of the data. In addition, we report somatic small variant calls and describe how they were generated, in particular how we used WGS somatic calls to train a random-forest classifier to detect variants in tumor-only RNA-seq.ConclusionsThis dataset will be critical to future studies relying on this PDTO biobank, such as drug screens for novel therapies and experiments investigating the mechanisms of carcinogenesis in these understudied diseases.
Automatic Ploidy Prediction and Quality Assessment of Human Blastocyst Using Time-Lapse Imaging
Authors: Rajendran Suraj , Brendel Matthew , Barnes Josue , Zhan Qiansheng , Malmsten Jonas E. , Zisimopoulos Pantelis , Sigaras Alexandros , Ofori-Atta Kwabena , Meseguer Marcos , Miller Kathleen A , Hoffman David , Rosenwaks Zev , Elemento Olivier , Zaninovic Nikica , Hajirasouliha Iman 
Published: September 2023

AbstractAssessing fertilized human embryos is crucial for in vitro-fertilization (IVF), a task being revolutionized by artificial intelligence and deep learning. Existing models used for embryo quality assessment and chromosomal abnormality (ploidy) detection could be significantly improved by effectively utilizing time-lapse imaging to identify critical developmental time points for maximizing prediction accuracy. Addressing this, we developed and compared various embryo ploidy status prediction models across distinct embryo development stages. We present BELA (Blastocyst Evaluation Learning Algorithm), a state-of-the-art ploidy prediction model surpassing previous image- and video-based models, without necessitating subjective input from embryologists. BELA uses multitask learning to predict quality scores that are used downstream to predict ploidy status. By achieving an AUC of 0.76 for discriminating between euploidy and aneuploidy embryos on the Weill Cornell dataset, BELA matches the performance of models trained on embryologists’ manual scores. While not a replacement for preimplantation genetic testing for aneuploidy (PGT-A), BELA exemplifies how such models can streamline the embryo evaluation process, reducing time and effort required by embryologists.
Sexually discordant selection is associated with trait specific morphological changes and a complex genomic response
Authors: Audet Tyler , Krol Joelle , Pelletier Katie , Stewart Andrew D. , Dworkin Ian 
Published: September 2023

AbstractSexes often have differing fitness optima, potentially generating intra-locus sexual conflict, as each sex bears a genetic ‘load’ of alleles beneficial to the other sex. One strategy to evaluate conflict in the genome is to artificially select populations discordantly, against established sexual dimorphism, reintroducing attenuated conflict. We investigate a long-term artificial selection experiment reversing sexual size dimorphism inDrosophila melanogasterduring ∼350 generations of sexually discordant selection. We explore morphological and genomic changes to identify loci under selection between the sexes in discordantly and concordantly size selected treatments. Despite substantial changes to overall size, concordant selection maintained ancestral sexual dimorphism. However, discordant selection altered size dimorphism in a trait-specific manner. We observe multiple, possible soft selective sweeps in the genome, with size related genes showing signs of selection. Patterns of genomic differentiation between the sexes within lineages identified potential sites maintained by sexual conflict. One discordant selection lineage shows a pattern of elevated genomic differentiation on chromosome 3L, consistent with the maintenance of sexual conflict. Our results suggest measurable signs of conflict and differentially segregating alleles between the sexes due to discordant selection.
Electrophoresis-Based Approach for Characterizing Dendrimer-Protein Interactions: A Proof-of-Concept Study
Authors: Douglas-Green Simone A. , Aleman Juan A. , Hammond Paula T. 
Published: September 2023

AbstractImproving the clinical translation of nanomedicine requires better knowledge about how nanoparticles interact with biological environments. As researchers are recognizing the importance of understanding the protein corona and characterizing how nanocarriers respond in biological systems, new tools and techniques are needed to analyze nanocarrier-protein interactions, especially for smaller-size (<10nm) nanoparticles like polyamidoamine (PAMAM) dendrimers. Here we developed a streamlined, semi-quantitative approach to assess dendrimer-protein interactions using a non-denaturing electrophoresis technique combined with mass spectrometry. With this protocol, we detect fluorescently tagged dendrimers and proteins simultaneously, enabling us to analyze when dendrimers migrate with proteins. We found PAMAM dendrimers mostly interact with complement proteins, particularly C3 and C4a, which aligns with previously published data, verifying our approach can be used to isolate and identify dendrimer-protein interactions.Abstract Figure
Recording neural reward signals in the real-world using mobile-EEG and augmented reality
Authors: Stringfellow Jaleesa , Liran Omer , Lin Mei-Heng , Baker Travis E. 
Published: September 2023

AbstractThe electrophysiological response to rewards recorded during laboratory-based tasks has been well documented over the past two decades, yet little is known about the neural response patterns in ‘real-world’ settings. To address this issue, we combined a mobile-EEG system with an augmented reality headset (which blends high definition “holograms” within the real-world) to record event-related brain potentials (ERP) while participants navigated an operant chamber to find rewards. 25 participants (age = 18-43, Male=6, Female=19) were asked to choose between two floating holograms marking a west or east goal-location in a large room, and once participants reached the goal location, the hologram would turn into a reward (5 cents) or no-reward (0 cents) cue. Following the feedback cue, participants were required to return to a hologram marking the start location, and once standing in it, a 3 second counter hologram would initiate the next trial. This sequence was repeated until participants completed 200 trials. Consistent with previous research, reward feedback evoked the reward positivity, an ERP component believed to index the sensitivity of the anterior cingulate cortex to reward prediction error signals. The reward positivity peaked around 235ms post-feedback with a maximal at channel FCz (M=-2.60μV, SD=1.73μV) and was significantly different than zero (p < 0.01). At a behavioral level, participants took approximately 3.38 seconds to reach the goal-location and exhibited a general lose-shift (68.3% ± 3.5) response strategy and were slightly slower to return to the start location following negative feedback (2.43 sec) compared to positive feedback (2.38 sec), evidence of post-error slowing. Overall, these findings provide the first evidence that combining mobile-EEG with augmented reality technology is a feasible solution to enhance the ecological validity of human electrophysiological studies of goal-directed behavior and a step towards a new era of human cognitive neuroscience research that blurs the line between laboratory and reality.
Identifying residues in unfolded whole proteins with a nanopore: a theoretical model based on linear inequalities
Authors: Sampath G. 
Published: September 2023

AbstractA theoretical model is proposed for the identification of individual amino acids (AAs) in an unfolded whole protein’s primary sequence. It is based in part on a recent report (Nat. Biotech. 41, 1130–1139, 2023) that describes the unfolding and translocation of whole proteins at constant speed through a biological nanopore (alpha-Hemolysin) of length 5 nm with a residue dwell time inside the pore of ∼10 μs. Here current blockade levels in the pore due to the translocating protein are assumed to be measured with a limited precision of 70 nm3and a bandwidth of 20 KHz for measurement with a low-bandwidth detector. Exclusion volumes in two pores of slightly different lengths are used as a computational proxy for the blockade signal; subsequence exclusion volume differences along the protein sequence are computed from the sampled translocation signals in the two pores relatively shifted multiple times. These are then converted into a system of linear inequalities that can be solved with linear programming and related methods; residues are coarsely identified as belonging to one of 4 subsets of the 20 standard AAs. To obtain the exact identity of a residue an artifice analogous to the use of base-specific tags for DNA sequencing with a nanopore (PNAS113, 5233–5238, 2016) is used. Conjugates that add volume are attached to a given AA type, this biases the set of inequalities toward the volume of the conjugated AA, from this biased set the position of occurrence of every residue of the AA type in the whole sequence is extracted. By applying this step separately to each of the 20 standard AAs the full sequence can be obtained. The procedure is illustrated with a protein in the human proteome (Uniprot id UP000005640_9606).