bluuebunny/crossref_metadata_2025_split huggingface dataset:
The dual role of Spn-E in supporting heterotypic ping-pong piRNA amplification in silkworms
Authors: Izumi Natsuko , Shoji Keisuke , Negishi Lumi , Tomari Yukihide 
Published: December 2023

AbstractThe PIWI-interacting RNA (piRNA) pathway plays a crucial role in silencing transposons in the germline. piRNA-guided target cleavage by PIWI proteins triggers biogenesis of new piRNAs from the cleaved RNA fragments. This process, known as the ping-pong cycle, is mediated by the two PIWI proteins, Siwi and BmAgo3, in silkworms. However, the detailed molecular mechanism of the ping-pong cycle remains largely unclear. Here, we show that Spindle-E (Spn-E), a putative ATP-dependent RNA helicase, is essential for BmAgo3-dependent production of Siwi-bound piRNAs in the ping-pong cycle and that this function of Spn-E requires its ATPase activity. Moreover, Spn-E acts to suppress homotypic Siwi-Siwi ping-pong, but this function of Spn-E is independent of its ATPase activity. These results highlight the dual role of Spn-E in facilitating proper heterotypic ping-pong in silkworms.
Carotenoid composition and sequestration in cassava (Manihot esculentumCrantz) roots
Authors: Drapal Margit , Ovalle Rivera Tatiana M. , Becerra Lopez-Lavalle Luis Augusto , Fraser Paul D. 
Published: December 2023

AbstractCassava (Manihot esculentum Crantz) is a staple food source for many developing countries. Its edible roots are high in starch but lack micronutrients such as β-carotene. In the present study, analysis of pedigree breeding populations has led to the identification of cassava accessions with enhanced β-carotene contents up to 40 μg/g DW. This represents 0.2% of the Recommended Daily Allowance (RDA) for vitamin A. The β-branch of the carotenoid pathway predominates in cassava roots, with dominant levels of β-carotene followed by other minor epoxides of β-ring derived carotenoids. Metabolomic analysis revealed that steady state levels of intermediary metabolism were not altered by the formation of carotenoids, similar to starch and carbohydrate levels. Apocarotenoids appeared to be independent of their carotenoid precursors. Lipidomic analysis provided evidence of a significant positive correlation between carotenoid and lipid content, in particular plastid specific galactolipids. Proteomic analysis of isolated amyloplasts revealed an abundance of carbohydrate/starch biosynthetic associated proteins (e.g. glucose-1-phosphate adenylyltransferase). No carotenoid related proteins were detected even in the highest carotenoid containing lines. Carotenoids were associated with fractions typically annotated as plastoglobuli and plastid membranes (particularly the envelope). Proteomic analysis confirmed these structures apart from plastoglobuli, thus potentially amyloplast structures may not contain classical plastoglobuli structures.HighlightCassava genotypes with enhanced provitamin A content (β-carotene) reveals interconnectivity between the carotenoid pathway, starch and lipid biosynthesis.
Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins
Authors: Parente Martina , Barthelemy Amélie , Tonini Claudia , Sacchi Alessandra , Leone Stefano , Segatto Marco , Pfrieger Frank W. , Pallottini Valentina 
Published: December 2023

AbstractNiemann-Pick type C disease (NPCD) is a lysosomal disorder whith patients presenting highly variable onset, neurovisceral symptoms and life spans due to defective lipid homeostasis. At present, therapeutic options are limited to palliative and disease-modifying drugs, and there is a continued need for new approaches. Here, we explored bromodomain and extraterminal (BET) proteins as new drug target for NPCD using patient-derived fibroblasts. Treatment of cells with JQ1, a prototype BET inhibitor, enhanced the level of NPC1 protein and increased its presence in lysosomes, diminished lysosomal expansion and cholesterol accumulation and induced extracellular release of lysosomal components in a time- and dose-dependent manner. The reversal of pathologic changes in an established cell model suggest inhibition of BET protein as new therapeutic approach for NPCD.
Intraspecific density changes the impact of interspecific competitors on parasite infection traits in multiple infections
Authors: Godinho Diogo P. , Rodrigues Leonor R. , Lefèvre Sophie , Magalhães Sara , Duncan Alison B. 
Published: December 2023

AbstractCo-infections are frequent, with consequences for parasite life-history traits expressed at within- and between-host levels. However, little is known about whether the effect of interspecific competitors on traits are correlated or independent or if they change with intraspecific competition. To address this, we investigated the occurrence of genetic correlations among within- and betweenhost traits at different intra-specific densities of inbred lines of the spider mite,Tetranychus urticaewith its competitorT. evansi. First, we foundT. evansipresence on a shared host leaf produced a negative (non-genetic) correlation between virulence (leaf damage) and number of daughters (transmitting stages) at intermediate intraspecific densities; this same relationship was not significant without competitors. Second, we show interspecific competitors increases transmission to adjacent leaf discs, measured as movement of adultT. urticaefemales, but only at low and intermediate intraspecific densities. Finally we tested whether within-host traits (virulence and transmitting stages) were correlated with between-host traits (movement to adjacent patches), with or without competitors, at different conspecific densities. We found traits were mostly independent; interspecific competitors may increase transmission across hosts without affecting virulence (or vice versa). These independent effects on within- and between-host traits indicate competition may impact epidemiology and parasite trait evolution.
Dynamical structure-function correlations provide robust and generalizable signatures of consciousness in humans
Authors: Castro Pablo , Luppi Andrea , Tagliazucchi Enzo , S-Perl Yonatan , Naci Lorina , Owen Adrian M. , Sitt Jacobo D. , Destexhe Alain , Cofré Rodrigo 
Published: December 2023

AbstractResting-state functional magnetic resonance imaging evolves through a repertoire of functional connectivity patterns which might reflect ongoing cognition, as well as the contents of conscious awareness. We investigated whether the dynamic exploration of these states can provide robust and generalizable markers for the state of consciousness in human participants, across loss of consciousness induced by general anaesthesia or slow wave sleep. By clustering transient states of functional connectivity, we demonstrated that brain activity during unconsciousness is dominated by a recurrent pattern primarily mediated by structural connectivity and with a reduced capacity to transition to other patterns. Our results provide evidence supporting the pronounced differences between conscious and unconscious brain states in terms of whole-brain dynamics; in particular, the maintenance of rich brain dynamics measured by entropy is a critical aspect of conscious awareness. Collectively, our results may have significant implications for our understanding of consciousness and the neural basis of human awareness, as well as for the discovery of robust signatures of consciousness that are generalizable among different brain conditions.
Emergence of a senescent and inflammatory pulmonary CD4+T cell population prior to lung allograft failure
Authors: Moshkelgosha Sajad , Levy Liran , Safavi Shahideh , Karunagaran Sumiha , Wilson Gavin , Renaud-Picard Benjamin , Madu Goodness , Ramchandani Rashi , Oliver Jillian , Watanabe Tatsuaki , Bei Ke Fan , Joe Betty , Li Qixuan , Huszti Ella , Cheung May , Hedley David , Yeung Jonathan , Keshavjee Shaf , Martinu Tereza , Juvet Stephen 
Published: December 2023

AbstractLung transplantation is a life-saving therapy for end-stage pulmonary disease, but its long-term outlook is poor due to a high incidence of chronic lung allograft dysfunction (CLAD). CLAD results from alloimmune-mediated progressive fibrosis and culminates in death or the need for re-transplantation after a median of 6 years. Existing immunosuppression fails to prevent CLAD, suggesting the existence of alloimmune pathways resistant to these drugs. Here, we used mass cytometry to identify cell populations enriched in the bronchoalveolar lavage (BAL) of patients with subsequent allograft dysfunction. We show that CD4+CD57+PD1+T cells emerge in stable lung transplant recipients in the first year post-transplant, conferring heightened risks for CLAD and death or re-transplantation. CD4+CD57+PD1+T cells display features of senescence and secrete inflammatory cytokines. Cellular indexing by transcriptomes and epitopes (CITE-Seq) on BAL CD4+T cells revealed the existence of 2 oligoclonal CD57+subsets with putative cytotoxic and follicular helper functions. Finally, we observed that CD4+CD57+PD1+T cells are associated with lung allograft fibrosis in a mouse model and in human explanted CLAD lungs, where they localize near airway epithelium and B cells. Together, our findings reveal the existence of an inflammatory T cell population that predicts future lung allograft dysfunction and may represent a rational therapeutic target in lung transplant recipients.
Modulation of prion protein expression through cryptic splice site manipulation
Authors: Gentile Juliana E. , Corridon Taylor L. , Mortberg Meredith A. , D’Souza Elston Neil , Whiffin Nicola , Minikel Eric Vallabh , Vallabh Sonia M. 
Published: December 2023

AbstractLowering expression of prion protein (PrP) is a well-validated therapeutic strategy in prion disease, but additional modalities are urgently needed. In other diseases, small molecules have proven capable of modulating pre-mRNA splicing, sometimes by forcing inclusion of cryptic exons that reduce gene expression. Here, we characterize a cryptic exon located in humanPRNP’s sole intron and evaluate its potential to reduce PrP expression through incorporation into the 5’ untranslated region (5’UTR). This exon is homologous to exon 2 in non-primate species, but contains a start codon that would yield an upstream open reading frame (uORF) with a stop codon prior to a splice site if included inPRNPmRNA, potentially downregulating PrP expression through translational repression or nonsense-mediated decay. We establish a minigene transfection system and test a panel of splice site alterations, identifying mutants that reduce PrP expression by as much as 78%. Our findings nominate a new therapeutic target for lowering PrP.
Reinforcement Learning for Control of Human Locomotion in Simulation
Authors: Dashkovets Andrii , Laschowski Brokoslaw 
Published: December 2023

AbstractControl of robotic leg prostheses and exoskeletons is an open challenge. Computer modeling and simulation can be used to study the dynamics and control of human walking and extract principles that can be programmed into robotic legs to behave similar to biological legs. In this study, we present the development of an efficient two-layer Q-learning algorithm, with k-d trees, that operates over continuous action spaces and a reward model that estimates the degree of muscle activation similarity between the agent and human state-to-action pairs and state-to-action sequences. We used a human musculoskeletal model acting in a high-dimensional, physics-based simulation environment to train and evaluate our algorithm to simulate biomimetic walking. We used imitation learning and artificial bio-mechanics data to accelerate training via expert demonstrations and used experimental human data to compare and validate our predictive simulations, achieving 79% accuracy. Also, when compared to the previous state-of-the-art that used deep deterministic policy gradient, our algorithm was significantly more efficient with lower computational and memory storage requirements (i.e., requiring 7 times less RAM and 87 times less CPU compute), which can benefit real-time embedded computing. Overall, our new two-layer Q-learning algorithm using sequential data for continuous imitation of human locomotion serves as a first step towards the development of bioinspired controllers for robotic prosthetic legs and exoskeletons. Future work will focus on improving the prediction accuracy compared to experimental data and expanding our simulations to other locomotor activities.
ElectroPhysiomeGAN: Generation of Biophysical Neuron Model Parameters from Recorded Electrophysiological Responses
Authors: Kim Jimin , Peng Minxian , Chen Shuqi , Liu Qiang , Shlizerman Eli 
Published: December 2023

AbstractRecent advances in connectomics, biophysics, and neuronal electrophysiology warrant modeling of neurons with further details in both network interaction and cellular dynamics. Such models may be referred to as ElectroPhysiome, as they incorporate the connectome and individual neuron electrophysiology to simulate neuronal activities. The nervous system ofC. elegansis considered a viable framework for such ElectroPhysiome studies due to advances in connectomics of its somatic nervous system and electrophysiological recordings of neuron responses. In order to achieve a simulated ElectroPhysiome, the set of parameters involved in modeling individual neurons need to be estimated from electrophysiological recordings. Here, we address this challenge by developing a deep generative estimation method called ElectroPhysiomeGAN (EP-GAN), which once trained, can instantly generate parameters associated with the Hodgkin-Huxley neuron model (HH-model) for multiple neurons with graded potential response. The method combines Generative Adversarial Network (GAN) architecture with Recurrent Neural Network (RNN) Encoder and can generate an extensive number of parameters (>170) given the neuron’s membrane potential responses and steady-state current profiles. We validate our method by estimating HH-model parameters for 200 synthetic neurons with graded membrane potential followed by 9 experimentally recorded neurons (where 6 of them newly recorded) in the nervous system ofC. elegans. Comparison of EP-GAN with existing estimation methods shows EP-GAN advantage in the accuracy of estimated parameters and in the inference speed. The advantage is especially significant when a large number of parameters is being inferred. In addition the architecture of EP-GAN permits inference of parameters even when partial membrane potential and steady-state currents profile are given as inputs. EP-GAN is designed to leverage the generative capability of GAN to align with the dynamical structure of HH-model, and thus able to achieve such performance.
CRISPRi screens identify the lncRNA,LOUP,as a multifunctional locus regulating macrophage differentiation epigenetically and inflammatory signaling through a short, encoded peptide
Authors: Halasz Haley , Malekos Eric , Covarrubias Sergio , Yitiz Samira , Montano Christy , Sudek Lisa , Katzman Sol , John Liu S , Holbeck Max A. , Weissman Jonathan S , Carpenter Susan 
Published: December 2023

AbstractLong non-coding RNAs (lncRNAs) account for the largest portion of RNA from the transcriptome, yet most of their functions remain unknown. Here we performed two independent high-throughput CRISPRi screens to understand the role of lncRNAs in monocyte function and differentiation. The first was a reporter-based screen to identify lncRNAs that regulate TLR4-NFkB signaling in human monocytes and the second screen identified lncRNAs involved in monocyte to macrophage differentiation. We successfully identified numerous novel non-coding and protein-coding genes that can positively or negatively regulate inflammation and differentiation. To understand the functional roles of lncRNAs in both processes, we chose to further study the lncRNALOUP(lncRNA originating from upstream regulatory element ofSPI1[also known as PU.1]), as it emerged as a top hit in both screens. Not only doesLOUPregulate its neighboring gene, the myeloid fate determining factorSPI1, thereby affecting monocyte to macrophage differentiation, but knockdown ofLOUPleads to a broad upregulation of NFkB-targeted genes at baseline and upon TLR4-NFkB activation.LOUPalso harbors three small open reading frames (sORFs) capable of being translated and are responsible forLOUP’s ability to negatively regulate TLR4/NFkB signaling. This work emphasizes the value of high-throughput screening to rapidly identify functional lncRNAs in the innate immune system.
A bipolar taxonomy of adult human brain sulcal morphology related to timing of fetal sulcation and trans-sulcal gene expression gradients
Authors: Snyder William E. , Vértes Petra E. , Kyriakopoulou Vanessa , Wagstyl Konrad , Williams Logan Z. J. , Moraczewski Dustin , Thomas Adam G. , Karolis Vyacheslav R. , Seidlitz Jakob , Rivière Denis , Robinson Emma C. , Mangin Jean-Francois , Raznahan Armin , Bullmore Edward T. 
Published: December 2023

SummaryWe developed a computational pipeline (now provided as a resource) for measuring morphological similarity between cortical surface sulci to construct a sulcal phenotype network (SPN) from each magnetic resonance imaging (MRI) scan in an adult cohort (N=34,725; 45-82 years). Networks estimated from pairwise similarities of 40 sulci on 5 morphological metrics comprised two clusters of sulci, represented also by the bipolar distribution of sulci on a linear-to-complex dimension. Linear sulci were more heritable and typically located in unimodal cortex; complex sulci were less heritable and typically located in heteromodal cortex. Aligning these results with an independent fetal brain MRI cohort (N=228; 21-36 gestational weeks), we found that linear sulci formed earlier, and the earliest and latest-forming sulci had the least between-adult variation. Using high-resolution maps of cortical gene expression, we found that linear sulcation is mechanistically underpinned by trans-sulcal gene expression gradients enriched for developmental processes.
The Garden of Forking Paths: Reinterpreting Haseman-Elston Regression for a Genotype-by-Environment Model
Authors: Chen Guo-Bo 
Published: December 2023

AbstractHaseman-Elston regression (HE-reg) has been known as a classic tool for detecting an additive genetic variance component. However, in this study we find that HE-reg can capture GxE under certain conditions, so we derive and reinterpret the analytical solution of HE-reg. In the presence of GxE, it leads to a natural discrepancy of linkage and association results, the latter of which is not able to capture GxE if the environment is unknown. Considering linkage and association as symmetric designs, we investigate how the symmetry can and cannot hold in the absence and presence of GxE, and consequently we propose a pair of statistical tests, Symmetry Test I and Symmetry Test II, both of which can be tested using summary statistics. Test statistics, and their statistical power issues are also investigated for Symmetry Tests I and II. Increasing the number of sib pairs is important to improve statistical power for detecting GxE.
Sensitization of Human and Rat Nociceptors by Low Dose Morphine is TLR4-dependent
Authors: Khomula Eugen V. , Levine Jon D. 
Published: December 2023

AbstractWhile opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the presentin vitropatch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that morphine (100 nM) reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as well as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors.
Transient formation of collaterals contributes to the restoration of the arterial tree during cardiac regeneration in neonatal mice
Authors: Sturny Rachel , Boulgakoff Lucie , Kelly Robert G , Miquerol Lucile 
Published: December 2023

AbstractRevascularization of ischemic myocardium following cardiac damage is an important step in cardiac regeneration. However, the mechanism of arteriogenesis has not been well described during cardiac regeneration. Here we investigated coronary artery remodeling and collateral growth during cardiac regeneration. Neonatal MI was induced by ligature of the left descending artery (LAD) in postnatal day (P) 1 or P7 pups from theCx40-GFPmouse line and the arterial tree was reconstructed in 3D from images of cleared hearts collected at 1, 2, 4, 7 and 14 days after infarction. We show a rapid remodeling of the left coronary arterial tree induced by neonatal MI and the formation of numerous collateral arteries, which are transient in regenerating hearts after MI at P1 and persistent in non-regenerating hearts after MI at P7. This difference is accompanied by restoration of a perfused or a non-perfused LAD following MI at P1 or P7 respectively. Interestingly, collaterals ameliorate cardiac perfusion and drive LAD repair, and lineage tracing analysis demonstrates that the restoration of the LAD occurs by remodeling of pre-existing arterial cells independently of whether they originate in large arteries or arterioles. These results demonstrate that the restoration of the LAD artery during cardiac regeneration occurs by pruning as the rapidly forming collaterals that support perfusion of the disconnected lower LAD subsequently disappear on restoration of a unique LAD. These results highlight a rapid phase of arterial remodeling that plays an important role in vascular repair during cardiac regeneration.HighlightsRapid remodeling of the arterial tree is induced by myocardial infarction.The endocardial response to ischemia differs between regenerated and non-regenerated hearts following myocardial infarction at postnatal days 1 or 7.Collateral growth is rapid and transient in regenerated hearts while delayed and persistent in non-regenerated hearts.Collateral arteries ameliorate cardiac perfusion and drive LAD repair.The restoration of the LAD occurs by remodeling of pre-existing arterial cells.