bluuebunny/crossref_metadata_2025_split huggingface dataset:
The stool microbiome in patients with psoriatic arthritis is altered but, unlike the skin microbiome, does not change following treatment: evidence for an underlying inflammatory drive from the intestine
Authors: Castelino Madhura , Ijaz Umer Z , Tutino Mauro , MacDonald Elizabeth , Fragoulis George E. , Ho Pauline , Mewar Devesh , Chelliah Gladston , McBain Andrew , O’Neill Catherine , Siebert Stefan , Barton Anne , Milling Simon 
Published: May 2023

AbstractObjectivesThere is growing recognition that interactions between bacteria and the immune response may contribute to inflammation in psoriatic arthritis (PsA). To identify how the skin and stool microbiota may contribute to pathogenesis, we analysed the microbiota and immunophenotype of patients with PsA before and after therapy.MethodsWe examined the phenotype of PBMCs as well as skin and stool microbiota from 22 healthy volunteers, 7 PsA patients receiving methotrexate, and 23 PsA patients treated with biologic DMARDs. Samples for microbiome analysis were collected before therapy and after 3-6 months. First, we identified differences in the skin and stool microbiota between PsA patients and health volunteers. We then assessed changes in the microbiome occurring after treatment.ResultsAs hypothesised, treatment responses were reflected by changes in both the skin microbiota and in the immunophenotype. However, in the stool samples, dysbiosis persisted after therapy. This dysbiosis was associated with changes in the peripheral blood immunophenotype. Correlation analysis enabled identification not only of specific microbial taxa (Clostridial species) that contributed to the persistent dysbiosis, but also of interactions between taxa and the immune response.ConclusionsThese analyses indicate that specific Clostridial species contribute to persistent gut dysbiosis in PsA, and their prevalence is associated with specific immunological changes that are not altered by treatment. Thus, an underlying inflammatory response in the intestine appears to contribute to the pathogenesis of PsA.Key MessagesWhat is already known about this subject?Intestinal bacterial populations are altered in people with inflammatory diseases, including psoriatic arthritis (PsA).Interactions between bacteria and the immune system may contribute to the pathogenesis of inflammatory diseases.What does this study add?While skin bacteria in patients with PsA revert towards normal after treatment, stool bacteria remain different from healthy individuals.Specific bacterial types are correlated with specific changes in the immune system in PsA.How might this impact on clinical practice or future developments?Identification of the bacteria that drive persistent underlying changes in the immune response may enable these to be targeted.
In uteropulse injection of isotopic amino acids quantifies protein turnover rates during murine fetal development
Authors: Baeza Josue , Coons Barbara E. , Lin Zongtao , Riley John , Mendoza Mariel , Peranteau William H. , Garcia Benjamin A 
Published: May 2023

AbstractProtein translational control is highly regulated step in the gene expression program during mammalian development that is critical for ensuring that the fetus develops correctly and that all of the necessary organs and tissues are formed and functional. Defects in protein expression during fetal development can lead to severe developmental abnormalities or premature death. Currently, quantitative techniques to monitor protein synthesis rates in a developing fetus (in utero) are limited. Here, we developed a novelin uterostable isotope labeling approach to quantify tissue-specific protein dynamics of the nascent proteome during mouse fetal development. Fetuses of pregnant C57BL/6J mice were injected with isotopically labeled lysine (Lys8) and arginine (Arg10) via the vitelline vein at various gestational days. After treatment, fetal organs/tissues including brain, liver, lung, and heart were harvested for sample preparation and proteomic analysis. We show that the mean incorporation rate for injected amino acids into all organs was 17.50 ± 0.6%. By analyzing the nascent proteome, unique signatures of each tissue were identified by hierarchical clustering. In addition, the quantified proteome-wide turnover rates (kobs) were calculated between 3.81E-5 and 0.424 hour-1. We observed similar protein turnover profiles for analyzed organs (e.g., liver versus brain), however, their distributions of turnover rates vary significantly. The translational kinetic profiles of developing organs displayed differentially expressed protein pathways and synthesis rates which correlated with known physiological changes during mouse development.
Regulation of metal homeostasis by two F-group bZIP transcription factors bZIP48 and bZIP50 in rice
Authors: Qing Tao , Xie Tian-Ci , Zhu Qiao-Yun , Lu Hai-Ping , Liu Jian-Xiang 
Published: May 2023

AbstractZinc (Zn) is an essential microelement for plants as well as for human beings, and it regulates numerous metabolic process and protein activity. Zn deficiency not only impairs plant growth and development, but also affects human health. Rice (Oryza sativaL.) is a staple food for more than half of the world’s population, but how Zn homeostasis in rice is maintained is largely unknown. Here, we demonstrate that two F-group bZIP transcription factors, OsbZIP48 and OsbZIP50, are important for metal homeostasis in rice. Mutation ofOsbZIP48andOsbZIP50impairs plant growth and reduces Zn, Fe, and Cu content in shoots. The N-terminus of either OsbZIP48 or OsbZIP50 contains two cysteine- and histidine-rich (CHR) domains, deletion or mutation of these CHR domains increases nucleus localization of OsbZIP48 and OsbZIP50. Both OsbZIP48 and OsbZIP50 have transcriptional activation activity, and the expression of 1117 genes involved in metal uptake, phenylpropanoid biosynthetic process, cell wall organization, et al., is reduced inOsbZIP48andOsbZIP50double mutant than that in wild-type ZH11 plant under Zn deficiency. Both OsbZIP48 and OsbZIP50 bind to the promoter region of the ZIP family transporter geneOsZIP10in rice, and activate the promoter activity of ZDREcis-element derived from theOsZIP10promoter in effector-reporter assays. Mutation of the CHR domain of OsbZIP48 inOsbZIP50mutant background increases the content of Zn/Fe/Cu in brown rice seeds and leaves. Thus, this study reveals that OsbZIP48 and OsbZIP50 regulate metal homeostasis, especially under Zn deficiency in rice, and provides candidate target genes for biofortification of micronutrients in future.significance statementZinc (Zn) is an essential microelement not only for plants but also for human beings. This paper shows that the N-terminal cysteine- and histidine-rich domain of OsbZIP48/50 is important for their nucleus localization, therefore transcriptional activity, and reveals the downstream genes of OsbZIP48/50 involved in metal homeostasis under Zn deficiency in rice.
Reproductive sexual dimorphisms in two willow species,Salix exiguaNutt.and S. nigraMarshall
Authors: Hu Nan , Hale Haley , Sanderson Brian , Feng Guanqiao , Guo Minghao , Gambhir Diksha , Olson Matt 
Published: May 2023

AbstractPremise of the ResearchThe prevalence of sexual dimorphisms, which evolve due to contrasting strategies to maximize reproductive success in males and females, is variable among dioecious plant species. In theSalicaceae, many traits have been assessed across many studies, but direct or indirect associations between these traits and reproductive allocation are often neglected. Given the dynamic evolution of sex determination systems and the strong interest in wood production in the family, we wondered whether sexual dimorphisms related to reproduction may have gone unreported. Here, we assess sexual dimorphism in reproductive traits in two species ofSalix. Recognition of reproductive sexually dimorphic traits will contribute to understanding the evolution of sex determination systems in the Salicaceae.MethodologyWe conducted observational studies in natural populations to assess the presence of sexual dimorphisms in early spring bud density, catkin number, and flower number per catkin across four sampling periods inSalix exigua. We also analyzed flower number and catkin number per flower inSalix nigra.Pivotal ResultsWe observed no sexual dimorphism in pre-season buds per branch inS. exiguabut did find that males produced more flowers per catkin and more catkins per branch than females in bothS. exiguaandS. nigra.ConclusionsHigher flower numbers in males compared to females is consistent with expectations from intra-sexual selection among males. The presence of reproductive sexual dimorphisms inSalixsuggests that sexual selection may affect the evolution of mating strategies inSalixspecies, and the evolution of the sex determination system within this genus.
BertNDA: A Model Based on Graph-Bert and Multi-scale Information Fusion for ncRNA-disease Association Prediction
Authors: Ning Zhiwei , Wu Jinyang , Ding Yidong , Wang Ying , Peng Qinke , Fu Laiyi 
Published: May 2023

AbstractNon-coding RNAs (ncRNAs) are a class of RNA molecules that lack the ability to encode proteins in human cells, yet play crucial roles in various biological process. Understanding these relationships and how different ncRNAs interact with each other to affect diseases can vastly contribute to their diagnosis, prevention, and treatment. However, predicting tertiary interactions between ncRNA-disease associations by utilizing structural information across multiple scales remains a challenging task. It should be noted that research on predicting tertiary interaction between trinary ncRNA-disease associations is scarce, highlighting the need for further studies in this area. In this work, we propose a predictive framework, called BertNDA, which aims to predict association between miRNA, lncRNA and disease. The framework employs Laplace transform of graph structure and WL (Weisfeiler-Lehman) absolute role coding to extract global information. Local information is identified by the connectionless subgraph which aggregates neighbor feature. Moreover, an EMLP (Element-wise MLP) structure is designed to fuse the multi-scale feature representation of nodes. Furtherly, feature representation is encoded by using a Transformer-encoder structure, the prediction-layer outputs the final correlation between miRNA, lncRNA and diseases. The 5-fold cross-validation result furtherly demonstrates that BertNDA outperforms the state-of-the-art method in predicting assignment. Furthermore, an online prediction platform that embeds our prediction model is designed for users to experience. Overall, our model provides an efficient, accurate, and comprehensive tool for predicting ncRNA-disease associations. The code of our method is available in:https://github.com/zhiweining/BertNDA-main.
ApoER2-Dab1 disruption as the origin of pTau-related neurodegeneration in sporadic Alzheimer’s disease
Authors: Ramsden Christopher E. , Zamora Daisy , Horowitz Mark S. , Jahanipour Jahandar , Keyes Gregory S. , Li Xiufeng , Murray Helen C. , Curtis Maurice A. , Faull Richard M. , Sedlock Andrea , Maric Dragan 
Published: May 2023

BACKGROUNDSporadic Alzheimer’s disease (sAD) is not a global brain disease. Specific regions, layers and neurons degenerate early while others remain untouched even in advanced disease. The prevailing model used to explain this selective neurodegeneration—prion-like Tau spread—has key limitations and is not easily integrated with other defining sAD features. Instead, we propose that in humans Tau hyperphosphorylation occurs locally via disruption in ApoER2-Dab1 signaling and thus the presence of ApoER2 in neuronal membranes confers vulnerability to degeneration. Further, we propose that disruption of the Reelin/ApoE/ApoJ-ApoER2-Dab1 P85α-LIMK1-Tau-PSD95 (RAAAD-P-LTP) pathway induces deficits in memory and cognition by impeding neuronal lipoprotein internalization and destabilizing actin, microtubules, and synapses. This new model is based in part on our recent finding that ApoER2-Dab1 disruption is evident in entorhinal-hippocampal terminal zones in sAD. Here, we hypothesized that neurons that degenerate in the earliest stages of sAD (1) strongly express ApoER2 and (2) show evidence of ApoER2-Dab1 disruption through co-accumulation of multiple RAAAD-P-LTP components.METHODSWe appliedin situhybridization and immunohistochemistry to characterize ApoER2 expression and accumulation of RAAAD-P-LTP components in five regions that are prone to early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD.RESULTSWe found that: (1) selectively vulnerable neuron populations strongly express ApoER2; (2) numerous RAAAD P-LTP pathway components accumulate in neuritic plaques and abnormal neurons; and (3) RAAAD-P-LTP components were higher in MCI and sAD cases and correlated with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTau and pPSD95Thr19accumulated together within dystrophic dendrites and soma of ApoER2-expressing neurons in the vicinity of ApoE/ApoJ enriched extracellular plaques. These observations provide evidence for molecular derangements that can be traced back to ApoER2-Dab1 disruption, in each of the sampled regions, layers, and neuron populations that are prone to early pTau pathology.CONCLUSIONFindings support the RAAAD-P-LTP hypothesis, a unifying model that implicates dendritic ApoER2-Dab1 disruption as the major driver of both pTau accumulation and neurodegeneration in sAD. This model provides a new conceptual framework to explain why specific neurons degenerate and identifies RAAAD-P-LTP pathway components as potential mechanism-based biomarkers and therapeutic targets for sAD.
Fatigue during acute systemic inflammation is associated with reduced mental effort expenditure while task accuracy is preserved
Authors: Lambregts B.I.H.M. , Vassena E. , Jansen A. , Stremmelaar D.E. , Pickkers P. , Kox M. , Aarts E. , van der Schaaf M.E. 
Published: May 2023

AbstractBackgroundEarlier work within the physical domain showed that acute inflammation changes motivational prioritization and effort allocation rather than physical abilities. It is currently unclear whether a similar motivational framework accounts for the mental fatigue and cognitive symptoms of acute sickness. Accordingly, this study aimed to assess the relationship between fatigue, cytokines and mental effort-based decision making during acute systemic inflammation.MethodsEighty-five participants (41 males; 18-30 years (M=23.0, SD=2.4)) performed a mental effort-based decision-making task before, 2 hours after, and 5 hours after intravenous administration of 1 ng/kg bacterial lipopolysaccharide (LPS) to induce systemic inflammation. Plasma concentrations of cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)) and fatigue levels were assessed at similar timepoints. In the task, participants decided whether they wanted to perform (i.e., ‘accepted’) arithmetic calculations of varying difficulty (3 levels: easy, medium, hard) in order to obtain rewards (3 levels: 5, 6 or 7 points). Acceptance rates were analyzed using a binomial generalized estimated equation (GEE) approach with effort, reward and time as independent variables. Arithmetic performance was measured per effort level prior to the decisions and included as a covariate. Associations between acceptance rates, fatigue (self-reported) and cytokine concentrations levels were analyzed using partial correlation analyses.ResultsPlasma cytokine concentrations and fatigue were increased at 2 hours post-LPS compared to baseline and 5 hours post-LPS administration. Acceptance rates decreased for medium, but not for easy or hard effort levels at 2 hours post-LPS versus baseline and 5 hours post-LPS administration, irrespective of reward level. This reduction in acceptance rates occurred despite improved accuracy on the arithmetic calculations itself. Reduced acceptance rates for medium effort were associated with increased fatigue, but not with increased cytokines.ConclusionFatigue during acute systemic inflammation is associated with alterations in mental effort allocation, similarly as observed previously for physical effort-based choice. Specifically, willingness to exert mental effort depended on effort and not reward information, while task accuracy was preserved. These results extend the motivational account of inflammation to the mental domain and suggest that inflammation may not necessarily affect domain-specific mental abilities, but rather affects domain-general effort-allocation processes.
Deconstructing the contributions of heterogeneity to combination treatment of hormone sensitive breast cancer
Authors: Linn Samantha , Moore-Ott Jenna A. , Shuttleworth Robyn , Zhang Wenjing , Craig Morgan , Jenner Adrianne L. 
Published: May 2023

AbstractCombination therapies are fundamental to cancer treatments, including in breast cancer the most common invasive malignancy in women. Breast cancer treatment is determined based on molecular subtypes, and since 2016, combination palbociclib and fulvestrant has been used to treat hormone receptor-positive breast cancer. However, the impact of heterogeneity of the tumour landscape and tumour composition dynamics on scheduling decisions remains poorly understood. To elucidate the contributions of variability at multiple scales to treatment outcomes in hormone receptor-positive breast cancer, we developed a simple mathematical model of two unique estrogen receptor positive (ER+) breast cancer cell types and their response to combination treatment with palbociclib and fulvestrant. We used this model to understand how the initial fraction of either cell type may impact the fraction remaining after treatment and examined how heterogeneity in pharmacokinetics and pharmacodynamics result in a large distribution of outcomes. Our results suggest that the pharmacokinetics and pharmacodynamics of fulvestrant were the major drivers of final tumour size and composition. We then leveraged our model to guide therapeutic scheduling of combination palbociclib and fulvestrant, demonstrating the use of mathematical modelling to improve our understanding of cancer biology and treatments.
Inference of annealed protein fitness landscapes with AnnealDCA
Authors: Sesta Luca , Pagnani Andrea , Fernandez-de-Cossio-Diaz Jorge , Uguzzoni Guido 
Published: May 2023

AbstractThe design of proteins with specific tasks is a major challenge in molecular biology with important diagnostic and therapeutic applications. High-throughput screening methods have been developed to systematically evaluate protein activity, but only a small fraction of possible protein variants can be tested using these techniques. Computational models that explore the sequence spacein-silicoto identify the fittest molecules for a given function are needed to overcome this limitation. In this article, we propose AnnealDCA, a machine-learning framework to learn the protein fitness landscape from sequencing data derived from a broad range of experiments that use selection and sequencing to quantify protein activity. We demonstrate the effectiveness of our method by applying it to antibody Rep-Seq data of immunized mice and screening experiments, assessing the quality of the fitness landscape reconstructions. Our method can be applied to most experimental cases where a population of protein variants undergoes various rounds of selection and sequencing, without relying on the computation of variant enrichment ratios, and thus can be used even in cases of disjoint sequence samples.
Neuromodulation via muscarinic acetylcholine pathway can facilitate distinct, complementary, and sequential roles for NREM and REM states during sleep-dependent memory consolidation
Authors: Satchell Michael , Fry Blaine , Noureddine Zahraa , Simmons Alexis , Ognjanovski Nicolette N. , Aton Sara J. , Zochowski Michal R. 
Published: May 2023

AbstractAcross vertebrate species, sleep consists of repeating cycles of NREM followed by REM. However, the respective functions of NREM, REM, and their stereotypic cycling pattern are not well understood. Using a simplified biophysical network model, we show that NREM and REM sleep can play differential and critical roles in memory consolidation primarily regulated, based on state-specific changes in cholinergic signaling. Within this network, decreasing and increasing muscarinic acetylcholine (ACh) signaling during bouts of NREM and REM, respectively, differentially alters neuronal excitability and excitatory/inhibitory balance. During NREM, deactivation of inhibitory neurons leads to network-wide disinhibition and bursts of synchronized activity led by firing in engram neurons. These features strengthen connections from the original engram neurons to less-active network neurons. In contrast, during REM, an increase in network inhibition suppresses firing in all but the most-active excitatory neurons, leading to competitive strengthening/pruning of the memory trace. We tested the predictions of the model againstin vivorecordings from mouse hippocampus during active sleep-dependent memory storage. Consistent with modeling results, we find that functional connectivity between CA1 neurons changes differentially at transition from NREM to REM sleep during learning. Returning to the model, we find that an iterative sequence of state-specific activations during NREM/REM cycling is essential for memory storage in the network, serving a critical role during simultaneous consolidation of multiple memories. Together these results provide a testable mechanistic hypothesis for the respective roles of NREM and REM sleep, and their universal relative timing, in memory consolidation.Significance statementUsing a simplified computational model andin vivorecordings from mouse hippocampus, we show that NREM and REM sleep can play differential roles in memory consolidation. The specific neurophysiological features of the two sleep states allow for expansion of memory traces (during NREM) and prevention of overlap between different memory traces (during REM). These features are likely essential in the context of storing more than one new memory simultaneously within a brain network.
SPLIT HAND/FOOT VARIANTS FAIL TO RESCUE PRDM1A MUTANT CRANIOFACIAL DEFECTS
Authors: Truong Brittany T. , Shull Lomeli C. , Lencer Ezra , Artinger Kristin B. 
Published: May 2023

AbstractBackgroundSplit Hand/Foot Malformation (SHFM) is a congenital limb disorder presenting with limb anomalies, such as missing, hypoplastic, or fused digits, and often craniofacial defects, including a cleft lip/palate, microdontia, micrognathia, or maxillary hypoplasia. We previously identified three novel variants in the transcription factor,PRDM1, that are associated with SHFM phenotypes. One individual also presented with a high arch palate. Studies in vertebrates indicate that PRDM1 is important for development of the skull; however, prior to our study, human variants inPRDM1had not been associated with craniofacial anomalies.MethodsUsing transient mRNA overexpression assays inprdm1a-/-mutant zebrafish, we tested whether thePRDM1SHFM variants were functional and could lead to a rescue of the craniofacial defects observed inprdm1a-/-mutants. We also mined a CUT&RUN and RNA-seq dataset to examine Prdm1a binding and the effect of Prdm1a loss on craniofacial genes.Resultsprdm1a-/-mutants exhibit craniofacial defects including a hypoplastic neurocranium, a loss of posterior ceratobranchial arches, a shorter palatoquadrate, and an inverted ceratohyal. Injection of wildtypehPRDM1inprdm1a-/-mutants partially rescues these structures. However, injection of each of the three SHFM variants fails to rescue the skeletal defects. Loss ofprdm1aleads to a decreased expression of important craniofacial genes, such asdlx5a/dlx6a, hand2, sox9b, col2a1a, andhoxbgenes.ConclusionThese data suggest that the three SHFM variants are not functional and may have led to the craniofacial defects observed in the humans. Finally, they demonstrate how Prdm1a can directly bind and regulate craniofacial gene expression.