bluuebunny/crossref_metadata_2025_split huggingface dataset:
Networks of Phenological Synchrony Reveal a Highly Interconnected Ecosystem and Potential Vulnerability to Climate-Driven Mismatches
Authors: Garretson Alexis , Feldsine Natalie , Napoli Megan , Long Elizabeth C , Forkner Rebecca E 
Published: July 2022

AbstractAs anthropogenic climate change alters species’ phenology, phenological shifts may cascade to disrupt species interactions to impact ecosystem functioning. We present a 108-year phenology dataset of 8,840 event dates for 251 phenophases for seven amphibian species, 58 birds, 14 insects, and 163 plant species, including 52 species introduced to New York. The dataset was collected at a single location in the Northeastern United States, providing continuity in monitoring since the early 1900s. We show that linear phenology analyses can underestimate the magnitude of phenological shift relative to circular methods, particularly for species experiencing extreme advancements. However, species phenologies are generally advancing, with faster advancements of insects and amphibians compared to birds and plants. Additionally, in our dataset, species with event dates later in the year are advancing more rapidly than species earlier in the year, and this relationship is stronger for animals than for plants. We present a novel, network-based approach for visualizing community and ecosystem-scale phenological synchrony. Using this approach, we find a high degree of synchrony between the monitored species, and this approach reveals that plants are more central in the phenological network, as well as species with phenological events earlier in the year. While many synchronous species are shifting at relatively similar rates and display similar temperature sensitivities, we highlight two species interactions potentially vulnerable to changing climate: Eastern Tent Caterpillars and Monarchs. Our results illustrate the utility of long-term ecological monitoring for investigating ecosystem responses to climate change and identifying potentially vulnerable phenological networks.Significance StatementThe purpose of this study is to understand how climate change has affected the phenology of an ecological community for over 100+ years. We present a novel approach to analyzing and visualizing community-level phenological data. We find that plants are central to phenological networks, as are species that flower, fruit, or undergo other phenological events earlier in the year. This is important because understanding which species are most central to an ecosystem, as well as which species are vulnerable to climate-driven mismatches (e.g., a butterfly emerges before the flowers that it feeds on bloom) that could cascade through an ecosystem.
Brassinosteroids signaling component SlBZR1 promotes fruit ripening in tomato
Authors: Meng Fanliang , Liu Haoran , Hu Songshen , Jia Chengguo , Zhang Min , Li Songwen , Li Yuanyuan , Lin Jiayao , Jian Yue , Wang Mengyu , Shao Zhiyong , Mao Yuanyu , Liu Lihong , Wang Qiaomei 
Published: July 2022

SUMMARYFruit ripening evolved to be attractive to frugivores that derive energy and nutrition from the fruits in exchange for assisting seed dispersal, which is accompanied by the dramatically change of fruit characteristics, including color, aroma, and texture. The plant hormone ethylene plays a key role in climacteric fruit ripening, while the role of other phytohormones as well as their cross talk with ethylene in modulating fruit ripening remains elusive. Here, we report growth-promoting phytohormone brassinosteroids promote fruit ripening in tomato through regulation of ethylene biosynthesis. Exogenous BR treatment and the increase of endogenous BR content in SlCYP90B3-OE promoted ethylene production and fruit ripening. SlBZR1, a central component and positive regulator of BR signaling pathway, promotes ethylene production and carotenoid accumulation through direct transcriptional regulation of SlACO1, SlACO3 and SlPSY1. Furthermore, SlBIN2, a negative regulator of BR signaling upstream of SlBZR1, decreases ethylene production and carotenoid accumulation. Together, our results demonstrate that BR signaling integrates ethylene and carotenoid biosynthetic pathway to regulate fruit ripening.
Yttrium-iron garnet magnetometer in MEG: Advance towards multi-channel arrays
Authors: Skidchenko E. , Butorina A. , Ostras M. , Vetoshko P. , Kuzmichev A. , Yavich N. , Malovichko M. , Koshev N. 
Published: July 2022

AbstractRecently, a new kind of sensor applicable in magnetoencephalography (MEG) has been presented: a solid-state yttrium-iron garnet magnetometer (YIGM). The feasibility of YIGM was proved in alpha-rhythm registration experiment. In the current paper, we propose the analysis of lead-field matrices for different possible YIGM multichannel on-scalp sensor layouts with respect to the information theory. We use real noise level of the new sensor to compute signal power, signal-to-noise ration (SNR) and total information capacity, and compare them with corresponding metrics that can be obtained with well-established MEG systems: based on superconducting quantum interference devices (SQUIDs) and optically-pumped magnetometers (OPMs). This simulation study is aimed to shed some light on the direction for further development of YIGM sensor, namely creation of multi-channel YIG-MEG.
A 2D Fragment-Assisted Protein Mimetic Approach to Rescue α-Synuclein Aggregation Mediated Early and Post-Disease Parkinson’s Phenotypes
Authors: Stillman Nicholas H. , Joseph Johnson A. , Ahmed Jemil , Dohoney Ryan A. , Ball Tyler D. , Thomas Alexandra G. , Fitch Tessa C. , Donnelly Courtney M. , Kumar Sunil 
Published: July 2022

ABSTRACTWe have developed a Oligopyridylamide (OP) based 2-Dimensional Fragment-Assisted Structure-based Technique (2D-FAST) to identify potent antagonists of α-Synuclein (αS) aggregation, a process central to Parkinson’s disease (PD). The 2D-FAST utilizes a fragment-based screening of large chemical space in OPs, which led to the identification of NS132 as an antagonist of the multiple facets of αS aggregation. We also identified a better cell permeability analog (NS163) without sacrificing activity. OPs rescue αS aggregation mediated PD phenotypes in muscle cells and dopaminergic (DA) neurons in C. elegans models. OPs prevent the progression of PD phenotypes in a novel post-disease onset PD model.This is one of the first examples of a synthetic mimetic-based 2D-FAST to identify antagonists of toxic αS self-assembly. We envision that 2D-FAST will have tremendous potential as it is expandable for other oligoamide scaffolds and for a much larger chemical space to identify lead therapeutics for various diseases.
Polygenic risk score analysis identifies deleterious protein-coding variants in novel immune pathway genesATP8B4, FCGR1A, andLILRB1that associate with Alzheimer’s disease
Authors: Reddy Joseph S. , Wang Xue , Allen Mariet , Carrasquillo Minerva M. , Biernacka Joanna M. , Jenkins Gregory D. , Coombes Brandon J. , Belbin Olivia , Golde Todd E. , Ertekin-Taner Nilüfer , Younkin Steven G. 
Published: July 2022

AbstractBackgroundAlterations in innate immunity are pathologically associated with and genetically implicated in Alzheimer’s disease (AD). In the whole exome sequence (WES) dataset generated by the Alzheimer’s Disease Sequencing Project (ADSP), only the previously identified p.R47H variant in the innate immunity gene,TREM2, shows study-wide association with risk of AD. Using a novel approach, we searched the ADSP WES data to identify additional immune pathway genes with deleterious variants that, likeTREM2.pR47H, show strong association with AD.MethodsUsing polygenic risk scores (PRS) to analyze association with AD, we evaluated deleterious variants (CADD Phred-scaled score > 20) with a minor allele count of 20 or more in 228 genes comprising an immune co-expression network containingTREM2(CENTREM2). A significant polygenic component composed of deleterious stop-gain and non-synonymous variants was identified, and false discovery rates were determined for the variants in this component. In genes harboring a significant variant, PRS for all variants in the genes were then analyzed.ResultsThe PRS for the 182 deleterious variants in CENTREM2showed significant association with AD that was driven by 142 deleterious variants (136 non-synonymous, 6 stop-gain). In the 142 variant polygenic component, four variants had significant AD risk association:TREM2.pR47H, two deleterious stop-gain variants (FCGR1A.pR92X, andLILRB1.pY331X) in novel AD genes and 1 non-synonymous variant(ATP8B4.pG395S). Remarkably, PRS for the 36 additional variants in these four genes also showed significant association with AD. The PRS for all 40 variants in the 4 genes, showed significant, replicable association with AD and 3 additional variants in this polygenic component had significant false discovery rates:ATP8B4.pR1059Q,LILRB1.pP7P, andLILRB1.pY327Y.ConclusionsHere, we identify 3 immune pathway genes (ATP8B4, LILRB1, andFCGR1A) with a variant that associates with AD. LikeTREM2.pR47H, each of the variants has a minor allele frequency less than 1% and is a deleterious, protein altering variant with a strong effect that increases or decreases (LILRB1.pY331X) risk of AD. Additional variants in these genes also alter risk of AD. The variants identified here are ideally suited for studies aimed at understanding how the innate immune system may be modulated to alter risk of AD.
Rare missense variants in the SH3 domain of PSTPIP1 are associated with hidradenitis suppurativa
Authors: Morales-Heil David J. , Cao Li , Sweeney Cheryl , Malara Anna , Brown Frank , Anadkat Milan , Kaffenberger Jessica , Kaffenberger Benjamin , Nagele Peter , Kirby Brian , Roberson Elisha D.O. 
Published: July 2022

AbstractHidradenitis suppurativa (HS) is a chronic, debilitating skin disease estimated to affect ∼1% of the population, for which few treatment options are available. Risk factors associated with HS include smoking, obesity, and some high penetrance genetic variants. Some rare families have autosomal dominant inheritance. Previous studies have shown that rare loss-of-function variants in genes of the gamma-secretase complex, particularly nicastrin, segregate with autosomal dominant HS in some kindred. However, these gamma-secretase variants do not explain much of the overall genetic risk for HS. We performed targeted DNA sequencing of 21 candidate genes in a cohort of 117 individuals with HS to test for an increased burden of rare genetic variants. Candidates included the genes of the gamma-secretase complex, Notch signaling genes, and PSTPIP1, a known risk factor for PAPA syndrome. We discovered two pathogenic loss-of-function variants in nicastrin that to the best of our knowledge have not been described in HS before. We did not identify significant enrichment of rare missense variants in any gamma-secretase gene, further supporting that loss-of-function in gamma-secretase genes is not a common risk factor. We did, however, identify a statistically significant enrichment of rare variants in the SH3 domain of PSTPIP1. Clinical overlap between HS and PSTPIP1 syndromic features has been noted clinically. Our data suggest that there is shared genetic risk as well, and highlights the need for further population-scale HS genetic research.
Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart
Authors: Read David F , Booth Gregory T , Daza Riza M , Jackson Dana L , Gladden Rula Green , Srivatsan Sanjay R , Ewing Brent , Franks Jennifer M , Spurrell Cailyn H , Gomes Anne Roshella , O’Day Diana , Gogate Aishwarya A , Martin Beth K , Starita Lea , Lin Yiing , Shendure Jay , Lin Shin , Trapnell Cole 
Published: July 2022

AbstractSex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex. Sex dependent alterations include pathways such as TGFβ signaling and metabolic shifts by sex, evident in both transcriptional alterations and differing presence of transcription factor (TF) motifs in accessible chromatin. Age was associated with changes such as immune activation-related transcriptional and chromatin accessibility differences, as well as changes in the relative proportion of cardiomyocytes, neurons, and perivascular cells. In addition, we compare our adult-derived ATAC-Seq profiles to analogous fetal cell types to identify putative developmental-stage-specific regulatory factors. Finally, we train predictive models of cell-type-specific RNA expression levels utilizing ATAC-Seq profiles to link distal regulatory sequences to promoters, quantifying the predictive value of a simple TF-to-expression regulatory grammar and identifying cell-type-specific TFs.
Peptide binding specificity prediction using fine-tuned protein structure prediction networks
Authors: Motmaen Amir , Dauparas Justas , Baek Minkyung , Abedi Mohamad H. , Baker David , Bradley Philip 
Published: July 2022

AbstractPeptide binding proteins play key roles in biology, and predicting their binding specificity is a long-standing challenge. While considerable protein structural information is available, the most successful current methods use sequence information alone, in part because it has been a challenge to model the subtle structural changes accompanying sequence substitutions. Protein structure prediction networks such as AlphaFold model sequence-structure relationships very accurately, and we reasoned that if it were possible to specifically train such networks on binding data, more generalizable models could be created. We show that placing a classifier on top of the AlphaFold network and fine-tuning the combined network parameters for both classification and structure prediction accuracy leads to a model with strong generalizable performance on a wide range of Class I and Class II peptide-MHC interactions that approaches the overall performance of the state-of-the-art NetMHCpan sequence-based method. The peptide-MHC optimized model shows excellent performance in distinguishing binding and non-binding peptides to SH3 and PDZ domains. This ability to generalize well beyond the training set far exceeds that of sequence only models, and should be particularly powerful for systems where less experimental data is available.Significance statementPeptide binding proteins carry out a variety of biological functions in cells and predicting their binding specificity could significantly improve our understanding of molecular pathways. Deep neural networks have achieved high structure prediction accuracy, but are not trained to predict binding specificity. Here we describe an approach to extending such networks to jointly predict protein structure and binding specificity. We incorporate AlphaFold into this approach, and fine-tune its parameters on peptide-MHC Class I and II structural and binding data. The fine-tuned model approaches state-of-the-art classification accuracy on peptide-MHC specificity prediction and generalizes to other peptide-binding systems such as the PDZ and SH3 domains.
Gene regulation modules in non-alcoholic fatty liver disease revealed by single-nucleus ATAC-seq
Authors: Takeuchi Fumihiko , Liang Yi-Qiang , Shimizu-Furusawa Hana , Isono Masato , Ang Mia Yang , Mori Kotaro , Mori Taizo , Kakazu Eiji , Yoshio Sachiyo , Kato Norihiro 
Published: July 2022

AbstractWe investigated the progression of non-alcoholic fatty liver disease (NAFLD) from fatty liver to steatohepatitis using single-nucleus and bulk ATAC-seq on the livers of rats fed a high-fat diet (HFD). Rats fed HFD for 4 weeks developed fatty liver, and those fed HFD for 8 weeks further progressed to steatohepatitis. We observed an increase in the proportion of inflammatory macrophages, consistent with the pathological progression. Utilizing machine learning, we divided global gene regulation into modules, wherein transcription factors within a module could regulate genes within the same module, reaffirming known regulatory relationships between transcription factors and biological processes. We identified core genes—central to co-expression and protein-protein interaction—for the biological processes discovered. Notably, a large part of the core genes overlapped with genes previously implicated in NAFLD. Single-nucleus ATAC-seq, combined with data-driven statistical analysis, offers insight intoin vivoglobal gene regulation as a combination of modules and assists in identifying core genes of relevant biological processes.Summary blurbThis study uncovers cell type-specific global gene regulation in NAFLD progression, identifying core genes and shedding light on the disease’s molecular mechanisms.
Development of aXenopus-based assay for high-throughput evaluation of mucociliary flow
Authors: Antoniades Ioanna , Koulle Andria , Chatzifrangkeskou Maria , Konstantinou Timothea , Skourides Paris 
Published: July 2022

AbstractMotile cilia are organelles lining the surfaces of major organs of the human body and generate directional fluid flow. Ciliary dysfunction has been linked to an emerging class of multisystem disorders, collectively known as motile ciliopathies. Drug screening for ciliopathies is challenging due to the unavailability of high-throughput assays that can evaluate ciliary flow generation. Here, we describe the development of a unique assay that enables the direct and rapid evaluation of mucociliary flow, which simultaneously facilitates high-throughput screening of potential therapeutic agents for motile ciliopathies. The assay relies on the ability ofXenopustadpoles to promote mixing of a two-phase differential density aqueous mixture, through the robust flow generated by the mucociliary epithelium on their epidermis. We show that the rate of phase mixing is proportional to the rate of cilia-driven flow, therefore it directly represents the effectiveness of flow generation. We also demonstrate that the assay can detect changes in ciliary flow elicited by defects in cilia, CBF modulation and rotational polarity, providing an ideal assay for the identification of CBF-modulating compounds, as potential drugs for motile ciliopathies. Importantly we use the assay to show that CBF modulating drugs can improve flow generation and could thus be used as a potential therapeutic approach in PCD patients. The assay we have developed thus represents a powerful new tool for research, as well as drug development.
Monocyte-derived peritoneal macrophages protect C57BL/6 mice against surgery-induced adhesions
Authors: Sahputra Rinal , Dejyong Krittee , Woolf Adrian S , Mack Matthias , Allen Judi , Ruckerl Dominik , Herrick Sarah E 
Published: July 2022

AbstractPeritoneal adhesions commonly occur after abdominal or pelvic surgery. These scars join internal organs to each other or to the cavity wall and can present with abdominal or pelvic pain, and bowel obstruction or female infertility. The mechanisms underlying adhesion formation remain unclear and thus, effective treatments are not forthcoming. Peritoneal macrophages accumulate after surgery and previous studies have attributed either pro- or anti-scarring properties to these cells. We propose that there are complex and nuanced responses after surgery with respect to both resident and also monocyte-derived peritoneal macrophage subpopulations. Moreover, we contend that differences in responses of specific macrophage subpopulations in part explain the risk of developing peritoneal scars. We characterised alterations in peritoneal macrophage subpopulations after surgery-induced injury using two strains of mice, BALB/c and C57BL/6, with known differences in macrophage response post-infection. At 14 days post-surgery, BALB/c mice displayed more adhesions compared with C57BL/6 mice. This increase in scarring correlated with a lower influx of monocyte-derived macrophages at day 3 post-surgery. Moreover, BALB/c mice showed distinct macrophage repopulation dynamics after surgery. To confirm a role for monocyte-derived macrophages, we used Ccr2-deficient mice as well as antibody-mediated depletion of CCR2 expressing cells during initial stages of adhesion formation. Both Ccr2-deficient and CCR2-depleted mice showed a significant increase in adhesion formation associated with the loss of peritoneal monocyte influx. These findings revealed an important protective role for monocyte-derived cells in reducing adhesion formation after surgery.
A CDKB/KRP/FB3 cell cycle core complex functions in rice gametes and zygotes
Authors: Xu Hengping , Bartley Laura , Libault Marc , Sundaresan Venkatesan , Fu Hong , Russell Scott 
Published: July 2022

AbstractThe cell cycle controls division and proliferation of all eukaryotic cells and is tightly regulated at multiple checkpoints by complexes of core cell cycle proteins. Due to the difficulty in accessing female gametes and zygotes of flowering plants, little is known about the molecular mechanisms underlying initiation embryogenesis despite the crucial importance of this process for seed crops. In this study, we reveal four levels of factors involved in rice zygotic cell cycle control and characterize their functions and regulation. Protein-protein interaction studies, including within zygote cells, and in vitro biochemical analyses delineate a model of the zygotic cell cycle core complex for rice. In this model, CDKB1, a major regulator of plant mitosis, is a cyclin (CYCD5)-dependent kinase; its activity is coordinately inhibited by two cell cycle inhibitors, KRP4 and KRP5; and both KRPs are regulated via F-box protein 3 (FB3)-mediated proteolysis. Supporting their critical role in controlling the rice zygotic cell cycle, mutations in KRP4, KRP5, and FB3 result in the compromised function of sperm cells and abnormal organization of female germ units, embryo and endosperm, thus significantly reducing seed-set rates. This work helps reveals regulatory mechanisms controlling the zygotic cell cycle toward seed formation in angiosperms.