bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive Network Analysis IdentifiesJMJD6and Other Novel Key Drivers in Alzheimer’s Disease
Authors: Merchant Julie P. , Zhu Kuixi , Henrion Marc Y.R. , Zaidi Syed S.A. , Branden Lau , Moein Sara , Alamprese Melissa L. , Pearse Richard V. , Bennett David A. , Ertekin-Taner Nilüfer , Young-Pearse Tracy L. , Chang Rui 
Published: October 2022

SummaryDespite decades of genetic studies on late onset Alzheimer’s disease (LOAD), the molecular mechanisms of Alzheimer’s disease (AD) remain unclear. Furthermore, different cell types in the central nervous system (CNS) play distinct roles in the onset and progression of AD pathology. To better comprehend the complex etiology of AD, we used an integrative approach to build robust predictive (causal) network models which were cross-validated over multiple large human multi-omics datasets in AD. We employed a published method to delineate bulk-tissue gene expression into single cell-type gene expression and integrated clinical and pathologic traits of AD, single nucleotide variation, and deconvoluted gene expression for the construction of predictive network models for each cell type in AD. With these predictive causal models, we are able to identify and prioritize robust key drivers of the AD-associated network state. In this study, we focused on neuron-specific network models and prioritized 19 predicted key drivers modulating AD pathology. These targets were validated via shRNA knockdown in human induced pluripotent stem cell (iPSC) derived neurons (iNs), in which 10 out of the 19 neuron-related targets (JMJD6, NSF, NUDT2, YWHAZ, RBM4, DCAF12, NDRG4, STXBP1, ATP1B1, andFIBP) significantly modulated levels of amyloid-beta and/or phosphorylated tau peptides in the postmitotic iNs. Most notably, knockdown ofJMJD6significantly altered the neurotoxic ratios of Aβ42 to 40 and p231-tau to total tau, indicating its potential therapeutic relevance to both amyloid and tau pathology in AD. Molecular validation by RNA sequencing (RNAseq) in iNs further confirmed the network structure, showing significant enrichment in differentially expressed genes after knockdown of the validated targets. Interestingly, our network model predicts that these 10 key drivers are upstream regulators of REST and VGF, two recently identified key regulators of AD pathogenesis.
Mating activates neuroendocrine pathways signaling hunger inDrosophilafemales
Authors: Laturney Meghan , Sterne Gabriella R. , Scott Kristin 
Published: October 2022

SummaryMated females reallocate resources to offspring production, causing changes in nutritional requirements and challenges to energy homeostasis. Although observed in most species, the neural and endocrine mechanisms that regulate the nutritional needs of mated females are not well understood. Here, we investigate the neural circuitry that regulates sugar appetite in matedDrosophila melanogasterfemales. During copulation, a male-derived sex peptide is transferred to females, silencing the mating status circuit to elicit many postmating behavioral changes1-3. We find that increased sucrose consumption is a postmated female behavior and show that it is mediated by the mating status circuit. We discovered that sexually dimorphic insulin receptor (Lgr3) neurons integrate mating status and nutritional state signals to adjust sucrose consumption. Lgr3+ cells receive inhibitory input from the mating status circuit via female specific pCd-2 neurons. In mated females, the inhibition of Lgr3 cells from pCd-2 is attenuated, transforming the mated signal into a long-term hunger signal that promotes sugar intake. Our results thus demonstrate that the mating circuit alters nutrient sensing centers in females to promote sugar consumption, providing a mechanism to increase intake in anticipation of the energetic costs associated with reproduction.
Genomic underpinnings of convergent adaptation to high altitudes for alpine plants
Authors: Zhang Xu , Kuang Tianhui , Dong Wenlin , Qian Zhihao , Zhang Huajie , Landis Jacob B. , Feng Tao , Li Lijuan , Sun Yanxia , Huang Jinling , Deng Tao , Wang Hengchang , Sun Hang 
Published: October 2022

AbstractEvolutionary convergence is one of the most striking examples of adaptation driven by natural selection. However, genomic evidence for convergent adaptation to extreme environments remains scarce. The Himalaya-Hengduan Mountains represent the world’s most species-rich temperate alpine biota, providing an ideal “natural laboratory” for studying convergent adaptation to high altitudes. Here, we generate reference genomes for two alpine plants,Saussurea obvallata(Asteraceae) andRheum alexandrae(Polygonaceae), with 37,938 and 61,463 annotated protein-coding genes. By integrating an additional five alpine genomes, we investigate genomic signatures of convergent adaptation to the hostile environments of high altitudes. We show that alpine genomes tend to mitigate their genetic load by contracting genes functioning in the immune system to survive such harsh environments with few pathogens present. We detect signatures of convergent positive selection on a set of genes involved in reproduction and development and reveal that molecular convergence has acted on genes involved in self-incompatibility, cell wall modification, DNA repair and stress resistance, which underlie adaptation to extremely cold, high UV radiation and hypoxia environments. Using gene expression profiles, we further demonstrate that genes associated with cuticular wax and flavonoid biosynthetic pathways exhibit higher expression levels in leafy bracts, shedding lights on the genetic mechanisms of the adaptive ‘greenhouse’ morphology. Our integrative data provide genomic insights into the convergent evolution at higher-taxonomic levels, aiding in deep understanding of genetic adaptation to complex environments.
Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition
Authors: Fermi Valentina , Warta Rolf , Rapp Carmen , Knoll Maximilian , Jungwirth Gerhard , Jungk Christine , Dao Trong Philip , von Deimling Andreas , Abdollahi Amir , Unterberg Andreas , Herold-Mende Christel 
Published: October 2022

AbstractTargeting immunosuppressive and protumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) holds great potential to improve patient outcomes. Although CSF1R has emerged as a promising target to reprogram anti-inflammatory M2-like GAMs, relevant treatment data on human, tumor-educated GAMs and innovative patient-derived 3D tumor organoid models to study the influence on adaptive immunity and the effectiveness of treatment in a complex and entirely autologous setting are largely lacking. We performed a comprehensive phenotypical, transcriptional and functional analysis of primary, patient-derived GAMs upon treatment with the CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to a downregulation of M2-related markers and signaling pathways, while M1-like markers, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming together with reduced tumor cell proliferation, indicating that treatment with GW2580 could be an important pillar in the future therapy of GBM.
Modulation of functional networks related to the serotonin neurotransmitter system by citalopram: evidence from a multimodal neuroimaging study
Authors: Boucherie Daphne E , Reneman Liesbeth , Booij Jan , Martins Daniel , Dipasquale Ottavia , Schrantee Anouk 
Published: October 2022

AbstractBackgroundSelective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of serotonin 1A receptors (5-HT1AR).AimWe investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge.MethodsWe analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [123I]FP-CIT single-photon emission computerized tomography.Results5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low dose group compared to the high dose group at rest and the placebo group during the task.ConclusionsTaken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.
Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity
Authors: Cha Jeeyeon , Tong Xin , Walker Emily , Dahan Tehila , Cochrane Veronica , Ashe Sudipta , Russell Ronan , Osipovich Anna , Mawla Alex , Guo Min , Liu Jin-hua , Huising Mark , Magnuson Mark , Hebrok Matthias , Dor Yuval , Stein Roland 
Published: October 2022

ABSTRACTType 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta (β) cells, characterized by inappropriate production of other islet cell-enriched hormones. Here we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin (Gast)-positive cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a gastrin (GAST)-positive gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repressGASTgene transcription. These results support a novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively, by repressing expression of Gast/GAST and other non-β cell hormones.
CWLP and PRP940 form plasma-membrane nanodomain complexes with aquaporins, interact with PP2A and contribute to dehydration tolerance
Authors: Honig Arik , Eilenberg Haviva , Zuther Ellen , Avisar Dror , Erster Oran , Eshkol Gad , Stein Hanan , Reznik Noam , Schuster Silvia , Belausov Eduard , Abu-Abied Muhammad , Hotta Takashi , Lee Yuh-Ru Julie , Liu Bo , Sadot Einat , Koncz Csaba , Zilberstein Aviah , Fichman Yosef 
Published: October 2022

AbstractThe C-type hybrid-proline-rich protein (HyPRP) AtCWLP and its homolog AtPRP940 are referred as cell wall (CW)-plasma-membrane (PM) linker proteins, but little is known about their functions. Here we show that N-terminal proline-rich domains of CWLP and PRP940, containing glycosylated hydroxyproline residues, contact the CW, while their C-terminal 8CM domains function as PM-scaffolds. Both proteins are detected in PM nanodomains (PM-ND) and show co-localization and co-immunoprecipitation with aquaporins PIP2;1 and PIP2;7. Inhibition of actin polymerization by latrunculin B promotes CWLP-endosome appearance, while blocking the actomyosin-based transport by a truncated form of myosin XI-K relaxes lateral boundaries of CWLP-PIP2;1 PD-NDs. Mass spectrometry data indicate that CWLP co-purifies with dynamins implicated in fission of endocytic PD-ND invaginations. Lack of co-localization and co-immunoprecipitation with aquaporin-binding flotillin (FLOT2) indicates that CWLP and PRP940 mark a new distinct type of PM-ND. Yeast two-hybrid and co-immunoprecipitation assays demonstrate that CWLP and PRP940 interact with multiple aquaporins and several protein phosphatase PP2A-B’’ regulatory subunits. By preventing irreversible separation of CW and PM, and likely assisting PP2A-mediated dephosphorylation of aquaporins and closure of their water channels, overexpression of CWLP confers tolerance to plasmolysis, dehydration and freezing in Arabidopsis and to water shortage in potato plants.Summary StatementArabidopsis Hybrid-Proline-Rich Proteins CWLP and PRP940 occur in association with dynamins, recruit PP2A protein phosphatases to aquaporin water channels in plasma-membrane (PM) nanodomains and elevate tolerance to cellular dehydration.
The priming effect of rewarding brain stimulation in rats depends on both the cost and strength of reward but survives blockade of D2-like dopamine receptors
Authors: Evangelista Czarina , Mehrez Norhan , Boisvert Esthelle Ewusi , Brake Wayne G. , Shizgal Peter 
Published: October 2022

AbstractReceipt of an intense reward boosts motivation to work for more of that reward. This phenomenon is called thepriming effect of rewards. Using a novel measurement method, we show that the priming effect of rewarding electrical brain stimulation depends on the cost, as well as on the strength, of the anticipated reward. Previous research on the priming effect of electrical brain stimulation utilized a runway paradigm in which running speed serves as the measure of motivation. In the present study, the measure of motivation was the vigor with which rats executed a two-lever response chain, in a standard operant-conditioning chamber, to earn rewarding electrical stimulation of the lateral hypothalamus. In a second experiment, we introduced a modification that entails self-administered priming stimulation and alternating blocks of primed and unprimed trials. Reliable, consistent priming effects of substantial magnitude were obtained in the modified paradigm, which is closely analogous to the runway paradigm. In a third experiment, the modified paradigm served to assess the dependence of the priming effect on dopamine D2-like receptors. The priming effect proved resilient to the effect of eticlopride, a selective D2-like receptor antagonist. These results are discussed within the framework of a new model of brain reward circuitry in which non-dopaminergic medial forebrain bundle fibers and dopamine axons provide parallel inputs to the final common paths for reward and incentive motivation.
Vutiglabridin improves neurodegeneration in MPTP-induced Parkinson’s disease mice by targeting mitochondrial paraoxonase-2
Authors: Kang Sora , Choi Leo S. , Im Suyeol , Kim Ji Hwan , Lee Keun Woo , Kim Dong Hwan , Park Jung Hee , Park Min-Ho , Lee Jaemin , Park Sun Kyung , Kim Kwang Pyo , Lee Hyeong Min , Jeon Hyun Ju , Park Hyung Soon , Yoo Sang-Ku , Pak Youngmi Kim 
Published: October 2022

AbstractParkinson’s disease (PD), characterized by degeneration of dopaminergic neurons, share pathogenic features with obesity, including mitochondrial dysfunction and oxidative stress. Paraoxonase 2 (PON2) is an inner mitochondrial membrane protein that is highly expressed in dopaminergic neurons and is involved in the regulation of mitochondrial oxidative stress. However, no drug targeting PON2 has ever been developed for the treatment of PD. Here, we show that vutiglabridin, a clinical phase 2-stage drug for the treatment of obesity, has therapeutic effects in PD models, targeting mitochondrial PON2. Vutiglabridin penetrates into the brain, binds to PON2, and restores 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction in SH-SY5Y neuroblastoma cells. Knockdown of PON2 by lentiviral shRNA infection abolished the effects of vutiglabridin on mitochondria. In mice, vutiglabridin significantly alleviated motor impairments and damage to dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, and these effects were also abolished in PON2-knockdown mice, suggesting that vutiglabridin is neuroprotective via PON2. Extensive in vitro and in vivo assessment of potential neurotoxicity showed vutiglabridin to be safe. Overall, these findings provide support for the clinical development of vutiglabridin as a novel PON2 modulator for the treatment of PD.One Sentence SummaryTargeting paraoxonase-2 by a clinical-stage compound vutiglabridin provides neuroprotective effects in preclinical models of Parkinson’s disease.
Hydrogen Cyanamide Causes Reversible G2/M Cell Cycle Arrest Accompanied by Oxidation of the Nucleus and Cytosol inArabidopsis thalianaRoot Apical Meristem Cells
Authors: Velappan Yazhini , De Simone Ambra , Signorelli Santiago , Considine John A , Foyer Christine H , Considine Michael J 
Published: October 2022

AbstractHydrogen cyanamide (HC) is known to stimulate the production of reactive oxygen species (ROS) and also alter growth through modification of the cell cycle. However, the mechanisms by which HC alters cell proliferation and redox homeostasis are largely unknown. This study used roGFP2 expressing Arabidopsis seedlings to measure the oxidation states of the nuclei and cytosol in response to HC treatment. The Cytrap dual cell cycle phase marker system and flow cytometry were used to study associated changes in cell proliferation. HC (1.5mM) reversibly inhibited root growth during a 24h treatment. Higher concentrations were not reversible. HC did not synchronize the cell cycle. In contrast to hydroxyurea, HC caused a gradual accumulation of cells in the G2/M phase and decline of G1/S phase cells 16 to 24h post-treatment. This was accompanied by increased oxidation of both the nuclei and cytosol. Taken together, HC impairs proliferation of embryonic root meristem cells in a reversible manner through restriction of G2/M transition accompanied by increased oxidative poise.
Neutral genetic structuring of pathogen populations during rapid adaptation
Authors: Saubin Méline , Stoeckel Solenn , Tellier Aurélien , Halkett Fabien 
Published: October 2022

AbstractPathogen species are experiencing strong joint demographic and selective events, especially when they adapt to a new host, for example through overcoming plant resistance. Stochasticity in the founding event and the associated demographic variations hinder our understanding of the expected evolutionary trajectories and the genetic structure emerging at both neutral and selected loci. What would be the typical genetic signatures of such a rapid adaptation event is not elucidated. Here, we build a demogenetic model to monitor pathogen population dynamics and genetic evolution on two host compartments (susceptible and resistant). We design our model to fit two plant pathogen life cycles, ‘with’ and ‘without’ host alternation. Our aim is to draw a typology of eco-evolutionary dynamics. Using time-series clustering, we identify three main scenarios: 1) small variations in the pathogen population size and small changes in genetic structure, 2) a strong founder event on the resistant host that in turn leads to the emergence of genetic structure on the susceptible host, and 3) evolutionary rescue that results in a strong founder event on the resistant host, preceded by a bottleneck on the susceptible host. We pinpoint differences between life cycles with notably more evolutionary rescue ‘with’ host alternation. Beyond the selective event itself, the demographic trajectory imposes specific changes in the genetic structure of the pathogen population. Most of these genetic changes are transient, with a signature of resistance overcoming that vanishes within a few years only. Considering time-series is therefore of utmost importance to accurately decipher pathogen evolution.
AtFZL is required for correct starch granule morphology in Arabidopsis chloroplasts
Authors: Esch Lara , Ngai Qi Yang , Barclay J. Elaine , Seung David 
Published: October 2022

AbstractThe control of starch granule number and morphology in plastids is poorly understood. Here, we demonstrate thatAtFZL, a protein involved in thylakoid membrane organisation, is required for correct starch granule morphology in Arabidopsis. Leaves of mutants lackingAtFZL had the same starch content as wild-type leaves, but their starch granules were smaller and had a distinct, uneven surface morphology. Most chloroplasts in the mutant were larger than those of the wild type.However, the difference in chloroplast size could not explain the difference in granule size and shape in theAtfzlmutants, since other mutants with larger chloroplasts than the wild type (arcmutants) had granules that were similar in size and shape to wild-type granules. As reported previously, theAtfzlmutant had aberrant thylakoid organisation. We found that this phenomenon was particularly pronounced in regions surrounding starch granules. The location of the thylakoid-bound granule initiation protein MFP1 was unaffected in theAtfzlmutant. We propose thatAtFZL affects starch granule size and shape by influencing thylakoid organisation at the periphery of starch granules. Our results are consistent with an important role for thylakoid architecture in determining granule morphology.
T-RHEX-RNAseq – A tagmentation-based, rRNA blocked, random hexamer primed RNAseq method for generating stranded RNAseq libraries directly from very low numbers of lysed cells
Authors: Gustafsson Charlotte , Hauenstein Julia , Frengen Nicolai , Krstic Aleksandra , Luc Sidinh , Månsson Robert 
Published: October 2022

ABSTRACTBackgroundRNA sequencing has become the mainstay for studies of gene expression. Still, analysis of rare cells with random hexamer priming – to allow analysis of a broader range of transcripts – remains challenging.ResultsWe here describe a tagmentation-based, rRNA blocked, random hexamer primed RNAseq approach (T-RHEX-RNAseq) for generating stranded RNAseq libraries from very low numbers of FACS sorted cells without RNA purification steps.ConclusionT-RHEX-RNAseq provides an easy-to-use, time efficient and automation compatible method for generating stranded RNAseq libraries from rare cells.
Small molecule modulatesα-Synuclein conformation and its oligomerization via Entropy Expansion
Authors: Menon Sneha , Mondal Jagannath 
Published: October 2022

AbstractAberrant misfolding and progressive aggregation of the intrinsically disordered protein (IDP),α-synuclein, are associated with the etiology of several neurodegenerative diseases. However, the structurally heterogeneous ensemble of this IDP and lack of a well-defined binding pocket make it difficult to probe the druggability ofα-synuclein. Here, by building a comprehensive statistical model of the fuzzy ensemble of a millisecond-long atomistic simulation trajectory of monomericα-synuclein interacting with the small-molecule drug fasudil, we identify exhaustive sets of metastable binding-competent states ofα-synuclein. The model reveals that the interaction with the drug primes this IDP to explore both more compact and more extended conformational sub-ensemble than those in neat water, thereby broadening its structural repertoire in presence of small-molecule via anentropy expansionmechanism. Subsequent simulation of the dimerisation process shows that similar motif of entropic-expansion mechanism helps fasudil to retard the self-aggregation propensity ofα-synuclein via trapping it into multiple distinct states of diverse compaction featuring aggregation-resistant long-range interactions. Furthermore, small-molecule binding interactions in dimerisation-competent relatively extended states have a screening effect that hinders the formation of stable dimer contacts. Together, the investigation demonstrates the ability of small-molecules to have an ensemble-modulatory effect on IDPs that can be effectively utilised in therapeutic strategies probing aggregation-related diseases.