bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic nurture effects on education: a systematic review and meta-analysis
Authors: Wang Biyao , Baldwin Jessie R. , Schoeler Tabea , Cheesman Rosa , Barkhuizen Wikus , Dudbridge Frank , Bann David , Morris Tim T. , Pingault Jean-Baptiste 
Published: January 2021

AbstractChild educational development is associated with major psychological, social, economic and health milestones throughout the life course. Understanding the early origins of educational inequalities and their reproduction across generations is therefore crucial. Recent genomic studies provide novel insights in this regard, uncovering “genetic nurture” effects, whereby parental genotypes influence offspring’s educational development via environmental pathways rather than genetic transmission. These findings have yet to be systematically appraised. We conducted the first systematic review and meta-analysis to quantify genetic nurture effects on educational outcomes and investigate key moderators. Twelve studies comprising 38,654 distinct parent(s)-offspring pairs or trios from eight cohorts were included, from which we derived 22 estimates of genetic nurture effects. Multilevel random effects models showed that the effect of genetic nurture on offspring’s educational outcomes (βgenetic nurture= 0.08, 95% CI [0.07, 0.09]) was about half the size of direct genetic effects (βdirect genetic= 0.17, 95% CI [0.13, 0.20]). Maternal and paternal genetic nurture effects were similar in magnitude, suggesting comparable roles of mothers and fathers in determining their children’s educational outcomes. Genetic nurture effects were largely explained by parental educational level and family socioeconomic status, suggesting that genetically influenced environments play an important role in shaping child educational outcomes. Even after accounting for genetic transmission, we provide evidence that environmentally mediated parental genetic influences contribute to the intergenerational transmission of educational outcomes. Further exploring these downstream environmental pathways may inform educational policies aiming to break the intergenerational cycle of educational underachievement and foster social mobility.Public Significance StatementThis meta-analysis demonstrates that parents’ genetics influence their children’s educational outcomes through the rearing environments that parents provide. This “genetic nurture” effect is largely explained by family socioeconomic status and parental education level, is similar for mothers and fathers (suggesting that both parents equally shape their children’s educational outcomes) and is about half the size of direct genetic effects on children’s educational outcomes. Interventions targeting such environmental pathways could help to break the intergenerational cycle of educational underachievement and foster social mobility.
Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5
Authors: Ichise Hiroshi , Tsukamoto Shoko , Hirashima Tsuyoshi , Konishi Yoshinobu , Oki Choji , Tsukiji Shinya , Iwano Satoshi , Miyawaki Atsushi , Sumiyama Kenta , Terai Kenta , Matsuda Michiyuki 
Published: January 2021

ABSTRACTNatural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is not known. Here we have combined ultra-sensitive bioluminescence whole body imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that a disseminated tumor cell in a pulmonary capillary interacts with an NK cell every 2 hrs on average. In the first 4 hrs after tumor cell arrival, 50% of such encounters lead to tumor cell death but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. This evasion of NK cell surveillance is mediated by thrombin-dependent loss of cell surface CD155/PVR/Necl-5, a ligand for the NK cell activating receptor DNAM-1. This loss prevents the NK cell signaling needed for effective killing of tumor targets. By quantitatively visualizing the evasion of NK cell surveillance, we have uncovered a molecular mechanism for cancer evasion and provided an explanation for the anti-metastatic effect of anticoagulants.SUMMARYIntravital functional two-photon microscopy reveals that metastatic tumor cells lodged in pulmonary capillaries acquire resistance to patrolling NK cells. Protease-mediated loss of the activating ligand CD155/PVR/Necl-5 on tumor cells prevents NK cells from ERK activation and tumor cell killing.
KIT is required for fetal liver erythropoiesis but dispensable for angiogenesis
Authors: Fantin Alessandro , Plein Alice , Tacconi Carlotta , Villa Emanuela , Ceccacci Elena , Denti Laura , Ruhrberg Christiana 
Published: January 2021

AbstractBlood vessels are fundamental to sustain organ growth and tissue metabolism. In the mouse embryo, endothelial cell (EC) progenitors almost concomitantly give rise to the first blood vessels in the yolk sac and the large vessels of the embryo proper. Thereafter, the vascular network expands by angiogenesis to vascularize developing organs such as the brain. Although the first blood cells form in the yolk sac before blood vessels have assembled, consecutive waves of hematopoietic progenitors subsequently bud from hemogenic endothelium located within the wall of yolk sac and large intraembryonic vessels in a process termed endothelial to hematopoietic transition (endoHT). The receptor tyrosine kinase KIT is required for late embryonic erythropoiesis, but KIT is also expressed earlier in the hemogenic endothelium, in hematopoietic progenitors that arise via endoHT from hemogenic endothelium and non-hemogenic ECs, such as in the brain. However, it remains unclear whether KIT has essential roles in early hematopoiesis or even blood vessel growth. Here, we have combined transcriptomic analysis to delineateKitexpression with the analysis of knockout mice to show that KIT is expressed during but dispensable for yolk sac endoHT or brain angiogenesis but required for transient definitive erythropoiesis in the fetal liver.
Proprotein Convertase Subtilisin/kexin Type 9 Links Inflammation to Vascular Endothelial Cell Dysfunction
Authors: Leucker Thorsten M. , Amat-Codina Nuria , Chelko Stephen , Gerstenblith Gary 
Published: January 2021

AbstractVascular endothelial cell (EC) dysfunction is a pathological mediator of he development, progression, and clinical manifestations of atherosclerotic disease. Inflammation is associated with EC dysfunction, but the responsible mechanisms are not well characterized. There is substantial evidence that serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is increased in pro-inflammatory states and that elevated PCSK9 levels are associated with adverse cardiovascular outcomes after controlling for traditional risk factors, including low-density lipoprotein (LDL) cholesterol.Here we investigate PCSK9 as a novel link between inflammation and vascular EC dysfunction, as assessed by nitric oxide (NO) bioavailability. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, increasedPCSK9mRNA expression and PCSK9 protein levels in isolated human aortic ECs, which were accompanied by reduced total and phosphorylated endothelial nitric oxide synthase (eNOS) protein levels and NO bioavailability. Finally, genetic PCSK9 reduction utilizing a PCSK9 specific siRNA in human aortic ECs resulted in the rescue of phosphorylated eNOS protein levels and NO bioavailability.Our results demonstrate that PCSK9 is increased in human aortic ECs exposed to a pro-inflammatory stimulus and that this increase is associated with EC dysfunction. Silencing of TNFα-mediated augmentation ofPCSK9expression utilizing a small interfering RNA againstPCSK9rescued the inflammation-induced EC dysfunction. These results indicate that PCSK9 is a causal link between inflammation and EC dysfunction, a potent driver of atherosclerotic cardiovascular disease.
Formation and Spontaneous Long-Term Repatterning of Headless Planarian Flatworms
Authors: Bischof Johanna , LaPalme Jennifer V. , Miller Kelsie A. , Morokuma Junji , Williams Katherine B. , Fields Chris , Levin Michael 
Published: January 2021

AbstractRegeneration requires the production of large numbers of new cells, and thus cell division regulators, particularly ERK signaling, are critical in regulating this process. In the highly regenerative planarian flatworm, questions remain as to whether ERK signaling controls overall regeneration or plays a head-specific role. Here we show that ERK inhibition in the 3 days following amputation delays regeneration, but that all tissues except the head can overcome this inhibition, resulting in headless regenerates. This prevention of head regeneration happens to a different degree along the anterior-posterior axis, with very anterior wounds regenerating heads even under ERK inhibition. Remarkably, 4 to 18 weeks after injury, the headless animals induced by ERK inhibition remodel to regain single-headed morphology, in the absence of further injury, in a process driven by Wnt/β-catenin signaling. Interestingly, headless animals are likely to exhibit unstable axial polarity, and cutting or fissioning prior to remodeling can result in body-wide reversal of anterior-posterior polarity. Our data reveal new aspects of how ERK signaling regulates regeneration in planaria and show anatomical remodeling on very long timescales.
Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease
Authors: Sánchez-Ceinos Julia , Guzmán-Ruiz Rocío , Rangel-Zúñiga Oriol A. , López-Alcalá Jaime , Moreno-Caño Elena , del Río-Moreno Mercedes , Romero-Cabrera Juan L. , Pérez-Martínez Pablo , Maymo-Masip Elsa , Vendrell Joan , Fernández-Veledo Sonia , Fernández-Real José M. , Laurencikiene Jurga , Rydén Mikael , Membrives Antonio , Luque Raúl M. , López-Miranda José , Malagón María M. 
Published: January 2021

AbstractPreadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we demonstrate that impaired alternative splicing and dysregulated endoplasmic reticulum (ER)- associated protein degradation (ERAD) represent marker pathways of dysfunctional preadipocytes in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). Down-regulation of a key member of the major spliceosome,PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery ofPRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of ERAD hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.
Applying cis-regulatory codes to predict conserved and variable heat and cold stress response in maize
Authors: Zhou Peng , Enders Tara A. , Myers Zachary A. , Magnusson Erika , Crisp Peter A , Noshay Jaclyn , Gomez-Cano Fabio , Liang Zhikai , Grotewold Erich , Greenham Kathleen , Springer Nathan 
Published: January 2021

AbstractChanges in gene expression are important for response to abiotic stress. Transcriptome profiling performed on maize inbred and hybrid genotypes subjected to heat or cold stress identifies many transcript abundance changes in response to these environmental conditions. Motifs that are enriched near differentially expressed genes were used to develop machine learning models to predict gene expression responses to heat or cold. The best performing models utilize the sequences both upstream and downstream of the transcription start site. Prediction accuracies could be improved using models developed for specific co-expression clusters compared to using all up- or down-regulated genes or by only using motifs within unmethylated regions. Comparisons of expression responses in multiple genotypes were used to identify genes with variable response and to identifycis-ortrans-regulatory variation. Models trained on B73 data have lower performance when applied to Mo17 or W22, this could be improved by using models trained on data from all genotypes. However, the models have low accuracy for correctly predicting genes with variable responses to abiotic stress. This study provides insights intocis-regulatory motifs for heat- and cold-responsive gene expression and provides a framework for developing models to predict expression response to abiotic stress across multiple genotypes.One sentence summaryTranscriptome profiling of maize inbred and hybrid seedlings subjected to heat or cold stress was used to identify key cis-regulatory elements and develop models to predict gene expression responses.
SCFFbxw5targets MCAK in G2/M to facilitate ciliogenesis in the following cell cycle
Authors: Schweiggert Jörg , Habeck Gregor , Hess Sandra , Mikus Felix , Meese Klaus , Hata Shoji , Knobeloch Klaus-Peter , Melchior Frauke 
Published: January 2021

AbstractThe microtubule depolymerase Kif2C/MCAK plays important roles in various cellular processes and is frequently overexpressed in different cancer types. Despite the importance of its correct abundance, remarkably little is known about how MCAK levels are regulated in cells.Using comprehensive screening on protein microarrays, we identified 161 candidate substrates of the multi-subunit ubiquitin E3 ligase SCFFbxw5, including MCAK.In vitroreconstitution assays demonstrate that MCAK and its closely related orthologs Kif2A and Kif2B become efficiently polyubiquitylated by neddylated SCFFbxw5and Cdc34, without requiring preceding modifications. In cells, SCFFbxw5targets MCAK for proteasomal degradation specifically during G2/M. While this seems largely dispensable for mitotic progression, loss of Fbxw5 leads to increased MCAK levels at basal bodies, which impair formation of primary cilia in the following G1. We have thus identified a novel regulatory event of ciliogenesis that occurs already within the G2/M phase of the preceding cell cycle.
Endothelial NRP2 influences angiogenesis by regulating actin pattern development and α5-integrin-p-FAK complex recruitment to assembling adhesion sites
Authors: Benwell Christopher J , Taylor James AGE , Robinson Stephen D 
Published: January 2021

AbstractThe ability to form a variety of cell-matrix connections is crucial for angiogenesis to take place. Without stable anchorage to the extracellular matrix (ECM), endothelial cells (ECs) are unable to sense, integrate and disseminate growth factor stimulated responses that drive growth of a vascular bed. Neuropilin-2 (NRP2) is a widely expressed membrane-bound multifunctional non-tyrosine kinase receptor, that has previously been implicated in influencing cell adhesion and migration by interacting with α5-integrin and regulating adhesion turnover. α5-integrin, and its ECM ligand fibronectin (FN) are both known to be upregulated during the formation of neo-vasculature. Despite being descriptively annotated as a candidate biomarker for aggressive cancer phenotypes, the EC-specific roles for NRP2 during developmental and pathological angiogenesis remain unexplored. The data reported here support a model whereby NRP2 actively promotes EC adhesion and migration by regulating dynamic cytoskeletal remodelling and by stimulating Rab11-dependent recycling of α5-integrin-p-FAK complexes to newly assembling adhesion sites. Furthermore, temporal depletion of EC-NRP2in vivoimpairs primary tumour growth by disrupting vessel formation. We also demonstrate that EC-NRP2 is required for normal postnatal retinal vascular development, specifically by regulating cell-matrix adhesion. Upon loss of endothelial NRP2, vascular outgrowth from the optic nerve during superficial plexus formation is disrupted, likely due to reduced FAK phosphorylation within sprouting tip cells.
Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model
Authors: Serra Ines , Manusama Olivia R. , Kaiser Fabian M. P. , Floriano Izi Izumi , Wahl Lucas , van der Zalm Christian , IJspeert Hanna , van Hagen P. Martin , van Beveren Nico J.M. , Arend Sandra M. , Okkenhaug Klaus , Pel Johan J.M. , Dalm Virgil A.S.H. , Badura Aleksandra 
Published: January 2021

AbstractThe phosphoinositide-3-kinase (PI3K) family plays a major role in cell signalling and is predominant in leukocytes. Gain-of-function (GOF) mutations in thePIK3CDgene lead to the development of activated PI3Kδ syndrome (APDS), a rare primary immunodeficiency disorder. A subset of APDS patients also displays neurodevelopmental delay symptoms, suggesting a potential role ofPIK3CDin cognitive and behavioural function. However, the extent and nature of the neurodevelopmental deficits has not been previously quantified. Here, we assessed the cognitive functions of two APDS patients, and investigated the causal role of thePIK3CDGOF mutation in neurological deficits using a murine model of this disease. We used E1020K knock-in mice, harbouring the most common APDS mutation in patients. We found that APDS patients present with visuomotor deficits, exacerbated by autism spectrum disorder comorbidity, whereas p110δE1020Kmice exhibited impairments in motor behaviour, learning and repetitive behaviour patterning. Our data indicate thatPIK3CDGOF mutations increase the risk for neurodevelopmental deficits, supporting previous findings on the interplay between the nervous and the immune system. Further, our results validate the knock-in mouse model, and offer an objective assessment tool for patients that could be incorporated in diagnosis and in the evaluation of treatments.
Using zebrafish to elucidate glial-vascular interactions during CNS development
Authors: Umans Robyn A. , Pollock Carolyn , Mills William A. , Sontheimer Harald 
Published: January 2021

AbstractAn emerging area of interest in Neuroscience is the cellular relationship between glia and blood vessels, as many of the presumptive support roles of glia require an association with the vasculature. These interactions are best studiedin vivoand great strides have been made using mice to longitudinally image glial-vascular interactions. However, these methods are cumbersome for developmental studies, which could benefit from a more accessible system. Zebrafish (Danio rerio) are genetically tractable vertebrates, and given their translucency, are readily amenable for daily live imaging studies. We set out to examine whether zebrafish glia have conserved traits with mammalian glia regarding their ability to interact with and maintain the developing brain vasculature. We utilized transgenic zebrafish strains in whicholigodendrocyte transcription factor 2(olig2) andglial fibrillary acidic protein(gfap) identify different glial populations in the zebrafish brain and document their corresponding relationship with brain blood vessels. Our results demonstrate thatolig2andgfapzebrafish glia have distinct lineages and each interact with brain vessels as previously observed in mouse brain. Additionally, we manipulated these relationships through pharmacological and genetic approaches to distinguish the roles of these cell types during blood vessel development.olig2glia use blood vessels as a pathway during their migration and Wnt signaling inhibition decreases their single-cell vessel co-option. By contrast, the ablation ofgfapglia at the beginning of CNS angiogenesis impairs vessel development through a reduction in Vascular endothelial growth factor (Vegf), supporting a role forgfapglia during new brain vessel formation in zebrafish. This data suggests that zebrafish glia, akin to mammalian glia, have different lineages that show diverse interactions with blood vessels, and are a suitable model for elucidating glial-vascular relationships during vertebrate brain development.
Meiosis-specific ZFP541 repressor complex promotes meiotic prophase exit during spermatogenesis
Authors: Horisawa-Takada Yuki , Kodera Chisato , Takemoto Kazumasa , Sakashita Akihiko , Horisawa Kenichi , Maeda Ryo , Usuki Shingo , Fujimura Sayoko , Tani Naoki , Matsuura Kumi , Shimada Ryuki , Akiyama Tomohiko , Suzuki Atsushi , Niwa Hitoshi , Tachibana Makoto , Ohba Takashi , Katabuchi Hidetaka , Namekawa Satoshi H. , Araki Kimi , Ishiguro Kei-ichiro 
Published: January 2021

SummaryDuring spermatogenesis, meiosis is accompanied by robust alteration in gene expression and chromatin status. However, it remained elusive how meiotic transcriptional program is established to ensure completion of meiotic prophase. Here, we identified a novel protein complex consisting of germ-cell-specific zinc-finger protein ZFP541 and its interactor KCTD19 as the key transcriptional regulator for meiotic prophase exit. Our genetic study showed that ZFP541 and KCTD19 are co-expressed from pachytene onward and play an essential role in the completion of meiotic prophase program in the testis. Furthermore, our ChIP-seq and transcriptome analyses revealed that ZFP541 binds to and suppresses a broad range of genes whose function is associated with biological processes of transcriptional regulation and covalent chromatin modification. The present study demonstrated that germ-cell specific ZFP541-KCTD19 containing complex promotes meiotic prophase exit in males, and triggers reconstruction of the transcription network and chromatin organization leading to post-meiotic development.
Mechanisms Driving Genome Reduction of a NovelRoseobacterLineage Showing Vitamin B12Auxotrophy
Authors: Feng Xiaoyuan , Chu Xiao , Qian Yang , Henson Michael W. , Celeste Lanclos V. , Qin Fang , Zhao Yanlin , Thrash J. Cameron , Luo Haiwei 
Published: January 2021

SummaryMembers of the marineRoseobactergroup are key players in the global carbon and sulfur cycles. While over 300 species have been described, only 2% possess reduced genomes (mostly 3-3.5 Mbp) compared to an average roseobacter (>4 Mbp). These taxonomic minorities are phylogenetically diverse but form a PelagicRoseobacterCluster (PRC) at the genome content level. Here, we cultivated eight isolates constituting a novelRoseobacterlineage which we named ‘CHUG’. Metagenomic and metatranscriptomic read recruitment analyses showed that CHUG members were globally distributed and active in marine environments. CHUG members possess some of the smallest genomes (~2.52 Mb) among all known roseobacters, but they do not exhibit canonical features of genome streamlining like higher coding density or fewer paralogues and pseudogenes compared to their sister lineages. While CHUG members are clustered with traditional PRC members at the genome content level, they show important differences. Unlike other PRC members, neither the relative abundances of CHUG members nor their gene expression levels are correlated with chlorophyll a concentration across the global samples. Moreover, CHUG members cannot synthesize vitamin B12, a key metabolite made by most roseobacters but not by many phytoplankton species and thus thought to mediate the roseobacter-phytoplankton interactions. This combination of features is evidence for the hypothesis that CHUG members may have evolved a free-living lifestyle decoupled from phytoplankton. This ecological transition was accompanied by the loss of signature genes involved in roseobacter-phytoplankton symbiosis, suggesting that relaxation of purifying selection is likely an important driver of genome reduction in CHUG.