bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modularity, homology, heterochrony: Gavin de Beer's legacy to the mammalian skull
Authors: Hall Brian K. , Hanken James 
Published: May 2023

Modularity (segmentation), homology and heterochrony were essential concepts embraced by Gavin de Beer in his studies of the development and evolution of the vertebrate skull. While his pioneering contributions have stood the test of time, our understanding of the biological processes that underlie each concept has evolved. We assess de Beer's initial training as an experimental embryologist; his switch to comparative and descriptive studies of skulls, jaws and middle ear ossicles; and his later research on the mammalian skull, including his approach to head segmentation. The role of cells of neural crest and mesodermal origin in skull development, and developmental, palaeontological and molecular evidence for the origin of middle ear ossicles in the evolutionary transition from reptiles to mammals are used to illustrate our current understanding of modularity, homology and heterochrony.
This article is part of the theme issue ‘The mammalian skull: development, structure and function’.
Developmental origin underlies evolutionary rate variation across the placental skull
Authors: Goswami Anjali , Noirault Eve , Coombs Ellen J. , Clavel Julien , Fabre Anne-Claire , Halliday Thomas J. D. , Churchill Morgan , Curtis Abigail , Watanabe Akinobu , Simmons Nancy B. , Beatty Brian L. , Geisler Jonathan H. , Fox David L. , Felice Ryan N. 
Published: May 2023

The placental skull has evolved into myriad forms, from longirostrine whales to globular primates, and with a diverse array of appendages from antlers to tusks. This disparity has recently been studied from the perspective of the whole skull, but the skull is composed of numerous elements that have distinct developmental origins and varied functions. Here, we assess the evolution of the skull's major skeletal elements, decomposed into 17 individual regions. Using a high-dimensional morphometric approach for a dataset of 322 living and extinct eutherians (placental mammals and their stem relatives), we quantify patterns of variation and estimate phylogenetic, allometric and ecological signal across the skull. We further compare rates of evolution across ecological categories and ordinal-level clades and reconstruct rates of evolution along lineages and through time to assess whether developmental origin or function discriminate the evolutionary trajectories of individual cranial elements. Our results demonstrate distinct macroevolutionary patterns across cranial elements that reflect the ecological adaptations of major clades. Elements derived from neural crest show the fastest rates of evolution, but ecological signal is equally pronounced in bones derived from neural crest and paraxial mesoderm, suggesting that developmental origin may influence evolutionary tempo, but not capacity for specialisation.This article is part of the theme issue ‘The mammalian skull: development, structure and function’.
Summary statistics from large-scale gene-environment interaction studies for re-analysis and meta-analysis
Authors: Pham Duy T. , Westerman Kenneth E. , Pan Cong , Chen Ling , Srinivasan Shylaja , Isganaitis Elvira , Vajravelu Mary Ellen , Bacha Fida , Chernausek Steve , Klug Rose Gubitosi- , Divers Jasmin , Pihoker Catherine , Marcovina Santica M. , Manning Alisa K. , Chen Han 
Published: May 2023

AbstractSummary statistics from genome-wide association studies enable many valuable downstream analyses that are more efficient than individual-level data analysis while also reducing privacy concerns. As growing sample sizes enable better-powered analysis of gene-environment interactions (GEIs), there is a need for GEI-specific methods that manipulate and use summary statistics. We introduce two tools to facilitate such analysis, with a focus on statistical models containing multiple gene-exposure and/or gene-covariate interaction terms. REGEM (RE-analysis of GEM summary statistics) uses summary statistics from a single, multi-exposure genome-wide interaction study (GWIS) to derive analogous sets of summary statistics with arbitrary sets of exposures and interaction covariate adjustments. METAGEM (META-analysis of GEM summary statistics) extends current fixed-effects meta-analysis models to incorporate multiple exposures from multiple studies. We demonstrate the value and efficiency of these tools by exploring alternative methods of accounting for ancestry-related population stratification in GWIS in the UK Biobank as well as by conducting a multi-exposure GWIS meta-analysis in cohorts from the diabetes-focused ProDiGY consortium. These programs help to maximize the value of summary statistics from diverse and complex GEI studies.
Risk factors affecting polygenic score performance across diverse cohorts
Authors: Hui Daniel , Dudek Scott , Kiryluk Krzysztof , Walunas Theresa L. , Kullo Iftikhar J. , Wei Wei-Qi , Tiwari Hemant K. , Peterson Josh F. , Chung Wendy K. , Davis Brittney , Khan Atlas , Kottyan Leah , Limdi Nita A. , Feng Qiping , Puckelwartz Megan J. , Weng Chunhua , Smith Johanna L. , Karlson Elizabeth W. , Center Regeneron Genetics , Jarvik Gail P. , Ritchie Marylyn D. 
Published: May 2023

AbstractApart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed effects of covariate stratification and interaction on body mass index (BMI) PGS (PGSBMI) across four cohorts of European (N=491,111) and African (N=21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R2differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R2being nearly double between best and worst performing quintiles for certain covariates. 28 covariates had significant PGSBMI-covariate interaction effects, modifying PGSBMIeffects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R2differences among strata and interaction effects – across all covariates, their main effects on BMI were correlated with their maximum R2differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGSBMIindividuals have highest R2and increase in PGS effect. Using quantile regression, we show the effect of PGSBMIincreases as BMI itself increases, and that these differences in effects are directly related to differences in R2when stratifying by different covariates. Given significant and replicable evidence for context-specific PGSBMIperformance and effects, we investigated ways to increase model performance taking into account non-linear effects. Machine learning models (neural networks) increased relative model R2(mean 23%) across datasets. Finally, creating PGSBMIdirectly from GxAge GWAS effects increased relative R2by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGSBMIperformance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.
“It All Rolls Downstream: Upstream Control of Physical Activity Regulation”
Authors: Breidenbach Brianne M. , Liu Liwen , La Troy , Castro-Padovani Tatiana N. , Keller Nathan , Pescatello Linda S , Robinson Matthew M. , Kelly Scott A. , Gerrish Kevin , Lightfoot J. Timothy 
Published: May 2023

AbstractPhysical activity is regulated by a variety of genetic molecules. However, the pathways through which those molecules work to regulate activity is largely unknown. The purpose of this study was to gather the known genetic molecules that are associated with activity regulation and define overall upstream regulator pathways through which these molecules work. We conducted a systematic review to gather all available published datasets related to physical activity regulation, standardized the data for genomic location and species, and used this data, in an unbiased manner to create a dataset that was used: (1) to physically map and visualize all identified molecules to homologous chromosome locations and (2) as the dataset for which an Upstream Regulator Analysis (URA) was conducted using Qiagen Ingenuity Pathway Analysis (IPA) software. Our search resulted in 469 genetic molecules (e.g. genomic variant, transcript, protein, micro-RNA) that were split into brain (n=366) and muscle (n=345) sub-groups, which was our attempt to separate differences in central vs peripheral pathways. The brain and muscle data sets had several potential upstream regulators, the top-rated being β-estradiol as a regulator for 19.5% and 21% of the brain and muscle datasets respectively. To our knowledge, β-estradiol’s identification as a potential regulator, is the first evidence to link the well-known effects of sex hormones on physical activity with genetic regulation of physical activity. There were a variety of potential upstream regulators for the molecules collected in this review, but interestingly, three of the top five for both brain and muscle are nuclear receptor binding ligands; estradiol (estrogen receptor), dexamethasone (glucocorticoid receptor), and tretinoin (retinoic acid receptor), indicating a potential role of nuclear receptors in the regulation of physical activity. Selective nuclear receptor modulation may be an area of interest in future mechanistic studies of the genetic regulation of physical activity.
Cytoplasmic polyadenylation is an ancestral hallmark of early development in animals
Authors: Rouhana Labib , Edgar Allison , Hugosson Fredrik , Dountcheva Valeria , Martindale Mark Q. , Ryan Joseph F. 
Published: May 2023

ABSTRACTDifferential regulation of gene expression has produced the astonishing diversity of life on Earth. Understanding the origin and evolution of mechanistic innovations for control of gene expression is therefore integral to evolutionary and developmental biology. Cytoplasmic polyadenylation is the biochemical extension of polyadenosine at the 3’-end of cytoplasmic mRNAs. This process regulates the translation of specific maternal transcripts and is mediated by the Cytoplasmic Polyadenylation Element Binding Protein family (CPEBs). Genes that code for CPEBs are amongst a very few that are present in animals but missing in non-animal lineages. Whether cytoplasmic polyadenylation is present in non bilaterian animals (i.e., sponges, ctenophores, placozoans, cnidarians) remains unknown. We have conducted phylogenetic analyses of CPEBs and our results show that CPEB1 and CPEB2 subfamilies originated in the animal stem lineage. Our assessment of expression in the sea anemone,Nematostella vectensis(Cnidaria), and the comb jelly,Mnemiopsis leidyi(Ctenophora), demonstrates that maternal expression of CPEB1 and the catalytic subunit of the cytoplasmic polyadenylation machinery (GLD2) is an ancient feature that is conserved across animals. Furthermore, our measurements of poly(A)-tail elongation reveal that key targets of cytoplasmic polyadenylation are shared between vertebrates, cnidarians, and ctenophores, indicating that this mechanism orchestrates a regulatory network that is conserved throughout animal evolution. We postulate that cytoplasmic polyadenylation through CPEBs was a fundamental innovation that contributed to animal evolution from unicellular life.
Antimitotic Activity ofSamanea samanLeaf Extract in the In Vitro Development ofTripneustes gratillaEmbryo
Authors: Lam Justin Riley Y. , Casimpan Guinevere A. , Batoy Christine May L. , Cebedo Ma. Felaine , Cuesta Jann Ycleo T. , Gervacio Jecell , Grapa Joshua Benjamin R. , Mabelin Ma. Katrina Ada F. , Pepito Merry Grace S. , Rama Justine Mae A. , Simporios Daniel Joseph Z. , Villanueva Zackaree Michael A. , Villaruel Jolienne Abbygail M. , Gwendolyn D. Pepito , Adrian Christopher A. Lu 
Published: May 2023

ABSTRACTTITLEAntimitotic Activity ofSamanea samanLeaf Extract in the In Vitro Development ofTripneustes gratillaEmbryoINTRODUCTIONCommercially available anticancer drugs are expensive and may have side effects. This led the researchers to look into alternative plant sources. One of these is acacia orS. saman.OBJECTIVETo determine whetherS. samanleaf extract possesses antimitotic activity onT. gratillaembryos using vincristine sulfate as positive control.METHODOLOGYS. samanleaves were extracted using hexane, CCl4, CHCl3, and water.T. gratillaembryos were fertilized in vitro. The fractions, vincristine sulfate, and DMSO in filtered sea water were added with the fertilized embryos in petri dishes. Samples were taken at 15 minutes after fertilization and every 30 minutes thereafter until the negative control reached a 32-cell stage. Fifty cells and their mean cell stage was evaluated per treatment. One-way ANOVA and Tukey tests were performed.RESULTSSignificant differences were seen starting at 75 minutes post fertilization up until the 165thminute using One-way ANOVA. The Tukey test showed that all aqueous and CCl4as well as hexane (200, 400, 800 ppm) extracts had no significant difference compared to vincristine sulfate; while all CHCl3, hexane (100 ppm), and CCl4(100 ppm) extracts showed a significant difference compared to vincristineCONCLUSIONThe aqueous, hexane, and carbon tetrachloride extracts possess potential antimitotic activity onT. gratillaembryos. Thus, it is a potential alternative to vincristine sulfate as an antimitotic agent.
Improvised AChE assay on homogenized rectal biopsy: An Alibi to AChE histochemistry in the diagnosis of Hirschsprung’s disease?
Authors: Kuvelkar Neha , Souza Serena D , Bukelo Maria Frances , Jadhav Vinay , Babu Narendra , Shankar Gowri , Noronha Santosh , Kini Usha 
Published: May 2023

AbstractThe surgical treatment of Hirschsprung’s disease (HD) is reliant on the accurate tissue diagnosis based on increased acetylcholine esterase enzyme (AChE) activity in frozen rectal biopsy sections demonstrated by histochemical staining techniques. The latter techniques used for ascertaining the presence of AChE mandates the use of inaccessible sophisticated instruments thereby limiting the performance of this technique to urban resource rich settings. This bottleneck translates into delayed treatment for patients who live in suburban, resource limited regions. Given the indispensable nature of the surgical treatment, scope for improving accessibility is restricted to the diagnostic modality of the disease.In our study, we attempted to quantitatively estimate AChE in homogenized rectal mucosal biopsy samples of paediatric population (n=68) using an in-house modified AChE (mACHE) assay. The assay procedure for homogenization of the tissue was modified to selectively extract the mucosal portion of the rectal mucosal biopsy sample to be used for the assay. The efficiency of specific mucosal extraction was confirmed by the absence of neurotrophic AChE nerve fibres in remnant tissue obtained post homogenization by histochemical AChE staining. The mAChE assay was carried out in a blinded manner and the results were compared with the gold standard histochemical AChE (hAChE) assay.Samples with activity lesser than 1 × 10-6mole/min/g wet weight of tissue were diagnosed as Non Hirschsprung’s Disease (NHD) and those above 1 × 10-6mole/min/g wet weight of tissue were diagnosed as HD. mAChE assay was found to have a specificity, sensitivity of 81.08 % and 92.85%; positive, negative predictive values of 78.78% and 93.75 % respectively. The mAChE assay was able to diagnose three cases which were deemed inconclusive as per hAChE.The improvised in-house mAChE assay had a mutually exclusive range to differentiate between control and test, thus crediting its use as a diagnostic tool for Hirschsprung’s Disease.
Late- life shift in caloric intake affects fly longevity and metabolism
Authors: Li Michael , Macro Jacob , Meadows Kali , Mishra Dushyant , Martin Dominique , Olson Sara , Huggins Billy Joe , Graveley Brenton , Li James Y. H. , Rogina Blanka 
Published: May 2023

AbstractCaloric restriction (CR) delays the onset of age-related changes and extends lifespan in most species, but how late in life organisms benefit from switching to a low-calorie (L) diet is unexplored. We transferred wild type male flies from a high- (H) to a L-calorie diet (HL) or vice versa (LH) at different times. Late-life HL shift immediately and profoundly reduces fly mortality rate to briefly lower rate than in flies on a constant L diet, and increases lifespan. Conversely, a LH shift increases mortality and hazard rate, which is temporarily higher than in flies aged on a H diet, and leads to shorter lifespan. Transcriptomic changes within 48 hours following diet shift uncover physiological adaptations to available nutrients. Unexpectedly, more abundant transcriptomic changes accompanied LH shift, including ribosome biogenesis, and promotion of growth, which likely contributes to higher mortality rate. Considering that the beneficial effects of CR on physiology and lifespan are conserved across many organisms, our findings suggest that CR interventions in older humans may counteract the detrimental effects of H diets even when initiated later in life.
Influence of oceanography and geographic distance on genetic structure: how varying the sampled domain influences conclusions inLaminaria digitata
Authors: Fouqueau L. , Reynes L. , Tempera F. , Bajjouk T. , Blanfuné A. , Chevalier C. , Laurans M. , Mauger S. , Sourisseau M. , Assis J. , Lévêque L. , Valero M. 
Published: May 2023

ABSTRACTUnderstanding the environmental processes shaping connectivity can greatly improve management and conservation actions which are essential in the trailing edge of species’ distributions. In this study, we used a dataset built from 32 populations situated in the southern limit of the kelp speciesLaminaria digitata. By extracting data from 11 microsatellite markers, our aim was to (1) refine the analyses of population structure, (2) compare connectivity patterns and genetic diversity between island and mainland populations and (3) evaluate the influence of sampling year, hydrodynamic processes, habitat discontinuity, spatial distance and sea surface temperature on the genetic structure using a distance-based redundancy analysis (db-RDA). Analyses of population structure enabled to identify well connected populations associated to high genetic diversity, and others which appeared genetically isolated from neighboring populations and showing signs of genetic erosion verifying contrasting ecological (and demographic) status in Brittany and the English Channel. By performing db-RDA analyses on various sampling sizes, geographic distance appeared as the dominant factor influencing connectivity between populations separated by great distances, while hydrodynamic processes were the main factor at smaller scale. Finally, Lagrangian simulations enabled to study the directionality of gene flow which has implications on source-sink dynamics. Overall, our results have important significance in regard to the management of kelp populations facing pressures both from global warming and their exploitation for commercial use.
Cardiac Effects of a Novel pH-Insensitive Sodium-Calcium Exchanger Mouse
Authors: Zhang Rui , Wu Xiaokang , Kim Brian , Xie Catherine , Gonzalez Devina , Norris Raven , Chin Nicholas , Li Liang , John Scott , Philipson Kenneth D. , Ottolia Michela , Goldhaber Joshua I. 
Published: May 2023

AbstractBACKGROUNDCardiac sodium-calcium exchange (NCX1) is the dominant calcium (Ca) efflux mechanism in cardiomyocytes and is strongly regulated by pH. However, the role of NCX1 pH sensitivity in normal cardiac function is unknown.METHODSWe used CRISPR/Cas9 to produce a pH-resistant NCX1 mouse by replacing the histidine at position 165 of NCX1 with an alanine (H165A). Hearts were studied using echocardiography and ECG. RNA and protein expression levels were assessed using qPCR and Western blotting. Isolated ventricular cardiomyocytes were loaded with Ca indicators and patch clamped to record intracellular Ca transients and membrane current and voltage.RESULTSH165A mice live into adulthood with slightly reduced LV systolic function, normal heart rate and shortened QT interval. Both male and female animals exhibit reduced growth, but females eventually reach normal body weight. In patch clamped myocytes, NCX current (INCX) evoked by voltage ramps was reduced by 35% (at +80 mV). Lowering pHito 6.5 using Na-Acetate hadno effecton INCXin H165A myocytes, whereas the same intervention in wildtype (WT) inhibited INCXby 69% (at +80 mV, p<0.01). There was no change in H165A ventricular cardiomyocyte Ca transients measured with fura-2 AM. However, action potential duration was reduced 68%, consistent with the shorter QT interval. This coincided with a 37% reduction in L-type Ca current and increased expression of repolarizing K+channels. H165A mice are also resistant to ischemia/reperfusion injury.CONCLUSIONSThe H165A mutation attenuates pH regulation of NCX1 in mice, is associated with reduced growth and accelerates cardiac repolarization without compromising excitation-contraction coupling. The mutation also confers cardioprotection. The H165A mouse is the first evidence that pH regulation of NCX1 affects cardiac physiology and is a potential model for studying the role of NCX1 pH-sensitivity on both physiological and pathophysiological cardiac function.
Septin 7 Interacts With Numb To Preserve Sarcomere Structural Organization And Muscle Contractile Function
Authors: Gasperi Rita De , Csernoch Laszlo , Dienes Beatrix , Gonczi Monika , Chakrabarty Jayanta K. , Goeta Shahar , Aslan Abdurrahman , Toro Carlos A. , Karasik David , Brown Lewis M. , Brotto Marco , Cardozo Christopher P. 
Published: May 2023

ABSTRACTHere, we investigated mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development including asymmetric cell division, cell-type specification and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (NumbL) in mouse myofibers caused weakness, disorganization of sarcomeres and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, NumbL knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb, that Septin 7 is a potential Numb binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.