bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spd-2 Gene Duplication Suggests Cell-Type Specific Assembly Mechanisms of Pericentriolar Material
Authors: O’Neill Ryan S. , Sodeinde Afeez K. , Welsh Frances C. , Fagerstrom Carey J. , Galletta Brian J. , Rusan Nasser M. 
Published: October 2021

AbstractCentrosomes are multi-protein complexes that function as the major microtubule organizing center (MTOC) for the cell. While centrosomes play tissue-specific MTOC functions, little is known about how particular centrosome proteins are regulated across cell types to achieve these different functions. To investigate this cell type-specific diversity, we searched for gene duplications of centrosome genes in the Drosophila lineage with the aim of identifying centrosome gene duplications where each copy evolved for specialized functions. Through in depth functional analysis of a Spd-2 gene duplication in the Willistoni group, we discovered differences in the regulation of PCM in somatic and male germline cells. The parental gene, Spd-2A, is expressed in somatic cells, where it can function to organize pericentriolar material (PCM) and the mitotic spindle in larval brain neuroblasts. Spd-2A is absent during male meiosis, and even when ectopically expressed in spermatocytes it fails to rescue PCM and spindle organization. In contrast, the new gene duplicate, Spd-2B, is expressed specifically in spermatocytes. During male meiosis, Spd-2B localizes to centrosomes, organizes PCM and spindles, and is sufficient for proper male fertility. Experiments using chimeric transgenes reveal that differences in the C-terminal tails of Spd-2A and Spd-2B are responsible for these functional changes. Thus, Spd-2A and Spd-2B have evolved complementary functions by specializing for distinct subsets of cells. Together, our results demonstrate that somatic cells and male germline cells have fundamentally different requirements for PCM, suggesting that PCM proteins such as Spd-2 is differentially regulated across cell types to satisfy distinct requirements.HighlightsSpd-2 gene duplication in the Willistoni group is rapidly evolvingParent gene Spd-2A is expressed in somatic cells, whereas the gene duplicate Spd-2B is expressed in spermatocytesSpd-2A organizes pericentriolar material during somatic cell mitosisSpd-2B is specialized for pericentriolar material organization during male meiosis
No robust coexistence in a canonical model of plant-soil feedbacks
Authors: Miller Zachary R. , Lechón-Alonso Pablo , Allesina Stefano 
Published: October 2021

AbstractPlant-soil feedbacks (PSFs) are considered a key mechanism generating frequency-dependent dynamics in plant communities. Negative feedbacks, in particular, are often invoked to explain coexistence and the maintenance of diversity in species-rich communities. However, the primary modeling framework used to study PSFs considers only two plant species, and we lack clear theoretical expectations for how these complex interactions play out in communities with natural levels of diversity. Here, we demonstrate that this canonical model for PSFs is equivalent to a well-studied model from evolutionary game theory, and use this equivalence to characterize the dynamics with an arbitrary number of plant species. Surprisingly, we find that coexistence of more than two species is virtually impossible, suggesting that alternative theoretical frameworks are needed to describe feedbacks observed in diverse natural communities. Drawing on our analysis, we discuss future directions for PSF models and implications for experimental study of PSF-mediated coexistence in the field.
Altered Salience Network Connectivity in 6-Week-Old Infants at Risk for Autism
Authors: Tsang Tawny , Green Shulamite , Liu Janelle , Lawrence Katherine , Jeste Shafali , Bookheimer Susan Y. , Dapretto Mirella 
Published: October 2021

AbstractConverging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network (SN) – an early-emerging neural network involved in orienting attention to the most salient aspects of one’s internal and external environment – may predict the development of ASD markers such as reduced social attention and atypical sensory processing. Six-week-old infants at high-risk for ASD exhibited stronger SN connectivity with sensorimotor regions; low-risk infants demonstrated stronger SN connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in SN connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with ASD risk.
Impact of the COVID-19 pandemic on routine immunization coverage in children under 2 years old in Ontario, Canada: A retrospective cohort study
Authors: Ji Catherine , Piché-Renaud Pierre-Philippe , Apajee Jemisha , Stephenson Ellen , Forte Milena , Friedman Jeremy N. , Science Michelle , Zlotkin Stanley , Morris Shaun K. , Tu Karen 
Published: October 2021

AbstractBackgroundThe COVID-19 pandemic has caused a disruption in childhood immunization coverage around the world. This study aimed to determine the change in immunization coverage for children under 2 years old in Ontario, Canada, comparing time periods pre-pandemic to during the pandemic.MethodsWe conducted an observational retrospective open cohort study, using primary care electronic medical record data from the University of Toronto Practice-Based Research Network (UTOPIAN) database, from January 2019 to December 2020. Children under 2 years old who had at least 2 visits recorded in UTOPIAN were included. We measured up-to-date (UTD) immunization coverage rates, overall and by type of vaccine (DTaP-IPV-Hib, Pneu-C-13, Rot, Men-C-C, MMR, Var), and on-time immunization coverage rates by age milestone (2, 4, 6, 12, 15 and 18 months). We compared average coverage rates over 3 periods of time: January 2019-March 2020 (T1); March-July 2020 (T2); and August-December 2020 (T3).Results12,313 children were included. Overall UTD coverage for all children was 71.0% in T1, dropped by 5.7% (95% CI: -6.2, -5.1) in T2, slightly increased in T3 but remained lower than in T1. MMR vaccine UTD coverage slightly decreased in T2 and T3 by approximately 2%. The largest decreases were seen at ages 15-month and 18-month old, with drops in on-time coverage of 14.7% (95% CI: -18.7, -10.6) and 16.4% (95% CI: -20.0, -12.8) respectively during T2. When stratified by sociodemographic characteristics, no specific subgroup of children was found to have been differentially impacted by the pandemic.ConclusionChildhood immunization coverage rates for children under 2 years in Ontario decreased significantly during the early period of the COVID-19 pandemic and only partially recovered during the rest of 2020. Public health and educational interventions for providers and parents are needed to ensure adequate catch-up of delayed/missed immunizations to prevent potential outbreaks of vaccine-preventable diseases.
Rapid health evaluation in migrant peoples in transit through Darien, Panama: Protocol for a multi-method qualitative and quantitative study
Authors: Gabster Amanda , Jhangimal Monica , Erausquin Jennifer Toller , Suárez José Antonio , Pinzón-Espinosa Justo , Baird Madeline , Katz Jennifer , Beltran-Henríquez Davis , Cabezas-Talavero Gonzalo , Henao-Martínez Andrés F. , Franco-Paredes Carlos , Agudelo-Higuita. Nelson I. , Pachar Mónica , González José Anel , Rodriguez Fátima , Pascale Juan Miguel ,   Migrant Peoples in Transit Study Group
Published: October 2021

AbstractBackgroundThe world is currently unprepared to deal with a the drastic increase in global migration. There is an urgent need to develop programs to protect the well being and health of migrant peoples. Increased population movement is already evident throughout the Americas as exemplified by the rising number of migrant peoples that pass through the Darien neotropical moist broadleaf forest along the border region between Panama and Colombia. The transit of migrant peoples through this area has an increase in the last years. In 2021 an average of 9,400 people entered the region per month compared to 2,000-3,500 people monthly in 2019. Along this trail, there is no access to healthcare, food provision, potable water, or housing. To date, much of what is known about health needs and barriers to healthcare within this population is based on journalistic reports and anecdotes. There is a need for a comprehensive approach to assess the healthcare needs migrant peoples in transit. This study aims to describe demographic characteristics, mental and physical health status and needs, and experiences of host communities, and to identify opportunities to improve healthcare provision to migrant peoples in transit in Panama.Study design and methodsThis multi-method study will include qualitative (n=70) and quantitative (n=520) components. The qualitative component includes interviews with migrant peoples in transit, national and international non-governmental organizations and agencies based in Panama. The quantitative component is a rapid epidemiological study which includes a questionnaire and four clinical screenings: mental health, sexual and reproductive health, general and tropical medicine, and nutrition.ConclusionThis study will contribute to a better understanding of the health status and needs of migrant peoples in transit through the region. Findings will be used to allocate resources and provide targeted healthcare interventions for migrant peoples in transit through Darien, Panama.
Evolutionarily divergent mTOR remodels the translatome to drive rapid wound closure and regeneration
Authors: Zhulyn Olena , Rosenblatt Hannah D. , Shokat Leila , Dai Shizhong , Kuzuoglu-Öztürk Duygu , Zhang Zijian , Ruggero Davide , Shokat Kevan M. , Barna Maria 
Published: October 2021

AbstractAn outstanding mystery in biology is why some species, such as the axolotl, can scarlessly heal and regenerate tissues while most mammals cannot. Here, we demonstrate that rapid activation of protein synthesis is a unique, and previously uncharacterized, feature of the injury response critical for limb regeneration in the axolotl (A. mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components, which do not change in their overall mRNA abundance but are selectively activated at the level of translation from pre-existing mRNAs in response to injury. In contrast, we show that protein synthesis is not activated in response to digit amputation in the non-regenerative mouse. We further identify the mTORC1 pathway as a key upstream signal that mediates this regenerative translation response in the axolotl. Inhibition of this pathway is sufficient to suppress translation and axolotl regeneration. Surprisingly, although mTOR is highly evolutionarily conserved, we discover unappreciated expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR in human cells, we demonstrate that this change creates a hypersensitive kinase that may allow axolotls to maintain this pathway in a highly labile state primed for rapid activation. This may underlie metabolic differences and nutrient sensing between regenerative and non-regenerative species that are key to regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.
Sciara coprophila larvae upregulate DNA repair pathways and downregulate developmental regulators in response to ionizing radiation
Authors: Urban John M. , Bateman Jack R. , Garza Kodie R. , Borden Julia , Jain Jaison , Brown Alexia , Thach Bethany J. , Bliss Jacob E. , Gerbi Susan A. 
Published: October 2021

AbstractRobust DNA damage prevention and repair strategies are crucial to faithful reproduction and inheritance of the genetic material. Although many molecular pathways that respond to DNA damage are well conserved through evolution, the quality and effectiveness of these systems can vary between species. Studies dating back for nearly a century document that the dark-winged fungus gnat Sciara coprophila (Order: Diptera; sub-order: Nematocera) is relatively resistant to irradiation-induced mutations that cause visible phenotypes when compared to the fruit fly Drosophila melanogaster (Order: Diptera; sub-order: Brachycera). However, the molecular responses to irradiation for S. coprophila have yet to be analyzed. To address this gap, we first characterized the effects of ionizing radiation on S. coprophila throughout its life cycle. Our data show that developing S. coprophila embryos are highly sensitive to even low doses of gamma-irradiation, whereas larvae can tolerate up to 80 Gy and still retain their ability to develop to adulthood with a developmental delay of 5 to 8 extra days in the larval stage. To survey the genes involved in the early transcriptional response to irradiation, we compared RNA-seq profiles of larvae with and without radiation treatment. Our analysis showed that 327 genes are differentially expressed in irradiated larvae, with 232 genes upregulated and 95 genes downregulated relative to controls. The upregulated genes were enriched for DNA damage response genes, including those involved in DNA repair, cell cycle arrest, and apoptosis, whereas the down-regulated genes were enriched for developmental regulators, consistent with the developmental delay observed in irradiated larvae. Thus, our study has laid the groundwork to further dissect how Sciara copes with radiation-induced damage.
The autophagy activator Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model
Authors: Freitag Kiara , Sterczyk Nele , Obermayer Benedikt , Schulz Julia , Houtman Judith , Fleck Lara , Braeuning Caroline , Sansevrino Roberto , Hoffmann Christian , Milovanovic Dragomir , Sigrist Stephan J. , Conrad Thomas , Beule Dieter , Heppner Frank L. , Jendrach Marina 
Published: October 2021

AbstractDeposition of amyloid beta (Aβ) along with glia cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature, contributing to AD progression and aging. Therefore, we assessed the effect of the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement and known to promote longevity, on glia cell-mediated neuroinflammation. Spermidine reduced TLR3- and TLR4- mediated inflammatory processes in microglia and astrocytes by decreasing cytotoxicity, inflammasome activity and NF-κB signaling. In line with these anti-inflammatory effects, oral treatment of the amyloid prone AD-like APPPS1 mice with Spermidine reduced neuroinflammation and neurotoxic soluble Aβ. Mechanistically, single nuclei sequencing revealed microglia as one of the main targets of Spermidine treatment, with increased expression of genes implicated in cell motility and phagocytosis. Thus, Spermidine provides a promising therapeutic potential to target glia cells in AD progression.
Inhibition of Metastatic Uveal Melanoma Cell Proliferation by the Histone Deacetylase 6 Inhibitor, Ricolinostat, is Linked to Altered Microphthalmia-associated Transcription Factor and Phospho-ERK Expression
Authors: Sundaramurthi Husvinee , García-Mulero Sandra , Slater Kayleigh , Marcone Simone , Piulats Josep M. , Watson R. William , Tobin Desmond J. , Jensen Lasse D. , Kennedy Breandán N. 
Published: October 2021

AbstractMetastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase 6 inhibitor (HDAC6i), to attenuate MUM cell growth in vitro and in vivo, and elucidate the underlying molecular mechanisms. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo regression of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry analysis revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0006) following 24 hours of treatment and significant apoptosis was triggered in a time- and dose-dependent manner (p = <0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome-profiling, attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329, significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of MUM cells and are potential therapeutic options for MUM.Simple SummaryUveal melanoma (UM) is the most common adult eye cancer. UM originates in the iris, ciliary body, or choroid (collectively known as the uvea), in the middle layer of the eye. This first or primary UM is treated by targeting the cancer cells using ocular radiation implants or by surgical removal of the eye. However, when UM spreads to the liver and other parts of the body, patients have a poor survival prognosis. Unfortunately, there are no effective treatment options for UM that has spread. Our aim is to help identify effective treatments for UM cancer that has spread. In our study, we identified that the drug ACY-1215 prevents the growth of UM cells from the liver. Our study has found a promising treatment approach for advanced UM.
A novel approach in heart-rate-variability analysis
Authors: Búzás András , Horváth Tamás , Dér András 
Published: October 2021

ABSTRACTHeart-rate variability (HRV), measured by the fluctuation of beat-to-beat intervals, has been growingly considered the most important hallmark of heart rate (HR) time series. HRV can be characterized by various statistical measures both in the time and frequency domains, or by nonlinear methods. During the past decades, an overwhelming amount of HRV data has been piled up in the research community, but the individual results are difficult to reconcile due to the different measuring conditions and the usually HR-dependent statistical HRV-parameters applied. Moreover, the precise HR-dependence of HRV parameters is not known. Using data gathered by a wearable sensor of combined heart-rate and actigraphy modalities, here, we introduce a novel descriptor of HRV, based on a modified Poincaré plot of 24-h RR-recordings. We show that there exists a – regressive biexponential – HRV versus HR “master” curve (“M-curve”) that is highly conserved for a healthy individual on short and medium terms (on the hours to months scale, respectively). At the same time, we reveal how this curve is related to age in the case of healthy people, and establish alterations of the M-curves of heart-attack patients. A stochastic neuron model accounting for the observed phenomena is also elaborated, in order to facilitate physiological interpretation of HRV data. Our novel evaluation procedure applied on the time series of interbeat intervals allows the description of the HRV(HR) function with unprecedented precision. To utilize the full strength of the method, we suggest a 24-hour-long registration period under natural, daily-routine circumstances (i.e., no special measuring conditions are required). By establishing a patient’s M-curve, it is possible to monitor the development of his/her status over an extended period of time. On these grounds, the new method is suggested to be used as a competent tool in future HRV analyses for both clinical and training applications, as well as for everyday health promotion.
Activating natural product synthesis using CRISPR interference and activation systems inStreptomyces
Authors: Ameruoso Andrea , Villegas Kcam Maria Claudia , Cohen Katherine Piper , Chappell James 
Published: October 2021

ABSTRACTThe rise of antibiotic-resistant bacteria represents a major threat to global health, creating an urgent need to discover new antibiotics. Natural products derived from the genusStreptomycesrepresent a rich and diverse repertoire of chemical molecules from which new antibiotics are likely to be found. However, a major challenge is that the biosynthetic gene clusters (BGCs) responsible for natural product synthesis are often poorly expressed under laboratory culturing conditions, thus preventing isolation and screening of novel chemicals. To address this, we describe a novel approach to activate silent BGCs through rewiring endogenous regulation using synthetic gene regulators based upon CRISPR-Cas. First, we create CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) systems that allow for highly programmable and effective gene repression and activation inStreptomyces. We then harness these tools to activate a silent BGC through perturbing its endogenous regulatory network. Together, this work advances the synthetic regulatory toolbox forStreptomycesand facilitates the programmable activation of silent BGCs for novel chemical discovery.
Modelling human zygotic genome activation in 8C-like cells in vitro
Authors: Taubenschmid-Stowers Jasmin , Rostovskaya Maria , Santos Fátima , Ljung Sebastian , Argelaguet Ricard , Krueger Felix , Nichols Jennifer , Reik Wolf 
Published: October 2021

AbstractThe remodelling of the epigenome and transcriptome of the fertilised oocyte to establish totipotency in the zygote and developing embryo is one of the most critical processes in mammalian embryogenesis. Zygotic or embryonic genome activation (ZGA, EGA) in the 2-cell embryo in mouse, and the 8-cell embryo in humans, constitutes the first major wave of transcription. Failure to initiate ZGA leads to developmental defects, and contributes to the high attrition rates of human pre-implantation embryos. Due to limitations in cell numbers and experimental tractability, the mechanisms that regulate human embryonic genome activation in the totipotent embryo remain poorly understood. Here we report the discovery of human 8-cell like cells (8CLCs) specifically among naïve embryonic stem cells, but not primed pluripotent cells. 8CLCs express ZGA marker genes such as ZSCAN4, LEUTX and DUXA and their transcriptome closely resembles that of the 8-cell human embryo. 8-cell like cells reactivate 8-cell stage specific transposable elements such as HERVL and MLT2A1 and are characterized by upregulation of the DNA methylation regulator DPPA3. 8CLCs show reduced SOX2 protein, and can be identified based on expression of the novel ZGA-associated protein markers TPRX1 and H3.Y in vitro. Overexpression of the transcription factor DUX4. as well as spliceosome inhibition increase ZGA-like transcription and enhance TPRX1+ 8CLCs formation. Excitingly, the in vitro identified 8CLC marker proteins TPRX1 and H3.Y are also expressed in 8-cell human embryos at the time of genome activation and may thus be relevant in vivo. The discovery of 8CLCs provides a unique opportunity to model and manipulate human ZGA-like transcriptional programs in vitro, and might provide critical functional insights into one of the earliest events in human embryogenesis in vivo.HighlightsZGA markers and transposable elements are expressed in 8CLCs among naïve human stem cellsThe transcription factor DUX4 and spliceosome inhibition induce ZGA-like transcription8CLC marker proteins TPRX1 and H3.Y are expressed in nuclei of 8-cell human embryos8CLCs serve as a novel in vitro model for human ZGA