bluuebunny/crossref_metadata_2025_split huggingface dataset:
SORLA mediates endocytic uptake of proIAPP and protects against islet amyloid deposition
Authors: Shih Alexis Z.L. , Chen Yi-Chun , Verchere C. Bruce , Willnow Thomas E. 
Published: May 2022

AbstractAims/ hypothesisSorting-related receptor with type A repeats (SORLA) is a neuronal sorting receptor that prevents accumulation of amyloid-beta peptides, the main constituent of senile plaques in Alzheimer disease. Recent transcriptomic studies show that SORLA transcripts are also found in pancreatic islet beta cells, yet the role of SORLA in islets is unclear so far. Based on its protective role in reducing amyloid burden in the brain, we hypothesized that SORLA may have a similar function in the pancreas, regulating islet amyloid plaque formation from islet amyloid polypeptide (IAPP).MethodsWe generated human IAPP transgenic mice lacking SORLA (hIAPP:SORLA KO) to assess the consequences of receptor deficiency for islet histopathology and functionin vivo. Using both primary islet cells and established cell lines, we further investigated the molecular mechanisms whereby SORLA controls the cellular metabolism and accumulation of IAPP.ResultsLoss of SORLA activity in hIAPP:SORLA KO resulted in a significant increase in islet amyloid deposits and associated islet cell death as compared to hIAPP:SORLA WT animals expressing the receptor. Aggravated islet amyloid deposition was observed in mice fed a normal chow diet, not requiring high-fat diet feeding typically needed to induce islet amyloidosis in mouse models. Furtherin vitrostudies showed that SORLA binds to and mediates the endocytic uptake of proIAPP, but not mature IAPP, delivering the propeptide to an endolysosomal fate.Conclusions/interpretationSORLA functions as a clearance receptor specific for proIAPP, protecting against islet amyloid deposition and associated cell death caused by IAPP.
Conservation and divergence of canonical and non-canonical imprinting in murids
Authors: Albert Julien Richard , Kobayashi Toshihiro , Inoue Azusa , Monteagudo-Sánchez Ana , Kumamoto Soichiro , Takashima Tomoya , Miura Asuka , Oikawa Mami , Miura Fumihito , Takada Shuji , Hirabayashi Masumi , Korthauer Keegan , Kurimoto Kazuki , Greenberg Maxim , Lorincz Matthew , Kobayashi Hisato 
Published: May 2022

ABSTRACTBackgroundGenomic imprinting affects gene expression in a parent-of-origin manner and has a profound impact on complex traits including growth and behaviour. While the rat is widely used to model human pathophysiology, few imprinted genes have been identified in this murid. To systematically identify imprinted genes and genomic imprints in the rat, we used low input methods for genome-wide analyses of gene expression and DNA methylation to profile embryonic and extra-embryonic tissues at allele-specific resolution.ResultsWe identify 14 and 26 imprinted genes in these tissues, respectively, with 10 of these genes imprinted in both tissues. Comparative analyses with mouse revealed that orthologous imprinted gene expression and associated canonical DNA methylation imprints are conserved in the embryo proper of the Muridae family. However, only 3 paternally expressed imprinted genes are conserved in the extra-embryonic tissue of murids, all of which are associated with non-canonical H3K27me3 imprints. The discovery of 8 novel non-canonical imprinted genes unique to the rat is consistent with more rapid evolution of extra-embryonic imprinting. Meta-analysis of novel imprinted genes revealed multiple mechanisms by which species-specific imprinted expression may be established, including H3K27me3 deposition in the oocyte, the birth of ZFP57 binding motifs and the insertion of endogenous retroviral promoters.ConclusionsIn summary, we provide a comprehensive list of imprinted loci in the rat, reveal the extent of conservation of imprinted gene expression, and identify potential mechanisms responsible for the evolution of species-specific imprinting.
Rising Temperature Drives Tipping Points in Mutualistic Networks†
Authors: Bhandary Subhendu , Deb Smita , Dutta Partha Sharathi 
Published: May 2022

AbstractThe effect of climate warming on species physiological parameters, including growth rate, mortality rate, and handling time, is well established from empirical data. However, with an alarming rise in global temperature more than ever, predicting the interactive influence of these changes on mutualistic communities remains uncertain. Using 139 real plant-pollinator networks sampled across the globe and a modelling approach, we study the impact of species’ individual thermal responses on mutualistic communities. We show that at low mutualistic strength plant-pollinator networks are at potential risk of rapid transitions at higher temperatures. Evidently, generalist species plays a critical role in guiding tipping points in mutualistic networks. Further, we derive stability criteria for the networks in a range of temperatures using a two-dimensional reduced model. We identify network structures that can ascertain the delay of a community collapse. Until the end of this century, many real mutualistic networks can be under the threat of sudden collapse, and we frame strategies to mitigate them. Together, our results indicate that knowing individual species thermal responses and network structure can improve predictions for communities facing rapid transitions.
Birth and Death in Terminal Complement Pathway
Authors: Sharma Ashutosh , Gupta Saumya , Patil Ajinkya Bharatraj , Vijay Nagarjun 
Published: May 2022

AbstractThe cytolytic activity of the membrane attack complex (MAC) has a crucial role in the complement-mediated elimination of pathogens. Terminal complement pathway (TCP) genes encode the proteins that form the MAC. Although the TCP genes are well conserved within most vertebrate species, the early evolution of the TCP genes is poorly understood. Based on the comparative genomic analysis of the early evolutionary history of the TCP homologs, we evaluated four possible scenarios that could have given rise to the vertebrate TCP. Currently available genomic data support a scheme of complex sequential protein domain gains that may be responsible for the birth of the vertebrateC6gene. The subsequent duplication and divergence of this vertebrateC6gene formed theC7, C8α,C8β, andC9genes. Compared to the widespread conservation of TCP components within vertebrates, we discovered thatC9has disintegrated in the genomes of galliform birds. Publicly available genome and transcriptome sequencing datasets of chicken from Illumina short read, PacBio long read, and Optical mapping technologies support the validity of the genome assembly at theC9locus. In this study, we have generated a >120X coverage whole-genome Chromium 10x linked-read sequencing dataset for the chicken and used it to verify the loss of theC9gene in the chicken. We find multiple CR1 (chicken repeat 1) element insertions within and near the remnant exons ofC9in several galliform bird genomes. The reconstructed chronology of events shows that the CR1 insertions occurred afterC9gene loss in an early galliform ancestor. Our study ofC6gene birth in an early vertebrate ancestor andC9gene death in galliform birds provides insights into the evolution of the TCP.
Towards Synthetic PETtrophy: EngineeringPseudomonas putidafor concurrent polyethylene terephthalate (PET) monomer metabolism and PET hydrolase expression
Authors: Brandenberg Oliver F. , Schubert Olga T. , Kruglyak Leonid 
Published: May 2022

BackgroundBiocatalysis offers a promising path for plastic waste management and valorization, especially for hydrolysable plastics such as polyethylene terephthalate (PET). Microbial whole-cell biocatalysts for simultaneous PET degradation and growth on PET monomers would offer a one-step solution toward PET recycling or upcycling. We set out to engineer the industry-proven bacteriumPseudomonas putidafor (i) metabolism of PET monomers as sole carbon sources, and (ii) efficient concurrent extracellular expression of PET hydrolases. We pursued this approach for both PET and the related polyester polybutylene adipate co-terephthalate (PBAT), aiming to learn about the determinants and potential applications of bacterial polyester-degrading biocatalysts.ResultsP. putidawas engineered to metabolize the PET and PBAT monomer terephthalic acid (TA) through genomic integration of four tphII operon genes fromComamonas sp. E6. Efficient cellular TA uptake was enabled by a point mutation in the nativeP. putidamembrane transporter mhpT. Metabolism of the PET and PBAT monomers ethylene glycol and 1,4-butanediol was achieved through adaptive laboratory evolution. We then used fast design-build-test-learn cycles to engineer extracellular PET hydrolase expression, including tests of (i) the three PET hydrolases LCC, HiC, and IsPETase; (ii) genomic versus plasmid-based expression, using expression plasmids with high, medium, and low cellular copy number; (iii) three different promoter systems; (iv) three membrane anchor proteins for PET hydrolase cell surface display; and (v) a 30-mer signal peptide library for PET hydrolase secretion. PET hydrolase surface display and secretion was successfully engineered but often resulted in host cell fitness costs, which could be mitigated by promoter choice and altering construct copy number. Plastic biodegradation assays with the best PET hydrolase expression constructs genomically integrated into our monomer-metabolizingP. putidastrains resulted in various degrees of plastic depolymerization, although self-sustaining bacterial growth remained elusive.ConclusionOur results show that balancing extracellular PET hydrolase expression with cellular fitness under nutrient-limiting conditions is a challenge. The precise knowledge of such bottlenecks, together with the vast array of PET hydrolase expression tools generated and tested here, may serve as a baseline for future efforts to engineerP. putidaor other bacterial hosts towards becoming efficient whole-cell polyester-degrading biocatalysts.
FGF signaling promotes precursor spreading for adult adipogenesis in Drosophila
Authors: Lei Yuting , Huang Yuwei , Yang Ke , Cao Xueya , Song Yuzhao , Martín-Blanco Enrique , Pastor-Pareja José C. 
Published: May 2022

ABSTRACTKnowledge of adipogenetic mechanisms is essential to understand and treat conditions affecting organismal metabolism and adipose tissue health. In Drosophila, mature adipose tissue (fat body) exists in larvae and adults. In contrast to the well-known development of the larval fat body from the embryonic mesoderm, adult adipogenesis has remained mysterious. Furthermore, conclusive proof of its physiological significance is lacking. Here, we show that the adult fat body originates from a pool of undifferentiated mesodermal precursors that migrate from the thorax into the abdomen during metamorphosis. Through in vivo imaging, we found that these precursors spread from the ventral midline and cover the inner surface of the abdomen in a process strikingly reminiscent of embryonic mesoderm migration, requiring FGF signaling as well. FGF signaling guides migration dorsally and regulates adhesion to the substrate. After spreading is complete, precursor differentiation involves fat accumulation and cell fusion that produces mature binucleate and tetranucleate adipocytes. Finally, we show that flies where adult adipogenesis is impaired by knock down of FGF receptor Heartless or transcription factor Serpent display ectopic fat accumulation in oenocytes and decreased resistance to starvation. Our results reveal that adult adipogenesis occurs de novo during metamorphosis and demonstrate its crucial physiological role.
Neuromuscular denervation and deafferentation but not motor neuron death are disease features in the Smn2B/- mouse model of SMA
Authors: Carlini Maria J. , Triplett Marina K. , Pellizzoni Livio 
Published: May 2022

AbstractSpinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons and skeletal muscle atrophy which is caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. Several cellular defects contribute to sensory-motor circuit pathology in SMA mice, but the underlying mechanisms have often been studied in one mouse model without validation in other available models. Here, we used Smn2B/- mice to investigate specific behavioral, morphological, and functional aspects of SMA pathology that we previously characterized in the SMNΔ7 model. Smn2B/- SMA mice on a pure FVB/N background display deficits in body weight gain and muscle strength with onset in the second postnatal week and median survival of 19 days. Morphological analysis revealed severe loss of proprioceptive synapses on the soma of motor neurons and prominent denervation of neuromuscular junctions (NMJs) in axial but not distal muscles. In contrast, no evidence of cell death emerged from analysis of several distinct pools of lumbar motor neurons known to be lost in the disease. Moreover, SMA motor neurons from Smn2B/- mice showed robust nuclear accumulation of p53 but lack of phosphorylation of serine 18 at its amino-terminal, which selectively marks degenerating motor neurons in the SMNΔ7 mouse model. These results indicate that NMJ denervation and deafferentation, but not motor neuron death, are conserved features of SMA pathology in Smn2B/- mice.
Breakpoint models shown no evidence of thresholds in recreational response to increasing wildfire smoke in the American West
Authors: Clark Matt , Killion Alexander , Williamson Matthew A. , Hillis Vicken 
Published: May 2022

AbstractAmbient wildfire smoke in the American West has worsened considerably in recent decades, while the number of individuals recreating outdoors has simultaneously surged. Wildfire smoke poses a serious risk to human health, especially during long periods of exposure and during exercise. Here we aggregate data on black carbon, a major component of wildfire smoke, and recreational visitation in 32 U.S. national parks from 1980 - 2019 to examine how visitors respond to wildfire smoke. We hypothesize that visitor response may exhibit a threshold effect where ambient smoke reduces visitation after a critical level, but not before. We develop a series of breakpoint models to test this hypothesis. Overall, these models show little to no effect of ambient smoke on visitation to the 32 parks tested, even when allowing for critical thresholds at the extreme upper ranges of the smoke data. This suggests that wildfire smoke does not significantly alter behavior of park attendance. This finding has implications for the management of recreation areas, public health, and climate change adaptation broadly.
RNA Pol II pausing facilitates phased pluripotency transitions by buffering transcription
Authors: Abuhashem Abderhman , Chivu Alexandra G. , Zhao Yixin , Rice Edward J. , Siepel Adam , Danko Charles G. , Hadjantonakis Anna-Katerina 
Published: May 2022

ABSTRACTPromoter-proximal RNA Pol II pausing is a critical step in transcriptional control. Pol II pausing has been studied predominantly in tissue culture systems. While Pol II pausing has been shown to be required for mammalian development, the phenotypic and mechanistic details of this requirement are unknown. Here, we find that loss of RNA Pol II pausing stalls pluripotent state transitions in the epiblast of the early mouse embryo. Using Nelfb-/- mice and a novel NELFB- degron mouse embryonic stem cells, we show that mouse ES cells (mESCs) representing the naive state of pluripotency successfully initiate a transition program, but fail to balance levels of induced and repressed genes and enhancers in the absence of NELF. Consistently, we find an increase in chromatin-associated NELF during pluripotency transitions. Overall, our work reveals the molecular and phenotypic roles of Pol II pausing in pluripotency and introduces Pol II pausing as a modulator of cell state transitions.
Rapid evolution of sex role specialization in a hermaphrodite under sex-limited selection
Authors: Nordén Anna K. , Ramm Steven A. , Abbott Jessica K. 
Published: May 2022

AbstractThe evolution of separate sexes from hermaphroditism is thought to have occurred independently many times, and is linked to the evolution of sex chromosomes. Even though we have a good understanding of the theoretical steps in the evolution of sex chromosomes from a hermaphrodite ancestor, the initial stages are still hard to study because many sex chromosome systems are old. We addressed this problem by experimentally selecting a hermaphrodite via sex-limited experimental evolution for several generations, simulating the early stages in the evolution of a sex chromosome. More specifically, we used a GFP (green fluorescent protein) marker as a proxy for a sex-determining locus, and selected replicate populations of the simultaneously hermaphroditic flatwormMacrostomum lignanofor fitness via the male sex role, female sex role, or both (i.e. a control). After 14 generations, a fitness assay revealed clear evidence for incipient sex role specialization, presumably reflecting the release from constraints usually imposed by selection on the other sex role. Importantly, however, this was not simply explained by differential sex allocation in the different selection regimes - insofar as morphological traits reflect the underlying trade-off over resource allocation to the male and female sex functions - because testis and ovary sizes did not diverge among treatments. Our study shows that sex role specialization can occur rapidly as a result of sex-limited selection, which is consistent with genetic constraints between sex-roles, and in line with the first predicted steps towards the evolution of a new sex chromosome system.
A highly diverse set of novel immunoglobulin-like transcript (NILT) genes in zebrafish indicates a wide range of functions with complex relationships to mammalian receptors
Authors: Wcisel Dustin J. , Dornburg Alex , McConnell Sean C. , Hernandez Kyle M. , Andrade Jorge , de Jong Jill L. O. , Litman Gary W. , Yoder Jeffrey A. 
Published: May 2022

AbstractMultiple novel immunoglobulin-like transcripts (NILTs) have been identified from salmon, trout and carp. NILTs typically encode activating or inhibitory transmembrane receptors with extracellular immunoglobulin (Ig) domains. Although predicted to provide immune recognition in ray-finned fish, we currently lack a definitive framework of NILT diversity, thereby limiting our predictions for their evolutionary origin and function. In order to better understand the diversity of NILTs and their possible roles in immune function, we identified five NILT loci in the Atlantic salmon (Salmo salar) genome, defined 86 NILT Ig domains within a 3 Mbp region of zebrafish (Danio rerio) chromosome 1, and described 41 NILT Ig domains as part of an alternative haplotype for this same genomic region. We then identified transcripts encoded by 43 different NILT genes which reflect an unprecedented diversity of Ig domain sequences and combinations for a family of non-recombining receptors within a single species. Zebrafish NILTs include a sole putative activating receptor but extensive inhibitory and secreted forms as well as membrane-bound forms with no known signaling motifs. These results reveal a higher level of genetic complexity, interindividual variation and sequence diversity for NILTs than previously described, suggesting that this gene family likely plays multiple roles in host immunity.
Accurate and sensitive mutational signature analysis with MuSiCal
Authors: Jin Hu , Gulhan Doga C. , Geiger Benedikt , Ben-Isvy Daniel , Geng David , Ljungstrom Viktor , Park Peter J. 
Published: May 2022

AbstractMutational signature analysis is a recent computational approach for interpreting somatic mutations in the genome. Its application to cancer data has enhanced our understanding of mutational forces driving tumorigenesis and demonstrated its potential to inform prognosis and treatment decisions. However, methodological challenges remain for discovering new signatures and assigning proper weights to existing signatures, thereby hindering broader clinical applications. Here we present MuSiCal (Mutational Signature Calculator), a rigorous analytical framework with novel algorithms that solves major problems in the standard workflow. Our simulation studies demonstrate that MuSiCal outperforms state-of-the-art algorithms for both signature discovery and assignment. By reanalyzing over 2,700 cancer genomes, we provide an improved catalog of signatures and their assignments, discover nine indel signatures absent in the current catalog, resolve long-standing issues with the ambiguous ‘flat’ signatures, and give insights into signatures with unknown etiologies. We expect MuSiCal and the improved catalog to be a step towards establishing best practices for mutational signature analysis.
Single-cell mosaicism analysis reveals cell-type-specific somatic mutational burden in Alzheimer’s Dementia
Authors: Kousi Maria , Boix Carles , Park Yongjin P. , Mathys Hansruedi , Sledzieski Samuel , Peng Zhuyu , Bennett David A. , Tsai Li-Huei , Kellis Manolis 
Published: May 2022

AbstractDespite significant advances in identifying genetic drivers of neurodegenerative disorders, the majority of affected individuals lack molecular genetic diagnosis, with somatic mutations proposed as one potential contributor to increased risk. Here, we report the first cell-type-specific map of somatic mosaicism in Alzheimer’s Dementia (AlzD), using 4,014 cells from prefrontal cortex samples of 19 AlzD and 17 non-AlzD individuals. We integrate full-transcript single-nucleus RNA-seq (SMART-Seq) with matched individual-level whole-genome sequencing to jointly infer mutational events and the cell-type in which they occurred. AlzD individuals show increased mutational burden, localized in excitatory neurons, oligodendrocytes, astrocytes and disease-associated “senescent” cells. High-mutational-burden cells showed mutational enrichment and similar single-cell expression profiles in AlzD cases versus non-AlzD individuals, indicating cellular-level genotype-to-phenotype correlation. Somatic mutations are specifically enriched for known AlzD genes, and implicate biologically meaningful cell-type specific processes, including: neuronal energy regulation, endocytic trafficking (NEFM), lipid metabolism (CNP, CRYAB), proteostasis (USP34), cytoskeleton, and microtubule dynamics (MACF1).
The kinase activity of the cancer stem cell marker DCLK1 drives gastric cancer progression by reprogramming the stromal tumor landscape
Authors: Afshar-Sterle Shoukat , Carli Annalisa L E , O’Keefe Ryan , Tse Janson , Fischer Stefanie , Azimpour Alexander I , Baloyan David , Elias Lena , Thilakasiri Pathum , Patel Onisha , Ferguson Fleur M , Eissmann Moritz F , Chand Ashwini L , Gray Nathanael S , Busuttil Rita , Boussioutas Alex , Lucet Isabelle S , Ernst Matthias , Buchert Michael 
Published: May 2022

AbstractGastric cancer (GC) is the 3rd leading cause of cancer mortality worldwide, therefore providing novel diagnostic and treatment options is crucial for at risk groups. The serine/threonine kinase doublecortin-like kinase 1 (DCLK1) is a proposed driver of GC with frequent amplification and somatic missense mutations yet the molecular mechanism how DCLK1 mediates tumorigenesis is poorly understood. We report how DCLK1 expression orchestrates complementary cancer cell intrinsic and extrinsic processes leading to a comprehensive pro-invasive and pro-metastatic reprogramming of cancer cells and tumor stroma in a DCLK1 kinase-dependent manner. Mechanistically, we identify the chemokine CXCL12 as a key promoter of the pro-tumorigenic properties downstream of DCLK1. Importantly, inhibition of the DCLK1 kinase domain reverses the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a promising, targetable master regulator of GC.TeaserDCLK1 is a druggable cancer driver of GC