bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid diversification of the Australian Amitermes group during late Cenozoic climate change
Authors: Heimburger Bastian , Schardt Leonie , Brandt Alexander , Scheu Stefan , Hartke Tamara R. 
Published: April 2021

AbstractLate Cenozoic climate change led to the progressive aridification of Australia over the past 15 million years. This gradual biome turnover fundamentally changed Australia’s ecosystems, opening new niches and prompting diversification of plants and animals. One example is the Australian Amitermes Group (AAG), consisting of the Australian Amitermes and affiliated genera. Although it represents the most speciose and diverse higher termite group in Australia, little is known about its evolutionary history. We used ancestral range reconstruction and diversification analyses to illuminate 1) the origin and phylogenetic relationships of the AAG, 2) biogeographical processes leading to the current continent-wide distribution, and 3) timing and pattern of diversification in the context of late Cenozoic climate change. By estimating the first time-calibrated phylogeny, we show that the AAG is a monophyletic group, whose ancestor arrived ~11-10 million years ago from Southeast Asia. Ancestral range reconstruction indicates that Australia’s monsoon region was the launching point for a continental radiation that has been shaped by range expansions and within-area speciation rather than vicariance. We found that multiple arid species diversified from mesic and tropical ancestors in the Plio-Pleistocene, but also observed diversification in the opposite direction. Finally, we show that two pulses of rapid diversification coincided with past climate change during the late Miocene and early Pliocene. Consistent with rapid diversification, species accumulation slowed, likely caused by progressive niche saturation. This study provides a stepping stone for predicting the future response of Australia’s termite fauna in the face of human-mediated climate change.
High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response
Authors: Ostrom Ethan L. , Valencia Ana P. , Marcinek David J. , Traustadóttir Tinna 
Published: April 2021

ABSTRACTIntroductionHigh intensity exercise is an increasingly popular mode of exercise to elicit similar or greater adaptive responses compared to traditional moderate intensity continuous exercise. However, the molecular mechanisms underlying these adaptive responses are still unclear. The purpose of this pilot study was to compare high and low intensity contractile stimulus on the Nrf2-mediated redox stress response in mouse skeletal muscle.MethodsAn intra-animal design was used to control for variations in individual responses to muscle stimulation by using a stimulated limb (STIM) and comparing to the contralateral unstimulated control limb (CON). High Intensity (HI – 100Hz), Low Intensity (LI – 50Hz), and Naïve Control (NC – Mock stimulation vs CON) groups were used to compare these effects on Nrf2-ARE binding, Keap1 protein content, and downstream gene and protein expression of Nrf2 target genes.ResultsMuscle stimulation significantly increased Nrf2-ARE binding in LI-STIM compared to LI-CON (p = 0.0098), while Nrf2-ARE binding was elevated in both HI-CON and HI-STIM compared to NC (p = 0.0007). The Nrf2-ARE results were mirrored in the downregulation of Keap1, where Keap1 expression in HI-CON and HI-STIM were both significantly lower than NC (p = 0.008) and decreased in LI-STIM compared to LI-CON (p = 0.015). In addition, stimulation increased NQO1 protein compared to contralateral control regardless of stimulation intensity (p = 0.019).ConclusionsTaken together, these data suggest a systemic redox signaling exerkine is activating Nrf2-ARE binding and is intensity gated, where Nrf2-ARE activation in contralateral control limbs were only seen in the HI group. Other research in exercise induced Nrf2 signaling support the general finding that Nrf2 is activated in peripheral tissues in response to exercise, however the specific exerkine responsible for the systemic signaling effects is not known. Future work should aim to delineate these redox sensitive systemic signaling mechanisms.
Single cell transcriptome profiling of the human developing spinal cord reveals a conserved genetic programme with human specific features
Authors: Rayon Teresa , Maizels Rory J. , Barrington Christopher , Briscoe James 
Published: April 2021

AbstractThe spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly and physiologically distinct neuronal subtypes that are generated in a characteristic spatial-temporal arrangement from progenitors in the embryonic neural tube. The systematic mapping of gene expression in mouse embryos has provided insight into the diversity and complexity of cells in the neural tube. For human embryos, however, less information has been available. To address this, we used single cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie Stages (CS) CS12, CS14, CS17 and CS19 from Gestational Weeks (W) 4-7. In total we recovered the transcriptomes of 71,219 cells. Analysis of progenitor and neuronal populations from the neural tube, as well as cells of the peripheral nervous system, in dorsal root ganglia adjacent to the neural tube, identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with existing mouse datasets revealed the overall similarity of mouse and human neural tube development while highlighting specific features that differed between species. These data provide a catalogue of gene expression and cell type identity in the developing neural tube that will support future studies of sensory and motor control systems and can be explored athttps://shiny.crick.ac.uk/scviewer/neuraltube/.
CCR4 blockade leads to clinical activity and prolongs survival in a canine model of advanced prostate cancer
Authors: Maeda Shingo , Motegi Tomoki , Iio Aki , Kaji Kenjiro , Goto-Koshino Yuko , Eto Shotaro , Ikeda Namiko , Nakagawa Takayuki , Nishimura Ryohei , Yonezawa Tomohiro , Momoi Yasuyuki 
Published: April 2021

AbstractTargeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, the efficacy of this strategy in advanced prostate cancer remains unclear. Here, we describe the therapeutic efficacy of this strategy in a canine model of advanced prostate cancer. We used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration into tumor tissues and the effect of anti-Treg treatment. We found that tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed that Treg infiltration was mediated by interaction between the tumor-producing chemokine, CCL17, and the receptor CCR4 expressed on Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with improved survival and low incidence of clinically relevant adverse events. Exploratory analyses showed urinary CCL17 concentration and BRAFV595Emutation to be independently predictive of the response to mogamulizumab. Analysis of a publicly available transcriptomic dataset of human prostate cancer showed that the CCL17/CCR4 axis correlated with the Treg marker, Foxp3. In silico survival analyses showed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer. These findings suggest that anti-Treg treatment through the blocking of CCR4 is a promising therapeutic approach for advanced prostate cancer.One Sentence SummaryTargeting regulatory T cell infiltration by CCR4 blockade induces objective responses and improves survival in a canine model of prostate cancer.
Midbrain organoids with anSNCAgene triplication model key features of synucleinopathy
Authors: Mohamed Nguyen-Vi , Sirois Julien , Ramamurthy Janani , Mathur Meghna , Lépine Paula , Deneault Eric , Maussion Gilles , Nicouleau Michael , Chen Carol X.-Q. , Abdian Narges , Soubannier Vincent , Cai Eddie , Nami Harris , Thomas Rhalena A. , Tabatabaei Mahdieh , Beitel Lenore K. , Dolt Karamjit Singh , Karamchandani Jason , Kunath Tilo , Fon Edward A. , Durcan Thomas M. 
Published: April 2021

AbstractSNCA,the first gene associated with Parkinson’s disease, encodes the α-synuclein (α-syn) protein, the predominant component within pathological inclusions termed Lewy bodies (LBs). The presence of LBs is one of the classical hallmarks found in the brain of patients with Parkinson’s disease, and LBs have also been observed in patients with other synucleinopathies. However, the study of α-syn pathology in cells has relied largely on two-dimensional culture models, which typically lack the cellular diversity and complex spatial environment found in the brain. Here, to address this gap, we use 3D midbrain organoids (hMOs), differentiated from human induced pluripotent stem cells derived from patients carrying a triplication of theSNCAgene and from CRISPR/Cas9 corrected isogenic control iPSCs. These hMOs recapitulate key features of α-syn pathology observed in the brains of patients with synucleinopathies. In particular, we find thatSNCAtriplication hMOs express elevated levels of α-syn and exhibit an age-dependent increase in α-syn aggregation, manifested by the presence of both oligomeric and phosphorylated forms of α-syn. These phosphorylated α-syn aggregates were found in both neurons and glial cells and their time-dependent accumulation correlated with a selective reduction in dopaminergic neuron numbers. Thus, hMOs from patients carrying SNCA gene multiplication can reliably model key pathological features of Parkinson’s disease and provide a powerful system to study the pathogenesis of synucleinopathies.
Molecular determinants of phase separation forDrosophilaDNA replication licensing factors
Authors: Parker Matthew W. , Kao Jonchee , Huang Alvin , Berger James M. , Botchan Michael R. 
Published: April 2021

ABSTRACTLiquid-liquid phase separation (LLPS) of intrinsically disordered regions (IDRs) in proteins can drive the formation of membraneless compartments in cells. Phase-separated structures enrich for specific partner proteins and exclude others. We have shown that the IDRs of metazoan DNA replication initiators drive DNA-dependent phase separationin vitroand chromosome bindingin vivo, and that initiator condensates selectively recruit specific partner proteins. How initiator IDRs facilitate LLPS and maintain compositional specificity is unknown. UsingD. melanogaster (Dm)Cdt1 as a model initiation factor, we show that phase separation results from a synergy between electrostatic DNA-bridging interactions and hydrophobic inter-IDR contacts. Both sets of interactions depend on sequence composition (but not sequence order), are resistant to 1,6- hexanediol, and do not depend on aromaticity. These findings demonstrate that distinct sets of interactions drive self-assembly and condensate specificity across different phase-separating systems and advance efforts to predict IDR LLPS propensity and specificitya priori.
Proteomic analysis of the role of the quality control protease LONP1 in mitochondrial protein aggregation
Authors: Pollecker Karen , Sylvester Marc , Voos Wolfgang 
Published: April 2021

AbstractThe mitochondrial matrix protease LONP1 is an essential part of the organellar protein quality control system. LONP1 has been shown to be involved in respiration control and apoptosis. Furthermore, a reduction in LONP1 level correlates with ageing processes. Up to now, the effects of a LONP1 defect were mostly studied by utilizing transient, siRNA-mediated knockdown approaches. We generated a new cellular model system for studying the impact of LONP1 on mitochondrial protein homeostasis by a CRISPR/Cas-mediated genetic knockdown (gKD). These cells show a stable reduction of LONP1 along with a mild phenotype characterized by absent morphological differences and only small negative effects on mitochondrial functions under normal culture conditions. To assess the consequences of a permanent LONP1 depletion on the mitochondrial proteome, we analyzed the alterations of protein levels by quantitative mass spectrometry, demonstrating small adaptive changes, in particular concerning mitochondrial protein biogenesis. In an additional proteomic analysis, we determined the temperature-dependent aggregation behavior of mitochondrial proteins and its dependence on a reduction of LONP1 activity, demonstrating the important role of the protease for mitochondrial protein homeostasis in mammalian cells. We identified a significant number of mitochondrial proteins that are affected by LONP1 activity concerning their stress-induced solubility. Taken together, our results suggest a very good applicability of the LONP1 gKD cell line as a model system for human ageing processes.
The Akt-mTOR pathway drives myelin sheath growth by regulating cap-dependent translation
Authors: Fedder-Semmes Karlie N. , Appel Bruce 
Published: April 2021

ABSTRACTIn the vertebrate central nervous system, oligodendrocytes produce myelin, a specialized proteolipid rich membrane, to insulate and support axons. Individual oligodendrocytes wrap multiple axons with myelin sheaths of variable lengths and thicknesses. Myelin grows at the distal ends of oligodendrocyte processes and multiple lines of work have provided evidence that mRNAs and RNA binding proteins localize to myelin, together supporting a model where local translation controls myelin sheath growth. What signal transduction mechanisms could control this? One strong candidate is the Akt-mTOR pathway, a major cellular signaling hub that coordinates transcription, translation, metabolism, and cytoskeletal organization. Here, using zebrafish as a model system, we found that Akt-mTOR signaling promotes myelin sheath growth and stability during development. Through cell-specific manipulations to oligodendrocytes, we show that the Akt-mTOR pathway drives cap-dependent translation to promote myelination and that restoration of cap-dependent translation is sufficient to rescue myelin deficits in mTOR loss-of-function animals. Moreover, an mTOR-dependent translational regulator co-localized with mRNA encoding a canonically myelin-translated protein in vivo and bioinformatic investigation revealed numerous putative translational targets in the myelin transcriptome. Together, these data raise the possibility that Akt-mTOR signaling in nascent myelin sheaths promotes sheath growth via translation of myelin-resident mRNAs during development.SIGNIFICANCE STATEMENTIn the brain and spinal cord oligodendrocytes extend processes that tightly wrap axons with myelin, a protein and lipid rich membrane that increases electrical impulses and provides trophic support. Myelin membrane grows dramatically following initial axon wrapping in a process that demands protein and lipid synthesis. How protein and lipid synthesis is coordinated with the need for myelin to be generated in certain locations remains unknown. Our study reveals that the Akt-mTOR signaling pathway promotes myelin sheath growth by regulating protein translation. Because we found translational regulators of the Akt-mTOR pathway in myelin, our data raise the possibility Akt-mTOR activity regulates translation in myelin sheaths to deliver myelin on demand to the places it is needed.
Long-read whole genome analysis of human single cells
Authors: Hård Joanna , Mold Jeff E , Eisfeldt Jesper , Tellgren-Roth Christian , Häggqvist Susana , Bunikis Ignas , Contreras-Lopez Orlando , Chin Chen-Shan , Nordlund Jessica , Rubin Carl-Johan , Feuk Lars , Michaëlsson Jakob , Ameur Adam 
Published: April 2021

AbstractWith long-read sequencing, we have entered an era where individual genomes are routinely assembled to near completion and where complex genetic variation can efficiently be resolved. Here, we demonstrate that long reads can be applied to study the genomic architecture of individual human cells. Clonally expanded CD8+ T-cells from a human donor were used as starting material for a droplet-based multiple displacement amplification (dMDA) to generate long molecules with minimal amplification bias. PacBio HiFi sequencing generated up to 20 Gb data and 40% genome coverage per single cell. The data allowed for accurate detection and haplotype phasing of single nucleotide variants (SNVs), structural variants (SVs), and tandem repeats, including in genomic regions inaccessible by short reads. Somatic SNVs were detected in the nuclear genome and mitochondrial DNA. An average of 1278 high-confidence SVs per cell were discovered in the PacBio data, nearly four times as many compared to those found in Illumina dMDA data from clonally related cells. Single-cellde novoassembly resulted in a genome size of up to 598 Mb and 1762 (12.8%) complete gene models. In summary, the work presented here demonstrates the utility of whole genome amplification combined with long-read sequencing toward the characterization of the full spectrum of genetic variation at the single-cell level.
Mediodorsal thalamus is critical for updating during extra-dimensional shifts but not reversals in the attentional set-shifting task
Authors: Ouhaz Zakaria , Perry Brook AL , Nakamura Kouichi , Mitchell Anna S 
Published: April 2021

AbstractCognitive flexibility, attributed to frontal cortex, is vital for navigating the complexities of everyday life. The mediodorsal thalamus (MD), interconnected to frontal cortex, may influence cognitive flexibility. Here male rats performed an attentional set-shifting task measuring intra-dimensional and extra-dimensional shifts in sensory discriminations. MD lesion rats needed more trials to learn the rewarded sensory dimension. However, once the choice response strategy was established, learning further two-choice discriminations in the same sensory dimension, and reversals of the reward contingencies in the same dimension, were unimpaired. Critically though, MD lesion rats were impaired during the extra-dimensional shift, when they must rapidly update the optimal choice response strategy. Behavioral analyses showed MD lesion rats had significantly reduced correct within trial second choice responses. This evidence shows transfer of information via the MD is critical when monitoring and rapid within trial updates in established choice response strategies are required after there is a rule change.Significance statementWe demonstrate for the first time that rodent mediodorsal (MD) thalamus is a critical node when choice response strategies need to change rapidly after a within session rule change but not after reversals of reward contingencies during reward guided learning. MD interactions with orbitofrontal cortex are critical for value based learning, while MD interactions with medial prefrontal cortex are critical for rapid within trial updating of optimal choice response rules. MD interactions with the orbitofrontal cortex are not always necessary for reversal learning.
From partial to whole genome imputation of SARS-CoV-2 for epidemiological surveillance
Authors: Ortuño Francisco M , Loucera Carlos , Casimiro-Soriguer Carlos S. , Lepe Jose A. , Martinez Pedro Camacho , Diaz Laura Merino , de Salazar Adolfo , Chueca Natalia , García Federico , Perez-Florido Javier , Dopazo Joaquin 
Published: April 2021

AbstractBackgroundthe current SARS-CoV-2 pandemic has emphasized the utility of viral whole genome sequencing in the surveillance and control of the pathogen. An unprecedented ongoing global initiative is increasingly producing hundreds of thousands of sequences worldwide. However, the complex circumstances in which viruses are sequenced, along with the demand of urgent results, causes a high rate of incomplete and therefore useless, sequences. However, viral sequences evolve in the context of a complex phylogeny and therefore different positions along the genome are in linkage disequilibrium. Therefore, an imputation method would be able to predict missing positions from the available sequencing data.ResultsWe developed impuSARS, an application that includes Minimac, the most widely used strategy for genomic data imputation and, taking advantage of the enormous amount of SARS-CoV-2 whole genome sequences available, a reference panel containing 239,301 sequences was built. The impuSARS application was tested in a wide range of conditions (continuous fragments, amplicons or sparse individual positions missing) showing great fidelity when reconstructing the original sequences. The impuSARS application is also able to impute whole genomes from commercial kits covering less than 20% of the genome or only from theSpikeprotein with a precision of 0.96. It also recovers the lineage with a 100% precision for almost all the lineages, even in very poorly covered genomes (< 20%)Conclusionsimputation can improve the pace of SARS-CoV-2 sequencing production by recovering many incomplete or low-quality sequences that would be otherwise discarded. impuSARS can be incorporated in any primary data processing pipeline for SARS-CoV-2 whole genome sequencing.
Horse Trading: Food Sourcing in the Twenty-First Century
Authors: Walker Russell 
Published: April 2021

In January 2013, Irish authorities were the first to uncover the year's first food sourcing scandal: horsemeat sold as beef on supermarket shelves. It was not long before regulators and retailers realized the problem was truly a continental one. The incident involved French exporters, Luxembourger production facilities, Cypriot and Dutch meat traders, British and Swedish retailers, and Romanian horsemeat. Food service providers and retailers were forced to test beef products to ensure they were horse-free, pulling products that contained traces of equine meat. British supermarkets alone disposed of an estimated 10 million “beef” burgers in the wake of the scandal.
This case is an example of the challenges of managing the complex global supply chains that make up the modern food industry. In this class discussion, students will use concepts from management, economics, and public policy to assess the damage of this event and to analyze strategies for preventing similar incidents in the future.
Chipotle Mexican Grill: Food with Integrity?
Authors: Walker Russell , Merkley Greg 
Published: April 2021

By any measure, Chipotle Mexican Grill was a success story in the restaurant business. It grew from one location in 1993 to over 2,000 locations by 2016 and essentially created the fast casual dining category. Its stock appreciated more than 1,000% in the ten years following its 2006 IPO.
However, after more than 20 years without a major reported food safety incident, Chipotle was revealed as the source of multiple outbreaks of illness from norovirus, salmonella, and E. coli that sickened nearly 600 people in 13 states in 2015. The company closed stores, spent several months under investigation by the U.S. Centers for Disease Control and Prevention (CDC) and other health organizations, and faced a criminal investigation in connection with the incidents.
After a much-publicized closing of all of its stores on February 8, 2016, and numerous changes to its food sourcing and preparation practices, Chipotle tried to win back customers with dramatically increased advertising and free food promotions.
However, on April 26, the chain announced its first-ever quarterly loss as a public company. Same-store sales for the first quarter were 29.7% lower than in the previous year. Operating margins fell from 27.5% to 6.8% over the same period, and the company's share price was down 41% from its summer 2015 high.