bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between Five-Year Blood Pressure Variability and Risk of Cardiovascular Events and Mortality
Authors: Zhou Jiandong , Lee Sharen , Wong Wing Tak , Wu William KK , Ming Wai Kit , Liu Tong , Jeevaratnam Kamalan , Yung Cheung Bernard Man , Tse Gary , Zhang Qingpeng
Published: December 2020

Introduction

Blood pressure variability, in addition to blood pressure itself, has been used as a predictor for mortality. This study examined the predictive power of baseline/latest/mean/median blood pressure and blood pressure variability measures for all-cause mortality and adverse cardiovascular outcomes.

Methods

The retrospective observational study analyzed patients who presented to family medicine clinics between 1st January, 2000 and 31st December, 2001. Blood pressure measurements were obtained over a five-year period. Standard deviation (SD), root mean square (RMS), coefficient of variation (CV) and a variability score (number of >=5 mmHg blood pressure change) were used as measures of blood pressure variability. The primary outcome was all-cause mortality and the secondary outcomes were heart failure, acute myocardial infarction, and transient ischemic attack (TIA)/stroke, with follow-up until 31 December 2019.

Results

This study included 37540 patients (n=29597 patients with >=3 blood pressure measurements). A nonlinear inverse U-shaped relationship was observed between baseline/latest/maximum/minimum/mean/median/RMS measures of diastolic blood pressure and time-to-death for all-cause mortality (P<0.001). Higher variance/SD/CV/variability score of both systolic and diastolic blood pressure was significantly associated with increased risks of all-cause mortality and heart failure, acute myocardial infarction and TIA/stroke (P<0.001). Low baseline/latest/maximum/minimum/mean/median/RMS systolic blood pressure was significantly associated with shorter time-to-death for all-cause mortality (P<0.001).

Conclusion

Nonlinear inverse U-shaped relationships were observed between blood pressure and its variability measures and all-cause mortality. Higher blood pressure variability was associated with increased risk of all-cause mortality, heart failure, acute myocardial infarction and TIA/stroke.
A non-enzymatic acetylation of lysine residues adversely affects the Rubisco activase protein stability
Authors: Yang Li-Li , Hong Hui , Gao Xiang , Essemine Jemaa , Fang Xin , Shu Zhan , Ablat Guljannat , Wu Meng , Mi Hua-Ling , Chen Xiao-Ya , Qu Mingnan , Chen Gen-Yun
Published: December 2020

The post-translational modifications of non-histone (PTMs) proteins functions are crucial for the plant adaption to the changing environment. The Rubisco activase (RCA) plays a key role in the CO2fixation through the Rubisco activation process. We reported that the RCA from tobacco leaf could be acetylated at several lysine residues including K126 and K164. The acetylation level changes under different light conditions (night and day) as well as under heat stress (45 °C). We further showed that the RCA can be non-enzymatically acetylatedin vitro, especially by the acetyl-CoA (Ac-CoA) through direct interaction between them. Our results of thein vitroassay with deuterium labeled Ac-CoA (D2-Ac-CoA) show that the two conserved RCA lysine residues (K126 and K164) were acetylated by Ac-CoA, entraining a dramatic decline in its ATPase activity and a slight effect on the Rubisco activation process. Furthermore, we revealed that the higher RCA acetylation level induced its faster degradation in the chloroplast, which was not a direct consequence of ubiquitination. Eventually, our findings unraveled a new prominent role for the protein acetylation in modulating the RCA stability, which could certainly regulate the carbon assimilation efficiency towards a different energy status of the plants.
SARS-CoV-2 RNA quantification using droplet digital RT-PCR
Authors: Kinloch Natalie N. , Ritchie Gordon , Dong Winnie , Cobarrubias Kyle D. , Sudderuddin Hanwei , Lawson Tanya , Matic Nancy , Montaner Julio S.G. , Leung Victor , Romney Marc G. , Lowe Christopher F. , Brumme Chanson J. , Brumme Zabrina L.
Published: December 2020

Quantitative viral load assays have transformed our understanding of – and ability to manage − viral diseases. They hold similar potential to advance COVID-19 control and prevention, but SARS-CoV-2 viral load tests are not yet widely available. SARS-CoV-2 molecular diagnostic tests, which typically employ real-time reverse transcriptase-polymerase chain reaction (RT-PCR), yield semi-quantitative results only. Reverse transcriptase droplet digital PCR (RT-ddPCR), a technology that partitions each reaction into 20,000 nanolitre-sized droplets prior to amplification, offers an attractive platform for SARS-CoV-2 RNA quantification. We evaluated eight primer/probe sets originally developed for real-time RT-PCR-based SARS-CoV-2 diagnostic tests for use in RT-ddPCR, and identified three (Charité-Berlin E-Sarbeco and Pasteur Institute IP2 and IP4) as the most efficient, precise and sensitive for RT-ddPCR-based SARS-CoV-2 RNA quantification. Analytical efficiency of the E-Sarbeco primer/probe set, for example, was ~83%, while assay precision, as measured by the coefficient of variation, was ~2% at 1000 input copies/reaction. Lower limits of quantification and detection for this primer/probe set were 18.6 and 4.4 input SARS-CoV-2 RNA copies/reaction, respectively. SARS-CoV-2 RNA viral loads in a convenience panel of 48 COVID-19-positive diagnostic specimens spanned a 6.2log10range, confirming substantial viral load variationin vivo. We further calibrated RT-ddPCR-derived SARS-CoV-2 E gene copy numbers against cycle threshold (Ct) values from a commercial real-time RT-PCR diagnostic platform. The resulting log-linear relationship can be used to mathematically derive SARS-CoV-2 RNA copy numbers from Ctvalues, allowing the wealth of available diagnostic test data to be harnessed to address foundational questions in SARS-CoV-2 biology.
Leri: a web-server for identifying protein functional networks from evolutionary couplings
Authors: Cheung Ngaam J. , Peter Arun T. John , Kornmann Benoit
Published: December 2020

Information on the co-evolution of amino acid pairs in a protein can be used for endeavors such as protein engineering, mutation design, and structure prediction. Here we report a method that captures significant determinants of proteins using estimated co-evolution information to identify networks of residues, termed “residue communities”, relevant to protein function. By taking advantage of recent developments in high-performance and parallel computing, we constructed a web-server,Leri, that identifies relevant residue communities to allow researchers to investigate how a protein evolves and folds for function(s). All the data of the computational results including high-quality images can be downloaded and presented for publication. This web-server, written in C++, is sufficiently rapid to enable the studies on proteins of up to 400 amino acids.
Annotation and analysis ofyellow genesinDiaphorina citri, vector for the Huanglongbing disease
Authors: Massimino Crissy , Vosburg Chad , Shippy Teresa , Hosmani Prashant S. , Flores-Gonzalez Mirella , Mueller Lukas A. , Hunter Wayne B. , Benoit Joshua B. , Brown Susan J. , D’Elia Tom , Saha Surya
Published: December 2020

Huanglongbing (HLB), also known as citrus greening disease, is caused by the bacteriumCandidatusLiberibacter asiaticus (CLas) and represents a serious threat to global citrus production. This bacteria is transmitted by the Asian citrus psyllid,Diaphorina citri(Hemiptera) and there are no effective in-planta treatments for CLas. Therefore, one strategy is to manage the psyllid population. Manual annotation of theD. citrigenome can identify and characterize gene families that could serve as novel targets for psyllid control. Theyellowgene family represents an excellent target asyellowgenes are linked to development and immunity due to their roles in melanization. Combined analysis of the genome with RNA-seq datasets, sequence homology, and phylogenetic trees were used to identify and annotate nineyellowgenes for theD. citrigenome. Phylogenetic analysis shows a unique duplication ofyellow-yinD. citri, with life stage specific expression for these two genes. Genomic analysis also indicated the loss of a gene vital to the process of melanization,yellow-f, and the gain of a gene which seems to be unique to hemipterans,yellow 9. We suggest thatyellow 9or the geneyellow 8(c), which consistently groups closely toyellow-f, may take on this role. Manual curation of genes inD. citrihas provided an in-depth analysis of theyellowfamily among hemipteran insects and provides new targets for molecular control of this psyllid pest. Manual annotation was done as part of a collaborative community annotation project (https://citrusgreening.org/annotation/index).
Developmental and evolutionary constraints on olfactory circuit selection
Authors: Hiratani Naoki , Latham Peter E.
Published: December 2020

Across species, neural circuits show remarkable regularity, suggesting that their structure has been driven by underlying optimality principles. Here, we ask whether we can predict the neural circuitry of diverse species by optimizing the neural architecture to make learning as efficient as possible. We focus on the olfactory system, primarily because it has a relatively simple evolutionarily conserved structure, and because its input and intermediate layer sizes exhibits a tight allometric scaling. In mammals, it has been shown that the number of neurons in layer 2 of piriform cortex scales as the number of glomeruli (the input units) to the 3/2 power; in invertebrates, we show that the number of mushroom body Kenyon cells scales as the number of glomeruli to the 7/2 power. To understand these scaling laws, we model the olfactory system as a three layered nonlinear neural network, and analytically optimize the intermediate layer size for efficient learning from a limited number of samples. We find that the 3/2 scaling observed in mammals emerges naturally, both in full batch optimization and under stochastic gradient learning. We extended the framework to the case where a fraction of the olfactory circuit is genetically specified, not learned. We show numerically that this makes the scaling law steeper when the number of glomeruli is small, and we are able to recover the 7/2 scaling law observed in invertebrates. This study paves the way for a deeper understanding of the organization of brain circuits from an evolutionary perspective.
T cell activation, highly armed cytotoxic cells and a sharp shift in monocytes CD300 receptors expression is characteristic of patients with severe COVID-19
Authors: Zenarruzabeitia Olatz , Astarloa-Pando Gabirel , Terrén Iñigo , Orrantia Ane , Pérez-Garay Raquel , Seijas-Betolaza Iratxe , Nieto-Arana Javier , Imaz-Ayo Natale , Pérez-Fernández Silvia , Arana-Arri Eunate , Borrego Francisco
Published: December 2020

COVID-19 manifests with a wide diversity of clinical phenotypes characterized by dysfunctional and exaggerated host immune responses. Many results have been described on the status of the immune system of patients infected with SARS-CoV-2, but there are still aspects that have not been fully characterized. In this study, we have analyzed a cohort of patients with mild, moderate and severe disease. We performed flow cytometric studies and correlated the data with the clinical features and clinical laboratory values of patients. Both conventional and unsupervised data analyses concluded that patients with severe disease are characterized, among others, by a higher state of activation in all T cell subsets, higher expression of perforin and granzyme B in cytotoxic cells, expansion of adaptive NK cells and the accumulation of activated and immature dysfunctional monocytes which are identified by a low expression of HLA-DR and an intriguing abrupt change in the expression pattern of CD300 receptors. More importantly, correlation analysis showed a strong association between the alterations in the immune cells and the clinical signs of severity. These results indicate that patients with severe COVID-19 have a broad perturbation of their immune system, and they will help to understand the immunopathogenesis of severe COVID-19 as well as could be of special value for physicians to decide which specific therapeutic options are most effective for their patients.
Active learning tools improve the learning outcomes, scientific attitude and critical thinking in higher education: Experiences in an online course during the COVID-19 pandemic
Authors: Rossi Izadora Volpato , de Lima Jordana Dinorá , Sabatke Bruna , Ferreira Nunes Maria Alice , Ramirez Graciela Evans , Ramirez Marcel Ivan
Published: December 2020

Active teaching methodologies have been placed as a hope for changing education at different levels, transiting from passive lecture-centered to student-centered learning. With the health measures of social distance, the COVID-19 pandemic forced a strong shift to remote education. With the challenge of delivering quality education through a computer screen, we validated and applied an online course model using active teaching tools for higher education. We incorporated published active-learning strategies into an online construct, with problem-based inquiry and design of inquiry research projects to serve as our core active-learning tool. The gains related to students’ science learning experiences and their attitudes towards science were assessed by applying questionnaires before, during and after the course. The course counted on the participation of 83 students, most of them (60,8%) from post-graduate students. Our results show that engagement provided by active learning methods can improve performance both in hard and soft skills. Students participation seems to be more relevant when activities require interaction of information, prediction and reasoning, such as open-ended questions and design of research projects. Therefore, our data shows that, in pandemic, active learning tools benefit students and improve their critical thinking and their motivation and positive positioning in science.
Graphic: Graph-Based Hierarchical Clustering for Single-Molecule Localization Microscopy
Authors: Pourya Mehrsa , Aziznejad Shayan , Unser Michael , Sage Daniel
Published: December 2020

We propose a novel method for the clustering of point-cloud data that originate from single-molecule localization microscopy (SMLM). Our scheme has the ability to infer a hierarchical structure from the data. It takes a particular relevance when quantitatively analyzing the biological particles of interest at different scales. It assumes a prior neither on the shape of particles nor on the background noise. Our multiscale clustering pipeline is built upon graph theory. At each scale, we first construct a weighted graph that represents the SMLM data. Next, we find clusters using spectral clustering. We then use the output of this clustering algorithm to build the graph in the next scale; in this way, we ensure consistency over different scales. We illustrate our method with examples that highlight some of its important properties.
Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection
Authors: Te Nigeer , Rodon Jordi , Ballester Maria , Pérez Mónica , Pailler-García Lola , Segalés Joaquim , Vergara-Alert Júlia , Bensaid Albert
Published: December 2020

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.

Author summary

Middle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.
Quantifying absolute gene expression profiles reveals distinct regulation of central carbon metabolism genes in yeast
Authors: Yu Rosemary , Vorontsov Egor , Sihlbom Carina , Nielsen Jens
Published: December 2020

In addition to specific regulatory circuits, gene expression is also regulated by global physiological cues such as the cell growth rate and metabolic parameters. Here we examine these global control mechanisms by analyzing an orthogonal multi-omics dataset consisting of absolute-quantitative abundances of the transcriptome, proteome, and intracellular amino acids in 22 steady-state yeast cultures. Our model indicates that transcript and protein abundance are coordinately controlled by the cell growth rate via RNA polymerase II and ribosome abundance, but are independently controlled by metabolic parameters relating to amino acid and nucleotide availability. Genes in central carbon metabolism, however, are regulated independently of these global physiological cues. Our findings can be used to augment gene expression profiling analyses in the distantly related yeastSchizosaccharomyces pombeand a human cancer cell model. Our results provide a framework to analyze gene expression profiles to gain novel biological insights, a key goal of systems biology.
From egg to adult: a developmental table of the antMonomorium pharaonis
Authors: Rajakumar Arjuna , Pontieri Luigi , Li Ruyan , Larsen Rasmus Stenbak , Vásquez-Correa Angelly , Frandsen Johanne KL , Rafiqi Ab Matteen , Zhang Guojie , Abouheif Ehab
Published: December 2020

Ants are one of the most ecologically and evolutionarily successful groups of animals and exhibit a remarkable degree of phenotypic diversity. This success is largely attributed to the fact that all ants are eusocial and live in colonies with a reproductive division of labor between morphologically distinct queen and worker castes. Yet, despite over a century of studies on caste determination and evolution in ants, we lack a complete ontogenetic series from egg to adult for any ant species. We therefore present a developmental table for the Pharaoh antMonomorium pharaonis, a species whose colonies simultaneously produce both reproductive queens and completely sterile workers. In total,M.pharaonisembryonic, larval, and pupal development lasts 45 days. During embryogenesis, the majority of developmental events are conserved betweenM.pharaonisand the fruit flyDrosophila melanogaster. However, we discovered two types of same-stage embryos prior to gastrulation: (1) embryos with internalized germ cells; and (2) embryos with germ cells outside of the blastoderm at the posterior pole. Moreover, we found two-types of embryos following germ band extension: (1) fertile embryos with primordial germ cells; and (2) sterile embryos with no germ cells. Together, our data shows that the queen (fertile) and worker (sterile) phenotypes are already determined and differentiated by early embryogenesis. During larval development, previous studies and our data find 3 larval instars reproductives and workers. However, there is considerable variation within each caste-specific instar, making it difficult to lineate instar boundaries. Here, we propose that developmental and anatomical markers can segregate larvae into gyne (unmatted queen), male and worker castes, including during the 1stlarval instar. Overall, we hope that the ontogenetic series we present here will serve as a blueprint for the generation of future ant developmental tables.
Phylogenetic and population structure analyses uncover pervasive misclassification and help assessing the biosafety of Pseudomonas alloputida for biotechnological applications
Authors: Passarelli-Araujo Hemanoel , Jacobs Sarah H. , Franco Glória R. , Venancio Thiago M.
Published: December 2020

The Pseudomonas putida group comprises strains with biotechnological and clinical relevance. P. alloputida was proposed as a new species and highlighted the misclassification of P. putida. Nevertheless, the population structure of P. alloputida remained unexplored. We retrieved 11,025 Pseudomonas genomes and used P. alloputida Kh7T to delineate the species. The P. alloputida population structure comprises at least 7 clonal complexes (CCs). Clinical isolates are mainly found in CC4 and acquired resistance genes are present at low frequency in plasmids. Virulence profiles support the potential of CC7 members to outcompete other plant or human pathogens through a type VI secretion system. Finally, we found that horizontal gene transfer had an important role in shaping the ability of P. alloputida to bioremediate aromatic compounds such as toluene. Our results provide the grounds to understand P. alloputida genetic diversity and safety for environmental applications.
KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism
Authors: Ruberto Anthony A. , Gréchez-Cassiau Aline , Guérin Sophie , Martin Luc , Revel Johana S. , Mehiri Mohamed , Subramaniam Malayannan , Delaunay Franck , Teboul Michèle
Published: December 2020

The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Krüppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver. Here, we show that the loss of the clock-controlled KLF10 in hepatocytes results in extensive reprogramming of the mouse liver circadian transcriptome, which in turn, alters the temporal coordination of pathways associated with energy metabolism. We also show that glucose and fructose induceKlf10,which helps mitigate glucose intolerance and hepatic steatosis in mice challenged with a sugar beverage. Functional genomics further reveal that KLF10 target genes are primarily involved in central carbon metabolism. Together, these findings show that in the liver, KLF10 integrates circadian timing and sugar metabolism related signaling, and serves as a transcriptional brake that protects against the deleterious effects of increased sugar consumption.
Transforming representations of movement from body- to world-centric space
Authors: Lu Jenny , Westeinde Elena A. , Hamburg Lydia , Dawson Paul M. , Lyu Cheng , Maimon Gaby , Druckmann Shaul , Wilson Rachel I.
Published: December 2020

When an animal moves through the world, its brain receives a stream of information about the body’s translational movement. These incoming movement signals, relayed from sensory organs or as copies of motor commands, are referenced relative to the body. Ultimately, such body-centric movement signals must be transformed into world-centric coordinates for navigation1. Here we show that this computation occurs in the fan-shaped body in theDrosophilabrain. We identify two cell types in the fan-shaped body, PFNd and PFNv2,3, that conjunctively encode translational velocity signals and heading signals in walking flies. Specifically, PFNd and PFNv neurons form a Cartesian representation of body-centric translational velocity – acquired from premotor brain regions4,5– that is layered onto a world-centric heading representation inherited from upstream compass neurons6–8. Then, we demonstrate that the next network layer, comprising hΔB neurons, is wired so as to transform the representation of translational velocity from body-centric to world-centric coordinates. We show that this transformation is predicted by a computational model derived directly from electron microscopy connectomic data9. The model illustrates the key role of a specific network motif, whereby the PFN neurons that synapse onto the same hΔB neuron have heading-tuning differences that offset the differences in their preferred body-centric directions of movement. By integrating a world-centric representation of travel velocity over time, it should be possible for the brain to form a working memory of the path traveled through the environment10–12.
GPCR-mediated Activation of PLCγ2 Initiates Dysregulated Recruitment of Neutrophils in Cold-induced Urticaria in PLAID Patients
Authors: Xu Xuehua , Wen Xi , Bhimani Smit , Moosa Amer , Parsons Dustin , Jin Tian
Published: December 2020

The current dogma is that chemoattractants G protein coupled receptors (GPCRs) activate β phospholipase C (PLCβ) while receptor tyrosine kinases (RTKs) activate γ phospholipase C (PLCγ). Here, we show that chemoattractant/GPCR-mediated membrane recruitment of PLCγ2 constitutes GPCR-mediated phospholipase C (PLC) signaling and is essential for neutrophil polarization and migration during GPCR-mediated chemotaxis. In response to a chemoattractant stimulation, cells lacking PLCγ2 (plcg2kd) displayed altered dynamics of diacylglycerol (DAG) production and calcium response; increased Ras/PI3K/Akt activation; elevated GSK3 phosphorylation and cofilin activation; impaired dynamics of actin polymerization; and consequently defects in cell polarization and migration during chemotaxis. At low temperature, neutrophils expressing the gain-of-function mutant of PLCγ2 (Δ686) displayed better chemotaxis than the cells expressing wild-type PLCγ2. The study provides a molecular mechanism for the dysregulated recruitment and activation of neutrophils in cold-induced urticaria in PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) patients bearing gain-of-function mutations of PLCγ2.
Sesbanimide R, a novel cytotoxic polyketide produced by magnetotactic bacteria
Authors: Awal Ram Prasad , Haack Patrick A. , Bader Chantal D. , Riese Cornelius N. , Schüler Dirk , Müller Rolf
Published: December 2020

Genomic information from various magnetotactic bacteria suggested that besides their common ability to form magnetosomes they potentially also represent a source of bioactive natural products. By using targeted deletion and transcriptional activation, we connected a large biosynthetic gene cluster (BGC) of thetrans-AT PKS type to the biosynthesis of a novel polyketide in the alphaproteobacteriumMagnetospirillum gryphiswaldense.Structure elucidation by mass spectrometry and NMR revealed that this secondary metabolite resembles sesbanimides which were very recently reported from other taxa. However, sesbanimide R exhibits an additional arginine moiety the presence of which reconciles inconsistencies in the previously proposed sesbanimide biosynthesis pathway when comparing the chemical structure and the potential biochemistry encoded in the BGC. In contrast to sesbanimides D, E and F, we were able to assign the stereocenter of the arginine moiety experimentally and two of the remaining three stereocenters by predictive biosynthetic tools. Sesbanimide R displayed strong cytotoxic activity against several carcinoma cell lines.

Importance

The finding of this study contributes a new secondary metabolite member to the glutarimide-containing polyketides. The determined structure of sesbanimide R correlates with its cytotoxic bioactivity characteristic for members of this family. Sesbanimide R represents the first natural product isolated from magnetotactic bacteria and identifies this highly diverse group as a so far untapped source for the future discovery of novel secondary metabolites.
Dynamic evolution of the MutS family in animals: multiple losses of MSH paralogues and gain of a viral MutS homologue in octocorals
Authors: Muthye Viraj , Lavrov Dennis V.
Published: December 2020

MutS is a key component of the Mismatch Repair (MMR) pathway. Members of the MutS family of proteins are present in bacteria, archaea, eukaryotes, and viruses. Six MutS homologues (MSH1-6), have been identified in yeast, three of which function in nuclear MMR, while MSH1 has been associated with mitochondrial DNA repair. MSH1 is believed to be lacking in animals, potentially reflecting the loss of MMR in animal mitochondria, and correlated with higher rates of mitochondrial sequence evolution. An intriguing exception has been found in octocorals, a group of marine animals from phylum Cnidaria, which encode a MutS-homologue (mtMutS) in their mitochondrial genome. It has been suggested that this protein functions in mitochondrial DNA repair, which would explain some of the lowest rates of mitochondrial sequence evolution observed in this group. To place the acquisition of mtMutS in a functional context, we investigated the evolution of the whole MutS family in animals. Our study confirmed the acquisition of octocoral mtMutS by horizontal gene transfer from a giant virus. Surprisingly, we found orthologues of yeast MSH1 in all hexacorals (the sister group of octocorals) and several sponges and placozoans. By contrast, MSH1 orthologues were lacking in octocorals, medusozoan cnidarians, ctenophores, and bilaterian animals. Furthermore, while we were able to identify MSH2 and MSH6 in all animals, MSH4, MSH5, and, especially, MSH3 were missing in multiple species. Overall, our analysis reveals a dynamic evolution of MSH family in animals, with multiple losses of MSH1, MSH3, some losses of MSH4 and MSH5, and a gain of octocoral mtMutS.
Structure of the antidiuretic hormone vasopressin receptor signalling complex
Authors: Bous Julien , Orcel Hélène , Floquet Nicolas , Leyrat Cédric , Lai-Kee-Him Joséphine , Gaibelet Gérald , Ancelin Aurélie , Saint-Paul Julie , Trapani Stefano , Louet Maxime , Sounier Rémy , Déméné Hélène , Granier Sébastien , Bron Patrick , Mouillac Bernard
Published: December 2020

Arginine-vasopressin (AVP) is a neurohypophysial peptide known as the antidiuretic hormone. It forms an active signalling complex with the V2 receptor (V2R) and the Gs protein, promoting a cAMP/PKA-dependent aquaporin insertion in apical membranes of principal cells of the renal collecting ducts and ultimately, water reabsorption. Molecular mechanisms underlying activation of this critical G protein-coupled receptor (GPCR) signalling system are still unknown. To fill this gap of knowledge, we report here the structure of the AVP-V2R-Gs complex using cryo-electron microscopy (cryo-EM). Single-particle analysis revealed the presence of three different states. The two best maps were combined with computational and NMR spectroscopy constraints to reconstruct two structures of the ternary complex. These structures differ in AVP and Gs binding modes and could thus represent distinct complex conformations along the signalling activation pathway. Importantly, as compared to those of other class A GPCR-Gs complexes, the structures revealed an original receptor-Gs interface in which the Gsα subunit penetrates deeper into the active V2R, notably forming an ionic bond between its free C-terminal carboxylic function and the side chain of R137 in the V2R. Interestingly, the structures help to explain how V2R R137H or R137L/C variants can lead to two severe genetic diseases with opposite clinical outcomes, cNDI or NSIAD respectively. Our study thus provides important structural insights into the function of this clinically relevant GPCR signalling complex.
Temporal stimulus segmentation by reinforcement learning in populations of spiking neurons
Authors: Donne Luisa Le , Urbanczik Robert , Senn Walter , Camera Giancarlo La
Published: December 2020

Abstract

Learning to detect, identify or select stimuli is an essential requirement of many behavioral tasks. In real life situations, relevant and non-relevant stimuli are often embedded in a continuous sensory stream, presumably represented by different segments of neural activity. Here, we introduce a neural circuit model that can learn to identify action-relevant stimuli embedded in a spatio-temporal stream of spike trains, while learning to ignore stimuli that are not behaviorally relevant. The model uses a biologically plausible plasticity rule and learns from the reinforcement of correct decisions taken at the right time. Learning is fully online; it is successful for a wide spectrum of stimulus-encoding strategies; it scales well with population size; and can segment cortical spike patterns recorded from behaving animals. Altogether, these results provide a biologically plausible theory of reinforcement learning in the absence of prior information on the relevance and timing of input stimuli.
AINTEGUMENTA and AINTEGUMENTA-LIKE6 directly regulate floral homeotic and growth genes in young flowers
Authors: Krizek Beth A. , Bantle Alexis T. , Heflin Jorman M. , Han Han , Freese Nowlan H. , Loraine Ann E.
Published: December 2020

Arabidopsis flower primordia give rise to floral organ primordia in stereotypical positions within four concentric whorls. Floral organ primordia in each whorl undergo distinct developmental programs to become one of four organ types (sepals, petals, stamens, and carpels). The Arabidopsis transcription factors AINTEGUMENTA (ANT) and AINTEGUMENTA-LIKE6 (AIL6) play critical and partially overlapping roles during floral organogenesis. They are required for correct positioning of floral organ initiation, contribute to the specification of floral organ identity, and regulate the growth and morphogenesis of developing floral organs. To gain insight into the molecular means by which ANT and AIL6 contribute to floral organogenesis, we identified the genome-wide binding sites of both ANT and AIL6 in stage 3 flower primordia, the developmental stage at which sepal primordia become visible and class B and C floral homeotic genes are first expressed. AIL6 binds to a subset of ANT sites, suggesting that AIL6 regulates some but not all of the same target genes as ANT. ANT and AIL6 binding sites are associated with genes involved in many biological processes related to meristem and flower organ development. Comparison of genes associated with both ANT and AIL6 ChIP-Seq peaks and those differentially expressed after perturbation of ANT or AIL6 activity identified likely direct targets of ANT and AIL6 regulation. These include the floral homeotic genesAPETALA3(AP3) andAGAMOUS(AG) and four growth regulatory genes:BIG BROTHER(BB),ROTUNDIFOLIA3(ROT3),ANGUSTIFOLIA3/GRF INTERACTING FACTOR(AN3/GIF1), andXYLOGLUCAN ENDOTRANSGLUCOLSYLASE/HYDROLASE9(XTH9).

One Sentence Summary

The transcription factors ANT and AIL6 directly regulate genes involved in different aspects of flower development including genes that specify floral organ identity and those that regulate growth.
SLIDR and SLOPPR: Flexible identification of spliced leadertrans-splicing and prediction of eukaryotic operons from RNA-Seq data
Authors: Wenzel Marius A. , Müller Berndt , Pettitt Jonathan
Published: December 2020

Background

Spliced leader (SL)trans-splicing replaces the 5’ end of pre-mRNAs with the spliced leader, an exon derived from a specialised non-coding RNA originating from elsewhere in the genome. This process is essential for resolving polycistronic pre-mRNAs produced by eukaryotic operons into monocistronic transcripts. SLtrans-splicing and operons may have independently evolved multiple times throughout Eukarya, yet our understanding of these phenomena is limited to only a few well-characterised organisms, most notablyC. elegansand trypanosomes. The primary barrier to systematic discovery and characterisation of SLtrans-splicing and operons is the lack of computational tools for exploiting the surge of transcriptomic and genomic resources for a wide range of eukaryotes.

Results

Here we present two novel pipelines that automate the discovery of SLs and the prediction of operons in eukaryotic genomes from RNA-Seq data. SLIDR assembles putative SLs from 5’ read tails present after read alignment to a reference genome or transcriptome, which are then verified by interrogating corresponding SL RNA genes for sequence motifs expected inbona fideSL RNA molecules. SLOPPR identifies RNA-Seq reads that contain a given 5’ SL sequence, quantifies genomewide SLtrans-splicing events and predicts operons via distinct patterns of SLtrans-splicing events across adjacent genes. We tested both pipelines with organisms known to carry out SLtrans-splicing and organise their genes into operons, and demonstrate that 1) SLIDR correctly detects expected SLs and often discovers novel SL variants; 2) SLOPPR correctly identifies functionally specialised SLs, correctly predicts known operons and detects plausible novel operons.

Conclusions

SLIDR and SLOPPR are flexible tools that will accelerate research into the evolutionary dynamics of SLtrans-splicing and operons throughout Eukarya and improve gene discovery and annotation for a wide-range of eukaryotic genomes. Both pipelines are implemented in Bash and R and are built upon readily available software commonly installed on most bioinformatics servers. Biological insight can be gleaned even from sparse, low-coverage datasets, implying that an untapped wealth of information can be derived from existing RNA-Seq datasets as well as from novel full-isoform sequencing protocols as they become more widely available.
feamiR: Feature selection based on Genetic Algorithms for predicting miRNA-mRNA interactions
Authors: Williams Eleanor C. , Calinescu Anisoara , Mohorianu Irina
Published: December 2020

microRNAs play a key role in RNA interference, the sequence-driven targeting of mRNAs that regulates their translation to proteins, through translation inhibition or the degradation of the mRNA. Around ~ 30% of animal genes may be tuned by microRNAs. The prediction of miRNA/mRNA interactions is hindered by the short length of the interaction (seed) region (~7- 8nt). We collate several large datasets overviewing validated interactions and proposefeamiR, a novel pipeline comprising optimised classification approaches (Decision Trees/Random Forests and an efficient feature selection based on embryonic Genetic Algorithms used in conjunction with Support Vector Machines) aimed at identifying discriminative nucleotide features, on the seed, compensatory and flanking regions, that increase the prediction accuracy for interactions. Common and specific combinations of features illustrate differences between reference organisms, validation techniques or tissue/cell localisation.feamiR revealed new key positions that drive the miRNA/mRNA interactions, leading to novel questions on the mode-of-action of miRNAs.
Modeling molecular development of breast cancer in canine mammary tumors
Authors: Graim Kiley , Gorenshteyn Dmitriy , Robinson David G. , Carriero Nicholas J. , Cahill James A. , Chakrabarti Rumela , Goldschmidt Michael H. , Durham Amy C. , Funk Julien , Storey John D. , Kristensen Vessela N. , Theesfeld Chandra L. , Sorenmo Karin U. , Troyanskaya Olga G.
Published: December 2020

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue and benign and malignant tumors from each patient. We showed human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We showed that multiple histological samples per patient is necessary to effectively capture these progression-related signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework.
Methodological Insights Experiencing and knowing in the field: an autoethnographic account of conducting audit fieldwork in China
Authors: Zou Yanru
Published: December 2020

Purpose

This paper provides a researcher's account of fieldwork experience in conducting audit research in China. By illustrating on-site fieldwork encounters, the paper reflects stages of access negotiation and management in the fieldwork, reveals the researcher's embodied “affects” in the fieldwork and reasserts the value of researcher's openness and attention in the fieldwork.

Design/methodology/approach

This paper uses autoethnography as its overall epistemology. Fieldwork diaries and vignettes are written in the first-person voice to present the researcher's embodied account of fieldwork experience, researcher’s learning and coping skills in managing the fieldwork.

Findings

The research findings are not detached from the researcher's experience of the fieldwork. The fieldwork experiences in this study highlight that the fieldwork access is an ongoing process. Different stages of access negotiations, from rejection to acceptance, reveal the tensions between researcher and participants. This study draws attention to the online platform, WeChat, in connecting with auditors to learn from them and suggests openness to the fieldwork encounters and a resilient engagement with auditors.

Originality/value

In reflecting on the researcher's transformation during the fieldwork, this paper argues for a relational and engaged way of conducting fieldwork, rather than a disengaged and judgemental approach in studying auditors' working lives. The paper pays attention to fieldwork as a process and how the knowledge learned in the field is infused with researcher's fieldwork experiences.
A framework for procurement process re-engineering in Industry 4.0
Authors: Tripathi Shubham , Gupta Manish
Published: December 2020

Purpose

Procurement is a crucial part of supply chain management, consistently becoming a strategic vantage point in global competition. The industry 4.0 paradigm is transforming supply chains to smarter systems, giving rise to the concept of procurement 4.0. A systematic framework to transform in current scenario is crucial.

Design/methodology/approach

This study brings together these current researches to propose a redesigned procurement process by combining several technologies. A BPR approach is taken to present the new process and its merits are discussed.

Findings

A re-designed procurement framework is proposed. Radical improvements of cost, cycle time, human effort, degree of automation, traceability, information availability and uncertainty are achievable with the proposed framework.

Practical implications

The proposed re-engineered process addresses the visualization barrier for managers. The proposed framework is grounded on BPR which provides a generic ground for developing redesign exercise along with the visualization of new process.

Originality/value

There is literature discussing implementation, impact and advantages of individual and combination of technologies on procurement process but lacks visualization of the transformed process combining these technologies.
Board diversity: female director participation and corporate innovation
Authors: Vafaei Alireza , Henry Darren , Ahmed Kamran , Alipour Mohammad
Published: December 2020

Purpose

This study aims to examine the impact of board female participation on Australian firms’ innovation.

Design/methodology/approach

Data are from the 500 largest Australian Securities Exchange (ASX)-listed companies for 2004–2015. Measures of innovation concern input (research and development expenditure and intangible assets) and output (patents registered) indicators.

Findings

A positive and significant association exists between female director participation and firm innovation activity. This association exists across industry classifications independent of technological importance and is particularly driven by materials and health-care sectors. Findings support calls for more board diversity in line with board female membership positively influencing innovative investment and development activities.

Practical implications

The economic efficacy of the latest revisions to the ASX Corporate Governance Council principles and recommendations (“ASX CGC revisions”) is supported. Diverse boards are a strong source of innovation. Regulators and corporations can use the findings to establish principles and practices that promote female board diversity.

Originality/value

This study is the first to examine the link between board diversity and corporate innovation in Australia where there is under-representation of women on corporate boards and in key management positions. Also lacking are formal legislative or governance policy mandates on board gender diversity. Beyond confirming a positive association between board diversity and levels of corporate innovation, this paper provides new findings that this relationship is driven by women who are non-executive (independent) directors, independent of the underlying technology intensity of firms and moderated by the nature of firm-level profitability and growth opportunities.