bluuebunny/crossref_metadata_2025_split huggingface dataset:
First and Second Wave Dynamics of Emergency Department Utilization during the COVID-19 Pandemic: a retrospective study
Authors: Dijk Robi , Plaum Patricia , Tummers Stan , van Osch Frits H.M. , Barten Dennis G. , Latten Gideon H.P. 
Published: December 2021

ABSTRACTBackgroundSince the COVID-19 pandemic, there has been a decrease in emergency department(ED) utilization. Although this has been thoroughly characterized for the first wave(FW), studies during the second wave(SW) are limited. We examined the changes in ED utilization between the FW and SW, compared to 2019 reference periods.MethodsWe performed a retrospective analysis of ED utilization in 3 Dutch hospitals in 2020. The FW and SW (March-June and September–December, respectively) were compared to the reference periods in 2019. ED visits were labeled as (non-)COVID-suspected.FindingsDuring the FW and SW ED visits decreased by 20.3% and 15.3%, respectively, when compared to reference periods in 2019. During both waves high urgency visits significantly increased with 3.1% and 2.1%, and admission rates (ARs) increased with 5.0% and 10.4%. Trauma related visits decreased by 5.2% and 3.4%. During the SW we observed less COVID-related visits compared to the FW (4,407 vs 3,102 patients). COVID-related visits were significantly more often in higher need of urgent care and ARs where at least 24.0% higher compared to non-COVID visits.InterpretationDuring both COVID-19 waves ED visits were significantly reduced, with the most distinct decline during the FW. ED patients were more often triaged as high urgent and the ARs were increased compared to the reference period in 2019, reflecting a high burden on ED resources. These findings indicate the need to gain more insight into motives of patients to delay or avoid emergency care during pandemics and prepare EDs for future pandemics.FundingNone
A co-opted endogenous retroviral envelope promotes cell survival by controlling SLC31A1/CTR1-mediated copper transport and homeostasis
Authors: Tury Sandrine , Chauveau Lise , Courgnaud Valérie , Battini Jean-Luc 
Published: December 2021

AbstractCopper is a critical element for eukaryotic life, involved in numerous cellular functions and in redox balance but it can be toxic in excess. Therefore, tight regulation of copper acquisition and homeostasis is essential for cell physiology and survival. Here, we identified a unique mechanism for cell survival involving the regulation of copper homeostasis by an endogenous retroviral (ERV) envelope glycoprotein called Refrex1. We show that extracellular copper sensing by cells increases Refrex1 expression, which in turn regulates copper acquisition through interaction with the main copper transporter SLC31A1/CTR1. Downmodulation of Refrex1 resulted in intracellular copper accumulation leading to ROS production and subsequent apoptosis, which could be reverted by copper chelator treatment. Our results demonstrate that Refrex1 has been co-opted for its ability to regulate copper entry through CTR1 interaction in order to limit copper excess for a proper redox balance, and suggests that other ERV may have similar metabolic functions among vertebrates.
Accurate measurement of microsatellite length by disrupting its tandem repeat structure
Authors: Levy Dan , Wang Zihua , Moffitt Andrea B. , Wigler Michael 
Published: December 2021

ABSTRACTReplication of tandem repeats of simple sequence motifs, also known as microsatellites, is error prone and variable lengths frequently occur during population expansions. Therefore, microsatellite length variations could serve as markers for cancer. However, accurate error-free quantitation of microsatellite lengths is difficult with current methods because of a high error rate during amplification and sequencing. We have solved this problem by using partial mutagenesis to disrupt enough of the repeat structure so that it can replicate faithfully, yet not so much that the flanking regions cannot be reliably identified. In this work we use bisulfite mutagenesis to convert a C to a U, later read as T. Compared to untreated templates, we achieve three orders of magnitude reduction in the error rate per round of replication. By requiring two independent first copies of an initial template, we reach error rates below one in a million. We discuss potential clinical applications of this method.
Plasticity across levels: relating epigenomic, transcriptomic, and phenotypic responses to osmotic stress in a halotolerant microalga
Authors: Leung Christelle , Grulois Daphné , Chevin Luis-Miguel 
Published: December 2021

AbstractPhenotypic plasticity, the ability of a given genotype to produce alternative phenotypes in response to its environment of development, is an important mechanism for coping with variable environments. While the mechanisms underlying phenotypic plasticity are diverse, their relative contributions need to be investigated quantitatively to better understand the evolvability of plasticity across biological levels. This requires relating plastic responses of the epigenome, transcriptome, and organismal phenotype, and how they vary with the genotype. Here we carried out this approach for responses to osmotic stress in Dunaliella salina, a green microalga that is a model organism for salinity tolerance. We compared two strains that show markedly different demographic responses to osmotic stress, and showed that these phenotypic responses involve strain- and environment-specific variation in gene expression levels, but a relative low - but significant - effect of strain × environment interaction. We also found an important genotype effect on the genome-wide methylation pattern, but little contribution from environmental conditions to the latter. However, we did detect a significant marginal effect of epigenetic variation on gene expression, beyond the influence of genetic differences on epigenetic state, and we showed that hypomethylated regions are correlated with higher gene expression. Our results indicate that epigenetic mechanisms are either not involved in the rapid plastic response to environmental change in this species, or involve only few changes in trans that are sufficient to trigger concerted changes in the expression of many genes, and phenotypic responses by multiple traits.
Integration of visual motion and pursuit signals in areas V3A and V6+ across cortical depth using 9.4T fMRI
Authors: Molaei-Vaneghi Fatemeh , Zaretskaya Natalia , van Mourik Tim , Bause Jonas , Scheffler Klaus , Bartels Andreas 
Published: December 2021

ABSTRACTNeural mechanisms underlying a stable perception of the world during pursuit eye movements are not fully understood. Both, perceptual stability as well as perception of real (i.e. objective) motion are the product of integration between motion signals on the retina and efference copies of eye movements. Human areas V3A and V6 have previously been shown to have strong objective (‘real’) motion responses. Here we used high-resolution laminar fMRI at ultra-high magnetic field (9.4T) in human subjects to examine motion integration across cortical depths in these areas. We found an increased preference for objective motion in areas V3A and V6+ i.e. V6 and possibly V6A towards the upper layers. When laminar responses were detrended to remove the upper-layer bias present in all responses, we found a unique, condition-specific laminar profile in V6+, showing reduced mid-layer responses for retinal motion only. The results provide evidence for differential, motion-type dependent laminar processing in area V6+. Mechanistically, the mid-layer dip suggests a special contribution of retinal motion to integration, either in the form of a subtractive (inhibitory) mid-layer input, or in the form of feedback into extragranular or infragranular layers. The results show that differential laminar signals can be measured in high-level motion areas in the human occipitoparietal cortex, opening the prospect of new mechanistic insights using non-invasive brain imaging.Significance StatementVisual stability and our ability to differentiate between self-induced and real motion are central to our visual sense. Both require the integration of two signals – retinal motion and copies of muscle commands used for eye movements (efference copies). A reasonable assumption is that either the efference copy or the result of integration will be conveyed to high-level visual regions along with visual retinal input, possibly differentially across cortical depth as the input sources differ. Our ultra-high field recordings present the first laminar evidence of differential signal processing of retinal and objective motion signals in area V6+, and present a first window into a mechanistic understanding of visual high-level motion processing.
SARS-CoV-2 Omicron Spike Glycoprotein Receptor Binding Domain Exhibits Super-Binder Ability with ACE2 but not Convalescent Monoclonal Antibody
Authors: Omotuyi I. O. , Olubiyi O. , Nash O. , Afolabi E.O. , Oyinloye B.E. , Fatumo S. , Femi-Oyewo M. N. , Bogoro S.E. 
Published: December 2021

AbstractBackgroundSARS-CoV-2, the causative virus for COVID-19 has now super-mutated into the Omicron (Om) variant. On its spike glycoprotein alone, more than 30 substitutions have been characterized with 15 within the receptor binding domain (RBD); It therefore calls to question the transmissibility and antibody escapability of Omicron. This study was setup to investigate the Omicron RBD’s interaction with ACE2 (host receptor) and a SARS-CoV-2 neutralizing monoclonal antibody (mAb).MethodsIn-silico mutagenesis was used to generate the Om-RBD in complex with ACE2 or mAb from the wildtype. All-atom molecular dynamics (MD) simulation trajectories were analyzed for interaction.ResultsMD trajectories showed that Omicron RBD has evolved into an efficient ACE2 binder, via pi-pi (Om-RBD-Y501/ACE2-Y41) and salt-bridge (Om-RBD-K493/ACE2-Y41) interactions. Conversely, in binding mAb, it has become less efficient (Center of mass distance of RBD from mAb complex, wildtype ≈ 30 Å, Omicron ≈ 41 Å). Disruption of Om-RBD/mAb complex resulted from loose interaction between Om-RBD and the light chain complementarity-determining region residues.ConclusionsOmicron is expected to be better transmissible and less efficiently interacting with neutralizing convalescent mAbs.General significanceOur results elucidate the mechanisms for higher transmissibility in Omicron variant.
Transcriptional response in a sepsis mouse model reflects transcriptional response in sepsis patients
Authors: Rosier Florian , Nuñez Nicolas Fernandez , Torres Magali , Loriod Béatrice , Rihet Pascal , Pradel Lydie C. 
Published: December 2021

AbstractMortality due to sepsis remains unacceptably high, especially for septic shock patients. Murine models have been used to better understand pathophysiology mechanisms. However, the mouse model is still under debate. Here we investigated the transcriptional response of mice injected with lipopolysaccharide (LPS) and compared it to either human cells stimulated in vitro with LPS or to blood cells of septic patients. We identified a molecular signature composed of 2331 genes with an FDR median of 0%. This molecular signature is highly enriched in regulated genes in peritoneal macrophages stimulated with LPS. There is a significant enrichment in several inflammatory signaling pathways, and in disease terms, such as pneumonia, sepsis, systemic inflammatory response syndrome, severe sepsis, an inflammatory disorder, immune suppression, and septic shock. A significant overlap between the genes up-regulated in mouse and human cells stimulated with LPS has been demonstrated. Finally, genes up-regulated in mouse cells stimulated with LPS are enriched in genes up-regulated in human cells stimulated in vitro and in septic patients, who are at high risk of death. Our results support the hypothesis of common molecular and cellular mechanisms between mouse and human sepsis.
Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma
Authors: Peña-Pérez Lucía , Frengen Nicolai , Hauenstein Julia , Gran Charlotte , Gustafsson Charlotte , Eisfeldt Jesper , Kierczak Marcin , Taborsak-Lines Fanny , Olsen Remi-André , Wallblom Ann , Krstic Aleksandra , Ewels Philip , Lindstrand Anna , Månsson Robert 
Published: December 2021

ABSTRACTMultiple myeloma (MM) is an incurable and aggressive plasma cell malignancy characterized by a complex karyotype with multiple structural variants (SVs) and copy number variations (CNVs). Linked-read whole-genome sequencing (lrWGS) allows for refined detection and reconstruction of SVs by providing long-range genetic information from standard short-read sequencing. This makes lrWGS an attractive solution for capturing the full genomic complexity of MM. Here we show that high-quality lrWGS data can be generated from low numbers of FACS sorted cells without DNA purification. Using this protocol, we analyzed FACS sorted MM cells from 37 MM patients with lrWGS. We found high concordance between lrWGS and FISH for the detection of recurrent translocations and CNVs. Outside of the regions investigated by FISH, we identified >150 additional SVs and CNVs across the cohort. Analysis of the lrWGS data allowed for resolving the structure of diverse SVs affecting the MYC and t(11;14) loci causing the duplication of genes and gene regulatory elements. In addition, we identified private SVs causing the dysregulation of genes recurrently involved in translocations with the IGH locus and show that these can alter the molecular classification of the MM. Overall, we conclude that lrWGS allows for the detection of aberrations critical for MM prognostics and provides a feasible route for providing comprehensive genetics. Implementing lrWGS could provide more accurate clinical prognostics, facilitate genomic medicine initiatives, and greatly improve the stratification of patients included in clinical trials.KEY POINTS- Linked-read WGS can be performed without DNA purification and allows for resolving the diverse structural variants found in multiple myeloma.- Linked-read WGS can, as a stand-alone assay, provide comprehensive genetics in myeloma and other diseases with complex genomes.
Neurexins in serotonergic neurons regulate serotonin transmission and complex mouse behaviors
Authors: Cheung Amy , Konno Kohtarou , Kawasawa Yuka Imamura , Matsui Aya , Abe Manabu , Sakimura Kenji , Sasaoka Toshikuni , Uemura Takeshi , Watanabe Masahiko , Futai Kensuke 
Published: December 2021

AbstractExtensive serotonin (5-HT) innervation throughout the brain corroborates 5-HT’s modulatory role in numerous cognitive activities. Volume transmission is the major mode for 5-HT transmission but mechanisms underlying 5-HT signaling are still largely unknown. Abnormal brain 5-HT levels and function have been implicated in autism spectrum disorder (ASD). Neurexin (Nrxn) genes encode presynaptic cell adhesion molecules important for the regulation of synaptic neurotransmitter release, notably glutamatergic and GABAergic transmission. Mutations in Nrxn genes are associated with neurodevelopmental disorders including ASD. However, the role of Nrxn genes in the 5-HT system is poorly understood. Here, we generated a mouse model with all three Nrxn genes disrupted specifically in 5-HT neurons to study how Nrxns affect 5-HT transmission. Loss of Nrxns in5-HT neurons reduced the number of serotonin neurons in the early postnatal stage, impaired 5-HT release, anddecreased 5-HT release sitesand serotonin transporter expression. Furthermore, 5-HT neuron-specific Nrxn knockout reduced sociability and increased depressive-like behavior. Our results highlight functional roles for Nrxns in 5-HT neurotransmission,5-HT neuron survival, and the execution of complex behaviors.
Iron treatment induces defense responses and disease resistance against Magnaporthe oryzae in rice
Authors: Sánchez-Sanuy Ferran , Cuadra Roberto Mateluna , Okada Kazunori , Sacchi Gian Attilio , Campo Sonia , Segundo Blanca San 
Published: December 2021

ABSTRACTBackgroundIron is an essential micronutrient required for plant growth and development. The impact of iron in plant-pathogen interactions is also well recognized. However, the molecular basis underlying the effect of plant iron status and immune function in plants is poorly understood. Here, we investigated the impact of treatment with high iron in rice immunity at the cellular and molecular level.ResultsWe show that treatment with high iron confers resistance to infection by the blast fungus M. oryzae in rice. Histochemical staining of M. oryzae-infected leaves revealed that iron and Reactive Oxygen Species (ROS) accumulate at high levels in cells in the vicinity of the infection site. During pathogen infection, a stronger induction of defense-related genes occurs in leaves of iron-treated plants. Notably, a superinduction of phytoalexin biosynthetic genes, both diterpene phytoalexins and sakuranetin, is observed in iron-treated plants during pathogen infection. As a consequence, phytoalexin accumulation was higher in iron-treated plants compared with control plants. Transcriptional alterations of iron homeostasis-related genes and a reduction in apoplastic iron content were observed in leaves of Fe-treated rice plants.ConclusionsThese results illustrate that the iron status plays a key role in the response of rice plants to pathogen infection, while reinforcing the notion that iron signaling and defense signaling must operate in a coordinated manner in controlling disease resistance in plants. This information provides a basis to better understand the molecular mechanisms involved in rice immunity.
Drosulfakinin signaling modulates female sexual receptivity in Drosophila
Authors: Wang Tao , Jing Biyang , Deng Bowen , Shi Kai , Li Jing , Ma Baoxu , Wu Fengming , Zhou Chuan 
Published: December 2021

AbstractFemale sexual behavior as an innate behavior is of prominent biological importance for survival and reproduction. However, molecular and circuit mechanisms underlying female sexual behavior is not well understood. Here, we identify the Cholecystokinin-like peptide Drosulfakinin (DSK) promotes female sexual behavior in Drosophila. Manipulation both Dsk and DSK neuronal activity impact female sexual receptivity. In addition, we reveal that Dsk-expressing neurons receive input signal from R71G01GAL4 neurons to promote female sexual receptivity. Based on intersectional technique, we further found the regulation of female sexual behavior relies mainly on medial DSK neurons rather than lateral DSK neurons, and medial DSK neurons modulate female sexual behavior by acting on its receptor CCKLR-17D3. Thus, we characterized DSK/CCKLR-17D3 as R71G01GAL4 neurons downstream signaling to regulate female sexual behavior.
Phosphate-induced resistance to pathogen infection in Arabidopsis
Authors: Val-Torregrosa Beatriz , Bundó Mireia , Martín-Cardoso Héctor , Bach-Pages Marcel , Chiou Tzyy-Jen , Flors Victor , San Segundo Blanca 
Published: December 2021

SUMMARYIn nature, plants are concurrently exposed to a number of abiotic and biotic stresses. Our understanding of convergence points between responses to combined biotic/abiotic stress pathways remains, however, rudimentary. Here we show that MIR399 overexpression, loss-of-function of PHO2 (PHOSPHATE2), or treatment with high Pi, is accompanied by an increase in phosphate (Pi) content and accumulation of reactive oxygen species (ROS) in Arabidopsis thaliana. High Pi plants (e.g. miR399 overexpressor, pho2 mutant, and plants grown under high Pi supply) exhibited resistance to infection by necrotrophic and hemibiotrophic fungal pathogens. In the absence of pathogen infection, the expression level of genes in the salicylic acid (SA)- and jasmonic acid (JA)-dependent signaling pathways was higher in high Pi plants compared to wild type plants, which is consistent with increased levels of SA and JA in non-infected high Pi plants. During infection, an opposite regulation in the two branches of the JA pathway (ERF1/PDF1.2 and MYC2/VSP2) occurs in high Pi plants. Thus, while the ERF1-PDF1 branch positively responds to fungal infection, the MYC2/VSP2 branch is negatively regulated during pathogen infection in high Pi plants. This study supports that Pi accumulation promotes resistance to infection by fungal pathogens in Arabidopsis, while providing a basis to better understand crosstalk between Pi signaling and hormonal signalling pathways for modulation of plant immune responses.Significance statementThis study highlights the importance of phosphate (Pi) in regulating immune responses, hence, disease resistance in Arabidopsis thaliana. Increasing Pi content either by MIR399 overexpression (or loss-of-function of PHOSPHATE2), as well as by Pi treatment enhances resistance to infection by necrotrophic and hemibiotrophic fungal pathogens through modulation of SA- and JA-dependent signaling pathways. These results also support that miR399 functions as a regulator of Arabidopsis immunity.
Stereotyped Behavioral Maturation and Rhythmic Quiescence in C. elegans Embryos
Authors: Ardiel Evan L. , Xu Stephen , Nurrish Stephen , Lauziere Andrew , Harvey Brandon J. , Kaplan Joshua M. , Shroff Hari 
Published: December 2021

AbstractSystematic analysis of rich behavioral recordings is being used to uncover how circuits encode complex behaviors. Here we apply this approach to embryos. What are the first embryonic behaviors and how do they evolve as early neurodevelopment ensues? To address these questions, we present a systematic description of behavioral maturation for Caenorhabditis elegans embryos. Posture libraries were built using a genetically encoded motion capture suit imaged with light-sheet microscopy and annotated using custom tracking software. Analysis of cell trajectories, postures, and behavioral motifs revealed a stereotyped developmental progression. Early movement is dominated by flipping between dorsal and ventral coiling, which gradually slows into a period of reduced motility. Late-stage embryos exhibit sinusoidal waves of dorsoventral bends, prolonged bouts of directed motion, and a rhythmic pattern of pausing, which we designate slow wave twitch (SWT). Synaptic transmission is required for late-stage motion but not for early flipping nor the intervening inactive phase. A high-throughput behavioral assay and calcium imaging revealed that SWT is elicited by the rhythmic activity of a quiescence-promoting neuron (RIS). Similar periodic quiescent states are seen prenatally in diverse animals and may play an important role in promoting normal developmental outcomes.