bluuebunny/crossref_metadata_2025 huggingface dataset:
A Recurrent Neural Network and Differential Equation Based Spatiotemporal Infectious Disease Model with Application to COVID-19
Authors: Li Zhijian , Zheng Yunling , Xin Jack , Zhou Guofa
Published: July 2020

The outbreaks of Coronavirus Disease 2019 (COVID-19) have impacted the world significantly. Modeling the trend of infection and realtime forecasting of cases can help decision making and control of the disease spread. However, data-driven methods such as recurrent neural networks (RNN) can perform poorly due to limited daily samples in time. In this work, we develop an integrated spatiotemporal model based on the epidemic differential equations (SIR) and RNN. The former after simplification and discretization is a compact model of temporal infection trend of a region while the latter models the effect of nearest neighboring regions. The latter captures latent spatial information. We trained and tested our model on COVID-19 data in Italy, and show that it out-performs existing temporal models (fully connected NN, SIR, ARIMA) in 1-day, 3-day, and 1-week ahead forecasting especially in the regime of limited training data.
Lenticular nucleus volume predicts performance in real-time strategy game - cross-sectional and training approach using voxel-based morphometry
Authors: Kowalczyk N. , Skorko M. , Dobrowolski P. , Kossowski B. , Myśliwiec M. , Hryniewicz N. , Gaca M , Marchewka A. , Kossut M. , Brzezicka A.
Published: July 2020

It is unclear why some people learn faster than others. We performed two independent studies in which we investigated the neural basis of real-time strategy (RTS) gaming and neural predictors of RTS games skill-acquisition. In the first (cross-sectional) study we found that experts in the RTS game StarCraft II (SC2) had a larger lenticular nucleus volume than non-RTS players. We followed a cross validation procedure where we used the volume of regions identified in the first study to predict the quality of learning a new, complex skill (SC2) in a sample of individuals who were naïve to RTS games (second training study). Our findings provide new insights into how the volume of lenticular nucleus, which is associated with motor as well as cognitive functions, can be utilized to predict successful skill-learning, and be applied to a much broader context than just video games, e.g. contributing to optimizing cognitive training interventions.
INTS13Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly
Authors: Mascibroda Lauren G. , Shboul Mohammad , Elrod Nathan D. , Colleaux Laurence , Hamamy Hanan , Huang Kai-Lieh , Peart Natoya , Singh Moirangthem Kiran , Lee Hane , Merriman Barry , Jodoin Jeanne N. , Lee Laura A. , Fathalla Raja , Al-Rawashdeh Baeth , Ababneh Osama , El-Khateeb Mohammad , Escande-Beillard Nathalie , Nelson Stanley F. , Wu Yixuan , Tong Liang , Kenney Linda J. , Russell William K. , Amiel Jeanne , Reversade Bruno , Wagner Eric J.
Published: July 2020

Oral-facial-digital syndromes (OFD) are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. To date, mutations in 12 ciliary-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline mutations inINTS13, a subunit of the Integrator complex. This 14-component complex associates with RNAPII and can cleave nascent RNA to modulate gene expression. We determined that INTS13 utilizes a discrete domain within its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germlineINTS13mutations. Depletion ofINTS13disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown inXenopusembryos lead to motile cilia anomalies. Altogether, we show that mutations inINTS13cause an autosomal recessive ciliopathy, which reveals key interactions within Integrator components.
Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types
Authors: Saez-Atienzar Sara , Bandres-Ciga Sara , Langston Rebekah G. , Kim Jonggeol J. , Choi Shing Wan , Reynolds Regina H. ,   the International ALS Genomics Consortium; ITALSGEN, Abramzon Yevgeniya , Dewan Ramita , Ahmed Sarah , Landers John E. , Chia Ruth , Ryten Mina , Cookson Mark R. , Nalls Michael A. , Chiò Adriano , Traynor Bryan J.
Published: July 2020

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namelyneuron projection morphogenesis, membrane trafficking, andsignal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic cortical interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated five differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, PLXNB2, andSCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.
Activation of a neural stem cell transcriptional program in parenchymal astrocytes
Authors: Magnusson Jens P. , Zamboni Margherita , Santopolo Giuseppe , Mold Jeff E. , Barrientos-Somarribas Mauricio , Talavera-López Carlos , Andersson Björn , Frisén Jonas
Published: July 2020

Neural stem cells, located in discrete niches in the adult brain, generate new neurons throughout life. These stem cells are specialized astrocytes, but astrocytes in other brain regions do not generate neurons under physiological conditions. After stroke, however, striatal astrocytes undergo neurogenesis in mice, triggered by decreased Notch signaling. We used single-cell RNA sequencing to characterize neurogenesis by Notch-depleted striatal astrocytesin vivo. Striatal astrocytes were located upstream of neural stem cells in the neuronal lineage. As astrocytes initiated neurogenesis, they became transcriptionally very similar to subventricular zone stem cells and progressed through a nearly identical neurogenic program. Surprisingly, in the non- neurogenic cortex, Notch-depleted astrocytes also initiated neurogenesis. Yet, the cortical astrocytes, and many striatal ones, stalled before entering transit- amplifying divisions. Infusion of epidermal growth factor enabled stalled striatal astrocytes to resume neurogenesis. We conclude that parenchymal astrocytes are latent neural stem cells and that targeted interventions can guide them through their neuronal differentiation.
FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer
Authors: Zhang Yanchun , Xiong Xuexue , Zhu Qi , Zhang Jiali , Wang Yuetong , Cao Jian , Chen Li , Chen Shengmiao , Hou Linjun , Zhao Xi , Hao Piliang , Zhuang Min , Li Dake , Fan Gaofeng
Published: July 2020

Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time and space dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer. Knockdown of the kinase attenuates metastatic phenotypes in tumor cells. Here we employed mass spectrometry and biochemical approaches to identify IRS4 as a novel substrate of FER. Using a proximity-based tagging system, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85β, the regulatory subunit of PI-3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4, delayed tumor cell proliferation bothin vitroandin vivo. Overall, we revealed a kinase-substrate regulatory mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.
Comparative genomics of StAR-related lipid transfer (START) domains across wild and cultivated rice
Authors: Mahtha Sanjeet Kumar , Purama Ravi Kiran , Yadav Gitanjali
Published: July 2020

START proteins, encoded by a plant amplified family of evolutionary conserved genes, are known to bind lipids/sterols in mammals. In the plant kingdom, they have been reported in proteins involved in lipid binding, transport, signaling, as well as modulation of transcriptional activity, but there is very limited information on sub-functionalization or evolution of new function within the amplified gene family. Availability of ten fully annotated wild and cultivated rice varieties enables a comprehensive analysis of this family across the rice pangenome, across functional categories, as well as across START sub-families. The presence of START domains in all seven wild and three cultivated rice genomes suggests low dispensability and critical functional roles for this family, further supported by chromosomal mapping, duplication analysis and conservation of domain structure. Analysis of synteny highlights a preponderance of segmental and dispersed modes of duplication among STARTs, while transcriptomic investigation of the main cultivated varietyOryza sativa var. japonicareveals sub-functionalization among START genes family members in terms of preferential expression across various developmental stages and anatomical parts, especially flowering related parts. Importance of this family was further supported by Ka/Ks ratios confirming strong negative/purifying selection, implying that START family duplication is strongly constrained and evolutionarily stable.
Braconidae revisited:Bracon brevicornisgenome showcases the potential of linked-read sequencing in identifying a putativecomplementary sex determinergene
Authors: Ferguson K. B. , Pannebakker B. A. , Centurión A. , van den Heuvel J. , Nieuwenhuis R. , Becker F. F. M. , Schijlen E. , Thiel A. , Zwaan B. J. , Verhulst E. C.
Published: July 2020

Bracon brevicornisis an ectoparasitoid of a wide range of larval-stage Lepidopterans, including several pests of important crops, such as the corn borer,Ostrinia nubilalis. It is also one of the earliest documented cases of complementary sex determination in Hymenoptera. Here, we present the linked-read genome ofB. brevicornis, complete with anab initio-derived annotation and protein comparisons with fellow braconids,Fopius arisanusandDiachasma alloem. We demonstrate the potential of linked-read assemblies in exploring regions of heterozygosity and search for structural and homology-derived evidence of thecomplementary sex determinergene (csd).
Temporal dynamics of neural activity in macaque frontal cortex assessed with large-scale recordings
Authors: Decramer Thomas , Premereur Elsie , Caprara Irene , Theys Tom , Janssen Peter
Published: July 2020

We make eye movements to objects before grasping these objects, and the gaze direction generally indicates where the object will be grasped. Hence, the brain has to coordinate eye-, arm- and hand movements. We performed large-scale recordings (more than 2000 responsive sites) in frontal cortex of monkeys during a saccade-reach-grasp task. When an object appeared in peripheral vision, the first burst of activity emerged in prearcuate areas (the FEF and area 45B), followed by dorsal and ventral premotor cortex, and a buildup of activity in primary motor cortex. After the saccade, prearcuate activity remained elevated while primary motor and premotor activity rose in anticipation of the upcoming arm and hand movement. Some premotor and prearcuate sites were equally active when the object appeared in peripheral vision and at the fovea, suggesting a role in eye-hand coordination. Thus, a large part of lateral frontal cortex is active during a saccade-reach-grasp task.
A Method for the Automatic Normalization and 3D Facial Mesh Extraction from Head Magnetic Resonance Imaging
Authors: Sevillano Xavier , Ureña David , Gonzàlez Rubèn , Fatjó-Vilas Mar , Salvador Raymond , Pomarol-Clotet Edith , Martínez-Abadías Neus
Published: July 2020

The analysis of 3D facial shape in medicine is motivated by the fact that certain diseases and syndromes are associated to specific facial dysmorphologies. In this context, 3D facial shape analysis constitutes a promising and non-invasive support to traditional diagnostic methods. In this work, we explore the use of head magnetic resonances to obtain accurate 3D facial meshes that enable subsequent facial shape analysis. We present a fully automatic method that normalizes the orientation and alignment of 3D point clouds corresponding to head magnetic resonances by detecting salient facial features. Moreover, using clustering techniques, our method also allows to eliminate noise and artifacts appearing in magnetic resonance imaging. Finally, through bidirectional ray tracing, we obtain a dense 3D facial mesh that accurately captures facial shape. The proposed method has been built and evaluated on a dataset of 185 head magnetic resonances, and it has demonstrated its ability to successfully orient, align and obtain a dense 3D facial mesh with a high accuracy rate.
The mechanism underlying J-waves and T-waves in the electrocardiogram of mice and zebra finches
Authors: Offerhaus Joost A. , Snelderwaard Peter C. , Faber Jaeike W. , Riebe Katharina , Jensen Bjarke , Boukens Bas J.
Published: July 2020

Brief cardiac cycles are required to achieve high heart rates as seen in endothermic animals. A main determinant of the cardiac cycle is the repolarization phase of the cardiac action potential, which is visible in the ECG as a T-wave. In mammals with high heart rates – such as rodents – the repolarization phase is short and the ECG is characterized by a positive deflection following the QRS-complex, the J-wave. It is unclear whether birds with high heart rates show similar ECG characteristics. Here we study cardiac repolarization and the ECG in the zebra finch which has high heart rates. Inex vivohearts of zebra finch (N=5) and mouse (N=5), pseudo-ECGs and optical action potentials were measured. In both species, total ventricular activation was fast with QRS durations shorter than 10ms. Ventricular activation progressed from the left to the right ventricle in zebra finch whereas the activation pattern was apex-to-base in mouse. In both species, phase 1 early repolarization followed the activation front, causing a positive J-wave in the pseudo-ECG. In zebra finch, late repolarization was directed from the right ventricle to the left ventricle, whereas late repolarization was directed opposite in mouse. Accordingly, on the zebra finch ECG, the J-wave and the T-wave have the same direction, whereas in the mouse the J-wave and the T-wave are discordant. Our findings demonstrate early repolarization and the associated J-wave are not restricted to mammals and that they also occur within birds. Early repolarization may have evolved by convergence in association with high heart rates.

Summary statement

Zebra finches are small birds with high heart rates. Similar to small rodents, the zebra finch ECG contains a J-wave, which is caused by early repolarization
Sexual differences in genetic architecture in UK Biobank
Authors: Bernabeu Elena , Canela-Xandri Oriol , Rawlik Konrad , Talenti Andrea , Prendergast James , Tenesa Albert
Published: July 2020

Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Gene by sex interactions (GxS) are thought to account for some of this sexual dimorphism. However, the extent and basis of these interactions are poorly understood.

Here we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We also found that, in some cases, sex-agnostic GWAS efforts might be missing loci of interest, and looked into possible improvements in the prediction of high-level phenotypes. Finally, we studied the potential functional role of the dimorphism observed through sex-biased eQTL and gene-level analyses.

This study marks a broad examination of the genetics of sexual dimorphism. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Our results suggest the need to consider sex-stratified analyses for future studies in order to shed light into possible sex-specific molecular mechanisms.
Mycobacterial HelD is a nucleic acids-clearing factor for RNA polymerase
Authors: Kouba Tomáš , Koval’ Tomáš , Sudzinová Petra , Pospíšil Jiří , Brezovská Barbora , Hnilicová Jarmila , Šanderová Hana , Janoušková Martina , Šiková Michaela , Halada Petr , Sýkora Michal , Barvík Ivan , Nováček Jiří , Trundová Mária , Dušková Jarmila , Skálová Tereza , Chon URee , Murakami Katsuhiko S. , Dohnálek Jan , Krásný Libor
Published: July 2020

RNA synthesis is central to life, and RNA polymerase depends on accessory factors for recovery from stalled states and adaption to environmental changes. Here we investigated the mechanism by which a helicase-like factor HelD recycles RNA polymerase. We report a cryo-EM structure of an unprecedented complex between theMycobacterium smegmatisRNA polymerase and HelD. The crescent-shaped HelD simultaneously penetrates deep into two RNA polymerase channels that are responsible for DNA binding and substrate delivery to the active site, thereby locking RNA polymerase in an inactive state. We show that HelD prevents non-specific interactions between RNA polymerase and DNA and dissociates transcription elongation complexes, but does not inhibit RNA polymerase binding to the initiation σ factor. The liberated RNA polymerase can either stay dormant, sequestered by HelD, or upon HelD release, restart transcription. Our results provide insights into the architecture and regulation of the highly medically-relevant mycobacterial transcription machinery and define HelD as a clearing factor that removes undesirable nucleic acids from RNA polymerase.
ALG-2 interacting protein-X (Alix) is required for activity-dependent bulk endocytosis at brain synapses
Authors: Laporte Marine H. , Chi Kwang Il , Caudal Laura C. , Zhao Na , Rolland Marta , Martinez-Hernandez José , Martineau Magalie , Chatellard Christine , Denarier Eric , Mercier Vincent , Lemaître Florent , Blot Béatrice , Moutaux Eve , Cazorla Maxime , Perrais David , Lanté Fabien , Fraboulet Sandrine , Hemming Fiona J. , Kirchhoff Frank , Sadoul Rémy
Published: July 2020

In chemical synapses undergoing high frequency stimulation, vesicle components can be retrieved from the plasma membrane via a clathrin-independent process called activity dependent bulk endocytosis (ADBE). Alix (ALG-2 interacting protein X)/ PDCD6IP) is an adaptor protein binding to ESCRT and endophilin-A proteins which is required for clathrin-independent endocytosis in fibroblasts. Alix is expressed in neurons and concentrates at synapses during epileptic seizures. Here, we used cultured neurons to show that Alix is recruited to presynapses where it interacts with, and concentrates endophilin-A during conditions triggering ADBE. Using Alix knockout (ko) neurons we showed that this recruitment, which requires interaction with the calcium-binding protein ALG-2, is necessary for ABDE. We also found that presynaptic compartments of Alix ko hippocampi display subtle morphological defects compatible with flawed synaptic activity and plasticity detected electrophysiologically. Furthermore, mice lacking Alix in the forebrain undergo less seizures during kainate-induced status epilepticus and reduced propagation of the epileptiform activity. These results thus show that impairment of ADBE due to the lack of neuronal Alix alters synaptic recovery during physiological or pathological repeated stimulations.
Sortase-mediated site-specific modification of interleukin-2 for the generation of a tumor targeting acetazolamide-cytokine conjugate
Authors: Gouyou Baptiste , Millul J , Villa A , Cazzamalli S , Neri D , Matasci M
Published: July 2020

1.

Small ligands specific to tumor-associated antigens can be used as alternatives to antibodies for the delivery of small payloads such as radionuclides, cytotoxic drugs and fluorophores. Their use as delivery moiety of bioactive proteins like cytokines remains largely unexplored. Here, we describe the preparation andin vivocharacterization of the first small molecule-cytokine conjugate targeting carbonic anhydrase IX (CAIX), a marker of renal cell carcinoma and hypoxia. Site-specific conjugation between interleukin-2 and acetazolamide was obtained by Sortase A-mediated transpeptidation. Binding of the conjugate to the cognate CAIX antigen was confirmed by surface plasmon resonance. Thein vivotargeting of structures expressing carbonic anhydrase IX was assessed by biodistribution experiments in tumor bearing mice. Optimization of manufacturability and tumor targeting performance of acetazolamide-cytokine products will be required in order to enable industrial applications.

Graphical abstract
Geographic drivers of diversification in loliginid squids with an emphasis on the western Atlantic species
Authors: Genty Gabrielle , Pardo-De la Hoz Carlos J , Montoya Paola , Ritschard Elena A.
Published: July 2020

Aim

Identifying the mechanisms driving divergence in marine organisms is challenging as opportunities for allopatric isolation are less conspicuous than in terrestrial ecosystems. Here, we aim to estimate a dated phylogeny of the squid family Loliginidae, and perform ecological niche analyses to explore biogeographic and evolutionary patterns giving rise to extant lineages in this group, with particular focus on cryptic species with population structure along the western Atlantic coast.

Location

World-wide.

Taxon

Class Cephalopoda, Family Loliginidae

Methods

We used three loci to infer gene trees and perform species delimitation analysis to detect putative cryptic speciation events. We then estimated a dated species tree under the Bayesian multispecies coalescent and used it to reconstruct ancestral distributions based on the currently known ranges of the species. Also, we tested the hypothesis of niche divergence in three recently diverged species subpopulations of the northwestern and southwestern Atlantic Ocean by ecological niche modeling and niche overlap measurement from occurrence data.

Results

The phylogenetic analyses confirmed the monophyly for the current twenty-six species of the Loliginidae family. Our ancestral area reconstruction and divergence estimation revealed the origin and geographical dispersal of loliginid lineages. Additionally, the phylogenetic analysis and the species delimitation analysis supported geographic structure withinD. pleii, D. pealeiiandL. brevis.The ecological niche models revealed unsuitable habitat in the immediately adjacent area of the Amazonian Orinoco Plume, yet suitable habitat characteristics beyond this area.

Main conclusions

Our study allowed us to confirm the monophyly of all currently recognized species within the Loliginidae family and we corroborate the biogeographical origin being the Indo-Pacific region in the Cretaceous. We found a possible new cryptic lineage and show evidence of the Amazon-Orinoco Plume as an ecological barrier, which influenced the diversification of this particular group of marine organisms.
Myofibroblast Forms Atherosclerotic Plaques
Authors: Wang Xinggang , Ge Junbo
Published: July 2020

For decades, smooth muscle cells (SMCs) and macrophages are considered as the main contributors to atherosclerotic plaques. However, we found that in the human coronary atherosclerotic plaques, SMCs were few, while lots of myofibroblasts infiltrated in the intima near the lumen (fibrous cap) and their distribution was highly positive related to intimal thickness. In addition to lots of foam cells formation, collagen fibers were forming in the thickening intima near the lumen (fibrous cap), and denaturing or calcifying gradually far from the lumen, which evolved into various complex plaques. In vitro, myofibroblasts could actively take lots of low-density lipoprotein (LDL) to enhance proliferation. Lots of collagen fibers, foam cells and extracellular lipids accumulation emerged in myofibroblasts cultured with 5% FBS high glucose DMEM without adding modified LDL. It is consistent with the characteristics of human coronary atherosclerotic plaques. It is the first time that lipid rich plaques with lots of foam cells, extracellular lipids and collagen fibers formed in vitro. It demonstrated that myofibroblast should be the direct and main source of collagen fibers, foam cells and extracellular lipids. This suggests that atherosclerosis is not as complicated as previously considered, and it might be mainly a process of myofibroblast remodeling to vascular injury caused by various risk factors. This study made the pathogenesis of atherosclerosis clearer. It would provide a target cell for future treatments of atherosclerotic diseases. In vitro atherosclerotic plaques model formed by human myofibroblasts would be an efficient and convenient way to study atherosclerosis.
Two isoforms of the essentialC. elegansArgonaute CSR-1 differentially regulate sperm and oocyte fertility
Authors: Charlesworth Amanda G. , Seroussi Uri , Lehrbach Nicolas J. , Renaud Mathias S. , Sundby Adam E. , Molnar Ruxandra I. , Lao Robert X. , Willis Alexandra R. , Woock Jenna R. , Aber Matthew J. , Diao Annette J. , Reinke Aaron W. , Ruvkun Gary , Claycomb Julie M.
Published: July 2020

TheC. elegansgenome encodes nineteen functional Argonaute proteins that utilize 22G-RNAs, 26G-RNAs, miRNAs, or piRNAs to regulate their target transcripts. Only one Argonaute is essential under normal laboratory conditions: CSR-1. While CSR-1 has been studied widely, nearly all studies have overlooked the fact that thecsr-1locus encodes two isoforms. These isoforms differ by an additional 163 amino acids present in the N-terminus of CSR-1a. Using CRISPR-Cas9 genome editing to introduce GFP::3xFLAG into the long (CSR-1a) and short (CSR-1b) isoforms, we found that CSR-1a is expressed during spermatogenesis and in several somatic tissues, including the intestine. CSR-1b is expressed constitutively in the germline. small RNA sequencing of CSR-1 complexes shows that they interact with partly overlapping sets of 22G-RNAs. Phenotypic analyses reveal that the essential functions ofcsr-1described in the literature coincide with CSR-1b, while CSR-1a plays tissue specific functions. During spermatogenesis, CSR-1a integrates into an sRNA regulatory network including ALG-3, ALG-4, and WAGO-10 that is necessary for fertility at 25°C. In the intestine, CSR-1a silences immunity and pathogen-responsive genes, and its loss results in improved survival from the pathogenPseudomonas aeruginosa. Our findings functionally distinguish the CSR-1 isoforms and highlight the importance of studying each AGO isoform independently.
Minimal net loss of vegetation via interior pond dynamics in an extensive unditched salt marsh
Authors: Smith Joseph , Pellew Michael
Published: July 2020

Ponds in salt marshes are often interpreted as a symptom of degradation, yet ponds can also be part of a cyclical process of pool formation, expansion, tidal breaching and vegetation recovery. Pond dynamics may be altered by accelerated sea level rise, with consequences for the long-term stability of ecosystems. We test the prediction that ponds are in dynamic equilibrium across one the largest expanses of unditched salt marsh in the Northeast USA by (1) examining change in pond and marsh area between 1970 and present and (2) by tracking individual pool dynamics across an 87-year time series. We found that net pond area has remained unchanged since 1970 because the amount of marsh conversion to ponds is equivalent to the amount pond recovery to marsh. The ratio of tidally-connected ponds is increasing relative to non-tidal ponds which suggests that some rates of change may be decoupling, which may be related to a decline in the rate of pond formation. A nuanced understanding of marsh pools needs to be incorporated into marsh condition assessments and establishment of restoration priorities so that ponds are not interpreted as evidence of degradation when they are exhibiting a recovery cycle. Unditched marshes around the world are a rare resource that remains essential for advancing scientific understanding and serving as reference sites for restoration of marshes altered by past management.
Comparative analysis of single-cell RNA Sequencing Platforms and Methods
Authors: Ashton John M. , Rehrauer Hubert , Myers Jason , Myers Jacqueline , Zanche Michelle , Balys Malene , Foox Jonathan , Mason Chistopher E. , Steen Robert , Kuentzel Marcy , Aquino Catharine , Garcia-Reyero Natàlia , Chittur Sridar V.
Published: July 2020

Single-cell RNA sequencing (scRNA-seq) offers great new opportunities for increasing our understanding of complex biological processes. In particular, development of an accurate Human Cell Atlas is largely dependent on the rapidly advancing technologies and molecular chemistries employed in scRNA-seq. These advances have already allowed an increase in throughput for scRNA-seq from 96 to 80,000 cells on a single instrument run by capturing cells within nano-liter droplets. While this increase in throughput is critical for many experimental questions, a thorough comparison between microfluidic-, plate-, and droplet-based technologies or between multiple available platforms utilizing these technologies is largely lacking. Here, we report scRNA-seq data from SUM149PT cells treated with the histone deacetylase inhibitor TSA vs. untreated controls across several scRNA-seq platforms (Fluidigm C1, WaferGen iCell8, 10X Genomics Chromium Controller, and Illumina/BioRad ddSEQ). The primary goal of this project was to demonstrate RNA sequencing (RNA-seq) methods for profiling the ultra-low amounts of RNA present in individual cells, and this report discusses the results of the study as well as technical challenges/lesson learned and present general guidelines for best practices in sample preparation and analysis.
Integrative Proteomic Analysis of Posttranslational Modification in The Inflammatory Response
Authors: Ji Feiyang , Zhou Menghao , Zhu Huihui , Jiang Zhengyi , Li Qirui , Ouyang Xiaoxi , Lv Yiming , Zhang Sainan , Wu Tian , Li Lanjuan
Published: July 2020

The posttranslational modification (PTM) of proteins, particularly acetylation, phosphorylation and ubiquitination, plays a critical role in the host innate immune response. PTMs’ dynamic changes and the crosstalk among them are complicated. To build a comprehensive dynamic network of inflammation related proteins, we integrated data from the whole cell proteome (WCP), acetylome, phosphoproteome and ubiquitinome of human and mouse macrophages. Our datasets of acetylation, phosphorylation and ubiquitination sites helped identify PTM crosstalk within and across proteins involved in the inflammatory response. Stimulation of macrophages by lipopolysaccharide (LPS) resulted in both degradative and non-degradative ubiquitination. Moreover, this study contributes to the interpretation of the roles of known inflammatory molecules and the discovery of novel inflammatory proteins.
Discovery of membrane-permeating cyclic peptides via mRNA display
Authors: Bowen John , Schloop Allison E. , Reeves Gregory T. , Menegatti Stefano , Rao Balaji M.
Published: July 2020

Small synthetic peptides capable of crossing biological membranes represent valuable tools in cell biology and drug delivery. While several cell-penetrating peptides (CPPs) of natural or synthetic origin have been reported, no peptide is currently known to cross both cytoplasmic and outer embryonic membranes. Here we describe a method to engineer membrane-permeating cyclic peptides (MPPs) with broad permeation activity by screening mRNA display libraries of cyclic peptides against embryos at different developmental stages. The proposed method was demonstrated by identifying peptides capable of permeatingDrosophila melanogaster(fruit fly) embryos and mammalian cells. The selected peptide cyclo[Glut-MRKRHASRRE-K*] showed a strong permeation activity of embryos exposed to minimal permeabilization pretreatment, as well as human embryonic stem cells and a murine fibroblast cell line. Notably, in both embryos and mammalian cells, the cyclic peptide outperformed its linear counterpart and the control MPPs. Confocal microscopy and single cell flow cytometry analysis were utilized to assess the degree of permeation both qualitatively and quantitatively. These MPPs have potential application in studying and non-disruptively controlling intracellular or intraembryonic processes.
Imaging biomarkers for motor outcome after stroke – should we include information from beyond the primary motor system?
Authors: Sperber Christoph , Rennig Johannes , Karnath Hans-Otto
Published: July 2020

Hemiparesis is a common consequence of stroke to the primary motor system. Previous studies suggested that damage to additional brain areas might play a causal role in the occurrence and severity of hemiparesis and its recovery. Knowledge of these regions might be applied in the creation of imaging biomarkers for motor outcome prediction if lesion information from such areas carries predictive value. We assessed acute and chronic paresis of the upper limb in 102 patients with unilateral stroke. In a first experiment, the neural correlates of acute and chronic upper limb paresis were mapped by lesion behaviour mapping. Following the same approach, a lesion biomarker of corticospinal tract (CST) damage was mapped. This analysis served as an artificial control condition as the biomarker, by definition, is only causally related to damage of the CST. Mapping acute or chronic upper limb paresis implicated areas outside of the primary motor system. Likewise, mapping the CST lesion biomarker implicated several areas outside of the CST with high correspondence to areas associated with upper limb paresis. Damage to areas outside of the primary motor system thus might, to some degree, not play a causal role in hemiparesis. In a second experiment, we showed that lesion information from these areas outside of the primary motor system can be used to predict motor outcome. This was even the case for the CST lesion biomarker. Although the only causal source underlying the CST lesion biomarker was damage to the CST, lesion information that mainly included non-CST regions was able to predict the biomarker (non-significantly) better than information taken from only the CST itself. These findings suggest that simple theory-based biomarkers or qualitative rules to infer post-stroke outcome from imaging data might perform sub-optimally, as they do not consider the complexity of lesion data. Instead, high-dimensional models with data-driven feature selection strategies might be required.
Global patterns of aegyptism without arbovirus
Authors: Olson Mark F. , Juarez José G. , Kraemer Moritz U. G. , Messina Jane P. , Hamer Gabriel L.
Published: July 2020

The world’s most important mosquito vector of viruses, Aedes aegypti, is found around the world in tropical, subtropical and even some temperate locations. While climate change may limit populations of Ae. aegypti in some regions, increasing temperatures will likely expand its territory thus increasing risk of human exposure to arboviruses in places like Europe, Northern Australia and North America, among many others. Most studies of Ae. aegypti biology and virus transmission focus on locations with high endemicity or severe outbreaks of human amplified urban arboviruses, such as dengue, Zika, and chikungunya viruses, but rarely on areas at the margins of endemicity. Our objective in this study is to explore global patterns in the environmental suitability for Ae. aegypti and dengue virus to reveal deviations in the probability of the vector and human disease occurring. We developed a map showing one end of the gradient being higher suitability of Ae. aegypti with low suitability of dengue and the other end of the spectrum being equal and higher environmental suitability for both Ae. aegypti and dengue. The regions of the world with Ae. aegypti environmental suitability and no endemic dengue transmission exhibits a phenomenon we term ‘aegyptism without arbovirus’. We then tested what environmental and socioeconomic variables influence this deviation map revealing a significant association with population density, suggesting that locations with lower population density were more likely to have a higher probability of aegyptism without arbovirus. Characterizing regions of the world with established populations of Ae. aegypti but little to no autochthonous transmission of human-amplified arboviruses is an important step in understanding and achieving aegyptism without arbovirus.
MHC class IIa haplotypes derived by high throughput SNP screening in an isolated sheep population
Authors: Dicks K.L. , Pemberton J.M. , Ballingall K.T. , Johnston S.E.
Published: July 2020

Investigating the current evolutionary processes acting on a highly polymorphic gene region, such as the major histocompatibility complex (MHC), requires extensive population data for both genotypes and phenotypes. The MHC consists of several tightly linked loci with both allelic and gene content variation, making it challenging to genotype. Eight class IIa haplotypes have previously been identified in the Soay sheep (Ovis aries) of St. Kilda using Sanger sequencing and cloning, but no single locus is representative of all haplotypes. Here, we exploit the closed nature of the island population of Soay sheep and its limited haplotypic variation to identify a panel of SNPs that enable imputation of MHC haplotypes. We compared MHC class IIa haplotypes determined by Sanger sequence-based genotyping of 135 individuals to their SNP profiles generated using the Ovine Infinium HD BeadChip. A panel of 11 SNPs could reliably determine MHC diplotypes, and two additional SNPs within theDQA1gene enabled detection of a recombinant haplotype affecting only the SNPs downstream of the expressed genes. The panel of 13 SNPs was genotyped in 5951 Soay sheep, of which 5349 passed quality control. Using the Soay sheep pedigree, we were able to trace the origin and inheritance of the recombinant SNP haplotype. This SNP-based method has enabled the rapid generation of locus-specific MHC genotypes for large numbers of Soay sheep. This volume of high-quality genotypes in a well-characterized population of free-living sheep will be valuable for investigating the mechanisms maintaining diversity at the MHC.
Regulation of immune receptor kinases plasma membrane nanoscale landscape by a plant peptide hormone and its receptors
Authors: Gronnier Julien , Franck Christina M. , Stegmann Martin , DeFalco Thomas A. , Abarca Alicia , Von Arx Michelle , Dünser Kai , Lin Wenwei , Yang Zhenbiao , Kleine-Vehn Jürgen , Ringli Christoph , Zipfel Cyril
Published: July 2020

Spatial partitioning is a propensity of biological systems orchestrating cell activities in space and time. The dynamic regulation of plasma membrane nano-environments has recently emerged as a key fundamental aspect of plant signaling, but the molecular components governing it are still mostly unclear. The receptor kinase FERONIA (FER) controls complex formation of the immune receptor kinase FLAGELLIN SENSING 2 (FLS2) with its co-receptor BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1), and this function is inhibited by the FER ligand RAPID ALKALANIZATION FACTOR 23 (RALF23). Here, we show that FER regulates the plasma membrane nanoscale organization of FLS2 and BAK1. Our study demonstrates that akin to FER, leucine-rich repeat (LRR) extensin (LRXs) proteins contribute to RALF23 responsiveness, regulate BAK1 nanoscale organization and immune signaling. Furthermore, RALF23 perception leads to rapid modulation of FLS2 and BAK1 nanoscale organization and its inhibitory activity on immune signaling relies on FER kinase activity. Our results suggest that perception of RALF peptides by FER and LRXs actively modulates the plasma membrane nanoscale landscape to regulate cell surface signaling by other receptor kinases.
Chemogenetic silencing of hippocampus and amygdala reveals a double dissociation in periadolescent obesogenic diet-induced memory alterations
Authors: Naneix Fabien , Bakoyiannis Ioannis , Santoyo-Zedillo Marianela , Bosch-Bouju Clémentine , Pacheco-Lopez Gustavo , Coutureau Etienne , Ferreira Guillaume ,   OBETEEN Consortium
Published: July 2020

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In addition to numerous metabolic comorbidities, obesity is associated with several adverse neurobiological outcomes, especially learning and memory alterations. Obesity prevalence is rising dramatically in youth and is persisting in adulthood. This is especially worrying since adolescence is a crucial period for the maturation of certain brain regions playing a central role in memory processes such as the hippocampus and the amygdala. We previously showed that periadolescent exposure to obesogenic high-fat diet (HFD) had opposite effects on hippocampus- and amygdala-dependent memory, impairing the former and enhancing the latter. However, the causal role of these two brain regions in periadolescent HFD-induced memory alterations remains unclear. Here, we first showed that periadolescent HFD induced long-term, but not short-term, object recognition memory deficits, specifically when rats were exposed to a novel context. Using chemogenetic approaches to inhibit targeted brain regions, we then demonstrated that recognition memory deficits are dependent on the activity of the ventral hippocampus, but not the basolateral amygdala. On the contrary, the HFD-induced enhancement of conditioned odor aversion requires specifically amygdala activity. Taken together, these findings suggest that HFD consumption throughout adolescence impairs long-term object recognition memory through the overactivation of the ventral hippocampus during memory acquisition. Moreover, these results further highlight the bidirectional effects of adolescent HFD on hippocampal and amygdala functions.
Identifying functional metabolic shifts in heart failure with the integration of omics data and a cardiomyocyte-specific, genome-scale model
Authors: Dougherty Bonnie V. , Rawls Kristopher D. , Kolling Glynis L. , Vinnakota Kalyan C. , Wallqvist Anders , Papin Jason A.
Published: July 2020

The heart is a metabolic omnivore, known to consume many different carbon substrates in order to maintain function. In diseased states, the heart’s metabolism can shift between different carbon substrates; however, there is some disagreement in the field as to the metabolic shifts seen in end-stage heart failure and whether all heart failure converges to a common metabolic phenotype. Here, we present a new, validated cardiomyocyte-specific GEnome-scale metabolic Network REconstruction (GENRE),iCardio, and use the model to identify common shifts in metabolic functions across heart failure omics datasets. We demonstrate the utility ofiCardioin interpreting heart failure gene expression data by identifying Tasks Inferred from Differential Expression (TIDEs) which represent metabolic functions associated with changes in gene expression. We identify decreased NO and Neu5Ac synthesis as common metabolic markers of heart failure across datasets. Further, we highlight the differences in metabolic functions seen across studies, further highlighting the complexity of heart failure. The methods presented for constructing a tissue-specific model and identifying TIDEs can be extended to multiple tissue and diseases of interest.
ThePIF1-MIR408-PlantacyaninRepression Cascade Regulates Light Dependent Seed Germination
Authors: Jiang Anlong , Guo Zhonglong , Pan Jiawei , Zhuang Yan , Zuo Daqing , Hao Chen , Gao Zhaoxu , Xin Peiyong , Chu Jinfang , Zhong Shangwei , Li Lei
Published: July 2020

Light-sensing seed germination is a vital process for the seed plants. A decisive event in light-induced germination is degradation of the central repressor PHYTOCHROME INTERACTING FACTOR1 (PIF1). It is also known that the balance between gibberellic acid (GA) and abscisic acid (ABA) critically controls germination. But the cellular mechanisms linking PIF1 turnover to hormonal rebalancing remain elusive. Here, employing far-red light-inducedArabidopsisseed germination as the experimental system, we identified Plantacyanin (PLC) as an inhibitor of germination, which is a storage vacuole-associated blue copper protein highly expressed in mature seed and rapidly silenced during germination. Molecular analyses showed that PIF1 directly binds to theMIR408promoter and represses miR408 accumulation, which in turn post-transcriptionally modulatesPLCabundance, thus forming thePIF1-MIR408-PLCrepression cascade for translating PIF1 turnover to PLC turnover during early germination. Genetic analysis, RNA-sequencing, and hormone quantification revealed thatPLCis necessary and sufficient to maintain thePIF1-mediated seed transcriptome and the low-GA-high-ABA state. Furthermore, we found that PLC domain organization and regulation by miR408 are conserved features in seed plants. These results unraveled a cellular mechanism whereby PIF1-relayed external light signals are converted through PLC-based copper mobilization into internal hormonal profiles for controlling seed germination.