bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial nucleoid organization and biogenesis of complex I require mTERF18/SHOT1 and ATAD3 inArabidopsis thaliana
Authors: Kim Minsoo , Schulz Vincent , Brings Lea , Schoeller Theresa , Kühn Kristina , Vierling Elizabeth
Published: May 2020

Mitochondria play critical roles in eukaryotes in ATP generation through oxidative phosphorylation (OXPHOS) and also produce both damaging and signaling reactive oxygen species (ROS). Originating from endosymbiosis, mitochondria have their own reduced genomes that encode essential subunits of the OXPHOS machinery. MTERF (Mitochondrial Transcription tERmination Factor-related) proteins have been shown to be involved in organelle gene expression by interacting with organellar DNA or RNA in multicellular eukaryotes. We previously identified mutations inArabidopsis thaliana MTERF18/SHOT1that enable plants to better tolerate heat and oxidative stresses, presumably due to low ROS and reduced oxidative damage. To understand molecular mechanisms leading toshot1phenotypes, we investigated mitochondrial defects ofshot1mutants and targets of the SHOT1 protein.shot1mutants have problems accumulating OXPHOS complexes that contain mitochondria-encoded subunits, with complex I and complex IV most affected. SHOT1 binds specific mitochondrial DNA sequences and localizes to mitochondrial nucleoids, which are diffuse inshot1mutants. Furthermore, three homologues of mammalian ATAD3A proteins, which are suggested to be involved in mitochondrial nucleoid organization, were identified as SHOT1-interacting proteins (designated SHOT1 BINDING ATPASES (SBA)1, 2 and 3). Importantly, disrupting SBA function also disrupts nucleoids, compromises accumulation of complex I and enhances heat tolerance. We conclude that proper nucleoid organization is critical for correct expression and accumulation of complex I, and propose that nucleoid disruption results in unique changes in mitochondrial metabolism and signaling that lead to heat tolerance.

Significance

In all eukaryotes, mitochondria are critical organelles that supply chemical energy for life, which is produced by the oxidative phosphorylation (OXPHOS) machinery on the inner mitochondrial membrane. The OXPHOS machinery comprises multiple protein complexes with subunits encoded by both nuclear and mitochondrial genes. Nuclear-encoded mTERF proteins are important for expression of mitochondrial genes, interacting with mitochondrial DNA or RNA. Our study reveals that the Arabidopsis mTERF18/SHOT1 protein interacts with mtDNA and homologs of human ATAD3A proteins, and that both proteins are critical for mitochondrial nucleoid organization and accumulation of OXPHOS Complex I. Further, the data indicate nucleoid disruption leads to unique mitochondrial and cellular responses such that mutant plants have enhanced heat tolerance.
Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease reveals the signatures of tau-associated synaptic dysfunction
Authors: Otero-Garcia Marcos , Xue Yue-Qiang , Shakouri Tamara , Deng Yongning , Morabito Samuel , Allison Thomas , Lowry William E. , Kawaguchi Riki , Swarup Vivek , Cobos Inma
Published: May 2020

Aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is closely associated with neuronal death and cognitive decline in Alzheimer’s disease (AD). To define the signatures that distinguish between aggregation-prone and resistant cell states in AD, we developed a FACS-based method for the high-throughput isolation and transcriptome profiling of individual cells with cytoplasmic aggregates and profiled 63,110 somas from human AD brains. By comparing NFT-bearing and NFT-free somas within and across neuronal subtypes, we identified the cell-type-specific and shared states. NFT-bearing neurons shared a marked upregulation of genes associated with synaptic transmission, including a core set of 63 genes enriched for synaptic vesicle cycle and transsynaptic signaling, whereas glucose metabolism and oxidative phosphorylation changes were highly neuronal-subtype-specific. Apoptosis was modestly enriched in NFT-bearing neurons despite the strong link between tau and cell death. Our datasets provide a resource for investigating tau-mediated neurodegeneration and a platform for biomarker and drug target discovery.
Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia
Authors: Xiao Wenbin , Chan Alexander , Waarts Michael R. , Mishra Tanmay , Liu Ying , Cai Sheng F. , Yao Jinjuan , Gao Qi , Bowman Robert L. , Koche Richard , Csete Isabelle S. , Baik Jeeyeon , Yanis Sophia , Famulare Christopher , Patel Minal , Arcila Maria E. , Stahl Maximilian , Rampal Raajit K. , Tallman Martin S. , Zhang Yanming , Dogan Ahmet , Goldberg Aaron D. , Roshal Mikhail , Levine Ross L.
Published: May 2020

Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess crosslineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without PDC expansion. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.
Post-reactivation mifepristone impairs generalisation of strongly-conditioned contextual fear memories
Authors: Flavell Charlotte R. , Gascoyne Rebecca M. , Lee Jonathan L. C.
Published: May 2020

The efficacy of pharmacological disruption of fear memory reconsolidation depends on several factors, including memory strength and age. We built on previous observations that systemic treatment with the nootropic nefiracetam potentiates cued fear memory destabilization to facilitate mifepristone-induced reconsolidation impairment. Here, we applied nefiratecam and mifepristone to strongly-conditioned, 1-week old contextual fear memories in male rats. Unexpectedly, the combined treatment did not result in impairment of contextual fear expression. However, mifepristone did reduce freezing to a novel context. These observations suggest that strong and established contextual fear memories do undergo destabilization without the need for pharmacological facilitation, and that impairments in strong context fear memory reconsolidation can manifest as a reduction in generalization.
Ion Identity Molecular Networking in the GNPS Environment
Authors: Schmid Robin , Petras Daniel , Nothias Louis-Félix , Wang Mingxun , Aron Allegra T. , Jagels Annika , Tsugawa Hiroshi , Rainer Johannes , Garcia-Aloy Mar , Dührkop Kai , Korf Ansgar , Pluskal Tomáš , Kameník Zdeněk , Jarmusch Alan K. , Caraballo-Rodríguez Andrés Mauricio , Weldon Kelly , Nothias-Esposito Melissa , Aksenov Alexander A. , Bauermeister Anelize , Orio Andrea Albarracin , Grundmann Carlismari O. , Vargas Fernando , Koester Irina , Gauglitz Julia M. , Gentry Emily C. , Hövelmann Yannick , Kalinina Svetlana A. , Pendergraft Matthew A. , Panitchpakdi Morgan W. , Tehan Richard , Le Gouellec Audrey , Aleti Gajender , Russo Helena Mannochio , Arndt Birgit , Hübner Florian , Hayen Heiko , Zhi Hui , Raffatellu Manuela , Prather Kimberly A. , Aluwihare Lihini I. , Böcker Sebastian , McPhail Kerry L. , Humpf Hans-Ulrich , Karst Uwe , Dorrestein Pieter C.
Published: May 2020

Molecular networking connects tandem mass spectra of molecules based on the similarity of their fragmentation patterns. However, during ionization, molecules commonly form multiple ion species with different fragmentation behavior. To connect ion species of the same molecule, we developed Ion Identity Molecular Networking. These new relationships improve network connectivity, are shown to reveal novel ion-ligand complexes, enhance annotation within molecular networks, and facilitate the expansion of spectral libraries.
CommDivMap: Modelling and mapping species richness at different spatial scales
Authors: Miller Julia E , Steinke Dirk
Published: May 2020

1. Modern ecosystem models have the potential to greatly enhance our capacity to predict community responses to change, but they demand comprehensive spatial distribution information, creating the need for new approaches to gather and synthesize biodiversity data.

2. Metabarcoding or metagenomics can generate comprehensive biodiversity data sets at species-level resolution but they are limited to point samples.

3. CommDivMap contains a number of functions that can be used to turn OTU tables resulting from metabarcoding runs of bulk samples into species richness maps. We tested the method on a series of arthropod bulk samples obtained from various experimental agricultural plots.

4. The script runs smoothly and is reasonably fast. We hope that our assemble first, predict later approach to statistical modelling of species richness will set the stage for the transition from data-rich but finite sets of point samples to spatially continuous biodiversity maps.
Viscoelastic mapping of mouse brain tissue: relation to structure and age
Authors: Antonovaite Nelda , Hulshof Lianne A. , Hol Elly M. , Wadman Wytse J. , Iannuzzi Davide
Published: May 2020

There is growing evidence that mechanical factors affect brain functioning. However, brain components responsible for regulating the physiological mechanical environment and causing mechanical alterations during maturation are not completely understood. To determine the relationship between structure and stiffness of the brain tissue, we performed high resolution viscoelastic mapping by dynamic indentation of hippocampus and cerebellum of juvenile brain, and quantified relative area covered by immunohistochemical staining of NeuN (neurons), GFAP (astrocytes), Hoechst (nuclei), MBP (myelin), NN18 (axons) of juvenile and adult mouse brain slices. When compared the mechanical properties of juvenile mouse brain slices with previously obtained data on adult slices, the latter was ~ 20-150% stiffer, which correlates with an increase in the relative area covered by astrocytes. Heterogeneity within the slice, in terms of storage modulus, correlates negatively with the relative area of nuclei and neurons, as well as myelin and axons, while the relative area of astrocytes correlates positively. Several linear regression models are suggested to predict the mechanical properties of the brain tissue based on immunohistochemical stainings.
Bifurcated Hydrogen Bonds and the Fold Switching of Lymphotactin
Authors: Khatua Prabir , Ray Alan J , Hansmann Ulrich H. E.
Published: May 2020

Lymphotactin (Ltn) exists under physiological conditions in an equilibrium between two interconverting structures with distinct biological functions. Using Replica-Exchange-with-Tunneling we study the conversion between the two folds. Unlike previously proposed, we find that the fold switching does not require unfolding of Lymphotactin, but proceeds through a series of intermediates that remain partially structured. This process relies on two bifurcated hydrogen bonds that connect theβ2andβ3strands and eases the transition between the hydrogen bond pattern by which the central three-strandedβ-sheet in the two forms differ.
Autoregulation of Many Yeast Ribosomal Proteins Discovered by Efficient Search for Feedback Regulation
Authors: Roy Basab , Granas David , Bragg Fredrick , Cher Jonathan A. Y. , White Michael A. , Stormo Gary D.
Published: May 2020

Post-transcriptional autoregulation of gene expression is common in bacterial systems but many fewer examples are known in eukaryotes. We used the yeast collection of genes fused to GFP as a rapid screen for examples of feedback regulation in ribosomal proteins by overexpressing a non-regulatable version of a gene and observing the effects on the expression of the GFP-fused version. We tested 95 ribosomal protein genes and found that 21 of them showed at least a three-fold repression. Two genes,RPS22BandRPL1B, showed over a 10-fold repression. In both cases the cis-regulatory segment resides in the 5’ UTR of the gene as shown by placing that segment of the mRNA upstream of GFP alone and demonstrating it is sufficient to cause repression of GFP when the protein is over-expressed. Further analyses showed that the intron in the 5’ UTR ofRPS22Bis required for regulation, presumably because the protein inhibits splicing that is necessary for translation. The 5’ UTR ofRPL1Bcontains a sequence and structure motif that is conserved in the binding sites of Rpl1 orthologs from bacteria to mammals, and mutations within the motif eliminate repression.
The Dynamics of Plant Nutation
Authors: Raja Vicente , Silva Paula L. , Holghoomi Roghaieh , Calvo Paco
Published: May 2020

In this article we advance a cutting-edge methodology for the study of the dynamics of plant movements of nutation. Our approach, unlike customary kinematic analyses of shape, period, or amplitude, is based on three typical signatures of adaptively controlled processes and motions, as reported in the biological and behavioral dynamics literature: harmonicity, predictability, and complexity. We illustrate the application of a dynamical methodology to the bending movements of shoots of common beans (Phaseolus vulgarisL.) in two conditions: with and without a support to climb onto. The results herewith reported support the hypothesis that patterns of nutation are influenced by the presence of a support to climb in their vicinity. The methodology is in principle applicable to a whole range of plant movements.
Sequential sequestrations increase the incorporation and retention of multiple growth factors in mineralized collagen scaffolds
Authors: Tiffany Aleczandria S. , Dewey Marley J. , Harley Brendan A.C.
Published: May 2020

Trauma induced injuries of the mouth, jaw, face, and related structures present unique clinical challenges due to their large size and complex geometry. Growth factor signaling coordinates the behavior of multiple cell types following an injury, and effective coordination of growth factor availability within a biomaterial can be critical for accelerating bone healing. Mineralized collagen scaffolds are a class of degradable biomaterial whose biophysical and compositional parameters can be adjusted to facilitate cell invasion and tissue remodeling. Here we describe the use of modified simulated body fluid treatments to enable sequential sequestration of bone morphogenic protein 2 and vascular endothelial growth factor into mineralized collagen scaffolds for bone repair. We report the capability of these scaffolds to sequester growth factors from solution without additional crosslinking treatments and show high levels of retention for individual and multiple growth factors that can be layered into the material via sequential sequestration steps. Sequentially sequestering growth factors allows prolonged release of growth factorsin vitroand suggests the potential to improve healing of large-scale bone injury modelsin vivo. Future work will utilize this sequestration method to induce cellular activities critical to bone healing such as vessel formation and cell migration.
Epidemiology, risk factors and clinical course of SARS-CoV-2 infected patients in a Swiss university hospital: an observational retrospective study
Authors: Regina Jean , Papadimitriou-Olivgeris Matthaios , Burger Raphael , Filippidis Paraskevas , Tschopp Jonathan , Desgranges Florian , Viala Benjamin , Kampouri Eleftheria , Rochat Laurence , Haefliger David , Belkoniene Mhedi , Fidalgo Carlos , Kritikos Antonios , Jaton Katia , Senn Laurence , Bart Pierre-Alexandre , Pagani Jean-Luc , Manuel Oriol , Lhopitallier Loic
Published: May 2020

Background
Coronavirus disease 2019 (COVID-19) is now a global pandemic with Europe and the USA at its epicenter. Little is known about risk factors for progression to severe disease in Europe. This study aims to describe the epidemiology of COVID-19 patients in a Swiss university hospital.

Methods
This retrospective observational study included all adult patients hospitalized with a laboratory confirmed SARS-CoV-2 infection from March 1 to March 25, 2020. We extracted data from electronic health records. The primary outcome was the need to mechanical ventilation at day 14. We used multivariate logistic regression to identify risk factors for mechanical ventilation. Follow-up was of at least 14 days.

Results
200 patients were included, of whom 37 (18.5%) needed mechanical ventilation at 14 days. The median time from symptoms onset to mechanical ventilation was 9.5 days (IQR 7.00, 12.75). Multivariable regression showed increased odds of mechanical ventilation in males (3.26, 1.21-9.8; p=0.025), in patients who presented with a qSOFA score ≥2 (6.02, 2.09-18.82; p=0.001), with bilateral infiltrate (5.75, 1.91-21.06; p=0.004) or with a CRP of 40 mg/l or greater (4.73, 1.51-18.58; p=0.013).

Conclusions
This study gives some insight in the epidemiology and clinical course of patients admitted in a European tertiary hospital with SARS-CoV-2 infection. Male sex, high qSOFA score, CRP of 40 mg/l or greater and a bilateral radiological infiltrate could help clinicians identify patients at high risk for mechanical ventilation.
Robust causal inference for long-term policy decisions: cost effectiveness of interventions for obesity using Mendelian randomization
Authors: Harrison Sean , Dixon Padraig , Jones Hayley E , Davies Alisha R , Howe Laura D , Davies Neil M
Published: May 2020

Objectives
To estimate the cost-effectiveness of interventions to reduce body mass index (BMI) using Mendelian randomization.
Design
We estimated the causal effect of differences in BMI on quality-adjusted life years (QALYs) and total healthcare costs using Mendelian randomization and applied our results to policy-relevant questions.
Setting
UK Biobank.
Participants
310,913 men and women of white British ancestry aged between 39 and 72 years, followed-up for an average of 8.1 years (6.1 years for secondary care healthcare costs).
Main outcome measures
Predicted average QALYs and total healthcare costs per year, and cost-effectiveness of interventions.
Results
A unit increase in BMI decreased QALYs by 0.65% of a QALY (95% confidence interval [CI]: 0.49% to 0.81%) per year and increased annual total healthcare costs by 42.23 (95% CI: 32.95 to 51.51) per person. When considering only health conditions usually considered in previous studies (cancer, cardiovascular disease, cerebrovascular disease and type 2 diabetes), we estimated that a unit increase in BMI decreased QALYs by only 0.16% of a QALY (95% CI: 0.10% to 0.22%) per year.
Compared to no intervention and over 20 years, a person in England or Wales aged 40-69 years with a BMI over 35 kg/m2 receiving laparoscopic bariatric surgery would have, on average, an increase of 0.92 QALYs (95% CI: 0.66 to 1.17) and a decrease in total healthcare costs of 5,096 (95% CI: 3,459 to 6,852), with a net monetary benefit (at 20,000 per QALY) of 13,936 (95% CI: 8,112 to 20,658).
Restricting volume promotions for high fat, salt and sugar products would, across the 21.7 million adults aged 40 to 69 years in England and Wales, increase QALYs by 20,551 per year (95% CI: 15,335 to 25,301), decrease total healthcare costs by 137 million per year (95% CI: 106 million to 170 million), with a net monetary benefit (at 20,000 per QALY) of 546 million per year (95% CI: 435 million to 671 million).
Between 1993 and 2017 in England and Wales, the increase in BMI of people aged 40 to 69 years led to a decrease of 1.13% of a QALY per person per year (95% CI: 0.90% to 1.38%) and an increase in annual healthcare costs of 69 per person (95% CI: 53 to 84).
Compared to if all people with a BMI above 25 kg/m2 aged 40 to 69 years in England and Wales in 2017 had a BMI of 25 kg/m2, QALYs are decreased by 580,494 in total per year (95% CI: 457,907 to 717,691) and annual healthcare costs are increased by 3.58 billion (95% CI: 2.75 billion to 4.34 billion).
Conclusions
Mendelian randomization can be used to estimate the impact of interventions on quality of life and healthcare costs. The effect of increasing BMI on health-related quality of life is much larger when accounting for 240 chronic health conditions, compared with only a limited selection.
Colorectal cancer in patients with single versus double positive faecal immunochemical test results: A retrospective cohort study
Authors: Lim Tian-Zhi , Lau Jerrald , Wong Gretel Jianlin , Tan Ker-Kan
Published: May 2020

BACKGROUND
Screening for colorectal cancer (CRC) using the faecal immunochemical test (FIT) is widely advocated. Few studies have compared the rate of detecting colonoscopic pathologies in single compared to double FIT-positive follow-up colonoscopy-compliant individuals in a two-sample national FIT screening program.

OBJECTIVE
To compare CRC incidence in double FIT-positive versus single FIT-positive individuals using a retrospective cohort of patients from a tertiary hospital in Singapore.

DESIGN
Retrospective cohort study.

SETTING
Data was extracted from one regional acute hospital in Singapore.

PARTICIPANTS
1,539 FIT-positive individuals from the national FIT screening program who were referred to the hospital from 1st January 2017 to 31st September 2019 for follow-up consultation and diagnostic colonoscopy.

MEASUREMENTS
The exposure of interest was a positive result on both FIT kits. The main outcome was a follow-up diagnostic colonoscopy finding of CRC. The secondary outcome was a diagnostic colonoscopy finding of a colorectal polyp.

RESULTS
Incidence density of CRC was 1.53 (95% CI = 0.61, 3.15) and 17.88 (95% CI = 11.67, 26.19) per 100,000 person-months, in the single and double FIT-positive group, respectively. This resulted in an incidence rate ratio of 11.71 (95% CI = 5.25, 29.08). Colorectal polyp detection was significantly higher (p < 0.01) in the double (107 of 157 participants; 68.2%) compared to the single (310 of 585 participants; 53.0%) FIT-positive group.

LIMITATIONS
The key limitation of this study was the relatively small cohort derived from a single regional hospital, as this had the effect of limiting the number of incident cases, resulting in comparatively imprecise CIs.

CONCLUSIONS
Double FIT-positive individuals are significantly more likely to have a colonoscopy finding of incident CRC or premalignant polyp than single FIT-positive individuals. Clinicians and policymakers should consider updating their CRC screening protocols accordingly.
Targeting the latent human cytomegalovirus reservoir with virus specific nanobodies
Authors: De Groof Timo W.M. , Elder Elizabeth G. , Heukers Raimond , Lim Eleanor Y. , Wills Mark , Sinclair John H. , Smit Martine J.
Published: May 2020

Latent reservoirs of viral pathogens are significant barriers to eradication of these viruses. During latency, herpesviruses maintain their genome, with little gene expression, making latent infections refractory to current treatments targeting viral replication. In the case of human cytomegalovirus (HCMV), sporadic reactivation events are well controlled by the immune system. However, in immunocompromised or immunosuppressed individuals, HCMV reactivation often results in morbidity in solid organ and stem cell transplant patients. Clearance of the latent reservoir could lower the incidence and severity of HCMV-associated disease. Here, we develop a virus specific nanobody (VUN100b) that partially inhibits signaling of the viral receptor US28. VUN100b treatment partially reverses latency without fully reactivating the virus. Moreover, VUN100b treatment drives recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals. This study shows the potential of VUN100b as a therapy to clear the HCMV latent reservoir of transplant patients.
Global view on virus infection in non-human primates and implication for public health and wildlife conservation
Authors: Liu Zhijin
Published: May 2020

The pandemic outbreak and rapid worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not only a threat for humans, but potentially also for many animals. Research has revealed that SARS-CoV-2 and other coronaviruses have been transmitted from animals to humans andvice versa, and across animal species, and hence, attracted public attention concerning host-virus interactions and transmission ways. Non-human primates (NHPs), as our evolutionary closest relatives, are susceptible to human viruses, and a number of pathogens are known to circulate between humans and NHPs. Here we generated global statistics of virus infection in NHPs (VI-NHPs). In total, 121 NHP species from 14 families have been reported to be infected by 139 DNA and RNA viruses from 23 virus families; 74.8 percent of viruses in NHPs have also been found in humans, indicative of the high potential for cross species transmission of these viruses. The top ten NHP species with high centrality in the NHP-virus network are two apes (Pan troglodytes, Pongo pygmaeus), seven Old World monkeys (Macaca mulatta, M. fascicularis, Papio cynocephalus, Lophocebus albigena, Chlorocebus aethiops, Cercopithecus ascanius, C. nictitans) and a lemur (Propithecus diadema). Besides apes, there is a high risk of virus circulation between humans and Old World monkeys, given the wide distribution of many Old World monkey species and their frequent contact with humans. We suggest epidemiological investigations in NHPs, specifically in Old World monkeys with close contact to humans, and other effective measures to prevent this potential circular transmission.
Cell-extracellular matrix interactions in the fluidic phase direct the topology and polarity of self-organized epithelial structures
Authors: Ouyang Mingxing , Yu Jiun-Yann , Chen Yenyu , Deng Linhong , Guo Chin-Lin
Published: May 2020

In vivo,cells are surrounded by extracellular matrix (ECM). To build organs from single cells, it is generally believed that ECM serves as scaffolds to coordinate cell positioning and differentiation. Nevertheless, how cells utilize cell-ECM interactions for the spatiotemporal coordination to different ECM at the tissue scale is not fully understood. Here, usingin vitroassay with engineered MDCK cells expressing H2B-mCherry (nucleus) and gp135/Podocalyxin-GFP (apical marker), we show in multi-dimensions that such coordination for epithelial morphogenesis can be determined by cell-soluble ECM interaction in the fluidic phase. The coordination depends on the native topology of ECM components such as sheet-like basement membrane (BM) and type I collagen (COL) fibers: scaffold formed by BM (COL) facilitates a close-ended (open-ended) coordination that leads to the formation of lobular (tubular) epithelium. Further, cells form apicobasal polarity throughout the entire lobule/tubule without a complete coverage of ECM at the basal side, and time-lapse two-photon scanning imaging reveals the polarization occurring early and maintained through the lobular expansion. During polarization, gp135-GFP was converged to the apical surface collectively in the lobular/tubular structures, suggesting possible intercellular communications. Under suspension culture, the polarization was impaired with multi-lumen formation in the tubules, implying the importance of ECM biomechanical microenvironment. Our results suggest a biophysical mechanism for cells to form polarity and coordinate positioning at tissue scale, and in engineering epithelium through cell-soluble ECM interaction and self-assembly.
An atlas of Arabidopsis protein S-Acylation reveals its widespread role in plant cell organisation of and function
Authors: Kumar Manoj , Carr Paul , Turner Simon
Published: May 2020

S-acylation is the addition of a fatty acid to a cysteine residue of a protein. While this modification may profoundly alter protein behaviour, its effects on the function of plant proteins remains poorly characterised, largely as a result to the lack of basic information regarding which proteins are S-acylated and where in the proteins the modification occurs. In order to address this gap in our knowledge, we have performed a comprehensive analysis of plant protein S-acylation from 6 separate tissues. In our highest confidence group, we identified 5185 cysteines modified by S-acylation, which were located in 4891 unique peptides from 2643 different proteins. This represents around 9% of the entire Arabidopsis proteome and suggests an important role for S-acylation in many essential cellular functions including trafficking, signalling and metabolism. To illustrate the potential of this dataset, we focus on cellulose synthesis and confirm for the first time the S-acylation of all proteins known to be involved in cellulose synthesis and trafficking of the cellulose synthase complex. In the secondary cell walls, cellulose synthesis requires three different catalytic subunits (CESA4, CESA7 and CESA8) that all exhibit striking sequence similarity. While all three proteins have been widely predicted to possess a RING-type zinc finger at their N-terminus, for CESA4 and CESA8, we find evidence for S-acylation of cysteines in this region that is incompatible with any role in coordinating metal ions. We show that while CESA7 may possess a RING type domain, the same region of CESA4 and CESA8 appear to have evolved a very different structure. Together, the data suggests this study represents an atlas of S-acylation in Arabidopsis that will facilitate the broader study of this elusive post-translational modification in plants as well as demonstrates the importance of undertaking further work in this area.
Mutations in Tomato ACC Synthase2 Uncover Its Role in Development beside Fruit Ripening
Authors: Sharma Kapil , Gupta Soni , Sarma Supriya , Rai Meenakshi , Sreelakshmi Yellamaraju , Sharma Rameshwar
Published: May 2020

The role of ethylene in plant development is mostly inferred from its exogenous application. The usage of the mutants affecting ethylene biosynthesis proffers a better alternative to decipher its role. In tomato, 1-aminocyclopropane carboxylic acid synthase2 (ACS2) is a key enzyme regulating ripening-specific ethylene biosynthesis. We characterized two contrastingacs2mutants;acs2-1overproduces ethylene, has higher ACS activity, and increased protein levels, whileacs2-2is an ethylene under-producer, displays lower ACS activity, and protein levels than wild type. Consistent with high/low ethylene emission, the mutants show opposite phenotypes, physiological responses, and metabolomic profiles than the wild type. Theacs2-1showed early seed germination, faster leaf senescence, and accelerated fruit ripening. Conversely,acs2-2had delayed seed germination, slower leaf senescence, and prolonged fruit ripening. The phytohormone profiles of mutants were mostly opposite in the leaves and fruits. The faster/slower senescence ofacs2-1/acs2-2leaves correlated with the endogenous ethylene/zeatin ratio. The genetic analysis showed that the metabolite profiles of respective mutants co-segregated with the homozygous mutant progeny. Our results uncover that besides ripening, ACS2 participates in vegetative and reproductive development of tomato. The distinct influence of ethylene on phytohormone profiles indicates intertwining of ethylene action with other phytohormones in regulating plant development.
Range reduction of the Oblong Rocksnail,Leptoxis compacta, shapes riverscape genetic patterns
Authors: Wright Aaliyah D. , Garrison Nicole L. , Williams Ashantye’ S. , Johnson Paul D. , Whelan Nathan V.
Published: May 2020

Many freshwater gastropod species face extinction, including 79% of species in the family Pleuroceridae. The Oblong Rocksnail,Leptoxis compacta, is a narrow range endemic pleurocerid from the Cahaba River basin in central Alabama that has seen rapid range contraction in the last 100 years. Such a decline is expected to negatively affect genetic diversity in the species. However, precise patterns of genetic variation and gene flow across the restricted range ofL. compactaare unknown. This lack of information limits our understanding of human impacts on the Cahaba River system and Pleuroceridae. Here, we show thatL. compactahas likely seen a species-wide decline in genetic diversity, but remaining populations have relatively high genetic diversity. We also report a contemporary range extension compared to the last published survey.Leptoxis compactadoes not display an isolation by distance pattern, contrasting patterns seen in many riverine taxa. Our findings also indicate that historical range contraction has resulted in the absence of common genetic patterns seen in many riverine taxa like isolation by distance as the small distribution ofL. compactaallows for relatively unrestricted gene flow across its remaining range despite limited dispersal abilities. Two collection sites had higher genetic diversity than others, and broodstock sites for future captive propagation and reintroduction efforts should utilize sites identified here as having the highest genetic diversity. Broadly, our results support the hypothesis that range contraction will result in the reduction of species-wide genetic diversity, and common riverscape genetic patterns cannot be assumed to be present in species facing extinction risk.
Comment on Pescott & Jitlal 2020: Failure to account for measurement error undermines their conclusion of a weak impact of nitrogen deposition on plant species richness
Authors: Smart SM , Stevens CJ , Tomlinson SJ , Maskell LC , Henrys PA
Published: May 2020

Estimation of the impacts of atmospheric nitrogen (N) deposition on ecosystems and biodiversity is a research imperative. Analyses of large-scale spatial gradients, where an observed response is correlated with measured or modelled deposition, have been an important source of evidence. A number of problems beset this approach. For example, if responses are spatially aggregated then treating each location as statistically independent can lead to biased confidence intervals and a greater probably of false positive results.

Using sophisticated methods that account for residual spatial autocorrelation Pescott & Jitlal (2020) re-analysed two large-scale spatial gradient datasets from Britain where modelled N deposition at 5×5km resolution had been previously correlated with species richness in small quadrats. They found that N deposition effects were weaker than previously demonstrated leading them to conclude that“..previous estimates of Ndep impacts on richness from space-for-time substitution studies are likely to have been over-estimated”. We use a simple simulation study to show that their conclusion is flawed. They failed to recognise that an influential fraction of the residual spatially structured variation could itself be attributable to N deposition. This arises because the covariate used was modelled N deposition at 5×5km resolution leaving open the possibility that measured or modelled N deposition at finer resolutions could explain more variance in the response. Explicitly treating this as spatially auto-correlated error ignores this possibility and leads directly to their unreliable conclusion. We further demonstrate the plausibility of this scenario by showing that significant variation in N deposition at the 1km square resolution is indeed averaged at 5×5km resolution.

Further analyses are required to explore whether estimation of the size of the N deposition effect on plant species richness and other measures of biodiversity is indeed dependent on the accuracy and hence measurement error of the N deposition covariate. Until then the conclusions of Pescott & Jitlal (2020) should be considered premature and not proven.
Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein
Authors: Zost Seth J. , Gilchuk Pavlo , Chen Rita E. , Case James Brett , Reidy Joseph X. , Trivette Andrew , Nargi Rachel S. , Sutton Rachel E. , Suryadevara Naveenchandra , Chen Elaine C. , Binshtein Elad , Shrihari Swathi , Ostrowski Mario , Chu Helen Y. , Didier Jonathan E. , MacRenaris Keith W. , Jones Taylor , Day Samuel , Myers Luke , Lee F. Eun-Hyung , Nguyen Doan C. , Sanz Ignacio , Martinez David R. , Baric Ralph S. , Thackray Larissa B. , Diamond Michael S. , Carnahan Robert H. , Crowe James E.
Published: May 2020

Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date1,2. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes based on their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of new antibody discovery methodologies.
Deep learning enables genetic analysis of the human thoracic aorta
Authors: Pirruccello James P. , Chaffin Mark D. , Fleming Stephen J. , Arduini Alessandro , Lin Honghuang , Khurshid Shaan , Chou Elizabeth L. , Friedman Samuel N. , Bick Alexander G. , Weng Lu-Chen , Choi Seung Hoan , Akkad Amer-Denis , Batra Puneet , Tucker Nathan R. , Hall Amelia W. , Roselli Carolina , Benjamin Emelia J. , Vellarikkal Shamsudheen K. , Gupta Rajat M. , Stegman Christian M. , Ho Jennifer E. , Hoffmann Udo , Lubitz Steven A. , Philippakis Anthony , Lindsay Mark E. , Ellinor Patrick T.
Published: May 2020

The aorta is the largest blood vessel in the body, and enlargement or aneurysm of the aorta can predispose to dissection, an important cause of sudden death. While rare syndromes have been identified that predispose to aortic aneurysm, the common genetic basis for the size of the aorta remains largely unknown. By leveraging a deep learning architecture that was originally developed to recognize natural images, we trained a model to evaluate the dimensions of the ascending and descending thoracic aorta in cardiac magnetic resonance imaging. After manual annotation of just 116 samples, we applied this model to 3,840,140 images from the UK Biobank. We then conducted a genome-wide association study in 33,420 individuals, revealing 68 loci associated with ascending and 35 with descending thoracic aortic diameter, of which 10 loci overlapped. Integration of common variation with transcriptome-wide analyses, rare-variant burden tests, and single nucleus RNA sequencing prioritizedSVIL, a gene highly expressed in vascular smooth muscle, that was significantly associated with the diameter of the ascending and descending aorta. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in the remaining 391,251 UK Biobank participants who did not undergo imaging (HR = 1.44 per standard deviation; P = 3.7·10−12). Defining the genetic basis of the diameter of the aorta may enable the identification of asymptomatic individuals at risk for aneurysm or dissection and facilitate the prioritization of potential therapeutic targets for the prevention or treatment of aortic aneurysm. Finally, our results illustrate the potential for rapidly defining novel quantitative traits derived from a deep learning model, an approach that can be more broadly applied to biomedical imaging data.
Promiscuous enzymes cooperate at the substrate level en route to lactazole A
Authors: Vinogradov Alexander A. , Shimomura Morito , Kano Naokazu , Goto Yuki , Onaka Hiroyasu , Suga Hiroaki
Published: May 2020

Enzymes involved in ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthesis often have relaxed specificity profiles and are able to modify diverse substrates. When several such enzymes act together during precursor peptide maturation, a multitude of products can form, and yet usually, the biosynthesis converges on a single natural product. For the most part, the mechanisms controlling the integrity of RiPP assembly remain elusive. Here, we investigate biosynthesis of lactazole A, a model thiopeptide produced by five promiscuous enzymes from a ribosomal precursor peptide. Using ourin vitrothiopeptide production (FIT-Laz) system, we determine the order of biosynthetic events at the individual modification level, and supplement this study with substrate scope analysis for participating enzymes. Combined, our results reveal a dynamic thiopeptide assembly process with multiple points of kinetic control, intertwined enzymatic action, and the overall substrate-level cooperation between the enzymes. This work advances our understanding of RiPP biosynthesis processes and facilitates thiopeptide bioengineering.
Tracing two causative SNPs reveals SARS-CoV-2 transmission in North America population
Authors: Ou Xumin , Yang Zhishuang , Zhu Dekang , Mao Sai , Wang Mingshu , Jia Renyong , Chen Shun , Liu Mafeng , Yang Qiao , Wu Ying , Zhao Xinxin , Zhang Shaqiu , huang Juan , Gao Qun , Liu Yunya , Zhang Ling , Peopplenbosch Maikel , Pan Qiuwei , Cheng Anchun
Published: May 2020

During the COVID-19 pandemic, precisely tracing the route of the SARS-CoV-2 transmission in human population remains challenging. Because this RNA virus can mutate massively without a specifically tracing maker. Herein, using a geographic stratified genome-wide association study (GWAS) of 2599 full-genome sequences, we identified that two SNPs (i.e., 1059.C>T and 25563.G>T) of linkage disequilibrium were presented in approximately half of North America SARS-CoV-2 population (p = 2.44 x 10−212and p = 2.98 x 10−261), resulting two missense mutations (i.e., Thr 265 Ile and Gln 57 His) in ORF1ab and ORF3a, respectively. Interestingly, these two SNPs exclusively occurred in the North America dominated clade 1, accumulated during mid to late March, 2020. We did not find any of these two SNPs by retrospectively tracing the two SNPs in bat and pangolin related SARS-CoV-2 and human SARS-CoV-2 from the first epicenter Wuhan or other regions of China mainland. This suggested that the SARS-CoV-2 population of Chinese mainland were different from the prevalent strains of North America. Time-dependently, we found that these two SNPs first occurred in Europe SARS-CoV-2 (26-Feb-2020) which was 3 days early than the occurring date of North America isolates and 17 days early for Asia isolates (Taiwan China dominated). Collectively, this population genetic analysis highlights a well-confidential transmission route of the North America isolates and the two SNPs we newly identified are possibly novel diagnosable or druggable targets for surveillance and treatment.
Structure of SARS-CoV-2 main protease in the apo state reveals the inactive conformation
Authors: Zhou Xuelan , Zhong Fangling , Lin Cheng , Hu Xiaohui , Zhang Yan , Xiong Bing , Yin Xiushan , Fu Jinheng , He Wei , Duan Jingjing , Fu Yang , Zhou Huan , Wang Qisheng , Li Jian , Zhang Jin
Published: May 2020

Mprois of considerable interest as a drug target in the treatment of COVID-19 since the proteolytic activity of this viral protease is essential for viral replication. Here we report the first insight of the structure Mprofor SARS-CoV-2 in the inactive conformation under conditions close to the physiological state (pH 7.5) to an overall resolution of 1.9 Å. The comparisons of Mproin different states reveal that substrate binding site and the active site are more flexible in the inactive conformation than that in the active conformations. Notably, compared with the active conformation of the apo state structure in pH7.6 of SARS, the SARS-CoV-2 apo state is in the inactive conformation under condition close to physiological state (pH7.5). Two water molecules are present in the oxyanion hole in our apo state structure, whereas in the ligand-bound structure, water molecular is absence in the same region. This structure provides novel and important insights that have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational, structure-based, approaches for the design of specific SARS-CoV-2 ligands as new therapeutic agents.
Splicing factor SRSF1 expands the regulatory logic of microRNA expression
Authors: Dargyte Marija , Philipp Julia , Palka Christina D. , Stone Michael D. , Sanford Jeremy R.
Published: May 2020

The serine and arginine-rich splicing factor SRSF1 is an evolutionarily conserved, essential pre-mRNA splicing factor. Through a global protein-RNA interaction survey we discovered SRSF1 binding sites 25-50nt upstream from hundreds of pre-miRNAs. Using primary miRNA-10b as a model we demonstrate that SRSF1 directly regulates microRNA biogenesis bothin vitroandin vivo. Selective 2’ hydroxyl acylation analyzed by primer extension (SHAPE) defined a structured RNA element located upstream of the precursor miRNA-10b stem loop. Our data support a model where SRSF1 promotes initial steps of microRNA biogenesis by relieving the repressive effects ofcis-regulatory elements within the leader sequence.
Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients
Authors: Joyner Michael , Wright R. Scott , Fairweather DeLisa , Senefeld Jonathon , Bruno Katelyn , Klassen Stephen , Carter Rickey , Klompas Allan , Wiggins Chad , Shepherd John RA , Rea Robert , Whelan Emily , Clayburn Andrew , Spiegel Matthew , Johnson Patrick , Lesser Elizabeth , Baker Sarah , Larson Kathryn , Ripoll Sanz Juan , Andersen Kylie , Hodge David , Kunze Katie , Buras Matthew , Vogt Matthew , Herasevich Vitaly , Dennis Joshua , Regimbal Riley , Bauer Philippe , Blair Janis , van Buskirk Camille , Winters Jeffrey , Stubbs James , Paneth Nigel , Casadevall Arturo
Published: May 2020

Background: Convalescent plasma is the only antibody based therapy currently available for COVID-19 patients. It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19. Methods: Thus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5,000 hospitalized adults with severe or life threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma. Results: The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (TACO; n=7), transfusion-related acute lung injury (TRALI; n=11), and severe allergic transfusion reactions (n=3). However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The seven-day mortality rate was 14.9%. Conclusion: Given the deadly nature of COVID-19 and the large population of critically-ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.