bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysregulated immunity in SARS-CoV-2 infected pregnant women
Authors: Sherer Morgan L. , Lei Jun , Creisher Patrick , Jang Minyoung , Reddy Ramya , Voegtline Kristin , Olson Sarah , Littlefield Kirsten , Park Han-Sol , Ursin Rebecca L. , Ganesan Abhinaya , Boyer Theresa , Brown Diane M. , Walch Samantha N. , Antar Annukka A. R. , Manabe Yukari C. , Jones-Beatty Kimberly , Golden William Christopher , Satin Andrew J. , Sheffield Jeanne S. , Pekosz Andrew , Klein Sabra L. , Burd Irina
Published: November 2020

Importance

The effects of SARS-CoV-2 infection on immune responses during pregnancy have not been systematically evaluated.

Objective

To assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women.

Design

Immune responses to SARS-CoV-2 were analyzed using samples from pregnant and non-pregnant women who had either tested positive or negative for SARS-CoV-2. We measured, proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) receptor expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we measured anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood.

Setting

Johns Hopkins Hospital (JHH)

Participants

Pregnant women were recruited through JHH outpatient obstetric clinics and the JHH Labor & Delivery unit. Non-pregnant women were recruited after receiving outpatient SARS-CoV-2 testing within Johns Hopkins Health System, USA. Adult non-pregnant women with positive RT-PCR results for SARS-CoV-2, within the age range of 18-48 years, were included in the study.

Exposures

SARS-CoV-2

Main Outcomes and Measures

Participant demographic characteristics, antibody titers, cytokine mRNA expression, and FcRn receptor expression.

Results

SARS-COV-2 positive pregnant women expressed more IL1β, but not IL6, in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test, with similar patterns observed in the fetal side of placentas, particularly among asymptomatic pregnant women. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of nAb was inhibited by SARS-CoV-2 infection during pregnancy.

Conclusions and Relevance

SARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.
Molecular and spectroscopic characterization of green and red cyanine fluorophores from the Alexa Fluor and AF series
Authors: Gebhardt Christian , Lehmann Martin , Reif Maria M. , Zacharias Martin , Cordes Thorben
Published: November 2020

The use of fluorescence techniques has had an enormous impact on various research fields including imaging, biochemical assays, DNA-sequencing and medical technologies. This has been facilitated by the availability of numerous commercial dyes, but often information about the chemical structures of dyes (and their linkers) are a well-kept secret. This can lead to problems for applications where a knowledge of the dye structure is necessary to predict (unwanted) dye-target interactions, or to establish structural models of the dye-target complex. Using a combination of spectroscopy, mass spectrometry and molecular dynamics simulations, we here investigate the molecular structures and spectroscopic properties of dyes from the Alexa Fluor (Alexa Fluor 555 and 647) and AF series (AF555, AF647, AFD647). Based on available data and published structures of the AF and Cy dyes, we present two possible structures for Alexa Fluor 555. We also resolve conflicting reports on the linker composition of Alexa Fluor 647. A comprehensive comparison between Alexa Fluor and AF dyes by continuous-wave absorption and emission spectroscopy, quantum yield determination, fluorescence lifetime and anisotropy spectroscopy of free and protein-attached dyes, supports the suggestion that the Alexa Fluor and AF dyes have a high degree of structural similarity. In addition, we compared Alexa Fluor 555 and Alexa Fluor 647 to their structural homologs AF555 and AF(D)647 in single-molecule FRET applications. Both pairs showed excellent performance in solution-based smFRET experiments using alternating laser excitation demonstrating that the AF-fluorophores are an attractive alternative to Alexa- and Cy-dyes for smFRET studies, and suggesting their usefulness for other fluorescence applications.
In silicoinvestigation ofAedes aegyptimale-determining factor (NIX): RNA recognition motif-3, structural model and selective nucleic acid binding mode
Authors: Coronado Monika A. , Olivier Danilo S. , Borsatto Kelly C. , Amaral Marcos S. , Arni Raghuvir K. , Eberle Raphael J.
Published: November 2020

Mosquito borne viruses and their corresponding human infections have a fast growing impact on worldwide public health systems; in particular,Aedes aegyptiandAedes albopictusare transmitting these viruses. Only female mosquitoes bite and spread diseases. Male development inA. aegyptiis initiated by male determining factors. These factors are potential candidates for the implementation of vector control strategies. Where at an early stage in gender development female mosquitoes are converted into harmless males. Among these factors, a novel gene, NIX, has been identified that shares moderate identity with transformer-2, one of the key sex-determination genes inDrosophila melanogaster. Hall et al. 2015 described two RNA recognition motifs (RRMs) in the NIX sequence, but a UniProt database search showed thatA. aegyptiNIX contains three RNA RRM. A homology model of NIX_RRM-3 was generated to investigate the interaction with RNA using molecular dynamics simulations. The sequence AGACGU was the most interesting result. During the binding process A1, G2 and G5 adopt an unusualsynconformation. The results let assume that the C-terminus of NIX_RRM-3 is involved in the recognition process of the target RNA motif (e.g. AG) and controls the interaction between target RNA andA. aegyptiNIX.
Synaptic plasticity regulated by phosphorylation of PSD-95 Serine 73 in dorsal CA1 is required for contextual fear extinction
Authors: Ziółkowska Magdalena , Borczyk Malgorzata , Nowacka Agata , Nalberczak-Skóra Maria , Śliwińska Małgorzata Alicja , Robacha Magdalena , Łukasiewicz Kacper , Cały Anna , Skonieczna Edyta , Tomaszewski Kamil F. , Wójtowicz Tomasz , Włodarczyk Jakub , Bernaś Tytus , Salamian Ahmad , Radwanska Kasia
Published: November 2020

The ability to extinguish fearful memories is essential for survival. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular basis of fear memory extinction remains poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic and chemogenetic manipulationsin vivocombined with PSD-95 immunostaining and 3D electron microscopyex vivo, we demonstrate that phosphorylation of PSD-95 at serine 73 PSD-95(S73) is necessary for contextual fear extinction-induced expression of PSD-95 and synaptic plasticity. Moreover, PSD-95(S73) phosphorylation is not necessary for fear memory formation and recall but is required for extinction of contextual fear. Overall, our data shows how PSD-95-dependent synaptic plasticity in the hippocampus contributes to the persistence of fear memories.
SMC Complexes Are Guarded by the SUMO Protease Ulp2 Against SUMO-Chain-Mediated Turnover
Authors: Psakhye Ivan , Branzei Dana
Published: November 2020

Structural maintenance of chromosomes (SMC) complexes, cohesin, condensin and Smc5/6, are essential for viability and participate in multiple processes, including sister chromatid cohesion, chromosome condensation, and DNA repair. Here we show that SUMO chains target all three SMC complexes and are antagonized by the SUMO protease Ulp2 to prevent their turnover. We uncover that the essential role of the cohesin-associated subunit Pds5 is to counteract SUMO chains jointly with Ulp2. Importantly, fusion of Ulp2 to kleisin Scc1 supports viability ofPDS5null cells and protects cohesin from proteasomal degradation mediated by the SUMO-targeted ubiquitin ligase Slx5/Slx8. The lethality ofPDS5deleted cells can also be bypassed by simultaneous loss of the PCNA unloader, Elg1, and the cohesin releaser, Wpl1, but only when Ulp2 is functional. Condensin and Smc5/6 complex are similarly guarded by Ulp2 against unscheduled SUMO-chain assembly, which we propose to time the availability of SMC complexes on chromatin.
Extracellular glutamate and GABA transients at the transition from interictal spiking to seizures
Authors: Shimoda Yoshiteru , Leite Marco , Graham Robert T , Marvin Jonathan S , Hasseman Jeremy , Kolb Ilya , Looger Loren L , Magloire Vincent , Kullmann Dimitri M
Published: November 2020

Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transients lasted longer than glutamate transients and were maximal ∼1.5 mm from the focus where they propagated centripetally. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing seizures to escape from local inhibitory restraint.
Alzheimer's-associated upregulation of mitochondria-associated ER membranes after traumatic brain injury
Authors: Agrawal Rishi R , Larrea Delfina , Xu Yimeng , Shi Lingyan , Zirpoli Hylde , Cummins Leslie G , Emmanuele Valentina , Song Donghui , Yun Taekyung D , Macaluso Frank P , Min Wei , Kernie Steven G , Deckelbaum Richard J , Area-Gomez Estela
Published: November 2020

Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-beta; as well as its precursor, APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated ER membranes (MAM domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD.
Design of intrinsically disordered proteins that undergo phase transitions with lower critical solution temperatures
Authors: Zeng Xiangze , Liu Chengwen , Fossat Martin J. , Ren Pengyu , Chilkoti Ashutosh , Pappu Rohit V.
Published: November 2020

Many naturally occurring elastomers are intrinsically disordered proteins (IDPs) built up of repeating units and they can demonstrate two types of thermoresponsive phase behavior. Systems characterized by lower critical solution temperatures (LCST) undergo phase separation above the LCST whereas systems characterized by upper critical solution temperatures (UCST) undergo phase separation below the UCST. There is congruence between thermoresponsive coil-globule transitions and phase behavior whereby the theta temperatures above or below which the IDPs transition from coils to globules serve as useful proxies for the LCST / UCST values. This implies that one can design sequences with desired values for the theta temperature with either increasing or decreasing radii of gyration above the theta temperature. Here, we show that the Monte Carlo simulations performed in the so-called intrinsic solvation (IS) limit version of the temperature-dependent the ABSINTH (self-Assembly of Biomolecules Studied by an Implicit, Novel, Tunable Hamiltonian) implicit solvation model, yields a useful heuristic for discriminating between sequences with known LCST versus UCST phase behavior. Accordingly, we use this heuristic in a supervised approach, integrate it with a genetic algorithm, combine this with IS limit simulations, and demonstrate that novel sequences can be designed with LCST phase behavior. These calculations are aided by direct estimates of temperature dependent free energies of solvation for model compounds that are derived using the polarizable AMOEBA (atomic multipole optimized energetics for biomolecular applications) forcefield. To demonstrate the validity of our designs, we calculate coil-globule transition profiles using the full ABSINTH model and combine these with Gaussian Cluster Theory calculations to establish the LCST phase behavior of designed IDPs.
Playbacks of Food-associated Calls Attract Chimpanzees Towards Known Food Patches in a Captive Setting
Authors: O’Bryan Lisa R. , Lambeth Susan P. , Schapiro Steven J. , Wilson Michael L.
Published: November 2020

Food-associated calls have attracted much research attention due to their potential to refer to discovered food in a word-like manner. Nevertheless, their effect on receiver behavior remains unclear for many species. While some studies suggest that food-associated calls attract other foragers, other studies indicate that they repel others. We conducted playback studies to differentiate between these two hypotheses for the function of the chimpanzee (Pan troglodytes) food-associated ‘rough grunt’. We tested how acoustic playbacks of rough grunts (or control calls) from one of two known, identical food patches affected receivers’ foraging decisions in a captive setting. We found that participants were more likely than chance to first investigate the patch from which rough-grunts, but not control calls, were broadcast. However, neither condition increased the likelihood that participants fed first from a given patch. Our results support the hypothesis that rough-grunts attract receivers. However, since receivers were already aware of the presence of food, our results question whether rough-grunts attract by conveying information about discovered food, or rather, the signaler’s motivational state.
ISA API: An open platform for interoperable life science experimental metadata
Authors: Johnson David , Cochrane Keeva , Davey Robert P. , Etuk Anthony , Gonzalez-Beltran Alejandra , Haug Kenneth , Izzo Massimiliano , Larralde Martin , Lawson Thomas N. , Minotto Alice , Moreno Pablo , Nainala Venkata Chandrasekhar , O’Donovan Claire , Pireddu Luca , Roger Pierrick , Shaw Felix , Steinbeck Christoph , Weber Ralf J. M. , Sansone Susanna-Assunta , Rocca-Serra Philippe
Published: November 2020

Background

The Investigation/Study/Assay (ISA) Metadata Framework is an established and widely used set of open-source community specifications and software tools for enabling discovery, exchange and publication of metadata from experiments in the life sciences. The original ISA software suite provided a set of user-facing Java tools for creating and manipulating the information structured in ISA-Tab – a now widely used tabular format. To make the ISA framework more accessible to machines and enable programmatic manipulation of experiment metadata, a JSON serialization ISA-JSON was developed.

Results

In this work, we present the ISA API, a Python library for the creation, editing, parsing, and validating of ISA-Tab and ISA-JSON formats by using a common data model engineered as Python object classes. We describe the ISA API feature set, early adopters and its growing user community.

Conclusions

The ISA API provides users with rich programmatic metadata handling functionality to support automation, a common interface and an interoperable medium between the two ISA formats, as well as with other life science data formats required for depositing data in public databases.
Patient-specific iPSCs carrying anSFTPCmutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease
Authors: Alysandratos Konstantinos-Dionysios , Russo Scott J. , Petcherski Anton , Taddeo Evan P. , Acín-Pérez Rebeca , Villacorta-Martin Carlos , Jean J. C. , Mulugeta Surafel , Blum Benjamin C. , Hekman Ryan M. , Vedaie Marall , Kook Seunghyi , Wambach Jennifer A. , Cole F. Sessions , Hamvas Aaron , Emili Andrew , Guttentag Susan H. , Shirihai Orian S. , Beers Michael F. , Kotton Darrell N.
Published: November 2020

The incompletely understood pathogenesis of pulmonary fibrosis (PF) and lack of reliable preclinical disease models have limited development of effective therapies. An emerging literature now implicates alveolar epithelial type 2 cell (AEC2) dysfunction as an initiating pathogenic event in the onset of a variety of PF syndromes, including adult idiopathic pulmonary fibrosis (IPF) and childhood interstitial lung disease (chILD). However, inability to access primary AEC2s from patients, particularly at early disease stages, has impeded identification of disease-initiating mechanisms. Here we present anin vitroreductionist model system that permits investigation of epithelial-intrinsic events that lead to AEC2 dysfunction over time using patient-derived cells that carry a disease-associated variant,SFTPCI73T, known to be expressed solely in AEC2s. After generating patient-specific induced pluripotent stem cells (iPSCs) and engineering their gene-edited (corrected) counterparts, we employ directed differentiation to produce pure populations of syngeneic corrected and mutant AEC2s, which we expand >1015foldin vitro, providing a renewable source of cells for modeling disease onset. We find that mutant iPSC-derived AEC2s (iAEC2s) accumulate large amounts of misprocessed pro-SFTPC protein which mistrafficks to the plasma membrane, similar to changes observedin vivoin the donor patient’s AEC2s. These changes result in marked reduction in AEC2 progenitor capacity and several downstream perturbations in AEC2 proteostatic and bioenergetic programs, including a late block in autophagic flux, accumulation of dysfunctional mitochondria with consequent time-dependent metabolic reprograming from oxidative phosphorylation to glycolysis, and activation of an NF-κB dependent inflammatory response. Treatment ofSFTPCI73Texpressing iAEC2s with hydroxychloroquine, a medication commonly prescribed to these patients, results in aggravation of autophagy perturbations and metabolic reprogramming. Thus, iAEC2s provide a patientspecific preclinical platform for modeling the intrinsic epithelial dysfunction associated with the inception of interstitial lung disease.
An open-access volume electron microscopy atlas of whole cells and tissues
Authors: Xu C. Shan , Pang Song , Shtengel Gleb , Müller Andreas , Ritter Alex T. , Hoffman Huxley K. , Takemura Shin-ya , Lu Zhiyuan , Pasolli H. Amalia , Iyer Nirmala , Chung Jeeyun , Bennett Davis , Weigel Aubrey V. , Freeman Melanie , van Engelenburg Schuyler B. , Walther Tobias C. , Farese Robert V. , Lippincott-Schwartz Jennifer , Mellman Ira , Solimena Michele , Hess Harald F.
Published: November 2020

Understanding cellular architecture is essential for understanding biology. Electron microscopy (EM) uniquely visualizes cellular structures with nanometer resolution. However, traditional methods, such as thin-section EM or EM tomography, have limitations inasmuch as they only visualize a single slice or a relatively small volume of the cell, respectively. Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM) demonstrated the ability to image cellular samples at 4-nm isotropic voxels with rather limited imageable volume. Here, we present 3D EM images of whole cells and tissues with two orders of magnitude increases in imageable volume at 4-nm voxels. Such data with a combined fine resolution scale and large sample size do not currently exist, and are enabled by the advances in higher precision and stability of FIB milling, together with enhanced signal detection and faster SEM scanning. More importantly, we have generated a volume EM atlas encompassing ten diverse datasets of whole cells and tissues, from cancer cells to immune cells, and from mouse pancreatic islets toDrosophilaneural tissues. These open-access data (viaOpenOrganelle)represent a foundation to nucleate a new field of high-resolution whole-cell volume EM and subsequent analyses, and invite biologists to explore this new paradigm and pose fundamentally new questions.
methylscaper: an R/Shiny app for joint visualization of DNA methylation and nucleosome occupancy in single-molecule and single-cell data
Authors: Knight Parker , Gauthier Marie-Pierre L. , Pardo Carolina E. , Darst Russell P. , Riva Alberto , Kladde Michael P. , Bacher Rhonda
Published: November 2020

Differential DNA methylation and chromatin accessibility are associated with disease development, particularly cancer. Methods that allow profiling of these epigenetic mechanisms in the same reaction and at the single-molecule or single-cell level continue to emerge. However, a challenge lies in jointly visualizing and analyzing the heterogeneous nature of the data and extracting regulatory insight. Here, we developed methylscaper, a visualization framework for simultaneous analysis of DNA methylation and chromatin landscapes. Methylscaper implements a weighted principle component analysis that orders sequencing reads, each providing a record of the chromatin state of one epiallele, and reveals patterns of nucleosome positioning, transcription factor occupancy, and DNA methylation. We demonstrate methylscaper’s utility on a long-read, single-molecule methyltransferase accessibility protocol for individual templates (MAPit) dataset and a single-cell nucleosome, methylation, and transcription sequencing (scNMT-seq) dataset. In comparison to other procedures, methylscaper is able to readily identify chromatin features that are biologically relevant to transcriptional status while scaling to larger datasets.

Availability and implementation

Methylscaper, is available on GitHub athttps://github.com/rhondabacher/methylscaper.

Contact

rbacher@ufl.edu
Prediction of Covid-19 Infections Through December 2020 for 10 US States Incorporating Outdoor Temperature and School Re-Opening Effects-October Update
Authors: Newell Ty
Published: November 2020

Control of SARS-CoV-2 transmission requires control of two human behaviors. A two-parameter, human behavior Covid-19 infection growth model continues to accurately predict total infections based on gross human interaction and local human interaction behaviors for 10 US States (NY, WA, GA, IL, MN, FL, OH, MI, CA, NC). Since prediction model initiation on July 27, 2020, total infections for 8 states have grown by more than 200%. Only New York (23% infection growth) and Florida (189% infection growth) have grown less.

October displays combined impacts of increased social interactions as schools and businesses increase physical gatherings, coupled with climate dependent local interactions. The US, on average as of the end of October, has an Infection Parameter (IP) of 3.4 representing accelerating infection growth. Gross human interactions must be reduced by 15% or local interaction behavior (eg, face mask usage, ventilation) must be improved to reduce disease transmission efficiency by 27% in order to reach the linear infection growth boundary separating accelerating infection growth from decaying infection growth regions.

Eastern States (NY and NC) have had mild fall temperatures, which increases outdoor activities and increases building fresh air ventilation rates that suppress virus transmission efficiency. Mild temperatures in southern States (GA, FL and CA) during October have also helped suppress virus transmission. Midwest States experienced highly elevated infection rates due to combined effects of school openings coupled with a truncated fall season. WA stayed in the beneficial 70F (22C) to 50F (10C) zone through October, with minimal accelerated infection growth, but is now entering its heating season with average outdoor temperatures below 50F that are contributing to increased disease transmission efficiency.
Structural Investigation of Oat Protein Isolate in Aqueous Medium by using Synchrotron Small-angle X-ray Scattering
Authors: Li Ji , Huang Qingrong
Published: November 2020

Oat protein isolate (OPI) is among the plant proteins with valuable functionalities (e.g. emulsification) during daily supplement intake. Understanding their structures helps to manipulate oat proteins at small scale, which enables the appropriate deployment of their functions. Based upon such understanding, the molecular structure of oat protein isolate (OPI) in aqueous medium was investigated by synchrotron small-angle X-ray scattering (SAXS), and this study allows a structural reconstitution of OPI in aqueous medium. Besides, this SAXS study is complimentary to the previous study (Liu et al.J. Agric. Food Chem. 2009, 57, 4552–4558)1. From form factor fitting, we confirmed that OPI aqueous solutions at low concentrations (0.3~2 mg/mL) obtained a disk conformation (41.4×41.4×10.2 Å3). Once protein concentration increased to 5 mg/mL and 10 mg/mL, the individual disk proteins formed large-dimensional rodlike aggregates, which was evidenced by the analyses of effective structure factor and pair distribution function (PDF). Based on the PDF results, theab initiomodels of OPI particles at low concentrations (0.3 mg/mL to 2.0 mg/mL) were restored by using GASBOR algorithm. Finally, we found that weak attraction between OPI particles occurred, which was verified by second virial coefficient and pair potential.
Mammary ductal epithelium controls cold-induced adipocyte thermogenesis
Authors: Santos Luis C. , Arneson Douglas , Alvarsson Alexandra , Krishnan Karthickeyan Chella , Centzone Alessia , Patel Sanil , Sadeh Shani , Ahn In Sook , Diamante Graciel , Cely Ingrid , Butte Atul J. , Blanpain Cédric , Stanley Sarah A. , Lusis Aldons J. , Yang Xia , Rajbhandari Prashant
Published: November 2020

Sympathetic activation during cold exposure increases adipocyte thermogenesis via expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies among various fat depots2–7. Here we report that cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT) is regulated by mammary gland ductal epithelial cells in the adipose niche. Single cell RNA-sequencing (scRNA-seq) show that under cold condition glandular alveolar and hormone-sensing luminal epithelium subtypes express transcripts that encode secretory factors involved in regulating adipocyte UCP1 expression. We term mammary duct secretory factors as “mammokines”. Using whole-tissue immunofluorescence 3D visualization, we reveal previously undescribed sympathetic nerve-ductal points of contact and show that sympathetic nerve-activated mammary ducts limit adipocyte UCP1 expression via cold-induced mammokine production. Bothin vivoandex vivoablation of mammary ductal epithelium enhances cold-induced scWAT adipocyte thermogenic gene program. The mammary duct network extends throughout most scWATs in female mice, which under cold exposure show markedly less UCP1 expression, fat oxidation, energy expenditure, and subcutaneous fat mass loss compared to male mice. These results show a previously uncharacterized role of sympathetic nerve-activated glandular epithelium in adipocyte thermogenesis. Overall, our findings suggest an evolutionary role of mammary duct luminal cells in defending glandular adiposity during cold exposure, highlight mammary gland epithelium as a highly active metabolic cell type, and implicate a broader role of mammokines in mammary gland physiology and systemic metabolism.
3D architecture and structural flexibility revealed in the subfamily of large glutamate dehydrogenases by a mycobacterial enzyme
Authors: Lázaro Melisa , Melero Roberto , Huet Charlotte , López-Alonso Jorge P. , Delgado Sandra , Dodu Alexandra , Bruch Eduardo M. , Abriata Luciano A. , Alzari Pedro M. , Valle Mikel , Lisa María-Natalia
Published: November 2020

Glutamate dehydrogenases (GDHs) are widespread metabolic enzymes that play key roles in nitrogen homeostasis. Large glutamate dehydrogenases composed of 180 kDa subunits (L-GDHs180) contain long N- and C-terminal segments flanking the catalytic core. Despite the relevance of L-GDHs180in bacterial physiology, the lack of structural data for these enzymes has limited the progress of functional studies. Here we show that the mycobacterial L-GDH180(mL-GDH180) adopts a quaternary structure that is radically different from that of related low molecular weight enzymes. Intersubunit contacts in mL-GDH180involve a C-terminal domain that we propose as a new fold and a flexible N-terminal segment comprising ACT-like and PAS-type domains that could act as metabolic sensors for allosteric regulation. These findings uncover unique aspects of the structure-function relationship in the subfamily of L-GDHs.
In silico analysis of single nucleotide polymorphisms (SNPs) in human C-C chemokine receptor type five (CCR5) gene
Authors: Ali Asma Ali Hassan , Ibrahim Muntaser
Published: November 2020

Introduction

Chemokines are small transmembrane proteins with immune surveillance and immune cell recruitment functions. the expression of CCR5 gene affects virus production and viral load(1). The CCR5 gene contains two introns, three exons, and two promoters, and it is necessary as a co-receptor for the entry of the macrophage-tropic HIV strains. Mutations in the coding region of CCR5 affect the protein structure, which will affect production, chemokine binding, transport, signaling and expression of the CCR5 receptor.

Methods

SNPs within CCR5 gene were retrieved from ensemble database. Coding SNPs were analyzed using SNPnexus. Coding non-synonymous SNPs in CCR5 binding domains with Viral gp120 were analyzed using SIFT, PolyPhen and I-mutant tools. Project HOPE then used to modelled the 3D structure of the protein resulting from these SNPs. Non-coding SNPs that affects miRNAs in 3’ rejoin were analyzing using PolymiRTS. SNPs that affect transcription factor binding were analyzed using regulomeDB.

Results

(178) non-synonyms missense SNPs were found to have deleterious and damaging effect on the structure and function of the protein. In CCR5 binding domains with Viral gp120: 3 SNPs rs145061115, rs199824195 and rs201797884 were found to affect both structure and function and stability of chemokine protein. The 2 SNPs rs185691679 and rs199722070 has a role in disruption and creation of the target sites in miRNA seeds due to their high conservation score.

Conclusion

Mutations in CCR5 gene may explain and represent the molecular basis of the resistance to HIV infection.
A domestic plant differs from its wild relative along multiple axes of within-plant trait variability and diversity
Authors: Robinson Moria L. , Schilmiller Anthony L. , Wetzel William C.
Published: November 2020

For 10,000 years humans have altered plant traits through domestication and ongoing crop improvement, shaping plant form and function in agroecosystems. To date, studies have focused on how these processes have shaped whole-plant or average traits; however, plants also have characteristic levels of trait variability among their repeated parts, which can be heritable and mediate critical ecological interactions. As concerns about sustainable pest management increase, there is growing interest in approaches that increase trait diversity in crop agroecosystems. Here, we examine an under-appreciated scale of trait variation – among leaves, within plants – that may have changed through the process of domestication and improvement in a key crop.

We explore how levels of within-plant, among-leaf trait variability differ between cultivars and wild relatives of alfalfa (Medicago sativa), a key forage crop with an 8,000 year cultivation history. We grew individual plants from 30 wild populations and 30 cultivars, encompassing a range of domestication and improvement histories. For each plant, we quantify variability in a broad suite of physical, nutritive, and chemical leaf traits, including measures of chemical dissimilarity (beta diversity) among leaves.

We find that intra-individual trait variability has changed over the course of domestication and crop improvement, with effects often larger than changes in trait means. Cultivated alfalfa had elevated variability in SLA, trichomes, and C:N; increased diversity in defensive compounds; and reduced variability in phytochemical composition. We also elucidate fundamental associations between trait means and overall investment in secondary metabolites with patterns of among-leaf variability and chemical diversity.

We conclude that within-plant variability is an overlooked dimension of trait diversity in this globally critical agricultural crop. We find that trait variability is actually higher in cultivated plants compared to wild progenitors for multiple nutritive, physical, and chemical traits, highlighting a scale of variation that may mitigate loss of trait diversity at other scales in alfalfa agroecosystems and in other crops with similar domestication and improvement histories.
Decreasing pdzd8-mediated mitochondrial-ER contacts in neurons improves fitness by increasing mitophagy
Authors: Hewitt Victoria L. , Miller-Fleming Leonor , Andreazza Simonetta , Mattedi Francesca , Prudent Julien , Polleux Franck , Vagnoni Alessio , Whitworth Alexander J.
Published: November 2020

The complex cellular architecture of neurons combined with their longevity makes maintaining a healthy mitochondrial network particularly important and challenging. One of the many roles of mitochondrial-ER contact sites (MERCs) is to mediate mitochondrial quality control through regulating mitochondrial turn over. Pdzd8 is a newly discovered MERC protein, the organismal functions of which have not yet been explored. Here we identify and provide the first functional characterization of theDrosophila melanogasterortholog of Pdzd8. We find that reducing pdzd8-mediated MERCs in neurons slows age-associated decline in locomotor activity and increases lifespan inDrosophila. The protective effects of pdzd8 knockdown in neurons correlate with an increase in mitophagy, suggesting that increased mitochondrial turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER-mitochondria tether disrupts mitochondrial transport and synapse formation, accelerates age-related decline in locomotion and reduces lifespan. We also show that depletion of pdzd8 rescues the locomotor defects characterizing an Alzheimer’s disease (AD) fly model over-expressing Amyloidβ1–42(Aβ42) and prolongs the survival of flies fed with mitochondrial toxins. Together, our results provide the firstin vivoevidence that MERCs mediated by the tethering protein pdzd8 play a critical role in the regulation of mitochondrial quality control and neuronal homeostasis.
Taxonomic description and genome sequence ofChristensenella intestinihominissp. nov., a novel cholesterol-lowering bacterium isolated from human gut
Authors: Zou Yuanqiang , Xue Wenbin , Lin Xiaoqian , Luo Guangwen , Lv Mei , Dai Ying , Xiao Liang
Published: November 2020

A Gram-staining-negative, non-spore-forming, short, straight rod, non-motile, obligate anaerobic bacterial strain, AF73-05CM02T, was isolated from faecal sample of thirty-years old healthy male. Colonies were approximately 0.2mm in diameter, beige and circular after 4 days of incubation on PYG agar under anaerobic conditions at 37°C. Strain AF73-05CM02Tgrew in a temperature range between 30-42°C and pH range from 6.0 to 8.5, with optimum growth at 37-42°C and pH 7.0. Base on the 16S rRNA gene sequence analysis, strain AF73-05CM02Tbelongs to the genusChristensenellaand showed the highest level of sequence similarity withChristensenella minutaYIT 12065T. The predominant fatty acids of strain AF73-05CM02Twere C10:0(7.5%), iso-C11:0(5.6%), C12:0(7.2%), C14:0(46.6%), iso-C15:0(7.4%), C16:0(9.7%) and C18:1ω 9c(6.9%). Acetic acid, formic acid, butyric acid and lactic acid were end products of glucose fermentation. The isolate was negative for catalase, indole production and hydrolysis of gelatin. Genomic relatedness analyses based on average nucleotide identity indicated strain AF73-05CM02Tsignificantly differed from other species of the genusChristensenella, showing ANI values under 82.89% with the phylogenetically closest species. The G+C content of the genomic DNA was 52.07 mol% from genome sequence, which differs from that ofChristensenella minuta. Several physiological biochemical and genotypic properties differentiated the novel bacterial strain from the related species, indicating that the isolate represent a new species of the genusChristensenellafor which the nameChristensenella intestinihominissp. nov. is proposed, with strain AF73-05CM02T(=CGMCC 1.5207T=DSM 103477T) being the type strain. The follow study approached the function of cholesterol-lowering for strains AF73-05CM02Tand DSM 22067Trevealed the two strains exhibit capacity for removing cholesterol with efficiency of 36.6% and 54.3%. Exopolysaccharide production of two strains were 234 and 271 mg/L, respectively.
Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure
Authors: Rämö Joel T. , Kiiskinen Tuomo , Karjalainen Juha , Krebs Kristi , Kurki Mitja , Havulinna Aki S. , Hämäläinen Eija , Häppölä Paavo , Hautakangas Heidi ,   FinnGen, Karczewski Konrad J. , Kanai Masahiro , Mägi Reedik , Palta Priit , Esko Tõnu , Metspalu Andres , Pirinen Matti , Ripatti Samuli , Milani Lili , Mäkitie Antti , Daly Mark J. , Palotie Aarno
Published: November 2020

Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood and treatment options are limited. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 2,413 cases and 762,382 controls. We identify 15 novel risk loci (p < 5*10−8) and replicate the regions of RELN and two previously reported candidate genes (TGFB1 and MEPE). Implicated genes in many loci are essential for bone remodelling or mineralization. Otosclerosis is genetically correlated with height and fracture risk, and the association loci overlap with severe skeletal disorders. Our results highlight TGFβ1 signalling for follow-up mechanistic studies.
A single origin of animal excretory organs
Authors: Gąsiorowski Ludwik , Andrikou Carmen , Janssen Ralf , Bump Paul , Budd Graham E. , Lowe Christopher J. , Hejnol Andreas
Published: November 2020

Excretion is an essential physiological process, carried out by all living organisms regardless of their size or complexity(1–3). Most animals, which include both protostomes (e.g. flies, flatworms) and deuterostomes (e.g. humans, sea urchins) (together Nephrozoa(4, 5)), possess specialized excretory organs. Those organs exhibit an astonishing diversity, ranging from units composed of just three distinct cells (e.g. protonephridia) to complex structures, built by millions of cells of multiple types with divergent morphology and function (e.g. vertebrate kidneys)(6, 7). Although some molecular similarities between the development of kidneys of vertebrates and the regeneration of the protonephridia of flatworms have been reported(8, 9), the molecular development of nephrozoan excretory organs has never been systematically studied in a comparative context(6). Here we show that a set of highly conserved transcription factors and structural proteins is expressed during the development of excretory organs of six species that represent major protostome lineages and non-vertebrate deuterostomes. We demonstrate that the molecular similarity witnessed in the vertebrate kidney and flatworm protonephridia(8) is also seen in the developing excretory organs of other Nephrozoa. In addition, orthologous structural proteins forming the ultrafiltration apparatus are expressed in all these organs in the filter-forming cells. Our results strongly suggest that excretory organs are homologous and are patterned by the conserved set of developmental genes. We propose that the last common nephrozoan ancestor possessed an ultrafiltration-based, ciliated excretory organ, a structure that later gave rise to the vast diversity of extant excretory organs, including the human kidney.

Significance statement

Most of the bilaterally symmetrical animals excrete through specialized excretory organs, such as kidneys and nephridia. However, due to the morphological diversity of these organs, it remains unknown whether those structures evolved from a common ancestral organ or appeared several times independently during evolution. In order to answer the question about the origin of excretory organs we investigated the molecular pathways and structural genes involved in the development of nephridia in 6 animal species representing major evolutionary lineages. We show that diverse excretory organs share an ancient molecular patterning and structural molecules. Our results provide strong evidence that all excretory organs originated from a single, simple organ that performed urine production by ultrafiltration in deep geological past.
Immunological memory to SARS-CoV-2 assessed for up to eight months after infection
Authors: Dan Jennifer M. , Mateus Jose , Kato Yu , Hastie Kathryn M. , Yu Esther Dawen , Faliti Caterina E. , Grifoni Alba , Ramirez Sydney I. , Haupt Sonya , Frazier April , Nakao Catherine , Rayaprolu Vamseedhar , Rawlings Stephen A. , Peters Bjoern , Krammer Florian , Simon Viviana , Saphire Erica Ollmann , Smith Davey M. , Weiskopf Daniela , Sette Alessandro , Crotty Shane
Published: November 2020

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
Multidimensional single-cell modeling of cellular signaling
Authors: Wade James D. , Lun Xiao-Kang , Bodenmiller Bernd , Voit Eberhard O.
Published: November 2020

Cell-to-cell differences in signaling components can lead to qualitatively different responses to stimuli. Understanding this heterogeneity in signaling response is limited by the inability of time-lapse methods to measure multiple pathway components simultaneously in situ. Here, we presentDistribution-Independent Single-Cell ODE modeling(DISCO), a computational method for inference of continuous single-cell signaling dynamics from multiplexed snapshot data. We used DISCO to analyze signaling in the MAPK/ERK pathway of HEK293T cells stimulated with the growth factor EGF. Our model recapitulates known features of the ERK signaling response and enables the detection of hidden cell-to-cell variation in seemingly homogeneous samples. Further, DISCO analysis suggested that the MAPK/ERK pathway transmits signal duration rather than amplitude, and that cell-to-cell variation in MAPK/ERK signaling response depends primarily on initial cell states. Finally, we applied an extended version of DISCO to explain changes in signaling kinetics due to overexpression of a disease-relevant protein. Overall, DISCO enables a deeper understanding of how single-cell variation affects cellular responses in complex signaling systems.
Desert Dingo (Canis lupus dingo) genome provides insights into their role in the Australian ecosystem
Authors: Yadav Sonu , Dudchenko Olga , Esvaran Meera , Rosen Benjamin D. , Field Matt A. , Skvortsova Ksenia , Edwards Richard J. , Gopalakrishnan Shyam , Keilwagen Jens , Cochran Blake J. , Manandhar Bikash , Bucknall Martin , Bustamante Sonia , Rasmussen Jacob Agerbo , Melvin Richard G. , Omer Arina , Colaric Zane , Chan Eva K. F. , Minoche Andre E. , Smith Timothy P.L. , Gilbert M. Thomas P. , Bogdanovic Ozren , Zammit Robert A. , Thomas Torsten , Aiden Erez L. , Ballard J. William O.
Published: November 2020

The dingo is Australia’s iconic top-order predator and arrived on the continent between 5,000-8,000 years ago. To provide an unbiased insight into its evolutionary affiliations and biological interactions, we coupled long-read DNA sequencing with a multiplatform scaffolding approach to produce anab initiogenome assembly of the desert dingo (85X coverage) we call CanLup_DDS. We compared this genome to the Boxer (CanFam3.1) and German Shepherd dog (CanFam_GSD) assemblies and characterized lineage-specific and shared genetic variation ranging from single– to megabase pair–sized variants. We identified 21,483 dingo-specific and 16,595 domestic dog-specific homozygous structural variants mediating genic and putative regulatory changes. Comparisons between the dingo and domestic dog builds detected unique inversions on Chromosome 16, structural variations in genes linked with starch metabolism, and seven differentially methylated genes. To experimentally assess genomic differences 17 dingoes and 15 German Shepherd dogs were fed parallel diets for 14 days. In dingoes, lowAMY2Bcopy number and serum amylase levels are linked with high cholesterol and LDL levels. Gut microbiome analyses revealed enrichment of the familyClostridiaceae, which can utilize complex resistant starch, while scat metabolome studies identified high phenylethyl alcohol concentrations that we posit are linked with territory marking. Our study provides compelling genomic, microbiome, and metabolomic links showing the dingo has distinct physiology from domestic breed dogs with a unique role in the ecosystem.