bluuebunny/crossref_metadata_2025 huggingface dataset:
Robustness of Collective Scenting in the Presence of Physical Obstacles
Authors: Nguyen Dieu My T. , Fard Golnar Gharooni , Iuzzolino Michael , Peleg Orit
Published: March 2021

Honey bees (Apis melliferaL.) aggregate around the queen by collectively organizing a communication network to propagate volatile pheromone signals. Our previous study shows that individual bees “scent” to emit pheromones and fan their wings to direct the signal flow, creating an efficient search and aggregation process. In this work, we introduce environmental stressors in the form of physical obstacles that partially block pheromone signals and prevent a wide open path to the queen. We employ machine learning methods to extract data from the experimental recordings, and show that in the presence of an obstacle that blocks most of the path to the queen, the bees need more time but can still effectively employ the collective scenting strategy to overcome the obstacle and aggregate around the queen. Further, we increase the complexity of the environment by presenting the bees with a maze to navigate to the queen. The bees require more time and exploration to form a more populated communication network. Overall, we show that given volatile pheromone signals and only local communication, the bees can collectively solve the swarming process in a complex unstructured environment with physical obstacles.
Rice MEL2 regulates the timing of meiotic transition as a component of cytoplasmic RNA granules
Authors: Mimura Manaki , Ono Seijiro , Nonomura Ken-Ichi
Published: March 2021

Cytoplasmic RNA granules play important roles in gene expression at the post-transcriptional level. In this study, we found that the rice RNA-binding protein MEIOSIS ARRESTED AT LEPTOTENE2 (MEL2), which contributes to the control of meiotic entry timing, was a constituent of RNA granules, frequently associating with processing bodies and stress granules in the cytoplasm of premeiotic spore mother cells. MEL2 has four conserved domains and a large intrinsically disordered region, which is often responsible for formation and maintenance of granular structures. MEL2-like proteins with diverse domain structures are widely conserved in land plants and charophyte algae. In basal land plants, MEL2-like proteins are exclusively expressed in the sporophyte, which expresses meiotic genes, suggesting the functional conservation of MEL2 among land plant species. We propose here that MEL2 participates in post-transcriptional regulation of meiotic genes as a component of RNA granules to ensure proper timing of the meiotic transition.
circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular cancer
Authors: Li Peng , Song Runjie , Liu Huijiao , Liu Mei , Yin Fan , Ma Shuoqian , Jia Xiaomeng , Lu Xiaohui , Zhong Yuting , Li Xiru , Li Xiangdong
Published: March 2021

Hepatocellular carcinoma (HCC), a common malignant tumor, is one of the main causes of cancer-related deaths worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancy. However, the functions of circRNAs in HCC remain unclear. In this study, through mining the RNA sequencing databases from GEO datasets and subsequent experimental verification, we identified that hsa_circ_0000384 (circMRPS35) was highly expressed in HCC. Knockdown of circMRPS35 suppressed the proliferation, migration, invasion, clone formation and cell cycle of HCC cell lines both in vitro and in a xenograft mouse model. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), which in turn regulated STX3-PTEN axis. Surprisingly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC cells. These results demonstrated that circMRPS35 might be a novel factor in HCC progress, and has a great potential as a new diagnosis and therapeutic target for treatment of HCC.
Human eosinophil cationic protein manifests alarmin activity through its basicity and ribonuclease activity
Authors: Attery Ayush , Saha Irene , Tailor Prafullakumar , Batra Janendra K.
Published: March 2021

Eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN), and human pancreatic ribonuclease (HPR) are members of the RNase A superfamily having similar catalytic residues and diverse functions. Alarmins are the endogenous mediators of innate immunity which activate or alarm the adaptive immune system by activating antigen presenting cells (APCs). EDN acts as an alarmin molecule and plays an important role in innate as well as adaptive immunity. EDN displays chemotactic activity for dendritic cells (DCs) and activates them, has antiviral and antiparasitic activities, and is rapidly released from immune cells. HPR only displays chemotactic activity while no such activity has been reported for ECP. In this study we show that ECP displays the chemotactic activity comparable to that of HPR and EDN. ECP also interacts with TLR-2 to activate NF-κB/AP-1 expression like EDN. The RNase activity of ECP, EDN and HPR, and basicity of ECP were found to be crucial determinants for their chemotactic activity for APCs, however for the DC maturation activity, RNase activity was not found to be essential. Bovine RNase A did not show any chemotactic activity despite having a very high RNase activity indicating that other determinants in addition to the RNase activity are involved in the chemotactic activity of ECP, EDN and HPR. The current study establishes that ECP also can act like an alarmin.
BacterialPxRdl2dsRNA increased the insecticidal activities of GABAR-targeting compounds againstPlutella xylostella
Authors: Li Ben-Jie , Wang Kun-Kun , Yu Ye , Wei Jia-Qi , Zhu Jian , Wang Jia-Li , Lin Fei , Xu Han-Hong
Published: March 2021

The utilization of RNA interference (RNAi) for pest management has garnered global interest. The bioassay results suggested the knockout ofPxRdl2significantly increased the insecticidal activities of theγ-aminobutyric acid receptor (GABAR) targeting compounds (Fipronil, two pyrazoloquinazolines and two isoxazolines), thereby presenting a viable target gene for RNAi-mediated pest control. Consequently, we suggest enhancing the insecticidal activities of GABAR-targeting compounds by knockdown the transcript level ofPxRdl2. Furthermore,PxRdl2dsRNA was expressed in HT115Escherichia colito reduce costs and protect dsRNA against degradation. In comparison toin vitrosynthesized dsRNA, the recombinant bacteria (ds-B) exhibited superior interference efficiencies and greater stability when exposed to UV irradiation. Collectively, our results provide a new strategy of insecticide spray which combined synergistically with insecticidal activities by suppressingPxRdl2using ds-B, and may be beneficial for reducing the usage of insecticide and slowing pest resistance.
A new chemoenzymatic semisynthetic approach provides novel insight into the role of phosphorylation beyond exon1 of Huntingtin and reveals N-terminal fragment length-dependent distinct mechanisms of aggregation
Authors: Kolla Rajasekhar , Gopinath Pushparathinam , Ricci Jonathan , Reif Andreas , Rostami Iman , Lashuel Hilal A.
Published: March 2021

Huntington’s disease is a neurodegenerative disorder caused by the expansion of a polyglutamine (poly Q) repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Htt exon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1. We also present a new chemoenzymatic semisynthetic strategy that enables site-specific phosphorylation of Htt beyond Httex1. These advances yielded novel insights into how PTMs and structured domains beyond Httex1 influence aggregation mechanisms, kinetics, and fibril morphology of longer N-terminal Htt fragments. We demonstrate that phosphorylation at T107 significantly slowed its aggregation, whereases phosphorylation at T107 and S116 accelerated the aggregation of Htt171, underscoring the importance of crosstalk between different PTMs. We demonstrate that mutant Htt171 proteins aggregate via a different mechanism and form oligomers and fibrillar aggregates with morphological properties that are distinct from that of mutant Httex1. These observations suggest that different N-terminal fragments could have distinct mechanisms of aggregation and that a single polyQ-targeting anti-aggregation strategy may not effectively inhibit the aggregation of all N-terminal Htt fragments. Finally, our results underscore the importance of further studies to investigate the aggregation mechanisms of Htt fragments and how the various fragments interact with each other and influence Htt toxicity, pathology formation, and disease progression.

Table of content
Genome-wide molecular recording using Live-seq
Authors: Chen Wanze , Guillaume-Gentil Orane , Dainese Riccardo , Rainer Pernille Yde , Zachara Magda , Gäbelein Christoph G. , Vorholt Julia A. , Deplancke Bart
Published: March 2021

Single-cell transcriptomics (scRNA-seq) has greatly advanced our ability to characterize cellular heterogeneity in health and disease. However, scRNA-seq requires lysing cells, which makes it impossible to link the individual cells to downstream molecular and phenotypic states. Here, we established Live-seq, an approach for single-cell transcriptome profiling that preserves cell viability during RNA extraction using fluidic force microscopy. Based on cell division, functional responses and whole-cell transcriptome read-outs, we show that Live-seq does not induce major cellular perturbations and therefore can function as a transcriptomic recorder. We demonstrate this recording capacity by preregistering the transcriptomes of individual macrophage-like RAW 264.7 cells that were subsequently subjected to time-lapse imaging after lipopolysaccharide (LPS) exposure. This enabled the unsupervised, genome-wide ranking of genes based on their ability to impact macrophage LPS response heterogeneity, revealing basalNFKBIAexpression level and cell cycle state as major phenotypic determinants. Furthermore, we show that Live-seq can be used to sequentially profile the transcriptomes of individual macrophages before and after stimulation with LPS, thus enabling the direct mapping of a cell’s trajectory. Live-seq can address a broad range of biological questions by transforming scRNA-seq from an end-point to a temporal analysis approach.
High Mobility Group Box 1 enhances ADP-mediated platelet activation by increasing platelet surface P2Y12localization
Authors: Nolfi-Donegan Deirdre , Annarapu Gowtham K , Maurer Lisa M , Hillery Cheryl A , Shiva Sruti
Published: March 2021

Thrombosis and inflammation are intimately linked and synergistically contribute to the pathogenesis of a number of vascular diseases. On a cellular level, while the platelet is central to thrombus formation as well as an active mediator of inflammation, the molecular mechanisms of cross-talk between thrombosis and inflammation remain elusive. High-Mobility Group Box 1 protein (HMGB1) is an inflammatory regulator that also stimulates platelet activation through its interaction with toll-like receptor 4 (TLR4). However, it remains unclear whether cross-talk between HMGB1 and traditional thrombotic agonists exists to modulate platelet activation. Using isolated human platelets, we tested whether HMGB1 treatment affects platelet activation mediated by traditional agonists. We found that HMGB1 enhances ADP-mediated platelet activation, but not platelet activation stimulated by thrombin or collagen. Further, inhibition of the canonical ADP purinergic P2Y12receptor attenuates HMGB1-dependent platelet activation. Mechanistically, we discovered that HMGB1 activates platelet surface TLR4 to release ADP from the platelet and concomitantly increase the localization of P2Y12on the platelet membrane. These data demonstrate that ADP-dependent P2Y12activation contributes to HMGB1 mediated platelet activation, while HMGB1 primes platelets for an enhanced activation response to ADP. These novel findings further our understanding of thrombo-inflammatory signaling and provide new insight for therapeutic P2Y12inhibition.

Key Points

HMGB1 enhances ADP-mediated platelet activation but not platelet activation stimulated by collagen or thrombin.

HMGB1 stimulates platelet ADP release and increases platelet surface localization of P2y12 receptors via TLR4-dependent mechanism(s).

Visual Abstract

Caption:HMGB1 activates TLR4 to activate platelets, release platelet ADP, and upregulate P2Y12at the platelet surface.
The capacity to produce hydrogen sulfide (H2S) via cysteine degradation is ubiquitous in the human gut microbiome
Authors: Braccia Domenick J. , Jiang Xiaofang , Pop Mihai , Hall A. Brantley
Published: March 2021

As one of the three mammalian gasotransmitters, hydrogen sulfide (H2S) plays a major role in maintaining physiological homeostasis. Endogenously produced H2S plays numerous beneficial roles including mediating vasodilation and conferring neuroprotection. Due to its high membrane permeability, exogenously produced H2S originating from the gut microbiota can also influence human physiology and is implicated in reducing intestinal mucosal integrity and potentiating genotoxicity and is therefore a potential target for therapeutic interventions. Gut microbial H2S production is often attributed to dissimilatory sulfate reducers such as Desulfovibrio and Bilophila species. However, an alternative source for H2S production, cysteine degradation, is present in gut microbes, but the genes responsible for cysteine degradation have not been systematically annotated in gut microbes. To better understand the potential for H2S production via cysteine degradation by the human gut microbiome, we performed a comprehensive search for genes encoding cysteine-degrading genes in 4,644 bacterial genomes from the Unified Human Gastrointestinal Genome (UHGG) catalogue. We identified 407 gut bacterial species as putative cysteine degrading bacteria, 328 of which have not been previously implicated in H2S production. We identified the presence of at least one putative cysteine degrading bacteria in metagenomic data of 100% of 6,644 healthy subjects and the expression of cysteine-degrading genes in metatranscriptomics data of 100% of 59 samples. Additionally, putative cysteine-degrading bacteria are more abundant than sulfate reducing bacteria (p<2.2e-16). Overall, this study improves our understanding of the capacity for H2S production by the human gut microbiome and may help to inform interventions to therapeutically modulate gut microbial H2S production.
Environmental genomics points to non-diazotrophicTrichodesmiumspecies abundant and widespread in the open ocean
Authors: Delmont Tom O.
Published: March 2021

Filamentous and colony-forming cells within the cyanobacterial genusTrichodesmiummight account for nearly half of nitrogen fixation in the sunlit ocean, a critical mechanism that sustains plankton’s primary productivity at large-scale. Here, we report the genome-resolved metagenomic characterization of two newly identified marine species we tentatively named ‘Ca.Trichodesmium miru’ and ‘Ca.Trichodesmium nobis’. Near-complete environmental genomes for those closely related candidate species revealed unexpected functional features including a lack of the entire nitrogen fixation gene apparatus and hydrogen recycling genes concomitant with the enrichment of nitrogen assimilation genes and apparent acquisition of thenirbgene from a non-cyanobacterial lineage. These comparative genomic insights were cross-validated by complementary metagenomic investigations. Our results contrast with the current paradigm thatTrichodesmiumspecies are necessarily capable of nitrogen fixation. The black queen hypothesis could explain gene loss linked to nitrogen fixation amongTrichodesmiumspecies, possibly triggered by gene acquisitions from the colony epibionts. Critically, the candidate species are not only widespread in the 3-2000 μm planktonic size fraction of the surface of the oceans and seas, but might also substantially expand the ecological niche ofTrichodesmium, stressing the need to disconnect taxonomic signal for this genus from a microbial community’s ability to fix nitrogen. Especially, differentiating diazotrophic from non-diazotrophic populations when countingTrichodesmiumfilaments and colonies might help refine our understanding of the marine nitrogen balance. While culture representatives are needed to move beyond metagenomic insights, we are reminded that established links between taxonomic lineages and functional traits might not always hold true.
Individual Variability in the Innate Functional Organization of the Human Brain
Authors: Molloy M. Fiona , Saygin Zeynep M.
Published: March 2021

The adult brain is organized into distinct functional networks, forming the basis of information processing and determining individual differences in behavior. Is this network organization genetically determined and present at birth? And what is the individual variability in this organization in neonates? Here, we use unsupervised learning to uncover intrinsic functional brain organization using resting-state connectivity from a large cohort of neonates (Developing Human Connectome Project). We identified a set of symmetric, hierarchical, and replicable networks: sensorimotor, visual, default mode, ventral attention, and high-level vision. We quantified individual variability across neonates, and found the most individual variability in the ventral attention networks. Crucially, the variability of these networks were not driven by SNR differences or differences from adult networks (Yeo et al., 2011). Finally, differential gene expression provided a potential explanation for the emergence of these distinct networks and identified potential genes of interest for future developmental and individual variability research. Overall, we found neonatal connectomes (even at the voxel-level) can reveal broad individual- specific information processing units. The presence of individual differences in neonates and the framework for personalized parcellations demonstrated here has the potential to improve prediction of behavior and future outcomes from neonatal and infant brain data.
The use of non-functional clonotypes as a natural calibrator for quantitative bias correction in adaptive immune receptor repertoire profiling
Authors: Smirnova Anastasia , Miroshnichenkova Anna , Olshanskaya Yulia , Maschan Michael , Lebedev Yuri , Chudakov Dmitriy , Mamedov Ilgar , Komkov Alexander
Published: March 2021

High-throughput sequencing of adaptive immune receptor repertoires is a valuable tool for receiving insights in adaptive immunity studies. Several powerful TCR/BCR repertoire reconstruction and analysis methods have been developed in the past decade. However, detecting and correcting the discrepancy between real and experimentally observed lymphocyte clone frequencies is still challenging. Here we discovered a hallmark anomaly in the ratio between read count and clone count-based frequencies of non-functional clonotypes in multiplex PCR-based immune repertoires. Calculating this anomaly, we formulated a quantitative measure of V- and J-genes frequency bias driven by multiplex PCR during library preparation called Over Amplification Rate (OAR). Based on the OAR concept, we developed an original software for multiplex PCR-specific bias evaluation and correction named iROAR: Immune Repertoire Over Amplification Removal (https://github.com/smiranast/iROAR). The iROAR algorithm was successfully tested on previously published TCR repertoires obtained using both 5’ RACE (Rapid Amplification of cDNA Ends)-based and multiplex PCR-based approaches and compared with a biological spike-in-based method for PCR bias evaluation. The developed approach can increase the accuracy and consistency of repertoires reconstructed by different methods making them more applicable for comparative analysis.
Extremely Fast pRF Mapping for Real-Time Applications
Authors: Bhat Salil , Lührs Michael , Goebel Rainer , Senden Mario
Published: March 2021

Population receptive field (pRF) mapping is a popular tool in computational neuroimaging that allows for the investigation of receptive field properties, their topography and interrelations in health and disease. Furthermore, the possibility to invert population receptive fields provides a decoding model for constructing stimuli from observed cortical activation patterns. This has been suggested to pave the road towards pRF-based brain-computer interface (BCI) communication systems, which would be able to directly decode internally visualized letters from topographically organized brain activity. A major stumbling block for such an application is, however, that the pRF mapping procedure is computationally heavy and time consuming. To address this, we propose a novel and fast pRF mapping procedure that is suitable for real-time applications. The method is build upon hashed-Gaussian encoding of the stimulus, which significantly reduces computational resources. After the stimulus is encoded, mapping can be performed using either ridge regression for fast offline analyses or gradient descent for real-time applications. We validate our model-agnostic approachin silico, as well as on empirical fMRI data obtained from 3T and 7T MRI scanners. Our approach is capable of estimating receptive fields and their parameters for millions of voxels in mere seconds. This method thus facilitates real-time applications of population receptive field mapping.
Independent Markov Decomposition: Towards modeling kinetics of biomolecular complexes
Authors: Hempel Tim , del Razo Mauricio J. , Lee Christopher T. , Taylor Bryn C. , Amaro Rommie E. , Noé Frank
Published: March 2021

In order to advance the mission ofin silicocell biology, modeling the interactions of large and complex biological systems becomes increasingly relevant. The combination of molecular dynamics (MD) and Markov state models (MSMs) have enabled the construction of simplified models of molecular kinetics on long timescales. Despite its success, this approach is inherently limited by the size of the molecular system. With increasing size of macromolecular complexes, the number of independent or weakly coupled subsystems increases, and the number of global system states increase exponentially, making the sampling of all distinct global states unfeasible. In this work, we present a technique called Independent Markov Decomposition (IMD) that leverages weak coupling between subsystems in order to compute a global kinetic model without requiring to sample all combinatorial states of subsystems. We give a theoretical basis for IMD and propose an approach for finding and validating such a decomposition. Using empirical few-state MSMs of ion channel models that are well established in electrophysiology, we demonstrate that IMD can reproduce experimental conductance measurements with a major reduction in sampling compared with a standard MSM approach. We further show how to find the optimal partition of all-atom protein simulations into weakly coupled subunits.

Significance Statement

Molecular simulations of proteins are often interpreted using Markov state models (MSMs), in which each protein configuration is assigned to a global state. As we explore larger and more complex biological systems, the size of this global state space will face a combinatorial explosion, rendering it impossible to gather sufficient sampling data. In this work, we introduce an approach to decompose a system of interest into separable subsystems. We show that MSMs built for each subsystem can be later coupled to reproduce the behaviors of the global system. To aid in the choice of decomposition we also describe a score to quantify its goodness. This decomposition strategy has the promise to enable robust modeling of complex biomolecular systems.
On-person adaptive evolution ofStaphylococcus aureusduring treatment for atopic dermatitis
Authors: Key Felix M. , Khadka Veda D. , Romo-González Carolina , Blake Kimbria J. , Deng Liwen , Lynn Tucker C. , Lee Jean C. , Chiu Isaac M. , García-Romero Maria Teresa , Lieberman Tami D.
Published: March 2021

Genetic variation among bacterial strains can contribute to heterogeneity in the severity of chronic inflammatory diseases1,2, but the degree of variation created byde novomutation during colonization is not well understood. The inflamed skin of people with atopic dermatitis (AD) is frequently colonized withStaphylococcus aureus, an opportunistic pathogen associated with both asymptomatic colonization of nasal passages and invasive disease3–6. While genetic risk and barrier disruption are critical to AD initiation7,8,S. aureuscolonization is thought to worsen disease severity by promoting skin damage9 1,4,5,10. Here we show, from tracking 23 children treated for AD over 9 months, thatS. aureusadapts viade novomutations during colonization. Patients’S. aureuspopulations are typically dominated by a single lineage, with infrequent invasion by distant lineages. Variants emerge within each lineage with mutation accumulation rates similar toS. aureusin other contexts. Some of these variants replace their ancestors across the body within months, with signatures of adaptive, rather than neutral, forces. Most strikingly, the capsule synthesis genecapDobtained four parallel mutations within one patient and was involved in mutational sweeps in multiple patients. We confirm that selection forcapDnegativity is common in AD, but not in other contexts, via reanalysis of publicS. aureusgenomes from 276 people. Our finding of disease-specific selection raises the possibility that adaptation of pathobionts during colonization prolongs the positive feedback cycle of inflammation.
New detection of SARS-CoV-2 in two cats height months after COVID-19 outbreak appearance in France
Authors: Fritz Matthieu , Nesi Nicolas , Denolly Solène , Boson Bertrand , Legros Vincent , Rosolen Serge G. , Briend-Marchal Alexandra , Gouilh Meriadeg Ar , Leroy Eric M.
Published: March 2021

Although there are several reports in the literature of SARS-CoV-2 infection in cats, few SARS-CoV-2 sequences from infected cats have been published. In this report, SARS-CoV-2 infection was evaluated in two cats by clinical observation, molecular biology (qPCR and NGS), and serology (Microsphere immunoassay and seroneutralization). Following the observation of symptomatic SARS-CoV-2-infection in two cats, infection status was confirmed by RT-qPCR and, in one cat, serological analysis for antibodies against N-protein and S-protein, as well as neutralizing antibodies. Comparative analysis of five SARS-CoV-2 sequence-fragments obtained from one of the cats showed that this infection was not with one of the three recently emerged variants of SARS-CoV-2. This study provides additional information on the clinical, molecular, and serological aspects of SARS-CoV-2 infection in cats.
Interchangeability of Periplasmic Adaptor Proteins AcrA and AcrE in forming functional efflux pumps with AcrD inSalmonellaTyphimurium
Authors: Alav Ilyas , Bavro Vassiliy N. , Blair Jessica M. A.
Published: March 2021

Background

RND efflux pumps are important mediators of antibiotic resistance. RND pumps including the principal multidrug-efflux pump AcrAB-TolC inSalmonella, are tripartite systems, with an inner membrane RND-transporter, a periplasmic adaptor protein (PAP) and an outer membrane factor (OMF). We previously identified the residues required for binding between the PAP AcrA and the RND-transporter AcrB and have demonstrated that PAPs can function with non-cognate transporters. AcrE and AcrD/AcrF are homologues of AcrA and AcrB, respectively. Here, we show that AcrE can interact with AcrD, which does not possess its own PAP, and establish that the residues previously identified in AcrB-binding are also involved in AcrD-binding.

Methods

TheacrDandacrEgenes were expressed into a strain lackingacrABDEF(Δ3RND). PAP residues involved in promiscuous interactions were predicted based on previously defined PAP-RND interactions and corresponding mutations generated inacrAandacrE. Antimicrobial susceptibility of the mutant strains was determined.

Results

Co-expression ofacrDandacrEsignificantly decreased susceptibility of the Δ3RND strain to AcrD substrates showing that AcrE can form a functional complex with AcrD. The substrate profile ofSalmonellaAcrD differed from that ofE. coliAcrD. Mutations targeting the previously defined PAP-RND interaction sites in AcrA/AcrE impaired efflux of AcrD-dependent substrates.

Conclusions

These data indicate that AcrE forms an efflux-competent pump with AcrD and thus presents an alternative PAP for this pump. Mutagenesis of the conserved RND-binding sites validates the interchangeability of AcrA and AcrE, highlighting them as potential drug targets for efflux inhibition.
A public vaccine-induced human antibody protects against SARS-CoV-2 and emerging variants
Authors: Schmitz Aaron J. , Turner Jackson S. , Liu Zhuoming , Aziati Ishmael D. , Chen Rita E. , Joshi Astha , Bricker Traci L. , Darling Tamarand L. , Adelsberg Daniel C. , Alsoussi Wafaa B. , Case James Brett , Lei Tingting , Thapa Mahima , Amanat Fatima , O’Halloran Jane A. , Shi Pei-Yong , Presti Rachel M. , Krammer Florian , Bajic Goran , Whelan Sean P.J. , Diamond Michael S. , Boon Adrianus C. M. , Ellebedy Ali H.
Published: March 2021

The emergence of antigenically distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility is a public health threat. Some of these variants show substantial resistance to neutralization by SARS-CoV-2 infection- or vaccination-induced antibodies, which principally target the receptor binding domain (RBD) on the virus spike glycoprotein. Here, we describe 2C08, a SARS-CoV-2 mRNA vaccine-induced germinal center B cell-derived human monoclonal antibody that binds to the receptor binding motif within the RBD. 2C08 broadly neutralizes SARS-CoV-2 variants with remarkable potency and reduces lung inflammation, viral load, and morbidity in hamsters challenged with either an ancestral SARS-CoV-2 strain or a recent variant of concern. Clonal analysis identified 2C08-like public clonotypes among B cell clones responding to SARS-CoV-2 infection or vaccination in at least 20 out of 78 individuals. Thus, 2C08-like antibodies can be readily induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern.

One Sentence Summary

Protection against SARS-CoV-2 variants by a potently neutralizing vaccine-induced human monoclonal antibody.
The role of the Andean uplift as an asymmetrical barrier to gene flow in the Neotropical leaf-cutting antAtta cephalotes
Authors: Muñoz-Valencia Vanessa , Vélez-Matínez Glever Alexander , Montoya-Lerma James , Díaz Fernando
Published: March 2021

Neotropical diversification by the Andean uplift is typically addressed on a large evolutionary scale (e.g. speciation), even though many species are still distributed in both sides of the mountains. The three parallel mountain ranges in the northern Andes (Colombia) impose a major geographical barrier to species’ migration from South to Central America. How important these barriers are for conspecific diversification of cross-Andean species such as the leaf-cutting ants remains largely unknown. To answer this question, we studied themtCOIgene ofAtta cephalotes, the most widely distributed leaf-cutting ant species. Our hierarchical analyzes evidenced substantial genetic structure among regions and populations, suggesting a more complex biogeographical history of Andean populations than previously thought. These mountains seem to isolate Central American and Western Colombian populations from the rest ofA. cephalotesin South America. Population and migration modelling are consistent with the origin of this species in South America and a major role of the Eastern cordillera as a geographical barrier to historical gene flow, restricting dispersion from north to south. These findings provide insights into the role of the Andean uplift as barrier to gene flow and, eventually, implications for monitoring and designing management strategies for leaf-cutting ants.
Loss of STAT5 in adipocytes increases subcutaneous fat mass via sex-dependent and depot-specific pathways
Authors: Richard Allison J. , Hang Hardy , Allerton Timothy D. , Zhao Peng , Ghosh Sujoy , Elks Carrie M. , Stephens Jacqueline M.
Published: March 2021

The STAT (Signal Transducers and Activators of Transcription) family of transcription factors contributes to adipocyte development and function. STAT5A and STAT5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH). Studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. We have generated a mouse model lacking both STAT5 genes specifically in adipocytes (STAT5AKO). Notably, both sexes of STAT5AKOmice have increased inguinal adipose tissue without any changes in gonadal fat mass. However, both depots exhibit substantial differences in fat cell size. Study of STAT5AKOmice also have revealed that GH’s ability to induce insulin resistance is dependent upon STAT5 in adipocytes, but its ability to reduce adipose tissue mass is STAT5 independent. Additional observations, which were not predicted, indicate that the causes and regulation of increased fat mass in STAT5AKOmice are sex- and depot-dependent.
C9ORF72dipeptide repeat proteins disrupt formation of GEM bodies and induce aberrant accumulation of survival of motor neuron protein
Authors: Kato Yuma , Yokogawa Minnie , Nakagawa Ikuma , Onodera Kazunari , Okano Hideyuki , Inoue Haruhisa , Hattori Mitsuharu , Okada Yohei , Tsuiji Hitomi
Published: March 2021

A GGGGCC repeat expansion in theC9ORF72gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. In the neurons of ALS patients, dipeptide repeat proteins (DPRs) are produced from repeat-containing RNAs by an unconventional form of translation, and some of these proteins, especially those containing poly(glycine-arginine) and poly(proline-arginine), are toxic to neurons. Gemini of coiled bodies (GEMs) are nuclear structures that harbor survival of motor neuron (SMN) protein, and SMN is essential for the assembly of U-rich small nuclear ribonucleoproteins (snRNPs) that are central for splicing. We previously reported that GEMs are lost and that snRNP biogenesis is misregulated in the motor neurons of ALS patients. Here we show that DPRs interfere with GEM formation and proper SMN localization in HeLa cells and iPSC-derived motor neurons from an ALS patient with theC9ORF72mutation. The accumulation of poly(glycine-arginine) markedly reduced the number of GEMs and caused the formation of aberrant cytoplasmic RNA granules that sequestered SMN. These findings indicate the functional impairment of SMN in motor neurons expressing DPRs and may provide a mechanism to explain the vulnerability of motor neurons of C9ORF72-ALS patients.
Inhibition of microbial deconjugation of micellar bile acids protects against intestinal permeability and liver injury
Authors: Li Darrick K. , Chaudhari Snehal N. , Sojoodi Mozhdeh , Lee Yoojin , Adhikari Arijit A. , Zukerberg Lawrence , Shroff Stuti , Barrett Stephen Cole , Tanabe Kenneth , Chung Raymond T. , Devlin A. Sloan
Published: March 2021

Altered host-microbe interactions and increased intestinal permeability have been implicated in the pathogenesis of a range of diseases. However, the mechanisms by which gut microbes affect epithelial barrier integrity remain unclear. Few host-produced metabolites that protect against epithelial damage have been identified, and whether microbial metabolism of host factors alters intestinal barrier function is unknown. Here, we investigate the effects of bacterial metabolism of host-produced bile acid (BA) metabolites on epithelial barrier integrity. We observe that rats fed a choline-deficient, high-fat diet (CDAHFD) exhibit reduced abundance of host-produced conjugated BAs in the intestine at early timepoints coinciding with increased permeability. We show that in vitro, conjugated BAs protect gut epithelial monolayers from damage caused by bacterially produced unconjugated BAs through micelle formation. We then demonstrate that inhibition of BA deconjugation using a small molecule inhibitor of gut bacterial bile salt hydrolase (BSH) enzymes prevents development of pathologic intestinal permeability and hepatic inflammation in CDAHFD-fed rats. Finally, we show that the predominant conjugated BAs in humans protect against epithelial barrier disruption in vitro. Our study identifies a protective role for conjugated BAs in intestinal epithelial barrier function and suggests that rational manipulation of microbial BA metabolism could be leveraged to regulate gut barrier integrity.
The N400 ERP component reflects a learning signal during language comprehension
Authors: Hodapp Alice , Rabovsky Milena
Published: March 2021

The functional significance of the N400 ERP component is still actively debated. Based on neural network modeling it was recently proposed that the N400 component can be interpreted as the change in a probabilistic representation corresponding to an internal temporal-difference prediction error at the level of meaning that drives adaptation in language processing. These computational modeling results imply that increased N400 amplitudes should correspond to greater adaptation. To investigate this model derived hypothesis, the current study manipulated expectancy in a sentence reading task, which influenced N400 amplitudes, and critically also later implicit memory for the manipulated word: reaction times in a perceptual identification task were significantly faster for previously unexpected words. Additionally, it could be demonstrated that this adaptation seems to specifically depend on the process underlying N400 amplitudes, as participants with larger N400 differences also exhibited a larger implicit memory benefit. These findings support the interpretation of the N400 as an implicit learning signal in language processing.
Autophagy promotes photomorphogenesis during seedling development in Arabidopsis in carbon limiting conditions
Authors: Wijerathna-Yapa Akila , Signorelli Santiago , Fenske Ricarda , Ganguly Diep R. , Stroeher Elke , Li Lei , Pogson Barry J. , Duncan Owen , Millar A. Harvey
Published: March 2021

Autophagy is a conserved catabolic process that plays an essential role under nutrient starvation condition and influences different developmental processes. We observed that seedlings of autophagy mutants (atg2,atg5,atg7,andatg9) germinated in the dark showed delayed chloroplast development following illumination. The delayed chloroplast development was characterized by a decrease in photosynthetic and chlorophyll biosynthetic proteins, lower chlorophyll content, reduced chloroplast size, and increased levels of proteins involved in lipid biosynthesis. Confirming the biological impact of these differences, photosynthetic performance was impaired in autophagy mutants 12h post illumination. We investigated if the delayed chloroplast development could be explained by lower lipid import to the chloroplast or lower triglyceride (TAG) turnover. We observed that the limitations in the chloroplast lipid import imposed bytrigalactosyldiacylglycerol1are unlikely to explain the delay in photomorphogenesis. However, we found that lower TAG mobility in the triacylglycerol lipase mutantsugardependent1significantly affected photomorphogenesis. Moreover, we showed that lower levels of carbon resources exacerbated the delay in photomorphogenesis whereas higher levels of carbon resources had an opposite effect. This work provides evidence that autophagic process operate during de-etiolation in a manner that contributes to photomorphogenesis through increasing lipid turnover to physically or energetically sustain photomorphogenesis.
WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma
Authors: Driskill Jordan H. , Zheng Yonggang , Wu Bo-Kuan , Wang Li , Cai Jing , Rakheja Dinesh , Dellinger Michael , Pan Duojia
Published: March 2021

Epithelioid hemangioendothelioma (EHE) is a poorly understood and devastating vascular cancer. Sequencing of EHE has revealed a unique gene fusion between the Hippo pathway nuclear effector TAZ (WWTR1) and the brain-enriched transcription factor CAMTA1 in ∼90% of cases. However, it remains unclear whether the TAZ-CAMTA1 gene fusion is a driver of EHE, and potential targeted therapies are unknown. Here, we show that TAZ-CAMTA1 expression in endothelial cells is sufficient to drive the formation of vascular tumors with the distinctive features of EHE, and inhibition of TAZ-CAMTA1 results in the regression of these vascular tumors. We further show that activated TAZ resembles TAZ-CAMTA1 in driving the formation of EHE-like vascular tumors, suggesting that constitutive activation of TAZ underlies the pathological features of EHE. We show that TAZ-CAMTA1 initiates an angiogenic and regenerative-like transcriptional program in endothelial cells, and disruption of the TAZ-CAMTA1-TEAD interaction or ectopic expression of a dominant negative TEAD in vivo inhibits TAZ-CAMTA1-mediated transformation. Our study provides the first genetic model of a TAZ fusion oncoprotein driving its associated human cancer, pinpointing TAZ-CAMTA1 as the key driver and a valid therapeutic target of EHE.
Mesoscopic transformation at initial corrosion stage of 20# steel in aqueous solution under gas–liquid two-phase stratified flow condition
Authors: Yang Guirong , Pan Zhaoxia , Zhang Zhenghai , Song Wenming , Ma Ying , Hao Yuan
Published: March 2021

Purpose

This study aims to investigate the initial corrosion behavior in aqueous solution of 20# seamless steel under (CO2/aqueous solution) gas–liquid two-phase stratified flow conditions.

Design/methodology/approach

The initial corrosion behavior was studied through the weight loss methods, scanning electron microscopy with energy-dispersive x-ray spectroscopy and x-ray diffraction.

Findings

The corrosion rate of 20# steel obviously increases with the increasing gas pressure at different corrosion time when the CO2 pressure is less than 0.11 MPa, and the increase of corrosion rate tends to be steady when the pressure exceeds 0.11 MPa. With the increase of CO2 pressure, the corrosion products changed from flocculent to acicular, granular and scaly. A four-stage model for the growth of the corrosion product layer was proposed, namely, the diffusion reaction stage, the local film formation stage, the complete film formation stage and the densification stage of the product film.

Originality/value

A four-stage model for the growth of the corrosion product layer on the pipe wall surface under this condition was proposed, namely, the diffusion reaction stage, the local film formation stage, the complete film formation stage and the densification stage of the product film. The growing process and densification mechanism of corrosion products layer were discussed.
Study on hydrogen permeation behavior of X80 steel under AC stray current interference
Authors: Wang Ailing , Deng Yong , Li Kaihong , Li Wenlei , Yu Dongliang , Cui Gan , Liu JianGuo , Li Zili
Published: March 2021

Purpose

Alternating current (AC) corrosion is a type of corrosion that occurs in buried pipelines under AC stray current interference, which can increase the hydrogen embrittlement sensitivity of pipelines. However, rare research works have been conducted on the hydrogen permeability characteristics of pipeline steel under AC stray current interference. The purpose of this paper is to study hydrogen permeation behavior of X80 steel under AC stray current interference.

Design/methodology/approach

In this paper, the hydrogen permeation behavior of X80 steel under AC interference is studied by AC hydrogen charging experiment in a dual electrolytic cell. The relationship between hydrogen evolution rate and hydrogen permeation flux is studied using the gas collection method. The difference between AC hydrogen permeability and direct current (DC) hydrogen permeability is also discussed.

Findings

The anodic dissolution caused by AC corrosion promotes the chemical desorption reaction of the adsorbed hydrogen atoms on the surface, reducing the hydrogen atom absorption ratio by 70%. When the AC is smaller than 150░ A/m2, the hydrogen permeation process is controlled by the hydrogen atom generation rate, and the hydrogen permeation flux increases with the increase in hydrogen atom generation rate. When the AC exceeds 400░ A/m2, the hydrogen permeation process is controlled by the absorption ratio. The hydrogen permeation flux decreases with the decrease in the absorption ratio. Under AC interference, there is a maximum hydrogen permeation flux that linearly correlates to the H+ concentration in the solutions.

Originality/value

The high-strength steel is very sensitive to hydrogen embrittlement, and X80 steel has been widely used in oil and gas pipelines. To date, no research has been conducted on the hydrogen permeation behavior of pipeline steel under AC interference, and the hydrogen permeability characteristics of pipeline steel under AC interference are not clear. The research results of this paper are of great significance for ensuring the intrinsic safety of high-strength pipelines under AC stray current interference.
Selecting Mutual Funds for Retirement Accounts (B)
Authors: Braun Phillip A.
Published: March 2021

Alice Monroe was an admissions officer at the Kellogg School of Management at Northwestern University. It was early January 2017 and Alice had enrolled in Northwestern's 403(b) retirement plan two months earlier. After spending a considerable amount of time examining the mutual funds available through the university's retirement plan, Alice had picked two to invest in: a large-cap equity growth fund and a mid-cap equity fund. (See the related case "Selecting Mutual Funds for Retirement Accounts (A).") Her initial allocations were 50% of her investment dollars in each fund.

Upon further reflection, however, she realized these initial allocations were somewhat simplistic. She recalled, from an investments class she had taken at college, the topic of modern portfolio theory, which held that by adding more funds to her portfolio she might be able to achieve greater diversification and thereby reduce the overall risk of her portfolio and/or achieve a higher expected return. Alice now was considering adding an intermediate-term bond fund and a real estate fund to her retirement account.

She hoped to use modern portfolio theory to prove that these new funds would indeed help her diversify her portfolio. If they did, she would also reassess her portfolio weights to determine the optimal allocation.