bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydroxide ions amplified by water entanglement underly the mechanism of general anesthesia
Authors: Qian Hao , Li Na , Yang Lei , Xu Younian , Chen Rong , Lu Dongshi , Zhao Ruihan , Liu Hui , Cui Nanxue , Zhou Qiao , Zhang Shihai
Published: January 2021

It is believed that inhaled anesthetics occupy hydrophobic pockets within target proteins, but how inhaled anesthetics with diverse shapes and sizes fit into highly structurally selective pockets is unknown. For hydroxide ions are hydrophobic, we determined whether hydroxide ions could bridge inhaled anesthetics and protein pockets. We found that small additional load of cerebral hydroxide ions decreases anesthetic potency. Multiple-water entanglement network, derived from Ising model, has a great ability to amplify ultralow changes in the cerebral hydroxide ion concentration, and consequently, amplified hydroxide ions account for neural excitability. Molecular dynamics simulations showed that inhaled anesthetics produce anesthesia by attenuating the formation of multiple-water entanglement network. This work suggests amplified hydroxide ions underlying a unified mechanism for the anesthetic action of inhaled anesthetics.
Improving antibody thermostability based on statistical analysis of sequence and structural consensus data
Authors: Jia Lei , Jain Mani , Sun Yaxiong
Published: January 2021

The use of Monoclonal Antibodies (MAbs) as therapeutics has been increasing over the past 30 years due to their high specificity and strong affinity towards the target. One of the major challenges towards their use as drugs is their low thermostability, which impacts both efficacy as well as manufacturing and delivery. To aid the design of thermally more stable mutants, consensus sequence-based method has been widely used. These methods typically have a success rate of about 50% with maximum melting temperature increment ranging from 10 to 32°C. In order to improve the prediction performance, we have developed a new and fast MAbs specific method by adding a 3D structural layer to the consensus sequence method. This is done by analyzing the close-by residue pairs which are conserved in more than eight hundred MAbs’ 3D structures. Major advantage of this structural level assessment is in significantly reducing the false positives by almost half from the consensus sequence method alone. In summary, combining consensus sequence and structural residue pair covariance methods, we developed an inhouse application for predicting human MAb thermostability to guide protein engineers to design more stable molecules. This application has shown success in designing MAb engineering panels in multiple biologics programs.
ACTIVA: realistic single-cell RNA-seq generation with automatic cell-type identification using introspective variational autoencoders
Authors: Heydari A. Ali , Davalos Oscar A. , Zhao Lihong , Hoyer Katrina K. , Sindi Suzanne S.
Published: January 2021

Motivation

Single-cell RNA sequencing (scRNAseq) technologies allow for measurements of gene expression at a single-cell resolution. This provides researchers with a tremendous advantage for detecting heterogeneity, delineating cellular maps, or identifying rare subpopulations. However, a critical complication remains the low number of single-cell observations due to limitations by the rarity of a subpopulation, tissue degradation, or cost. This absence of sufficient data may cause inaccuracy or irreproducibility of downstream analysis. In this work, we present ACTIVA (Automated Cell-Type-informed Introspective Variational Autoencoder): a novel framework for generating realistic synthetic data using a single-stream adversarial variational autoencoder conditioned with cell-type information. Within a single framework, ACTIVA can generate data representative of the entire population, or specific subpopulations on demand, as opposed to two separate models (such as scGAN and cscGAN). Data generation and augmentation with ACTIVA can enhance scRNAseq pipelines and analysis, such as benchmarking new algorithms, studying the accuracy of classifiers, and detecting marker genes. ACTIVA will facilitate analysis of smaller datasets, potentially reducing the number of patients and animals necessary in initial studies.

Results

We train and evaluate models on multiple public scRNAseq datasets. In comparison to GAN-based models (scGAN and cscGAN), we demonstrate that ACTIVA generates cells that are more realistic and harder for classifiers to identify as synthetic, which also have better pair-wise correlations between genes. We show that data augmentation with ACTIVA significantly improves the classification of rare subtypes (more than 45% improvement compared to not augmenting and 4% better than cscGAN) all while reducing training time by an order of magnitude in comparison to both models.

Availability of data and code

Links to raw, pre- and post-processed data, source code and tutorials are available at https://github.com/SindiLab.

Supplementary information

Supplementary material can be found as a separate file with the same pre-print submission.
Multiple Monkey Pose Estimation Using OpenPose
Authors: Blanco Negrete Salvador , Labuguen Rollyn , Matsumoto Jumpei , Go Yasuhiro , Inoue Ken-ichi , Shibata Tomohiro
Published: January 2021

This paper proposes a system for pose estimation on monkeys, in diverse and challenging scenarios, and under complex social interactions by using OpenPose. In comparison to most animals used for research, Monkeys present additional difficulties for pose estimation. Multiple degrees of freedom, unique complex postures, intricated social interactions, among others. Our monkey OpenPose trained model is robust against these difficulties. It achieves similar performance as in human pose estimation models, and it can run in Realtime.
Mentorship as a strategy to improve research ability of students and young researchers in Africa: an exploratory study and initial findings on the CORE Africa Research Mentorship Scheme
Authors: Ngongalah Lem , Rawlings Ngwa Niba , Musisi James , Awanchiri Kimonia , Akwah Emmanuella , Ngeh Etienne , Ssemwanga Andrew
Published: January 2021

Mentorship provides an opportunity to support skill development, improve research ability, promote interest in research and offer career advice. The need for research mentorship in Africa is well-recognised. However, there is scarce literature on the development of such programmes and their potential impacts on students and young researchers in Africa (SYRIA). This study documents the development of the CORE Africa Research Mentorship Scheme (CARMS), and reports the outcomes and challenges experienced over a two-year period, from 2018 to 2020.

41 mentors and mentees from Cameroon, Uganda and Nigeria participated in the programme. Mentors were based in Africa and the UK, while mentees were all based in Africa. Mentees gained knowledge and skills in various research areas including proposal writing, research methods, data analysis, report writing and research publication. Nine mentees gained their first research publication through the CARMS and three successfully completed their first grant proposal. Three mentees were supported by their mentor to develop PhD research proposals and five others gained skills that helped them secure paid research jobs. Eleven mentees have ‘graduated’ from the programme, seven of which are currently enrolled as trainee mentors. Mentees appreciated the opportunity to improve on their research skills and felt that the programme gave them a ‘safe’ environment to freely express their concerns.

Main challenges encountered were: difficulty finding suitable mentors, communication barriers, poorly defined mentorship goals, dealing with mentee’s lack of knowledge/experience of ‘basic’ research concepts and funding limitations. This programme had several positive impacts on the knowledge and skills of mentees and demonstrates the importance of mentorship in research capacity strengthening. Sustaining such programmes requires investments in training and development, to ensure that mentees are continuously and adequately supported.
Engineering of a fluorescent chemogenetic reporter with tunable color for advanced live-cell imaging
Authors: Benaissa Hela , Ounoughi Karim , Aujard Isabelle , Fischer Evelyne , Goïame Rosette , Nguyen Julie , Tebo Alison G. , Li Chenge , Saux Thomas Le , Danglot Lydia , Pietrancosta Nicolas , Morin Xavier , Jullien Ludovic , Gautier Arnaud
Published: January 2021

Biocompatible fluorescent reporters with spectral properties spanning the entire visible spectrum are indispensable tools for imaging the biochemistry of living cells and organisms in real time. Here, we present the engineering of a fluorescent chemogenetic reporter with tunable optical and spectral properties. A collection of live-cell compatible fluorogenic chromophores with various electronic properties enables to generate bimolecular fluorescent assemblies that cover the visible spectrum from blue to red using a single protein tag engineered and optimized by directed evolution and rational design. We showed that the ability to tune the fluorescence color and properties through simple molecular modulation provides an unprecedent experimental versatility for imaging proteins in live cells, including delicate cultured hippocampal neurons, and in multicellular organisms. The ability to tune the spectral properties and fluorescence performance enables to match the spectral specifications and requirements of the most advanced imaging techniques, and allowed us to achieve efficient stimulated emission depletion (STED) nanoscopy of fusion proteins in live cells and live primary cultured neurons.
Wild to domesticates: genomes of edible diploid bananas hold traces of several undefined genepools
Authors: Sardos Julie , Breton Catherine , Perrier Xavier , Van Den Houwe Ines , Paofa Janet , Rouard Mathieu , Roux Nicolas
Published: January 2021

This study is an unprecedent exploration of the diversity of 226 diploid bananas genotyped with restriction-site-associated DNA sequencing data (RADseq) to clarify the processes that led to the creation of edible diploid AA bananas. This wide set included 72 seedy bananas, mostlyM. acuminatafrom different genepools, and 154 edible, i.e. parthenocarpic and sterile, AA accessions obtained from genebanks and recent collecting missions. We highlighted the geographic organisation of the diversity of edible AAs and confirmed the admixed nature of many and further conducted introgressions tests within AAs from South East Asia and New Guinea. Lastly, taking advantage of the presence of an important number ofM. acuminatassp.banksii(22) and of AA from Papua New Guinea (76) in the set, we investigated the patterns of differentiation between wild and cultivated bananas seemingly belonging to the same genepool. We discovered a few cultivated AAs that may be of pure origins both in South-East Asia and in New Guinea. We also detected two undefined parental genepools in South East Asia for which regions of origin could be Thailand and a region between north Borneo and the Philippines, respectively. Finally, we suggest the existence of a third genepool in New Guinea island that might be a source population for both edible AAs and the localM. acuminatassp.banksii.
Midkine-a regulates the formation of a fibrotic scar during zebrafish heart regeneration
Authors: Grivas Dimitrios , González-Rajal Álvaro , la Pompa José Luis de
Published: January 2021

The adult zebrafish heart regenerates after injury, unlike the hearts of mammals. Heart cryoinjury triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role ofmdkain zebrafish heart regeneration. We show thatmdkaexpression is strongly induced at 1-day post cryoinjury (dpci) throughout the epicardium, whereas by 7 dpci expression has become restricted to epicardial cells covering the injured area. To study the role ofmdkain heart regeneration, we generatedmdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss ofmdkadecreased endothelial cell proliferation and resulted in a blockade of heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and TGFβ signalling activity. These results reveal a critical role formdkain fibrosis regulation during heart regeneration.
Tracing back variations in archaeal cell division to protein domain architectures
Authors: Frohn Béla , Härtel Tobias , Cox Jürgen , Schwille Petra
Published: January 2021

The Endosomal Sorting Complex Required for Transport (ESCRT) system is a multi-protein machinery that is involved in cell division of both Eukaryotes and Archaea. This spread across super-phyla suggests that a precursor ESCRT machinery existed already at an evolutionary early stage of life, making it a promising candidate for the (re)construction of a minimal cell division machinery. There are, however, only few experimental data about ESCRT machineries in Archaea, due to high technical challenges in cultivation and microscopy. Here, we analyse the proteins of archaeal ESCRT machineries bioinformatically on a domain level, to enable mechanistical comparison without such challenging experiments. First, we infer that there are at least three different cell division mechanisms utilizing ESCRT proteins in archaea, probably similar in their constriction mechanisms but different in membrane tethering. Second, we show that ESCRT proteins in Asgard archaea are highly similar to eukaryotic ESCRT proteins, strengthening the recently developed idea that all Eukaryotes descended from archaea. Third, we reconstruct a plausible evolutionary development of ESCRT machineries and suggest that a simple ESCRT-based constriction machinery existed in the last archaeal common ancestor. These findings not only give very interesting insights into the evolution of cell division in Archaea and Eukaryotes, but also reveal new research avenues by suggesting hypothesis-driven experiments for both, cell biology and bottom-up synthetic biology.
The stem cell-specific protein TRIM71 inhibits maturation and activity of the pro-differentiation miRNA let-7 via two independent molecular mechanisms
Authors: Torres-Fernández Lucia A. , Mitschka Sibylle , Ulas Thomas , Dahm Kilian , Becker Matthias , Händler Kristian , Windhausen Julia , Schultze Joachim L. , Kolanus Waldemar
Published: January 2021

The stem cell-specific RNA-binding protein TRIM71/LIN-41 was the first identified target of the pro-differentiation and tumor suppressor miRNA let-7. TRIM71 has essential functions in embryonic development and a proposed oncogenic role in several cancer types, such as hepatocellular carcinoma. Here, we show that TRIM71 regulates let-7 expression and activity via two independent mechanisms. On the one hand, TRIM71 enhances pre-let-7 degradation through its direct interaction with LIN28 and TUT4, thereby inhibiting let-7 maturation and indirectly promoting the stabilization of let-7 targets. On the other hand, TRIM71 represses the activity of mature let-7 via its RNA-dependent interaction with the RNA-Induced Silencing Complex (RISC) effector protein AGO2. We found that TRIM71 directly binds and stabilizes let-7 targets, suggesting that let-7 activity inhibition occurs on active RISCs. MiRNA enrichment analysis of several transcriptomic datasets from mouse embryonic stem cells and human hepatocellular carcinoma cells suggests that these let-7 regulatory mechanisms shape transcriptomic changes during developmental and oncogenic processes. Altogether, our work reveals a novel role for TRIM71 as a miRNA repressor and sheds light on the precise mechanistic dual regulation of let-7.
Development of first linkage map forSilphium integrifolium(Asteraceae) enables identification of sporophytic self-incompatibility locus
Authors: Price John H. , Raduski Andrew R. , Brandvain Yaniv , Van Tassel David L. , Smith Kevin P.
Published: January 2021

Silphium integrifolium(Asteraceae) has been identified as a candidate for domestication as a perennial oilseed crop and has a sporophytic self-incompatibility system—the genetic basis of which is not well understood in theAsteraceae. To address this gap, we sought to map the genomic location of the self-recognition locus (S-locus) in this species.

We used a biparental population and genotyping-by-sequencing to create the first genetic linkage map for this species. Then we developed a novel crossing scheme and set of analysis methods in order to infer S-locus genotypes for a subset of these individuals, allowing us to map the trait. Finally, we identified potential gene candidates using synteny analysis with the annual sunflower (Helianthus annuus) genome.

Our linkage map contains 198 SNP markers and resolved into the correct number of linkage groups. We were able to successfully map the S-locus and identify several potential gene candidates in the sunflower syntenic region.

Our method is effective and efficient, allowed us to map theS. integrifoliumS-locus using fewer resources than previous studies, and could be readily be applied to other species. Our best gene candidate appears to be worthy of future work inS. integrifoliumand otherAsteraceaespecies.
A New ‘Comprehensive’ Annotation of Leucine-Rich Repeat-Containing Receptors in Rice
Authors: Gottin Céline , Dievart Anne , Summo Marilyne , Droc Gaëtan , Périn Christophe , Ranwez Vincent , Chantret Nathalie
Published: January 2021

Rice plays an essential food security role for more than half of the world’s population. Obtaining crops with high levels of disease resistance is a major challenge for breeders, especially today given the urgent need for agriculture to be more sustainable. Plant resistance genes are mainly encoded by three large Leucine-Rich Repeat (LRR)-containing receptor (LRR-CR) subfamilies: the LRR-Receptor-Like Kinase (RLK), LRR-Receptor-Like Protein (RLP) and Nucleotide-binding LRR Receptor (NLR) subfamilies. Using LRRprofiler, a pipeline we developed to annotate and classify those proteins, we compared three publicly available annotations of the rice Nipponbare reference genome. The extended discrepancies we observed for LRR-CR gene models led us to perform in-depth manual curation of their annotations while paying special attention to nonsense mutations. We then transferred this manually curated annotation to Kitaake, a Nipponbare closely related cultivar, using an optimised strategy. Here we discuss the breakthrough achieved by manual curation when comparing genomes and, in addition to ‘functional’ and ‘structural’ annotations, we propose the community to adopt this new approach, which we call ‘comprehensive’ annotation. The resulting data are crucial for further studies on the natural variability and evolution of LRR-CR in order to promote their use in breeding future resilient varieties.
Recombinant production of a functional SARS-CoV-2 spike receptor binding domain in the green algaeChlamydomonas reinhardtii
Authors: Berndt A. , Smalley T. , Ren B. , Badary A. , Sproles A. , Fields F. , Torres-Tiji Y. , Heredia V. , Mayfield S.
Published: January 2021

Recombinant production of viral proteins can be used to produce vaccine antigens or reagents to identify antibodies in patient serum. Minimally, these proteins must be correctly folded and have appropriate post-translation modifications. Here we report the production of the SARS-CoV-2 spike protein Receptor Binding Domain (RBD) in the green algaeChlamydomonas.RBD fused to a fluorescent reporter protein accumulates as an intact protein when targeted for ER-Golgi retention or secreted from the cell, while a chloroplast localized version is truncated, lacking the amino terminus. The ER-retained RBD fusion protein was able to bind the human ACE2 receptor, the host target of SARS-CoV-2, and was specifically out-competed by mammalian cell-produced recombinant RBD, suggesting that the algae produced proteins are sufficiently post-translationally modified to act as authentic SARS-CoV-2 antigens. Because algae can be grown at large scale very inexpensively, this recombinant protein may be a low cost alternative to other expression platforms.
Distinct classes of lagging chromosome underpin age-related oocyte aneuploidy in mouse
Authors: Mihajlović Aleksandar I. , Haverfield Jenna , FitzHarris Greg
Published: January 2021

Chromosome segregation errors that cause oocyte aneuploidy increase in frequency with maternal age and are considered a major contributing factor of age-related fertility decline in females. A common age-associated chromosome segregation phenomenon in oocytes is the lagging anaphase chromosome, but whether anaphase laggards actually missegregate and cause aneuploidy is unclear. Here we show unexpectedly that lagging chromosomes in mouse oocytes comprise two mechanistically distinct classes of motion that we refer to as ‘Class-I’ and ‘Class-II’. We use imaging approaches and mechanistic interventions to dissociate the two classes, and find that whereas Class-II laggards are benign, Class-I laggards can directly cause aneuploidy. Most notably, a controlled prolongation of meiosis-I specifically lessens Class-I lagging to prevent aneuploidy. Our data thus reveal lagging chromosomes to be a cause of age-related aneuploidy in mouse oocytes and suggest that manipulating the cell cycle could increase the yield of useful oocytes in some contexts.
Impact of Prior Infection on Protection and Transmission of SARS-CoV-2 in Golden Hamsters
Authors: Zhang Cheng , Guo Zhendong , Li Nan , Cui Huan , Meng Keyin , Liu Lina , Zhao Li , Zhang Shanshan , Qin Chengfeng , Liu Juxiang , Gao Yuwei , Zhang Chunmao
Published: January 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 100 million confirmed human infections, and 2 million more deaths globally since its emergence in the end of 2019. Several studies have shown that prior infection provided protective immunity against SARS-CoV-2 in non-human primate models. However, the effect of prior infection on blocking SARS-CoV-2 transmission is not clear. Here, we evaluated the impact of prior infection on protection and transmission of the SARS-CoV-2 virus in golden hamsters. Our results showed that prior infection provided protective immunity against SARS-CoV-2 re-challenge, but it was not sterizing immunity. The transmission experiment results showed that SARS-CoV-2 was efficiently transmitted from naive hamsters to prior infected hamsters by direct contact and airborne route, but not by indirect contact. Further, the virus was efficiently transmitted from prior infected hamsters to naive hamsters by direct contact, but not by airborne route and indirect contact. Surprisingly, the virus can be transmitted between prior infected hamsters by direct contact during a short period of early infection. Taken together, our study demonstrated that prior infected hamsters with good immunity can still be naturally re-infected, and the virus can be transmitted between prior infected hamsters and the naive through different transmission routes, implying the potential possibility of human re-infection and the risk of virus transmission between prior infected population and the healthy. Our study will help to calculate the herd immunity threshold more accurately, make more reasonable public health decisions, formulate an optimized population vaccination program, as well as aid the implementation of appropriate public health and social measures to control COVID-19.
SARS-CoV-2 binding and neutralizing antibody levels after vaccination with Ad26.COV2.S predict durable protection in rhesus macaques
Authors: Roozendaal Ramon , Solforosi Laura , Stieh Daniel , Serroyen Jan , Straetemans Roel , Wegmann Frank , Rosendahl Huber Sietske K. , van der Lubbe Joan E. M. , Hendriks Jenny , le Gars Mathieu , Dekking Liesbeth , Czapska-Casey Dominika N. , Guimera Nuria , Janssen Sarah , Tete Sarah , Chandrashekar Abishek , Mercado Noe , Yu Jingyou , Koudstaal Wouter , Sadoff Jerry , Barouch Dan H. , Schuitemaker Hanneke , Zahn Roland
Published: January 2021

The first COVID-19 vaccines have recently gained authorization for emergency use.1,2At this moment, limited knowledge on duration of immunity and efficacy of these vaccines is available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short lived,3,4and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection.5Here we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike (S) protein in rhesus macaques6,7,8and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We find that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of S-binding and neutralizing antibodies. These results suggest that Ad26.COV2.S could confer durable protection in humans and that immunological correlates of protection may enable the prediction of durability of protection.
Geography, not host identity, shapes bacterial community in reindeer lichens
Authors: Alonso-García Marta , Villarreal A. Juan Carlos
Published: January 2021

Background and Aims

Tremendous progress have been recently achieved in host-microbe research, however, there is still a surprising lack of knowledge in many taxa. Despite its dominance and crucial role in boreal forest, reindeer lichens have until now received little attention. We characterize, for the first time, the bacterial community of four species of reindeer lichens from Eastern North America’s boreal forests. We analysed the effect of two factors (host-identity and geography) in the bacterial community composition, we verified the presence of a common core bacteriota and identified the most abundant core taxa.

Methods

Morphological and molecular lichen species delimitation was performed based on the ITS region. The bacterial community of around 200 lichen samples was characterised using the 16S rRNA gene.

Key Results

Our results showed that host-lichen identity does not determine bacterial community composition in reindeer lichens, but we confirmed the influence of geography in shaping the diversity and abundance of bacteria associated to the speciesCladonia stellarisfrom lichen woodlands. We also revealed that reindeer lichens share a reduced common core bacteriota composed exclusively by Proteobacteria.

Conclusions

The bacterial community in reindeer lichens is not host-selective. Northern lichen woodlands exhibit a significant higher diversity and abundance of bacteria associated toCladonia stellaris. Nevertheless, the specific role of those bacteria as well as the process of host colonization remains to be determined. Elucidating these two aspects would be key to have a better understanding of the whole boreal ecosystems. The reduced and not diverse core bacteriota of reindeer lichens might be due to the larger size of our study area. The presence of the speciesMethylorosula polarisin the core bacteriota is evident and might have a particular importance for reindeer lichens.
Annelids win again: the first evidence of Hox antisense transcription in Spiralia
Authors: Novikova Elena L. , Bakalenko Nadezhda I. , Kulakova Milana A.
Published: January 2021

To date it is becoming more and more obvious that multiple non-coding RNAs, once considered to be transcriptional noise, play a huge role in gene regulation during animal ontogenesis. Hox genes are key regulators of embryonic development, growth and regeneration of all bilaterian animals. It was shown that mammalian Hox loci are transcribed in both directions and noncoding RNAs maintain and control the normal functioning of Hox clusters. We revealed antisense transcripts of most of Hox genes in two lophotrochozoans, errant annelidsAlitta virensandPlatynereis dumerilii.It is for the first time when non-coding RNAs associated with Hox genes are found in spiralian animals. All these asRNAs can be referred to as natural antisense transcripts (NATs). We analyzed the expression of all detected NATs using sense probes to their Hox mRNAs during larval and postlarval development and regeneration by whole mount in situ hybridization (WMISH). We managed to clone several asRNAs(Avi-antiHox4-1, Avi-antiHox4-2andAvi-antiHox5)of these annelids and analyzed their expression patterns as well. Our data indicate variable and complicated interplay between sense and antisense Hox transcripts during development and growth of two annelids. The presence of Hox antisense transcription in the representatives of different bilaterian clades (mammals, myriapods and annelids) and similar expression relationships in sense-antisense pairs suggest that this can be the ancestral feature of Hox cluster regulation.
Effects of conjugated linoleic acid on proliferation and differentiation of bovine intramuscular preadipocytein vitro
Authors: Wan Rong , Meng Qingxiang , Zhenming Zhou , hao Wu
Published: January 2021

Conjugated linoleic acid (CLA), a mixture of isomers of linoleic acid, has previously been shown to be able to increase intramuscular fat contentin vivoand stimulate adipogenesis in intramuscular preadipocytes invitroin pig. Unfortunately, there is little data to evaluate the effect of CLA on proliferation and differentiation of bovine intramuscular preadipocytes. This study investigated the regulation by CLA in proliferation and differentiation of bovine intramuscular preadipocytes. The results demonstrated that CLA significantly induced the expression of PPARγ and C/EBPα mRNA of bovine intramuscular preadipocytes as well as the accumulation of lipid in cultured intramuscular preadipocytes. Additionally, CLA significantly decreased the cell proportion of phase G0/G1, and remarkably increased the proportion of phase S+G2/M. Collectively, these results suggest that CLA promotes bovine intramuscular preadipocyte proliferation and differentiation.
A neuronal social trait space for first impressions in the human amygdala and hippocampus
Authors: Cao Runnan , Lin Chujun , Li Xin , Todorov Alexander , Brandmeir Nicholas J , Wang Shuo
Published: January 2021

People instantaneously evaluate faces with significant agreement on evaluations of social traits. However, the neural basis for such rapid spontaneous face evaluation remains largely unknown. Here, we recorded from 490 neurons in the amygdala and hippocampus in 5 neurosurgical patients and show that amygdala and hippocampal neurons encode a social trait space. We further investigated the temporal evolution and modulation on the social trait representation, and we employed encoding and decoding models to reveal the critical social traits for the trait space. We also recorded from another 259 neurons and replicated our findings using different social traits. Lastly, the neuronal social trait space may have a behavioral consequence likely involved in the abnormal processing of social information in autism. Together, our results suggest that there exists a neuronal population code for a comprehensive social trait space in the human amygdala and hippocampus that underlie spontaneous first impressions.
Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin mediated endocytosis
Authors: Anderson Ruthellen H. , Sochacki Kem A. , Vuppula Harika , Scott Brandon L. , Bailey Elizabeth M. , Schultz Maycie M. , Kerkvliet Jason G. , Taraska Justin W. , Hoppe Adam D. , Francis Kevin R.
Published: January 2021

As the principal internalization mechanism in mammalian cells, clathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of disrupted cholesterol synthesis, sterol specificity, mechanisms involved, and relevance to disease pathology. Using genome-edited cell lines, we demonstrate that inhibition of post-squalene cholesterol biosynthesis as observed in inborn errors of cholesterol metabolism, results in striking immobilization of CME and impaired transferrin uptake. Imaging of membrane bending dynamics and CME pit ultrastructure revealed prolonged clathrin pit lifetimes and accumulation of shallow clathrin-coated structures that scaled with diminishing sterol abundance. Moreover, fibroblasts derived from Smith-Lemli-Opitz syndrome subjects displayed reduced CME function. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest reduced CME contributes to cellular phenotypes observed within disorders of cholesterol metabolism.
Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis
Authors: Keppie Stuart J. , Mansfield Jessica C. , Tang Xiaodi , Philp Christopher J. , Graham Helen K. , Önnerfjord Patrik , Wall Alanna , McLean Celia , Winlove C. Peter , Sherratt Michael J. , Pavlovskaya Galina E. , Vincent Tonia L
Published: January 2021

Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis (OA). The tissue has low intrinsic repair especially in aged and osteoarthritic joints. Here we describe three pro-regenerative factors; fibroblast growth factor 2 (FGF2), connective tissue growth factor, bound to transforming growth factor-beta (CTGF-TGFβ), and hepatoma-derived growth factor (HDGF), that are rapidly released from the pericellular matrix (PCM) of articular cartilage upon mechanical injury. All three growth factors bound heparan sulfate, and were displaced by exogenous NaCl. We hypothesised that sodium, sequestered within the aggrecan-rich matrix, was freed by injurious compression, thereby enhancing the bioavailability of pericellular growth factors. Indeed, growth factor release was abrogated when cartilage aggrecan was depleted by IL-1 treatment, and in severely damaged human osteoarthritic cartilage. A flux in free matrix sodium upon mechanical compression of cartilage was visualised by23Na magnetic resonance imaging (MRI) just below the articular surface. This corresponded to a region of reduced tissue stiffness, measured by scanning acoustic microscopy and second harmonic generation microscopy, and where Smad2/3 was phosphorylated upon cyclic compression. Our results describe a novel intrinsic repair mechanism, controlled by matrix stiffness and mediated by the free sodium concentration, in which heparan sulfate-bound growth factors are released from cartilage upon injurious load. They identify aggrecan as a depot for sequestered sodium, explaining why osteoarthritic tissue loses its ability to repair. Treatments that restore matrix sodium to allow appropriate release of growth factors upon load are predicted to enable intrinsic cartilage repair in osteoarthritis.

Significance Statement

Osteoarthritis is the most prevalent musculoskeletal disease, affecting 250 million people worldwide1. We identify a novel intrinsic repair response in cartilage, mediated by aggrecan-dependent sodium flux, and dependent upon matrix stiffness, which results in the release of a cocktail of pro-regenerative growth factors after injury. Loss of aggrecan in late-stage osteoarthritis prevents growth factor release and likely contributes to disease progression. Treatments that restore matrix sodium in osteoarthritis may recover the intrinsic repair response to improve disease outcome.
Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes
Authors: Kannan Suraj , Miyamoto Matthew , Lin Brian L. , Kwon Chulan
Published: January 2021

A primary limitation in the clinical application of pluripotent stem cell derived cardiomyocytes (PSC-CMs) is the failure of these cells to achieve full functional maturity.In vivo, cardiomyocytes undergo numerous adaptive changes during perinatal maturation. By contrast, PSC-CMs fail to fully undergo these developmental processes, instead remaining arrested at an embryonic stage of maturation. To date, however, the precise mechanisms by which directed differentiation differs from endogenous development, leading to consequent PSC-CM maturation arrest, are unknown. The advent of single cell RNA-sequencing (scRNA-seq) has offered great opportunities for studying CM maturation at single cell resolution. However, perinatal cardiac scRNA-seq has been limited owing to technical difficulties in the isolation of single CMs. Here, we used our previously developed large particle fluorescence-activated cell sorting approach to generate an scRNA-seq reference of mousein vivoCM maturation with extensive sampling of perinatal time periods. We subsequently generated isogenic embryonic stem cells and created anin vitroscRNA-seq reference of PSC-CM directed differentiation. Through trajectory reconstruction methods, we identified a perinatal maturation program in endogenous CMs that is poorly recapitulatedin vitro. By comparison of our trajectories with previously published human datasets, we identified a network of nine transcription factors (TFs) whose targets are consistently dysregulated in PSC-CMs across species. Notably, we demonstrated that these TFs are only partially activated in commonex vivoapproaches to engineer PSC-CM maturation. Our study represents the first direct comparison of CM maturationin vivoandin vitroat the single cell level, and can be leveraged towards improving the clinical viability of PSC-CMs.

Significance Statement

There is a significant clinical need to generate mature cardiomyocytes from pluripotent stem cells. However, to date, most differentiation protocols yield phenotypically immature cardiomyocytes. The mechanisms underlying this poor maturation state are unknown. Here, we used single cell RNA-sequencing to compare cardiomyocyte maturation pathways in endogenous and pluripotent stem cell-derived cardiomyocytes. We found thatin vitro, cardiomyocytes fail to undergo critical perinatal gene expression changes necessary for complete maturation. We found that key transcription factors regulating these changes are poorly expressedin vitro.Our study provides a better understanding of cardiomyocyte maturation bothin vivoandin vitro, and may lead to improved approaches for engineering mature cardiomyocytes from stem cells.
From heterogeneous datasets to predictive models of embryonic development
Authors: Dutta Sayantan , Patel Aleena L. , Keenan Shannon E. , Shvartsman Stanislav Y.
Published: January 2021

Modern studies of embryogenesis are increasingly quantitative, powered by rapid advances in imaging, sequencing, and genome manipulation technologies. Deriving mechanistic insights from the complex datasets generated by these new tools requires systematic approaches for data-driven analysis of the underlying developmental processes. Here we use data from our work on signal-dependent gene repression in theDrosophilaembryo to illustrate how computational models can compactly summarize quantitative results of live imaging, chromatin immunoprecipitation, and optogenetic perturbation experiments. The presented computational approach is ideally suited for integrating rapidly accumulating quantitative data and for guiding future studies of embryogenesis.
Experiencing literature on the e‐reader: the effects of reading narrative texts on screen
Authors: Schwabe Annika , Brandl Lukas , Boomgaarden Hajo G. , Stocker Günther
Published: January 2021

Background

The digitalisation of literature is proliferating, and the increasing spread of digital reading devices and the availability of digital texts is likely to make books on screen a lasting phenomenon, but little attention has been paid to the consequences of digitalisation for the experience of narrative fiction. While on the one hand, reading literature on a digital reading device might trigger a superficial processing of the text, and problems regarding orientation within the narrative, the awareness of reading a literary text might, on the other hand, lead to more in‐depth and complex processing, independent of reading medium. This study examines whether the reading performance and the emotional and cognitive experiences of the reception of a literary text vary between reading a printed book or an e‐reader.

Methods

Using a between‐subjects experimental design, 207 participants read the beginning of a novel either in a printed book or on an e‐reader. They then completed a reading comprehension test and questionnaires about their cognitive and emotional experiences.

Results

Overall, the results do not suggest the clear superiority of either of the two reading media. Neither reading speed nor reading comprehension differed significantly between the two groups. Even though a broad range of reading experiences was measured, neither cognitive nor emotional reading experiences differed significantly between the groups.

Conclusion

An e‐reader does not affect either reading performance or cognitive and emotional experience of reading a narrative text, compared with a printed book.
Diffused effort, asset heterogeneity, and real estate brokerage
Authors: Li Zhaohui , Li Qiang , Sun Hua , Sun Li
Published: January 2021

We generalize the classic Williams (1998, Review of Financial Studies, 11, 239–280) brokerage model by introducing diffused effort and asset heterogeneity. The term “diffused effort” refers to the fact that an agent can cross‐utilize effort spending on one listing to another . One counterintuitive finding in Williams' paper is the absence of the agency problem . As a special case in our model, we recover the agency problem. We demonstrate the positive externality due to the diffused effort and show it depends on the agent's inventory size. Hence, there is a trade‐off between agents' effort committed to existing listings and expanding network size by soliciting new listings.
Outcome of relapsed and refractory nodular lymphocyte‐predominant Hodgkin lymphoma: a North American analysis
Authors: Strati Paolo , Cheng Phoebe T. M. , Steiner Raphael E. , Alcedo Andrade Pedro E. , Feng Lei , Sano Dahlia , Rao Veeramaneni A. , Singh Prachee , Miranda Roberto , Gunther Jillian R. , Pinnix Chelsea C. , Dabaja Bouthaina S. , Cuglievan Branko , Xing Katharine , Villa Diego , Skinnider Brian , Sehn Laurie H. , Connors Joseph M , Nieto Yago , Ahmed Sairah , Lee Hun J. , Savage Kerry J.
Published: January 2021

Nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is a rare entity, with limited data on the outcome in the relapsed/refractory setting. We evaluated the outcome of all patients diagnosed between 04/1979 and 01/2019 with relapsed or progressive NLPHL after initial active therapy at two institutions, refractory disease being defined as lack of response to treatment and/or relapse within three months of treatment. NLPHL patients with histological evidence of transformation at time of first relapse or progression were excluded. In total, 69 patients with recurrent NLPHL were included in the study. After a median follow‐up after initial diagnosis of 14 years (range, 0·5–46 years), median progression‐free survival after front‐line treatment (PFS‐1) was four years. Second‐line therapy included chemotherapy in 28 (41%) patients, biological therapy (rituximab, lenalidomide or brentuximab vedotin) in 14 (20%), high‐dose chemotherapy followed by autologous stem cell transplant in 14 (20%) and radiation therapy (RT) alone in 10 (15%). The five‐year PFS after second‐line therapy (PFS‐2) was 68% [95% confidence interval (CI), 54–79%] but the five‐year overall survival (OS) after second‐line therapy (OS‐2) remained excellent, at 94% (95% CI, 85–99%). Due to excellent outcome in case of recurrence, studies aimed at characterizing its biology to guide therapy de‐escalation are needed.
Zooming across cultures: Can a telecollaborative video exchange between language learning partners further the development of intercultural competences?
Authors: Freiermuth Mark R. , Huang Hsin‐chou
Published: January 2021

In the context of learning a second language, the passing on of cultural information as a means to further the development of intercultural competences is primarily viewed as being unidirectional—the “native‐speaking culture” passing on information to the language learning student. However, in EFL (English as a foreign language) environments, the most relatable cultural norms available to the learners tend to be those associated with their homeland—the place they presently reside. As such, teaching language learning students using a unidirectional cultural frame ignores the wealth of cultural knowledge that such language learners possess. Offering cultural exchanges between groups of different language learners is one way to facilitate cultural learning in a bidirectional manner. In this study, 11 university students, six Japanese and five Taiwanese, took part in a cultural exchange project using the videoconferencing application Zoom. Findings from the data suggest that such telecollaborative video activities are mutually beneficial for exchanging local cultural information. We conclude that such exchanges develop intercultural competences via increased verbosity, the application of polite language, and of the utmost importance, by building interpersonal relationships. For language teachers who ascribe to a belief in the value of intercultural exchanges, applications like Zoom open up avenues for student interactions that are real, meaningful, and culturally rich.
Talking about breast symmetry in the breast cancer clinic: What can we learn from an examination of clinical interaction?
Authors: Mace Stephanie , Collins Sarah , Speer Susan
Published: January 2021

Background

Breast asymmetry is a common post‐operative outcome for women with breast cancer. Quality of cosmetic result is viewed clinically as a critical endpoint of surgery. However, research suggests that aesthetic standards governing breast reconstruction can be unrealistic and may problematically enforce feminine appearance norms. The aim of reconstructive procedures is to help women live well with and beyond breast cancer. Therefore, understanding how patients and clinicians talk about surgical outcomes is important. However, we lack evidence about such discussions.

Objective

To examine clinical communication about breast symmetry in real‐time consultations in a breast cancer clinic.

Design

Seventy‐three consultations between 16 clinicians and 47 patients were video‐recorded, transcribed and analysed using conversation analysis.

Results

In most cases, patients do considerable interactional work to persuade clinicians of the validity of their concerns regarding breast asymmetry, and clinicians legitimize these concerns, aligning with patients. In a significant minority of cases, patients appear more accepting of their treatment outcome, but clinicians prioritize symmetry or treat symmetry with the presence of breast tissue as normative, generating misalignment between clinician and patient.

Conclusion

Current clinical communication guidelines and practices may inadvertently reinforce culturally normative assumptions regarding the desirability of full, symmetrical breasts that are not held by all women. Clinicians and medical educators may benefit from detailed engagement with recordings of clinical communication like those analysed here, to reflect on which communicative practices may work best to attend to a patient's individual stance on breast symmetry, and optimize doctor‐patient alignment.