bluuebunny/crossref_metadata_2025 huggingface dataset:
Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research
Authors: Mädler Sophia Clara , Julien-Laferriere Alice , Wyss Luis , Phan Miroslav , Kang Albert S. W. , Ulrich Eric , Schmucki Roland , Zhang Jitao David , Ebeling Martin , Badi Laura , Kam-Thong Tony , Schwalie Petra C. , Hatje Klas
Published: August 2020

Single-cell RNA sequencing (scRNA-seq) revolutionised our understanding of disease biology and presented the promise of transforming translational research. We developedBesca, a toolkit that streamlines scRNA-seq analyses according to current best practices. A standard workflow covers quality control, filtering, and clustering. Two complementaryBescamodules, utilizing hierarchical cell signatures or supervised machine learning, automate cell annotation and provide harmonised nomenclatures across studies. Subsequently,Bescaenables estimation of cell type proportions in bulk transcriptomics studies. Using multiple heterogeneous scRNA-seq datasets we show howBescaaids acceleration, interoperability, reusability, and interpretability of scRNA-seq data analysis, crucial aspects in translational research and beyond.
Red deerCervus elaphusblink more in larger groups
Authors: Rowe Zeke W. , Robins Joseph H. , Rands Sean A.
Published: August 2020

Most animals need to spend time being vigilant for predators, at the expense of other activities such as foraging. Group-living animals can benefit from the shared vigilance effort of other group members, with individuals reducing personal vigilance effort as group size increases. Behaviours like active scanning or head lifting are usually used to quantify vigilance, but may not be accurate measures as the individual could be conducting them for other purposes. We suggest that measuring an animal’s blinking rate gives a meaningful measure of vigilance: increased blinking implies reduced vigilance, as the animal cannot detect predators when its eyes are closed. We demonstrate that as group size increases in red deer, individuals increase their blink rate, confirming the prediction that vigilance should decrease. Blinking is a simple non-invasive measure, and offers a useful metric for assessing the welfare of animals experiencing an increase in perceived predation risk or other stressors.
Critical Assessment of Protein Intrinsic Disorder Prediction
Authors: Necci Marco , Piovesan Damiano ,   CAID Predictors,   DisProt Curators, Tosatto Silvio C.E.
Published: August 2020

Intrinsically disordered proteins defying the traditional protein structure-function paradigm represent a challenge to study experimentally. As a large part of our knowledge rests on computational predictions, it is crucial for their accuracy to be high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in predicting intrinsically disordered regions in proteins and the subset of disordered residues involved in binding other molecules. A total of 43 methods, 32 for disorder and 11 for binding regions, were evaluated on a dataset of 646 novel manually curated proteins from DisProt. The best methods use deep learning techniques and significantly outperform widely used earlier physicochemical methods across different types of targets. Disordered binding regions remain hard to predict correctly. Depending on the definition used, the top disorder predictor has an FMaxof 0.483 (DisProt) or 0.792 (DisProt-PDB). As the top binding predictor only attains an FMaxof 0.231, this suggests significant potential for improvement. Intriguingly, computing times among the top performing methods vary by up to four orders of magnitude.
IGF targeting perturbs global replication through ribonucleotide reductase dysfunction
Authors: Rieunier Guillaume , Wu Xiaoning , Harris Letitia , Mills Jack , Nandakumar Ashwin , Colling Laura , Seraia Elena , Hatch Stephanie B. , Ebner Daniel , Folkes Lisa K. , Weyer-Czernilofsky Ulrike , Bogenrieder Thomas , Ryan Anderson J. , Macaulay Valentine M.
Published: August 2020

IGF receptor (IGF-1R) inhibition delays repair of radiation-induced DNA double-strand breaks (DSBs), prompting us to investigate whether IGF-1R influences endogenous DNA damage. We demonstrate that IGF-1R inhibition generates endogenous DNA lesions protected by 53BP1 bodies, indicating under-replicated DNA. We detect delayed replication fork progression in IGF-inhibited or IGF-1R depleted cancer cells, with activation of ATR-CHK1 signaling and the intra-S-phase checkpoint. This phenotype reflects unanticipated regulation of global replication by IGF-1, mediated via AKT, MEK/ERK and JUN to influence expression of ribonucleotide reductase (RNR) subunit RRM2. IGF-1R inhibition or depletion downregulate RRM2, compromising RNR function and dNTP supply. The resulting delay in fork progression and hallmarks of replication stress are rescued by RRM2 overexpression, confirming RRM2 as the critical factor through which IGF-1 regulates replication. Following targeted compound screens, we identify synergy between IGF inhibition and ATM loss, with evidence that IGF inhibition compromises growth of ATM null cells and xenografts. This synthetic lethal effect reflects conversion of single-stranded lesions in IGF-inhibited cells into toxic DSBs upon ATM inhibition. These data implicate IGF-1R in alleviating replication stress, and the identified reciprocal IGF:ATM co-dependence provides an approach to exploit this effect in ATM-deficient cancers.
Cisplatin is more mutagenic than carboplatin or oxaliplatin at equitoxic concentrations
Authors: Szikriszt Bernadett , Póti Ádám , Németh Eszter , Kanu Nnennaya , Swanton Charles , Szüts Dávid
Published: August 2020

Platinum-based drugs are a mainstay of cancer chemotherapy. However, their mutagenic effect can increase tumour heterogeneity, contribute to the evolution of treatment resistance, and also induce secondary malignancies. We coupled whole genome sequencing with phenotypic investigations on two cell line models to compare the magnitude and understand the mechanism of mutagenicity of cisplatin, carboplatin and oxaliplatin. Cisplatin induced significantly more base substitution mutations than carboplatin or oxaliplatin when used at equitoxic concentrations on human TK6 or chicken DT40 cells, and also induced the highest number of short insertions and deletions. Assessment through histone H2AX phosphorylation and single cell agarose gel electrophoresis suggested that cisplatin caused more DNA damage than carboplatin or oxaliplatin. The analysis of base substitution spectra revealed that all three tested platinum drugs elicit both a direct mutagenic effect at purine dinucleotides, and an indirect effect of accelerating endogenous mutagenic processes. Whereas the direct mutagenic effect correlated with the level of DNA damage caused, the indirect mutagenic effects were equal. The different mutagenicity and DNA damaging effect of equitoxic platinum drug treatments suggests that DNA damage independent mechanisms significantly contribute to their cytotoxicity. Thus, the comparatively high mutagenicity of cisplatin should be taken into account in the design of chemotherapeutic regimens.
Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions
Authors: Rombouts Jan , Gelens Lendert
Published: August 2020

Bistability is a common mechanism to ensure robust and irreversible cell cycle transitions. Whenever biological parameters or external conditions change such that a threshold is crossed, the system abruptly switches between different cell cycle states. Experimental studies indicate that the shape of the bistable response curve changes dynamically in time. Here, we show how such a dynamically changing bistable switch can provide a cell with better control over the timing of cell cycle transitions. Moreover, cell cycle oscillations built on bistable switches are more robust when the bistability is modulated in time. Our results are not specific to cell cycle models and may apply to other bistable systems in which the bistable response curve is time-dependent.

Author summary

Many systems in nature show bistability, which means they can evolve to one of two stable steady states under exactly the same conditions. Which state they evolve to depends on where the system comes from. Such bistability underlies the switching behavior that is essential for cells to progress in the cell division cycle. A quick switch happens when the cell jumps from one steady state to another steady state. Typical of this switching behavior is its robustness and irreversibility. In this paper, we expand this viewpoint of the dynamics of the cell cycle by considering bistable switches which themselves are changing in time. This gives the cell an extra layer of control over transitions both in time and in space, and can make those transitions more robust. Such dynamically changing bistability can appear very naturally. We show this in a model of mitotic entry, in which we include a nuclear and cytoplasmic compartment. The activity of a crucial cell cycle protein follows a bistable switch in each compartment, but the shape of its response is changing in time as proteins are imported and exported from the nucleus.
Same, Same, but Different: Molecular Analyses ofStreptococcus pneumoniaeImmune Evasion Proteins Identifies new Domains and Reveals Structural Differences between PspC and Hic Variants
Authors: Du Shanshan , Vilhena Claudia , King Samantha , Sahagun Alfredo , Hammerschmidt Sven , Skerka Christine , Zipfel Peter F.
Published: August 2020

PspC and Hic proteins ofStreptococcus pneumoniaeare some of the most variable microbial immune evasion proteins identified to date. Due to structural similarities and conserved binding profiles it was assumed over a long time that these pneumococcal surface proteins represent a protein family, comprising eleven subgroups. Recently, however, by evaluating more proteins larger diversity of individual proteins became apparent. In contrast to previous assumptions a pattern evaluation of six PspC and five Hic variants, each representing one of the previously defined subgroups, revealed distinct structural and likely functionally regions of the proteins, and identified nine new domains and new domain alternates. Several domains are unique to PspC and Hic variants, while other domains are shared with otherS. pneumoniaeand bacterial virulent determinants. This understanding improved pattern evaluation on the level of full-length proteins, allowed a sequence comparison on the domain level and furthermore identified domains with a modular composition. This novel concept allows a better characterization of variability, and modular domain composition of individual proteins, enables a structural and functional characterization at the domain level and furthermore shows substantial structural differences between PspC and Hic proteins. Such knowledge will also be useful for molecular strain typing, characterizing PspC and Hic proteins from new clinicalS. pneumoniaestrains, including those derived from patients who present with pneumococcal hemolytic uremic syndrome. Furthermore this analysis explains the role of multifaceted intact PspC and Hic proteins in pathogen host interactions. and can provide a basis for rational vaccine design.

Author Summary

The human pathobiontStreptococcus pneumoniaeexpresses highly polymorphic PspC or Hic proteins, which bind a repertoire of host immune regulators and combine antigenic variation with conserved immune evasion features. Understanding domain composition of each protein encoded by more than 60 000pspCorhicgenes deposited in the data banks defines their diversity, a role in immune escape and can furthermore delineate structure function approach for single protein domains. PspC and Hic proteins show variable domain composition and sequence diversity, which explain differences in binding of human regulators and likely in immune escape. The results of our analyses provide insights in the domain composition of these diverse immune evasion proteins, identifies new domains, defines domains which are unique to PspC or Hic variants, and identifies domains which are shared with other bacterial immune evasion proteins. These data have implication on cell wall attachment, surface distribution and in immune escape.
Phylogenomic Discordance in the Eared Seals is best explained by Incomplete Lineage Sorting following Explosive Radiation in the Southern Hemisphere
Authors: Lopes Fernando , Oliveira Larissa R. , Kessler Amanda , Beux Yago , Crespo Enrique , Cárdenas-Alayza Susana , Majluf Patricia , Sepúlveda Maritza , Brownell Robert L. , Franco-Trecu Valentina , Páez-Rosas Diego , Chaves Jaime , Loch Carolina , Robertson Bruce C. , Acevedo-Whitehouse Karina , Elorriaga-Verplancken Fernando R. , Kirkman Stephen P. , Peart Claire R. , Wolf Jochen B. W. , Bonatto Sandro L.
Published: August 2020

Abstract

The phylogeny and systematics of fur seals and sea lions (Otariidae) have long been studied with diverse data types, including an increasing amount of molecular data. However, only a few phylogenetic relationships have reached acceptance because of strong gene-tree species tree discordance. Divergence times estimates in the group also vary largely between studies. These uncertainties impeded the understanding of the biogeographical history of the group, such as when and how trans-equatorial dispersal and subsequent speciation events occurred. Here we used high-coverage genome-wide sequencing for 14 of the 15 species of Otariidae to elucidate the phylogeny of the family and its bearing on the taxonomy and biogeographical history. Despite extreme topological discordance among gene trees, we found a fully supported species tree that agrees with the few well-accepted relationships and establishes monophyly of the genusArctocephalus. Our data support a relatively recent trans-hemispheric dispersal at the base of a southern clade, which rapidly diversified into six major lineages between 3 to 2.5 Ma.Otariadiverged first, followed byPhocarctosand then four major lineages withinArctocephalus. However, we foundZalophusto be non-monophyletic, with California(Z. californianus)and Steller sea lions(Eumetopias jubatus)grouping closer than the Galapagos sea lion (Z. wollebaeki)with evidence for introgression between the two genera. Overall, the high degree of genealogical discordance was best explained by incomplete lineage sorting resulting from quasi-simultaneous speciation within the southern clade with introgresssion playing a subordinate role in explaining the incongruence among and within prior phylogenetic studies of the family.
The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function
Authors: Oftedal Bergithe E , Maio Stefano , Handel Adam , White Madeleine PJ , Howie Duncan , Davis Simon , Prevot Nicolas , Rota Ioanna A. , Deadman Mary E , Kessler Benedikt M , Fischer Roman , Trede Nikolaus S , Sezgin Erdinc , Maizels Rick M , Holländer Georg A
Published: August 2020

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. Additionally, Th2 polarization digresses in the absence of CCT-controlled protein folding resulting paradoxically in continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.
Purinergic signaling controls spontaneous activity in the auditory system throughout early development
Authors: Babola Travis A. , Li Sally , Wang Zhirong , Kersbergen Calvin , Elgoyhen Ana Belén , Coate Thomas , Bergles Dwight
Published: August 2020

Spontaneous bursts of electrical activity in the developing auditory system arise within the cochlea prior to hearing onset and propagate through future sound processing circuits of the brain to promote maturation of auditory neurons. Studies in isolated cochleae revealed that this intrinsically generated activity is initiated by ATP release from inner supporting cells (ISCs), resulting in activation of purinergic autoreceptors, K+efflux and subsequent depolarization of inner hair cells (IHCs). However, little is known about when this activity emerges or whether different mechanisms underlie distinct stages of development. Here we show that spontaneous electrical activity in mouse cochlea emerges within ISCs during the late embryonic period, preceding the onset of spontaneous correlated activity in IHCs and spiral ganglion neurons (SGNs), which begins at birth and follows a base to apex developmental gradient. At all developmental stages, pharmacological inhibition of P2Y1 metabotropic purinergic receptors dramatically reduced spontaneous activity in these three cell types. Moreover,in vivoimaging within the inferior colliculus of awake mice revealed that auditory neurons within future isofrequency zones exhibit coordinated neural activity at birth. The frequency of these discrete bursts increased progressively during the postnatal prehearing period, yet remained dependent on P2RY1. Analysis of mice with disrupted cholinergic signaling in the cochlea, indicate that this input modulates, rather than initiates, spontaneous activity before hearing onset. Thus, the auditory system uses a consistent mechanism involving ATP release from ISCs and activation of purinergic autoreceptors to elicit coordinated excitation of neurons that will process similar frequencies of sound.

SIGNIFICANCE STATEMENT

In developing sensory systems, groups of neurons that will process information from similar sensory space exhibit highly correlated electrical activity that is critical for proper maturation and circuit refinement. Defining the period when this activity is present, the mechanisms responsible and the features of this activity are crucial for understanding how spontaneous activity influences circuit development. We show that, from birth to hearing onset, the auditory system relies on a consistent mechanism to elicit correlate firing of neurons that will process similar frequencies of sound. Targeted disruption of this activity will increase our understanding of how these early circuits mature and may provide insight into processes responsible for developmental disorders of the auditory system.
Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia
Authors: Ding Baojin , Tang Yu , Ma Shuaipeng , Akter Masuma , Liu Meng-Lu , Zang Tong , Zhang Chun-Li
Published: August 2020

DYT1 dystonia is a hereditary neurological disease caused by a heterozygous mutation intorsin A(TOR1A). While animal models provide insights into disease mechanisms, significant species-dependent differences exist since mice with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-derived motor neurons. These neurons with the heterozygousTOR1Amutation show markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport, whereas they lack the perinuclear “blebs” that are often observed in animal models. Importantly, we further uncover that the nuclear lamina protein LMNB1 is specifically dysregulated in expression and subcellular localization. LMNB1 downregulation can largely ameliorate all the cellular defects in DYT1 motor neurons. These results reveal the value of disease modeling with human neurons and provide novel molecular mechanisms underlying DYT1 dystonia and potentially other neurological diseases with impaired nucleocytoplasmic transport.
Temporal modulation of the NF-κB RelA network in response to different types of DNA damage
Authors: Campbell Amy , Franco Catarina Ferraz , Su Ling-I , Perkins Simon , Jones Andrew R. , Brownridge Philip J. , Perkins Neil D. , Eyers Claire E.
Published: August 2020

Different types of DNA damage can initiate phosphorylation-mediated signalling cascades that result in stimulus specific pro- or anti-apoptotic cellular responses. Amongst its many roles, the NF-κB transcription factor RelA is central to these DNA damage response pathways. However, we still lack understanding of the co-ordinated signalling mechanisms that permit different DNA damaging agents to induce distinct cellular outcomes through RelA. Here, we use label-free quantitative phosphoproteomics to examine the temporal effects of exposure of U2OS cells to either etoposide (ETO) or hydroxyurea (HU) by monitoring the phosphorylation status of RelA and its protein binding partners. Although few stimulus-specific differences were identified in the constituents of phosphorylated RelA interactome after exposure to these DNA damaging agents, we observed subtle, but significant, changes in their phosphorylation states, as a function of both type and duration of treatment. The DNA double strand break (DSB)-inducing ETO invoked more rapid, sustained responses than HU, with regulated targets primarily involved in transcription, cell division and canonical DSB repair. Kinase substrate prediction of ETO-regulated phosphosites suggest abrogation of CDK1 and ERK1 signalling, in addition to the known induction of ATM/ATR. In contrast, HU-induced replicative stress mediated temporally dynamic regulation, with phosphorylated RelA binding partners having roles in rRNA/mRNA processing and translational initiation, many of which contained a 14-3-3ε binding motif, and were putative substrates of the dual specificity kinase CLK1. Our data thus point to differential regulation of key cellular processes and the involvement of distinct signalling pathways in modulating DNA damage-specific functions of RelA.
Cytokine priming of naïve CD8+T lymphocytes modulates chromatin accessibility that partially overlaps with changes induced by antigen simulation
Authors: Quenum Akouavi Julite , Cloutier Maryse , Santharam Madanraj Appiya , Mayhue Marian , Ramanathan Sheela , Ilangumaran Subburaj
Published: August 2020

Background

Naïve CD8+T lymphocytes undergo antigen non-specific proliferation following exposure to certain synergistic combination of inflammatory (IL-6, IL-21) and homeostatic (IL-7, IL-15) cytokines. Such cytokine-stimulated naïve CD8+T cells display increased T cell antigen receptor (TCR) sensitivity, allowing them to respond to limiting concentrations of cognate antigenic peptides and altered peptide ligands of lower affinity towards the TCR. The purpose of this study is to gain insight into the molecular mechanisms of such ‘cytokine priming’.

Methods

Naïve CD8+T lymphocytes expressing the PMEL-1 transgenic TCR were stimulated with IL-15 and IL-21, and chromatin accessibility was assessed using the assay for transposase-accessible chromatin (ATAC) sequencing. Cells stimulated by the cognate antigenic peptide mgp10025-33were used as controls.

Results

Compared to naïve cells, cytokine-primed cells showed 212 opening and 484 closing peaks, whereas antigen-stimulated cells showed 12087 opening and 6982 closing peaks. However, a significant fraction of the opening (33%) and closing (63%) peaks of cytokine-primed cells overlapped with those of the antigenic stimulated cells. Chromatin accessibility peaks modulated in cytokine-primed cells were strongly represented in gene ontology pathways for T cell signaling, activation, regulation and effector functions. Many of the transcription factor binding motifs located close to the opening and closing peaks of cytokine-primed cells also occurred in antigen-stimulated cells.

Conclusions

Our data suggest that by modulating the gene expression programs involved in TCR signaling, cytokine priming induces a poised state that lowers the TCR signaling threshold in naïve CD8+T cells and increases their antigen responsiveness.
Does retraction after misconduct have an impact on citations? A pre-post study
Authors: Candal-Pedreira Cristina , Ruano-Ravina Alberto , Fernández E , Ramos-Castaneda Jorge A. , Campos-Varela I , Pérez-Ríos Mónica
Published: August 2020

Background

Retracted articles continue to be cited after retraction, and this could have consequences for the scientific community and general population alike. This study was conducted to analyze the impact of retraction on citations received by retracted papers in two-time frames: during a post-retraction period equivalent to the time the article had been in print before retraction; and during the total post-retraction period.

Results

The results indicated an increase in post-retraction citations when compared with citations received pre-retraction. There were some exceptions however: first, citations received by articles published in first-quartile journals decreased immediately after retraction (p<0.05), only to increase again after some time had elapsed; and second, post-retraction citations decreased significantly in the case of articles that had received many citations before their retraction (p<0.05).

Conclusions

The results indicate that retraction of articles has no impact on citations in the long term, since the retracted articles continue to be cited, thus circumventing their retraction. More effective mechanisms should be established to prevent the citation of retracted articles in scientific papers.

Methods

Quasi-experimental, pre-post evaluation study. A total of 304 retracted original articles and literature reviews indexed in Medline fulfilled the exclusion criteria. Articles were required to have been published in Pubmed from January 2013 through December 2016 and been retracted between January 2014 and December 2016. The main outcome was the number of citations received before and after retraction. Results were broken down by journal quartile according to impact factor and the most cited papers (pre-retraction) were specifically analyzed.
Puffaligner: An Efficient and Accurate Aligner Based on the Pufferfish Index
Authors: Almodaresi Fatemeh , Zakeri Mohsen , Patro Rob
Published: August 2020

Motivation

Sequence alignment is one of the first steps in many modern genomic analyses, such as variant detection, transcript abundance estimation and metagenomic profiling. Unfortunately, it is often a computationally expensive procedure. As the quantity of data and wealth of different assays and applications continue to grow, the need for accurate and fast alignment tools persists.

Results

In this paper, we introduce PuffAligner, a fast, accurate and versatile aligner built on top of the Pufferfish index. PuffAligner is able to produce highly-sensitive alignments, similar to those of Bowtie2, but much more quickly. While exhibiting similar speed to the ultrafast STAR aligner, PuffAligner requires considerably less memory to construct its index and align reads. PuffAligner strikes a desirable balance with respect to the time, space, and accuracy tradeoffs made by different alignment tools, and provides a promising foundation on which to test new alignment ideas over large collections of sequences.

Availability

PuffAligner is a free and open-source software. It is implemented in C++14 and can be obtained fromhttps://github.com/COMBINE-lab/pufferfish/tree/cigar-strings
Learning with uncertainty for biological discovery and design
Authors: Hie Brian , Bryson Bryan , Berger Bonnie
Published: August 2020

Machine learning that generates biological hypotheses has transformative potential, but most learning algorithms are susceptible to pathological failure when exploring regimes beyond the training data distribution. A solution is to quantify predictionuncertaintyso that algorithms can gracefully handle novel phenomena that confound standard methods. Here, we demonstrate the broad utility of robust uncertainty prediction in biological discovery. By leveraging Gaussian process-based uncertainty prediction on modern pretrained features, we train a model on just 72 compounds to make predictions over a 10,833-compound library, identifying and experimentally validating compounds with nanomolar affinity for diverse kinases and whole-cell growth inhibition ofMycobacterium tuberculosis. We show how uncertainty facilitates a tight iterative loop between computation and experimentation, improves the generative design of novel biochemical structures, and generalizes across disparate biological domains. More broadly, our work demonstrates that uncertainty should play a key role in the increasing adoption of machine learning algorithms into the experimental lifecycle.
The chromatin remodeler ISWI acts duringDrosophiladevelopment to regulate adult sleep
Authors: Gong Naihua N. , Dilley Leela Chakravarti , Williams Charlette E. , Moscato Emilia H. , Szuperak Milan , Wang Qin , Jensen Matthew , Girirajan Santhosh , Tan Tiong Yang , Deardorff Matthew A. , Li Dong , Song Yuanquan , Kayser Matthew S.
Published: August 2020

Sleep disruptions are among the most commonly-reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From aDrosophilascreen of human NDD-associated risk genes, we identified the chromatin remodelerImitation SWItch/SNF(ISWI) to be required for adult fly sleep. Loss ofISWIalso results in disrupted circadian rhythms, memory, and social behavior, butISWIacts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically,ISWIexpression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the humanISWIhomologsSMARCA1andSMARCA5differentially rescue adult phenotypes. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs, and point towards chromatin remodeling machinery as critical for sleep circuit formation.
Molecular signatures of sexual communication in the phlebotomine sand flies
Authors: Hickner Paul V. , Timoshevskaya Nataliya , Nowling RJ , Labbé Frédéric , Nguyen Andrew D. , McDowell Mary Ann , Spiegel Carolina N. , Syed Zainulabeuddin
Published: August 2020

Phlebotomine sand flies employ an elaborate system of pheromone communication wherein males produce pheromones that attracts other males to leks (thus acting as aggregation pheromone) and females to the lekking males (sex pheromone). In addition, the type of pheromone produced varies among populations. Despite the numerous studies on sand fly chemical communication, little is known of their chemosensory genome. Chemoreceptors interact with chemicals in an organism’s environment to elicit essential behaviors such as the identification of suitable mates and food sources, thus, they play important roles during adaptation and speciation. Major chemoreceptor gene families, odorant receptors (ORs), gustatory receptors (GRs) and ionotropic receptors (IRs) together detect and discriminate the chemical landscape. Here, we annotated the chemoreceptor repertoire in the genomes ofLutzomyia longipalpisandPhlebotomus papatasi, major phlebotomine vectors in the New World and Old World, respectively. Comparison with other sequenced Diptera revealed a large and unique expansion where over 80% of the ~140 ORs belong to a single, taxonomically restricted clade. We next conducted comprehensive analysis of the chemoreceptors in 63Lu. longipalpisindividuals from four different locations in Brazil representing allopatric and sympatric populations and three aggregation-sex pheromone types (chemotypes). Population structure based on single nucleotide polymorphisms (SNPs) and gene copy number in the chemoreceptors corresponded with their putative chemotypes, and corroborate previous studies that identified multiple populations. Our work provides genomic insights into the underlying behavioral evolution of sexual communication in theL. longipalpisspecies complex in Brazil, and highlights the importance of accounting for the ongoing speciation in central and South AmericanLutzomyiathat could have important implications for vectorial capacity.
Transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis
Authors: Yarani Reza , Palasca Oana , Doncheva Nadezhda T. , Anthon Christian , Pilecki Bartosz , Svane Cecilie A. S. , Mirza Aashiq H. , Litman Thomas , Holmskov Uffe , Bang-Berthelsen Claus Heiner , Vilien Mogens , Jensen Lars J. , Gorodkin Jan , Pociot Flemming
Published: August 2020

1.

BACKGROUND & AIMS

Ulcerative colitis (UC) is an inflammatory bowel disorder with unknown etiology. Given its complex nature,in vivostudies to investigate its pathophysiology is vital. Animal models play an important role in molecular profiling necessary to pinpoint mechanisms that contribute to human disease. Thus, we aim to identify common conserved gene expression signatures and differentially regulated pathways between human UC and a mouse model hereof, which can be used to identify UC patients from healthy individuals and to suggest novel treatment targets and biomarker candidates.

METHODS

Therefore, we performed high-throughput total and small RNA sequencing to comprehensively characterize the transcriptome landscape of the most widely used UC mouse model, the dextran sodium sulfate (DSS) model. We used this data in conjunction with publicly available human UC transcriptome data to compare gene expression profiles and pathways.

RESULTS

We identified differentially regulated protein-coding genes, long non-coding RNAs and microRNAs from colon and blood of UC mice and further characterized the involved pathways and biological processes through which these genes may contribute to disease development and progression. By integrating human and mouse UC datasets, we suggest a set of 51 differentially regulated genes in UC colon and blood that may improve molecular phenotyping, aid in treatment decisions, drug discovery and the design of clinical trials.

CONCLUSION

Global transcriptome analysis of the DSS-UC mouse model supports its use as an efficient high-throughput tool to discover new targets for therapeutic and diagnostic applications in human UC through identifying relationships between gene expression and disease phenotype.
Curcumin-Sophorolipid nano-conjugate inhibitsCandida albicansfilamentation and biofilm development
Authors: Rajasekar Vidhyashree , Darne Priti , Prabhune Asmita , Kao Richard Y. T. , Solomon Adline Princy , Ramage Gordon , Samaranayake Lakshman , Neelakantan Prasanna
Published: August 2020

Candida albicansis an opportunistic fungal pathogen that is highly resistant to contemporary antifungals, and a major reason for this appears to be their predominant, filamentation-mediated, biofilm lifestyle. Hence, agents that inhibit biofilms and filamentation of the yeast offer promise as next-generation antifungals. Curcumin is a natural polyphenol with several beneficial pharmacological attributes, yet limitations such as poor solubility, acid, and enzyme tolerance have impeded its practical utility. Sophorolipids are biologically-derived surfactants that serve as efficient carriers and delivery agents of hydrophobic molecules, such as curcumin, into biofilms. The aim of this study was to investigate the effects of a novel, curcumin-sophorolipid (CU-ASL) nano-conjugate onCandida albicansbiofilms and filamentation. The effects of CU and ASL, in combination, and alone, were investigated on planktonic cells of the yeast. The effects of sub-inhibitory concentrations of the compounds were investigated on biofilm biomass and biofilm architecture. Their effects on filamentation was compared by scanning electron microscopic imaging, and gene expression analysis by qRT-PCR. Our results demonstrated that sub-inhibitory concentration of CU-ASL (9.37 µg/mL) significantly inhibited candidal adhesion to substrates, and subsequent biofilm development, maturation, and filamentation. This effect was associated with significant downregulation of a select group of biofilm, adhesins, and hyphal regulatory genes. In conclusion, the curcumin-sophorolipid nano-conjugate is a potent inhibitor of the two major virulence attributes ofC. albicans, biofilm formation and filamentation, thus highlighting its promise as a putative anti-candidal agent with low toxicity and biofilm penetrative potential.
Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection
Authors: Wang Cheng , Wang Shaobo , Chen Yin , Zhao Jianqi , Han Songling , Zhao Gaomei , Kang Jing , Liu Yong , Wang Liting , Wang Xiaoyang , Xu Yang , Wang Song , Huang Yi , Wang Junping , Zhao Jinghong
Published: August 2020

The ongoing COVID-19 epidemic worldwide necessitates the development of novel effective agents against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 protein and mediates viral entry into host cells. Herein, the membrane nanoparticles prepared from ACE2-rich cells are discovered with potent capacity to block SARS-CoV-2 infection. The membrane of human embryonic kidney-239T cell highly expressing ACE2 is screened to prepare nanoparticles. The nanomaterial termed HEK-293T-hACE2 NPs contains 265.1 ng mg−1of ACE2 on the surface and acts as a bait to trap SARS-CoV-2 S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to host cells. Interestingly, SARS-CoV-2 S1 can translocate to the cytoplasm and affect the cell metabolism, which is also inhibited by HEK-293T-hACE2 NPs. Further studies reveal that HEK-293T-hACE2 NPs can efficiently suppress SARS-CoV-2 S pseudovirions entry into human proximal tubular cells and block viral infection with a low half maximal inhibitory concentration. Additionally, this biocompatible membrane nanomaterial is sufficient to block the adherence of SARS-CoV-2 D614G-S1 mutant to sensitive cells. Our study demonstrates a easy-to-acheive memrbane nano-antagonist for curbing SARS-CoV-2, which enriches the existing antiviral arsenal and provides new possibilities to treat COVID-19.

Graphical Table of Contents
Regression dynamic causal modeling for resting-state fMRI
Authors: Frässle Stefan , Harrison Samuel J. , Heinzle Jakob , Clementz Brett A. , Tamminga Carol A. , Sweeney John A. , Gershon Elliot S. , Keshavan Matcheri S. , Pearlson Godfrey D. , Powers Albert , Stephan Klaas E.
Published: August 2020

Abstract

“Resting-state” functional magnetic resonance imaging (rs-fMRI) is widely used to study brain connectivity. So far, researchers have been restricted to measures of functional connectivity that are computationally efficient but undirected, or to effective connectivity estimates that are directed but limited to small networks.

Here, we show that a method recently developed for task-fMRI – regression dynamic causal modeling (rDCM) – extends to rs-fMRI and offers both directional estimates and scalability to whole-brain networks. First, simulations demonstrate that rDCM faithfully recovers parameter values over a wide range of signal-to-noise ratios and repetition times. Second, we test construct validity of rDCM in relation to an established model of effective connectivity, spectral DCM. Using rs-fMRI data from nearly 200 healthy participants, rDCM produces biologically plausible results consistent with estimates by spectral DCM. Importantly, rDCM is computationally highly efficient, reconstructing whole-brain networks (>200 areas) within minutes on standard hardware. This opens promising new avenues for connectomics.
Wnt/PCP-primed intestinal stem cells directly differentiate into enteroendocrine or Paneth cells
Authors: Böttcher Anika , Büttner Maren , Tritschler Sophie , Sterr Michael , Aliluev Alexandra , Oppenländer Lena , Burtscher Ingo , Sass Steffen , Irmler Martin , Beckers Johannes , Ziegenhain Christoph , Enard Wolfgang , Schamberger Andrea C. , Verhamme Fien M. , Eickelberg Oliver , Theis Fabian J. , Lickert Heiko
Published: August 2020

A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required to better treat chronic intestinal diseases. However, different models of ISC lineage hierarchy1–6and segregation7–12are debated. Here we report the identification of Lgr5+ISCs that expressFlattop(Fltp), a Wnt/planar cell polarity (PCP) reporter and effector gene. Lineage labelling revealed that Wnt/PCP-activatedFltp+ISCs are primed either towards the enteroendocrine or the Paneth cell lineagein vivo. Integration of time-resolved lineage labelling with genome-wide and targeted single-cell gene expression analysis allowed us to delineate the ISC differentiation path into enteroendocrine and Paneth cells at the molecular level. Strikingly, we found that both lineages are directly recruited from ISCs via unipotent transition states, challenging the existence of formerly predicted bi- or multipotent secretory progenitors7–12. Transitory cells that mature into Paneth cells are quiescent and express both stem cell and secretory lineage genes, indicating that these cells are the previously described Lgr5+labelretaining cells7. Wnt/PCP-activated Lgr5+ISCs are indistinguishable from Wnt/β-catenin-activated Lgr5+ISCs based on the expression of stem-cell signature or secretory lineagespecifying genes but possess less self-renewal activity. This suggests that lineage priming and cell-cycle exit is triggered at the post-transcriptional level by polarity cues and a switch from canonical to non-canonical Wnt/PCP signalling. Taken together, we identified the Wnt/PCP pathway as a new niche signal and polarity cue regulating stem cell fate. Active Wnt/PCP signalling represents one of the earliest events in ISC lineage priming towards the Paneth and enteroendocrine cell fate, preceding lateral inhibition and expression of secretory lineagespecifying genes. Thus, our findings provide a better understanding of the niche signals and redefine the mechanisms underlying ISC lineage hierarchy and segregation.
L1CAM is not Associated with Extracellular Vesicles in Human Cerebrospinal Fluid or Plasma
Authors: Norman Maia , Ter-Ovanesyan Dmitry , Trieu Wendy , Lazarovits Roey , Kowal Emma J.K. , Lee Ju Hyun , Chen-Plotkin Alice S. , Regev Aviv , Church George M. , Walt David R.
Published: August 2020

Neuron-derived extracellular vesicles (NDEVs) present a tremendous opportunity to learn about the biochemistry of brain cells in living patients. L1CAM is a transmembrane protein expressed in neurons that is presumed to be found on NDEVs in human biofluids. Previous studies have used L1CAM immuno-isolation from human plasma to isolate NDEVs for neurodegenerative disease diagnostics. We developed a panel of ultrasensitive Single Molecule Array (Simoa) assays for known EV markers, as well as L1CAM, and applied it to study EVs in human plasma and cerebrospinal fluid (CSF). We fractionated plasma and CSF by size exclusion chromatography (SEC) and density gradient centrifugation (DGC) to separate EVs from free proteins. We observed that L1CAM did not elute in the EV fractions, but rather eluted in the free protein fractions. We found that L1CAM is present as a free protein in human plasma and CSF, possibly due to proteolytic cleavage and/or alternative splicing. We further demonstrate that the isoforms found in CSF and plasma are different. These data collectively establish that L1CAM in plasma is not EV associated and should therefore not be used for NDEV isolation. Importantly, the framework and tools described herein will allow for evaluation of other potential candidate markers for isolation of NDEVs.
Coronacept – a potent immunoadhesin against SARS-CoV-2
Authors: Cohen-Dvashi Hadas , Weinstein Jonathan , Katz Michael , Eilon Maayan , Mor Yuval , Shimon Amir , Strobelt Romano , Shemesh Maya , Fleishman Sarel J , Diskin Ron
Published: August 2020

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Computational analysis of mammalian ACE2 orthologues suggests various residues at the interface with the viral receptor binding domain that could facilitate tighter interaction compared to the human-ACE2. Introducing several mutations to the human-ACE2 resulted with significantly augmented affinity to the viral spike complex. This modified human-ACE2 fused to an Fc portion of an antibody makes a potent immunoadhesin that effectively targets SARS-CoV-2.
The SOD-2 protein is the single active SOD enzyme inC. elegans
Authors: Fernando Lourds M. , Adeel Silwat , Basar Mohammed Abul , Allen Anna K. , Duttaroy Atanu
Published: August 2020

The nematodeC. eleganshas a contingent of fivesodgenes, one of the largest among aerobic organism. Earlier studies revealed each of the fivesodgenes is capable of making perfectly active SOD proteins in heterologous expressions systems therefore none appears to be a pseudogene. Yet deletion of the entire contingent ofsodgenes fails to impose any effect on the survival ofC. elegansexcept these animals appear more sensitive to extraneously applied oxidative stress condition. We asked how many of the fivesodgenes are actually active inC. elegansthrough an in-gel SOD activity analysis. Here we provide evidence that out of the five genes only the mitochondrial SOD gene is active inC. elegans, albeit at a much lesser amount compared toD. melanogasterandE. coli. Mutant analysis further confirmed that among the mitochondrial forms, SOD-2 is the only naturally active SOD inC. elegans.
Diverse roles ofMAX1homologues in rice
Authors: Marzec Marek , Situmorang Apriadi , Brewer Philip B. , Brąszewska-Zalewska Agnieszka
Published: August 2020

Cytochrome P450 enzymes encoded byMORE AXILLARY GROWTH1(MAX1)-like genes produce most of the structural diversity of strigolactones during the final steps of strigolactone biosynthesis. The diverse copies ofMAX1inOryza sativaprovide a resource to investigate why plants produce such a wide range of strigolactones. Here we performedin silicoanalyses of transcription factors and microRNAs that may regulate each riceMAX1, and compared the results with available data aboutMAX1expression profiles and genes co-expressed withMAX1genes. Data suggest that distinct mechanisms regulate the expression of eachMAX1. Moreover, there may be novel functions forMAX1homologues, such as the regulation of flower development or responses to heavy metals. In addition, individualMAX1scould be involved in specific functions, such as the regulation of seed development or wax synthesis in rice. Our analysis reveals potential new avenues of strigolactone research that may otherwise not be obvious.
Interhemispheric transfer of working memories
Authors: Brincat Scott L. , Donoghue Jacob A. , Mahnke Meredith K. , Kornblith Simon , Lundqvist Mikael , Miller Earl K.
Published: August 2020

Visual working memory (WM) storage is largely independent between the left and right visual hemifields/cerebral hemispheres, yet somehow WM feels seamless. We studied how WM is integrated across hemifields by recording neural activity bilaterally from lateral prefrontal cortex. An instructed saccade during the WM delay shifted the remembered location from one hemifield to the other. Before the shift, spike rates and oscillatory power showed clear signatures of memory laterality. After the shift, the lateralization inverted, consistent with transfer of the memory trace from one hemisphere to the other. Transferred traces initially used different neural ensembles from feedforward-induced ones but they converged at the end of the delay. Around the time of transfer, synchrony between the two prefrontal hemispheres peaked in theta and beta frequencies, with a directionality consistent with memory trace transfer. This illustrates how dynamics between the two cortical hemispheres can stitch together WM traces across visual hemifields.