bluuebunny/crossref_metadata_2025 huggingface dataset:
Glioblastoma stem cells express non-canonical proteins and exclusive mesenchymal-like or non-mesenchymal-like protein signatures
Authors: Babačić Haris , Galardi Silvia , Umer Husen M. , Cardinali Deborah , Pellegatta Serena , Hellström Mats , Uhrbom Lene , Maturi Nagaprathyusha , Michienzi Alessandro , Trevisi Gianluca , Mangiola Annunziato , Lehtiö Janne , Ciafrè Silvia Anna , Pernemalm Maria
Published: February 2022

Glioblastoma’s (GBM) origin, recurrence and resistance to treatment are driven by GBM cancer stem cells (GSCs). Existing transcriptomic characterisations of GBM classify the tumours to three subtypes: classical, proneural, and mesenchymal. The comprehension of how expression patterns of the GBM subtypes are reflected at global proteome level in GSCs is limited.

To characterise protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry proteomics. We identified and quantified over 10,000 proteins in two independent GSCs panels, and propose a GSC-associated proteomic signature (GSAPS) that defines two distinct morphological conditions; one defined by a set of proteins expressed in non-mesenchymal - proneural and classical - GSCs (GPC-like), and another expressed in mesenchymal GSCs (GM-like). The expression of GM-like protein set in GBM tissue was associated with hypoxia, necrosis, recurrence, and worse overall survival in GBM patients.

In a proof-of-concept proteogenomic approach, we discovered 252 non-canonical peptides expressed in GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered protein-non-coding. We report new variants of the heterogeneous ribonucleoproteins (HNRNPs), which are implicated in mRNA splicing. Furthermore, we show that per-gene mRNA-protein correlations in GSCs are moderate and vary compared to GBM tissue.
Directional Absolute Coherence: a phase-based measure of effective connectivity for neurophysiology data
Authors: Scherer Maximilian , Wang Tianlu , Guggenberger Robert , Milosevic Luka , Gharabaghi Alireza
Published: February 2022

Communication between neural structures is a topic of much clinical and scientific interest and has been linked to a variety of behavioural, cognitive, and psychiatric measures. Here, we introduce a novel effective connectivity measure, termed the directional absolute coherence (DAC). Combining aspects of magnitude squared coherence, imaginary coherence, and phase slope index, DAC provides an estimate of connectivity that is resistant to volume conduction, encapsulates the directionality of neural communication, and is bound to the interval of –1 and 1. To highlight the properties of this newly proposed method, we compare DAC to a number of established connectivity methods using data recorded from the subthalamic nucleus of patients with Parkinson’s disease with deep brain stimulation electrodes. By applying a combination of real and simulated data, we demonstrate that DAC provides a reliable estimate of the magnitude and direction of connectivity, independent of the phase difference between brain signals. As such, DAC facilitates a reliable investigation of inter-regional neural communication, rendering it a valuable tool for gaining a deeper understanding of the functional architecture of the brain and its relationship to behaviour and cognition. A Python implementation of DAC is freely available at https://github.com/neurophysiological-analysis/FiNN.

Highlights

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Volume conduction and limited interpretability affect many connectivity methods.

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DAC is a combined approach to overcome these pitfalls.

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DAC augments information content and interpretability in comparison to other methods.

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DAC allows for reliable estimation of effective connectivity.
Omics-informed CNV calls reduce false positive rate and improve power for CNV-trait associations
Authors: Lepamets Maarja , Auwerx Chiara , Nõukas Margit , Claringbould Annique , Porcu Eleonora , Kals Mart , Jürgenson Tuuli ,   Estonian Biobank Research Team, Morris Andrew Paul , Võsa Urmo , Bochud Murielle , Stringhini Silvia , Wijmenga Cisca , Franke Lude , Peterson Hedi , Vilo Jaak , Lepik Kaido , Mägi Reedik , Kutalik Zoltán
Published: February 2022

Copy number variations (CNV) are believed to play an important role in a wide range of complex traits but discovering such associations remains challenging. Whilst whole genome sequencing (WGS) is the gold standard approach for CNV detection, there are several orders of magnitude more samples with available genotyping microarray data. Such array data can be exploited for CNV detection using dedicated software (e.g., PennCNV), however these calls suffer from elevated false positive and negative rates. In this study, we developed a CNV quality score that weights PennCNV calls (pCNV) based on their likelihood of being true positive. First, we established a measure of pCNV reliability by leveraging evidence from multiple omics data (WGS, transcriptomics and methylomics) obtained from the same samples. Next, we built a predictor of omics-confirmed pCNVs, termed omics-informed quality score (OQS), using only PennCNV software output parameters. Promisingly, OQS assigned to pCNVs detected in close family members was up to 35% higher than the OQS of pCNVs not carried by other relatives (P < 3.0−10−90), outperforming other scores. Finally, in an association study of four anthropometric traits in 89,516 Estonian Biobank samples, the use of OQS led to a relative increase in the trait variance explained by CNVs of up to 34% compared to raw pCNVs or previous quality scores. Overall, we put forward a flexible framework to improve any CNV detection method leveraging multi-omics evidence, applied it to improve PennCNV calls and demonstrated its utility by improving the statistical power for downstream association analyses.
Single-cell immune repertoire sequencing of B and T cells in murine models of infection and autoimmunity
Authors: Shlesinger Danielle , Hong Kai-Lin , Shammas Ghazal , Page Nicolas , Sandu Ioana , Agrafiotis Andreas , Kreiner Victor , Fonta Nicolas , Vincenti Ilena , Wagner Ingrid , Piccinno Margot , Mariotte Alexandre , Klimek Bogna , Dizerens Raphael , Manero-Carranza Marcos , Kuhn Raphael , Ehling Roy , Frei Lester , Khodaverdi Keywan , Panetti Camilla , Joller Nicole , Oxenius Annette , Merkler Doron , Reddy Sai T. , Yermanos Alexander
Published: February 2022

Adaptive immune repertoires are composed by the ensemble of B and T cell receptors (BCR, TCR) within an individual and reflect both past and current immune responses. Recent advances in single-cell sequencing enable recovery of the complete adaptive immune receptor sequences in addition to transcriptional information. Such high-dimensional datasets enable the molecular quantification of clonal selection of B and T cells across a wide variety of conditions such as infection and disease. Due to costs, time required for the analysis and current practices of academic publishing, small-scale sequencing studies are often not made publicly available, despite having informative potential to elucidate immunological principles and guide future-studies. Here, we performed single-cell sequencing of B and T cells to profile clonal selection across murine models of viral infection and autoimmune disease. Specifically, we recovered transcriptome and immune repertoire information for polyclonal T follicular helper cells following acute and chronic viral infection, CD8+ T cells with binding specificity restricted to two distinct peptides of lymphocytic choriomeningitis virus, and B and T cells isolated from the nervous system in the context of experimental autoimmune encephalomyelitis. We could relate repertoire features such as clonal expansion, germline gene usage, and clonal convergence to cell phenotypes spanning activation, memory, naive, antibody secretion, T cell inflation, and regulation. Together, this dataset provides a resource for experimental and computational immunologists that can be integrated with future single-cell immune repertoire and transcriptome sequencing datasets.
Conservative Significance Testing of Tripartite Interactions in Multivariate Neural Data
Authors: Fomins Aleksejs , Sych Yaroslav , Helmchen Fritjof
Published: February 2022

An important goal in systems neuroscience is to understand the structure of neuronal interactions, frequently approached by studying functional relations between recorded neuronal signals. Commonly used pairwise metrics (e.g. correlation coefficient) offer limited insight, neither addressing the specificity of estimated neuronal interactions nor potential synergistic coupling between neuronal signals. Tripartite metrics, such as partial correlation, variance partitioning, and partial information decomposition, address these questions by disentangling functional relations into interpretable information atoms (unique, redundant and synergistic). Here, we apply these tripartite metrics to simulated neuronal recordings to investigate their sensitivity to impurities (like noise or other unexplained variance) in the data. We find that all considered metrics are accurate and specific for pure signals but experience significant bias for impure signals. We show that permutation-testing of such metrics results in high false positive rates even for small impurities and large data sizes. We present a conservative null hypothesis for significance testing of tripartite metrics, which significantly decreases false positive rate at a tolerable expense of increasing false negative rate. We hope our study raises awareness about the potential pitfalls of significance testing and of interpretation of functional relations, offering both conceptual and practical advice.

Author Summary

Tripartite functional relation metrics enable the study of interesting effects in neural recordings, such as redundancy, functional connection specificity and synergistic coupling. However, common estimators of such relations are designed for pure (e.g. non-noisy) signals rare for such recordings. We study the performance of tripartite estimators using simulated impure neural signals. We demonstrate that permutation-testing is not a robust procedure for inferring ground truth interactions from studied estimators. We develop an adjusted conservative testing procedure, reducing false positive rate of studied estimators for impure data. Besides addressing significance testing, our results should aid in accurate interpretation of tripartite functional relations and functional connectivity.
Strong genotype by environment interactions in the rice Global MAGIC population across seedling stage drought
Authors: Moyers Brook T. , Henry Amelia , Raghavan Chitra , Zaw Hein , Marrano Annarita , Leung Hei , McKay John
Published: February 2022

Crop adaptation is required to sustainably increase the rate of yield gains to meet projected future needs under the challenging conditions of climate change and competition for resources. Future adaptation will likely need to harness both highly polygenic traits and genotype-by-environment interactions (GxE), the study of which is aided by complex recombinant populations. We used the diverse Oryza sativa Global Multiparent Advanced Generation InterCross (MAGIC) population to study the genetic architecture and contributions of seedling emergence, establishment, and development to yield components under dry-direct seeding and seedling stage drought across three growing seasons. Dry-direct seeding is an establishment practice that has the potential to reduce methane emissions, water use, and labor demands for rice farmers, but increases the possibility of early-season drought conditions. We found substantial evidence for large roles of environmental variation and GxE in controlling trait variation. Maintenance of shoot growth during seedling stage drought was positively correlated with crown root number and both directly and indirectly influenced agronomic traits. Other than the major green revolution locus sd1, most allelic effects were conditionally neutral (affecting trait values in some environments but not others) and most alleles had their strongest effect in an environmental extreme. This discovery is both a challenge and a potential opportunity: with variable genetic architecture, selection in any one environment may not result in stable trait gains across environments. However, conditionally neutral GxE is a potential route to sustainable yield stability through allele pyramiding.
First cases of infection with the 21L/BA.2 Omicron variant in Marseille, France
Authors: Colson Philippe , Delerce Jérémy , Beye Mamadou , Levasseur Anthony , Boschi Céline , Houhamdi Linda , Tissot-Dupont Hervé , Yahi Nouara , Million Matthieu , La Scola Bernard , Fantini Jacques , Raoult Didier , Fournier Pierre-Edouard
Published: February 2022

The SARS-CoV-2 21K/BA.1, 21L/BA.2, and BA.3 Omicron variants have recently emerged worldwide. To date, the 21L/BA.2 Omicron variant has remained very minority globally but became predominant in Denmark instead of the 21K/BA.1 variant. Here we describe the first cases diagnosed with this variant in south-eastern France. We identified thirteen cases using variant-specific qPCR and next-generation sequencing between 28/11/2021 and 31/01/2022, the first two cases being diagnosed in travellers returning from Tanzania. Overall, viral genomes displayed a mean (±standard deviation) number of 65.9±2.5 (range, 61-69) nucleotide substitutions and 31.0±8.3 (27-50) nucleotide deletions, resulting in 49.6±2.2 (45-52) amino acid substitutions (including 28 in the spike protein) and 12.4±1.1 (12-15) amino acid deletions. Phylogeny showed the distribution in three different clusters of these genomes, which were most closely related to genomes from England and South Africa, from Singapore and Nepal, or from France and Denmark. Structural predictions pointed out a significant enlargement and flattening of the 21L/BA.2 N-terminal domain surface compared with that of the 21K/BA.2 Omicron variant, which may facilitate initial viral interactions with lipid rafts. Close surveillance is needed at global, country and center scales to monitor the incidence and clinical outcome of the 21L/BA.2 Omicron variant.
Symptoms and severity in vaccinated and unvaccinated patients hospitalised with SARS-CoV-2 delta (B.1.617.2) variant infection
Authors: Epaulard Olivier , Abgrall Sophie , Lefebvre Maeva , Faucher Jean-François , Michon Jocelyn , Frentiu Emilia , Janssen Cécile , Charbonnier Gabrielle , Fresse Audrey , Laurent Simon , Sandjakian Lena , Casez Pierre , Mahamat Aba , Béraud Guillaume
Published: February 2022

Background

The diffusion of the SARS-CoV-2 delta (B.1.617.2) variant and the waning of immune response after primary Covid-19 vaccination favoured the breakthrough SARS-CoV-2 infections in vaccinated subjects. To assess the impact of vaccination, we determined the severity of infection in hospitalised patients according to vaccine status.

Methods

We retrospectively analysed data from patients hospitalised in 10 centres with a SARS-CoV-2 infection (delta variant) from July to November 2021: i) all patients who had completed their primary vaccination at least 14 days before hospital admission; and ii) the same number of completely unvaccinated patients. We assessed the impact of vaccination and other risk factors through logistic regression.

Findings

We included 955 patients (474 vaccinated and 481 unvaccinated). Vaccinated patients were significantly older, more frequently males, and with more comorbidities. They were less often admitted for Covid-19 (59·3% vs. 75·1%, p<0·001), showed fewer lung lesions, and required oxygen less frequently (57·5% vs. 73·0%, p<0·001), at a lower flow (3·0 vs. 6·0 L/min, p<0·001), and for a shorter duration (3 vs. 6 days, p<0·001). They less frequently required intensive care unit admission (16·2 % vs. 36·0 %, p<0·001). Mortality at day 28 was not different between the two groups (16·7% vs. 12.2%, p=0·075), but multivariate logistic regression showed that vaccination significantly decreased the risk of negative outcomes, including mortality, even when considering older patients, and those with comorbidities.

Conclusions

Among patients hospitalised with a delta variant SARS-CoV-2 infection, vaccination was associated with less severe forms, even in the presence of comorbidities.
Innovative Randomized Phase 1 Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir
Authors: Singh Ravi Shankar P. , Toussi Sima S. , Hackman Frances , Chan Phylinda L. , Rao Rohit , Allen Richard , Van Eyck Lien , Pawlak Sylvester , Kadar Eugene P. , Clark Frances , Shi Haihong , Anderson Annaliesa S. , Binks Michael , Menon Sandeep , Nucci Gianluca , Bergman Arthur
Published: February 2022

Background

COVID-19 is a continued leading cause of hospitalization and death. Safe and efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, SARS-CoV-2 Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile.

Methods

We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase 1 study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a 3-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (BID) dosing was evaluated over 10 days in 5 parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase 2/3 clinical trials were supported by integrating modelling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP).

Results

In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase 2/3 trials (300/100 mg BID), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients and prevent development of severe disease, hospitalization, and death.

Conclusions

An innovative and seamless trial design expedited establishment of phase 1 safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase 2/3 dose selection and accelerated pivotal trials’ initiation. NCT04756531
DMARD disruption, disease flare, and prolonged symptom duration after acute COVID-19 among participants with rheumatic disease: A prospective study
Authors: Di Iorio Michael , Cook Claire E. , Vanni Kathleen M.M. , Patel Naomi J. , D’Silva Kristin M. , Fu Xiaoqing , Wang Jiaqi , Prisco Lauren C. , Kowalski Emily , Zaccardelli Alessandra , Martin Lily W. , Qian Grace , Hsu Tiffany Y-T. , Wallace Zachary S. , Sparks Jeffrey A.
Published: February 2022

Objective

To describe disease-modifying antirheumatic drug (DMARD) disruption, rheumatic disease flare/activity, and prolonged COVID-19 symptom duration among COVID-19 survivors with systemic autoimmune rheumatic diseases (SARDs).

Methods

We surveyed patients with SARDs after confirmed COVID-19 at Mass General Brigham to investigate post-acute sequelae of COVID-19. We obtained data on demographics, clinical characteristics, COVID-19 symptoms/course, and patient-reported measures. We examined baseline predictors of prolonged COVID-19 symptom duration (defined as lasting ≥28 days) using logistic regression.

Results

We analyzed surveys from 174 COVID-19 survivors (mean age 52 years, 81% female, 80% White, 50% rheumatoid arthritis) between March 2021 and January 2022. Fifty-one percent of 127 respondents on any DMARD reported a disruption to their regimen after COVID-19 onset. For individual DMARDs, 56-77% had any change, except for hydroxychloroquine (23%) and rituximab (46%). SARD flare after COVID-19 was reported by 41%. Global patient-reported disease activity was worse at the time of survey than before COVID-19 (mean 6.6±2.9 vs. 7.6±2.3, p<0.001). Median time to COVID-19 symptom resolution was 14 days (IQR 9,29). Prolonged symptom duration of ≥28 days occurred in 45%. Hospitalization for COVID-19 (OR 3.54, 95%CI 1.27-9.87) and initial COVID-19 symptom count (OR 1.38 per symptom, 95%CI 1.17-1.63) were associated with prolonged symptom duration. Respondents experiencing prolonged symptom duration had higher RAPID3 scores (p=0.007) and more pain (p<0.001) and fatigue (p=0.03) compared to those without prolonged symptoms.

Conclusion

DMARD disruption, SARD flare, and prolonged symptom duration were common in this prospective study of COVID-19 survivors, suggesting substantial impact on SARDs after acute COVID-19.
Genome-wide association reveals host-specific genomic traits in Escherichia coli
Authors: Tiwari Sumeet K. , van der Putten Boas C.L. , Fuchs Thilo M. , Vinh Trung N. , Bootsma Martin , Oldenkamp Rik , La Ragione Roberto , Matamoros Sebastien , Hoa Ngo T. , Berens Christian , Leng Joy , Álvarez Julio , Ferrandis-Vila Marta , Ritchie Jenny M. , Fruth Angelika , Schwarz Stefan , Domínguez Lucas , Ugarte-Ruiz María , Bethe Astrid , Huber Charlotte , Johanns Vanessa , Stamm Ivonne , Wieler Lothar H. , Ewers Christa , Fivian-Hughes Amanda , Schmidt Herbert , Menge Christian , Semmler Torsten , Schultsz Constance
Published: February 2022

Escherichia coli is an opportunistic pathogen that can colonize or infect various host species. There is a significant gap in our understanding to what extent genetic lineages of E. coli are adapted or restricted to specific hosts. In addition, genomic determinants underlying such host specificity are unknown.By analyzing a randomly sampled collection of 1198 whole-genome sequenced E. coli isolates from four countries (Germany, UK, Spain, and Vietnam), obtained from five host species (human, pig, cattle, chicken, and wild boar) over 16 years, from both healthy and diseased hosts, we demonstrate that certain lineages of E. coli are frequently detected in specific hosts. We report a novel nan gene cluster, designated nan-9, putatively encoding acetylesterases and determinants of uptake and metabolism of sialic acid, to be associated with the human host as identified through genome wide association studies. In silico characterization predicts nan-9 to be involved in sialic acid (Sia) metabolism. In vitro growth experiments with a representative Δnan E. coli mutant strain, using sialic acids 5-N-acetyl neuraminic acid (Neu5Ac) and N-glycolyl neuraminic acid (Neu5Gc) as the sole carbon source, indicate an impaired growth behaviour compared to the wild-type. In addition, we identified several additional E. coli genes that are potentially associated with adaptation to human, cattle and chicken hosts, but not for the pig host. Collectively, this study provides an extensive overview of genetic determinants which may mediate host specificity in E. coli. Our findings should inform risk analysis and epidemiological monitoring of (antimicrobial resistant) E. coli.
Parasites make hosts more profitable but less available to predators
Authors: Prosnier Loïc , Loeuille Nicolas , Hulot Florence D. , Renault David , Piscart Christophe , Bicocchi Baptiste , Deparis Muriel , Lam Matthieu , Médoc Vincent
Published: February 2022

Parasites are omnipresent, and their eco-evolutionary significance has aroused much interest from scientists. Parasites may affect their hosts in many ways with changes in density, appearance, behaviour and energy content, likely to modify their value to predators (profitability) within the optimal foraging framework. Consequently, parasites could impact predators’ diet and the trophic links through food webs. Here, we investigate the consequences of the infection by the iridovirus Daphnia iridescent virus 1 (DIV-1) on the reproductive success, mortality, appearance, mobility, and biochemical composition of water fleas (Daphnia magna), a widespread freshwater crustacean. We do predation tests and compare search time, handling time and feeding preference between infected and uninfectedDaphniawhen preyed upon byNotonectasp., a common aquatic insect. Our findings show that infection does not change fecundity but reduces lifespan and thereby constrains fitness. InfectedDaphniashow reduced mobility and increased color reflectance in the UV and visible domains, which potentially affects their appearance and thus vulnerability to predators. Infection increases body size and the amount of proteins but does not affect carbohydrate and lipid contents. Although infectedDaphniaare longer to handle, they are preferred over uninfected individuals by aquatic insects. Taken together, our findings show that DIV-1 infection could makeDaphniamore profitable to predators (24% energy increase), a positive effect that should be balanced with a lower availability due to the higher mortality of infected specimens. We also highlight that exposure to infection in asymptomatic individuals leads to ecological characteristics that differ from both healthy and symptomatic infected individuals.

Recommender:Luis Schiesari

Reviewers:Thierry De Meeus and Eglantine Mathieu-Bégné

Cite as:Prosnier L., N. Loeuille, F.D. Hulot, D. Renault, C. Piscart, B. Bicocchi, M, Deparis, M. Lam, & V. Médoc. (2023).

Parasites make hosts more profitable but less available to predators. BioRxiv, ver. 4 peer-reviewed and recommended by Peer Community in Ecology.https://doi.org/10.1101/2022.02.08.479552
A Systematic Approach for Explaining Time and Frequency Features Extracted by CNNs from Raw EEG Data
Authors: Ellis Charles A. , Miller Robyn L. , Calhoun Vince D.
Published: February 2022

In recent years, the use of convolutional neural networks (CNNs) for raw electroencephalography (EEG) analysis has grown increasingly common. However, relative to earlier machine learning and deep learning methods with manually extracted features, CNNs for raw EEG analysis present unique problems for explainability. As such, a growing group of methods have been developed that provide insight into the spectral features learned by CNNs. However, spectral power is not the only important form of information within EEG, and the capacity to understand the roles of specific multispectral waveforms identified by CNNs could be very helpful. In this study, we present a novel model visualization-based approach that adapts the traditional CNN architecture to increase interpretability and combines that inherent interpretability with a systematic evaluation of the model via a series of novel explainability methods. Our approach evaluates the importance of spectrally distinct first-layer clusters of filters before examining the contributions of identified waveforms and spectra to cluster importance. We evaluate our approach within the context of automated sleep stage classification and find that, for the most part, our explainability results are highly consistent with clinical guidelines. Our approach is the first to systematically evaluate both waveform and spectral feature importance in CNNs trained on EEG data.
TEMPRANILLOhomologs in apple regulate flowering time in the woodland strawberryFragaria vesca
Authors: Dejahang Ata , Maghsoudi Naeimeh , Mousavi Amir , Farsad-Akhtar Nader , Hernandez Luis Matias , Pelaz Soraya , Folta Kevin , Mahna Nasser
Published: February 2022

Many economically valuable fruit trees belong to theRosaceaefamily. The long juvenile period of fruit trees makes their breeding costly and time-consuming. Therefore, flowering time regulation and shortening the juvenile phase have been a breeding priority for genetic improvement of fruit tree crops.TEMPRANILLOgenes act as floral inhibitors in Arabidopsis and so, two orthologs of this gene were isolated here from apple (Malus domestica) and functionally analysed in Arabidopsis and woodland strawberry by being overexpressed in both model plants, and partially silenced in strawberry. The overexpression ofMdTEMgenes down-regulatedFvFT1, FvGA3OX1, andFvGA3OX2genes in strawberry. The overexpression lines exhibited delayed flowering, both in terms of days to flowering and the number of leaves at flowering.RNAi-mediatedsilencing ofTEMresulted in early flowering plants. These plants flowered approximately five days earlier than wild type plants with a lower number of leaves. However, the overexpression ofMdTEMgenes could not functionally rescue theArabidopsismutants. According to the results, it can be concluded thatMdTEM1andMdTEM2are orthologs ofFvTEMgene, which play an important role in regulating the juvenile phase and flowering time through controllingFTand GA biosynthetic gene expression.
Transformation of alignment files improves performance of variant callers for long-read RNA sequencing data
Authors: de Souza Vladimir B. C. , Jordan Ben T. , Tseng Elizabeth , Nelson Elizabeth A. , Hirschi Karen K. , Sheynkman Gloria , Robinson Mark D.
Published: February 2022

Long-read RNA sequencing (lrRNA-seq) produces detailed information about full-length transcripts, including novel and sample-specific isoforms. Furthermore, there is opportunity to call variants directly from lrRNA-seq data. However, most state-of-the-art variant callers have been developed for genomic DNA. Here, there are two objectives: first, we perform a mini-benchmark on GATK, DeepVariant, Clair3, and NanoCaller primarily on PacBio Iso-Seq, data, but also on Nanopore and Illumina RNA-seq data; second, we propose a pipeline to process spliced-alignment files, making them suitable for variant calling with DNA-based callers. With such manipulations, high calling performance can be achieved using DeepVariant on Iso-seq data.
Maternally inherited siRNAs initiate piRNA cluster formation
Authors: Luo Yicheng , He Peng , Kanrar Nivedita , Toth Katalin Fejes , Aravin Alexei A.
Published: February 2022

PIWI-interacting RNAs (piRNAs) guide repression of transposable elements in germlines of animals. In Drosophila, piRNAs are produced from heterochromatic genomic loci, called piRNA clusters, that act as a repositories of information about genome invaders. piRNA generation by dual-strand clusters depend on the chromatin-bound Rhino-Deadlock-Cutoff (RDC) complex, which is deposited on clusters guided by piRNAs, forming a feed-forward loop in which piRNAs promote their own biogenesis. However, how piRNA clusters are formed initially, before cognate piRNAs are present, remained unknown. Here we report spontaneous de novo formation of a piRNA cluster from repetitive transgenic sequences. We show that cluster formation occurs gradually over several generations and requires continuous trans-generational transmission of small RNAs from mothers to their progeny. We discovered that maternally-supplied siRNAs are responsible for triggering de novo cluster activation in progeny. In contrast, the siRNA pathway is dispensable for cluster function after its establishment. These results revealed an unexpected cross-talk between the siRNA and piRNA pathways and suggest a mechanism for de novo formation of piRNA clusters triggered by production of siRNAs.

Highlights

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A transcribed repetitive transgene is spontaneously converted into dual-strand piRNA cluster

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Establishment of piRNA cluster occurs over multiple generations and requires cytoplasmic inheritance of cognate small RNA from mothers

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Cognate siRNAs initiate the activation of piRNA cluster, but are dispensable after its establishment
The Chromosome-level Genome of Dracaena cochinchinesis Provides Insights into its Biological Features and the Mechanism of Dragon’s Blood Formation
Authors: Xu Yanhong , Zhang Kaijian , Zhang Zhonglian , Liu Yang , Lv Feifei , Sun Peiwen , Gao Shixi , Wang Qiuling , Yu Cuicui , Jiang Jiemei , Li Chuangjun , Song Meifang , Gao Zhihui , Sui Chun , Li Haitao , Jin Yue , Guo Xinwei , Wei Jianhe
Published: February 2022

Dracaena, a remarkably long-lived and slowly maturing species, is famous all over the world for the production of dragon’s blood, a precious traditional medicine used by different cultures since ancient times. However, lacking a high-quality genome,the molecular mechanisms underlying these traits are largely unknown and that greatly restricts the protection and regeneration of the rare and endangered plant resources. Here, we sequenced and assembled a chromosome-level genome of the Dracaena cochinchinensis, the first to be sequenced of Dracaena Vand. ex L. The D. cochinchinensis genome covering 1.21 Gb with a scaffold N50 of 50.06 Mb, and encodes 31,619 predicted protein-coding genes. We found D. cochinchinensis has undergone two whole genome duplications (WGDs) and two long terminal repeats (LTRs) insertion burst events. The expansion of cis-zeatin O-glucosyltransferase (cZOGT) and small auxin up-regulated RNA (SAUR) genes is account for its longevity and slow growth. In flavonoids biosynthesis pathway, transcription factors bHLH and MYB were predicted as the core regulators, and ROS as the specific signal molecule during the process of injury-induced dragon’s blood formation. Our study not only provides high-quality genomic knowledge of D. cochinchinensis, but also deciphered the mystery of its longevity, and preliminarily elucidated the molecular mechanism of dragon’s blood formation, which will facilitate the resource protection and sustainable utilization of Dracaena.

SHORT SUMMARY

This study reports a chromosome-level genome assembly for D. cochinchinensis, the first genome of Dracaena Vand. ex L. It 29 provides valuable genetic resources and creates a large scope for studying Dracaena. We found the significant expansion of genes associated with its longevity and slow growth, and genes in flavonoids biosynthesis were first completely identified. Moreover, transcription factors bHLH and MYB as the core regulator of flavonoids biosynthesis, and ROS as the specific signal molecule during the process of injury-induced dragon’s blood formation were also identified. These results not only deciphered the mystery of its longevity, but also elucidated the molecular mechanism of dragon[s blood formation preliminarily, which will facilitate the resource protection and sustainable utilization of Dracaena.
Modulation of RNA polymerase processivity affects double-strand break repair in the presence of a DNA end-binding protein
Authors: Sivaramakrishnan Priya , Bradley Catherine C. , Artsimovitch Irina , Hagstrom Katelin M. , Ramirez Laura Deus , Wen Alice Xueyin , Cooke Matthew Brandon , Shaulsky Maya , Herman Christophe , Halliday Jennifer A.
Published: February 2022

Homologous recombination is the predominant double-strand DNA break repair pathway in Escherichia coli. A recent report of non-homologous end joining involving the Ku-like Gam protein of bacteriophage Mu (MuGam) has sparked interest in understanding the functions of DNA end-binding proteins in bacteria. MuGam binds to DNA ends, but how it interferes with DNA repair or transcription in live bacteria remains elusive. In E. coli, RNA polymerase secondary channel interactors, such as the Gre factors, play a role in coordinating transcription with DNA replication and break repair. Here we show that MuGam inhibits break repair by slowing down DNA resection and impeding recombination in living cells. Loss of GreA restores break repair in the presence of MuGam by allowing for increased DNA resection due to a potential release of MuGam from the DNA. Using MuGam as a DNA break sensor, we found that breaks are generated when translation is inhibited, more so in the presence of GreA, supporting the model where transcription-translation uncoupling increases transcription/replication collisions. Significantly, this work reveals that modulation of RNA polymerase can impact DNA break repair in presence of a Ku-like protein.
A rose flavor compound activating the NRF2 pathway in dendritic cells ameliorates contact hypersensitivity in mice
Authors: Kodama Naoki , Okada Hikaru , Hachisu Masakazu , Ando Miki , Ito Naoto , Nagata Kazuki , Yasuda Yayoi , Hiroki Ikumi , Yashiro Takuya , Ichihara Gaku , Yamamoto Masayuki , Nishiyama Chiharu
Published: February 2022

Dendritic cells (DCs), which are typical antigen-presenting cells, localize to various sites in the body, particularly the front line of infection as sentinels, and are involved in innate and adaptive immune responses. Although the functions of DCs, such as pathogen-induced cytokine production and antigen-specific T cell activation, are important for host defenses against infection and tumorigenesis, the hyper- and/or extended activation of DCs leads to inflammatory and autoimmune diseases. In the present study, β-damascone, a major ingredient of rose fragrance, was selected from an aroma library as a candidate compound that suppresses antigen-induced immune responses. β-Damascone inhibited the functions of DCs, including the antigen-dependent proliferation of T cells, DC-induced Th1 development, and the TLR ligand-induced production of inflammatory cytokines by DCs. The β-damascone treatment also increased the protein level of the transcription factor NRF2, which plays key roles in antioxidant responses, and the transcription ofHmox1, a target gene of NRF2, in DCs.Nrf2−/−DCs induced Th1-development and produced large amount of IL-12p40 even in the presence of β-damascone, whereas these functions byNrf2+/−DCs were inhibited by β-damascone under the same conditions. The intake of β-damascone suppressed ear swelling in contact hypersensitivity (CHS) model mice, but not in CHS-inducedNrf2−/−mice. Collectively, the present results indicate the potential of the rose aroma compound β-damascone, which suppresses DC-mediated immune responses by activating the NRF2 pathway in DCs, for the prevention and/or attenuation of immune-mediated diseases.
Comparing dormancy in two distantly related tunicates reveals morphological, molecular, and ecological convergences and repeated co-option
Authors: Hiebert Laurel S. , Scelzo Marta , Alié Alexandre , De Tomaso Anthony , Brown Federico , Tiozzo Stefano
Published: February 2022

Many asexually-propagating marine invertebrates can survive extreme environmental conditions by developing dormant structures, i.e., morphologically simplified bodies that retain the capacity to completely regenerate a functional adult when conditions return to normal. Here, we examine the environmental, morphological, and molecular characteristics of dormancy in two distantly related clonal tunicate species: Polyandrocarpa zorritensis and Clavelina lepadiformis. In both species, we report that the dormant structures are able to withstand harsher temperature and salinity conditions compared to the adult, and are the dominant forms these species employ to survive the colder winter months. By finely controlling the entry and exit of dormancy in laboratory-reared individuals, we were able to select and characterize the morphology of dormant structures associated with their transcriptome dynamics. In both species, we identified putative stem and nutritive cells in structures that resemble the earliest stages of asexual propagation. By characterizing gene expression during dormancy and regeneration into the adult body plan (i.e., germination), we observed that genes which control dormancy and environmental sensing in other metazoans, notably HIF-α and insulin signaling genes, are also expressed in tunicate dormancy. Germination-related genes in these two species, such as the retinoic acid pathway, are also found in other unrelated clonal tunicates during asexual development. These results are suggestive of repeated exaptation of conserved eco-physiological and regeneration programs for the origin of novel dormancy-germination processes across distantly related animal taxa.
Impacts of Spaceflight Experience on Human Brain Structure
Authors: McGregor Heather R. , Hupfeld Kathleen E. , Pasternak Ofer , Beltran Nichole E. , Dios Yiri E. De , Bloomberg Jacob J. , Wood Scott J. , Mulavara Ajitkumar P. , Riascos Roy F. , Reuter-Lorenz Patricia A. , Seidler Rachael D.
Published: February 2022

Spaceflight induces widespread changes in human brain morphology. It is unclear if these brain changes differ with varying mission durations or one’s history of spaceflight experience (e.g., number of prior missions, time between missions). Here we addressed this issue by quantifying voxelwise post-flight changes in gray matter volume, white matter microstructure, extracellular free water (FW), and ventricular volume in a sample of 28 astronauts. We found that longer missions induced greater ventricular expansion and larger FW displacement at the top of the brain. A greater number of prior missions was associated with white matter microstructure declines in a tract supporting voluntary leg movement. Longer inter-mission intervals were associated with greater ventricle expansion, with compensatory ventricular expansion observed only in those crewmembers with inter-missions intervals of 3 years or longer. Longer missions therefore induce more extensive brain fluid shifts, and the ventricles may require at least 3 years to recover post-flight.
Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies
Authors: Molitor Lena , Klostermann Melina , Bacher Sabrina , Merl-Pham Juliane , Spranger Nadine , Burczyk Sandra , Ketteler Carolin , Rusha Ejona , Tews Daniel , Pertek Anna , Proske Marcel , Busch Anke , Reschke Sarah , Feederle Regina , Hauck Stefanie M. , Blum Helmut , Drukker Micha , Fischer-Posovszky Pamela , König Julian , Zarnack Kathi , Niessing Dierk
Published: February 2022

The RNA-binding protein PURA has been implicated in the rare, monogenetic, neurodevelopmental disorder PURA Syndrome. PURA binds both DNA and RNA and has been associated with various cellular functions. Only little is known about its main cellular roles and the molecular pathways affected uponPURAdepletion. Here, we show that PURA is predominantly located in the cytoplasm, where it binds to thousands of mRNAs. Many of these transcripts change abundance in response toPURAdepletion. The encoded proteins suggest a role for PURA in immune responses, mitochondrial function, autophagy and processing (P)-body activity. Intriguingly, reduced PURA levels decrease the expression of the integral P-body components LSM14A and DDX6 and strongly affect P-body formation in human cells. Furthermore,PURAknockdown results in stabilization of P-body-enriched transcripts, whereas other mRNAs decrease. Hence, reduced PURA levels, as reported in patients with PURA Syndrome, influence the formation and composition of this phase-separated RNA processing machinery. Our study proposes PURA Syndrome as a new model to study the tight connection between P-body-associated RNA regulation and neurodevelopmental disorders.

Graphical Abstract
SPRI: Spatial Pattern Recognition using Information based method for spatial gene expression data
Authors: Hu Jin-Xian , Hu Zhi-Rui , Yuan Ye , Shen Hong-Bin
Published: February 2022

The rapid development of spatially resolved transcriptomics has made it possible to analyze spatial gene expression patterns in complex biological tissues. To identify spatially differential expressed genes, we propose a novel and robust nonparametric information-based approach, SPRI. SPRI converts the problem of identifying spatial gene expression patterns into the detection of dependencies between spatial coordinates with observed frequencies measured by read counts. It directly models spatial transcriptome raw count without assuming a parametric model. SPRI was applied to spatial datasets with different resolutions, suggesting that SPRI outperforms previous methods, by robustly detecting more genes with significant spatial expression patterns, and revealing biological insights that cannot be identified by other methods.
Cerebellar and cortico-striatal-midbrain contributions to reward-cognition processes and apathy within the psychosis continuum
Authors: Bègue Indrit , Brakowski Janis , Seifritz Erich , Dagher Alain , Tobler Philippe N. , Kirschner Matthias , Kaiser Stefan
Published: February 2022

Negative symptoms in the psychosis continuum are linked to impairments in reward processing and cognitive function. Processes at the interface of reward processing and cognition and their relation to negative symptoms remain little studied, despite evidence suggestive of integration in mechanisms and neural circuitry. Here, we investigated brain activation during reward-dependent modulation of working memory (WM) and their relationship to negative symptoms in subclinical and early stages of the psychosis continuum. We included 27 persons with high schizotypal personality traits and 23 patients with first episode psychosis as well as 27 healthy controls. Participants underwent functional magnetic resonance imaging while performing an established 2-back WM task with two reward levels (5 CHF vs. no reward), which allowed us to assess common reward-cognition regions through whole-brain conjunction analyses and to investigate relations with clinical scores of negative symptoms. As expected for behavior, reward facilitated performance while cognitive load diminished it. At the neural level, the conjunction of high reward and high cognitive load contrasts across the psychosis continuum showed increased hemodynamic activity in the thalamus and the cerebellar vermis. During high cognitive load, more severe apathy but not diminished expression in the psychosis continuum was associated with reduced activity in right lateral orbitofrontal cortex, midbrain, posterior vermal cerebellum, caudate and lateral parietal cortex. Our results suggest that hypoactivity in the cerebellar vermis and the cortical-striatal-midbrain-circuitry in the psychosis continuum relates to apathy possibly via impaired flexible cognitive resource allocation for effective goal pursuit.
CD8 memory precursor cells generation is a continuous process
Authors: Todorov Helena , Prieux Margaux , Laubreton Daphne , Bouvier Matteo , Wang Shaoying , de Bernard Simon , Arpin Christophe , Cannoodt Robrecht , Saelens Wouter , Bonnaffoux Arnaud , Gandrillon Olivier , Crauste Fabien , Saeys Yvan , Marvel Jacqueline
Published: February 2022

In this work, we studied the generation of memory precursor cells following an acute infection by analyzing single-cell RNA-seq data that contained CD8 T cells collected during the postinfection expansion phase. We used different tools to reconstruct the developmental trajectory that CD8 T cells followed after activation. Cells that exhibited a memory precursor signature were identified and positioned on this trajectory. We found that memory precursors are generated continuously with increasing numbers being generated over time. Similarly, expression of genes associated with effector functions was also found to be raised in memory precursors at later time points. The ability of cells to enter quiescence to differentiate into memory cells was confirmed by BrdU pulse-chase experiment in vivo. Analysis of cell counts indicates that the vast majority of memory cells are generated at later time points from cells that have extensively divided.