bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intratumoral Delivered Novel Circular mRNA Encoding Cytokines for Immune Modulation and Cancer Therapy
Authors: Yang Jiali , Zhu Jiafeng , Chen Yiyun , Du Yaran , Tan Yiling , Wu Linpeng , Sun Jiaojiao , Zhai Mengting , Wei Lixiang , Li Na , Huang Ke , Hou Qiangbo , Tong Zhenbo , Bechthold Andreas , Sun Zhenhua , Zuo Chijian 
Published: November 2021

AbstractThe application of mRNA as a novel kind of vaccine has been proved recently, due to the emergence use authorization (EUA) by FDA for the two COVID-19 mRNA vaccines developed by Moderna and BioNTech. Both of the two vaccines are based on canonical linear mRNA, and encapsulated by lipid nanoparticle (LNP). Circular mRNA, which is found to mediate potent and durable protein expression, is an emerging technology recently. Owing to its simplicity of manufacturing and superior performance of protein expression, circular mRNA is believed to be a disruptor for mRNA area. However, the application of circular mRNA is still at an initiation stage, proof of concept for its usage as future medicine or vaccine is necessary. In the current study, we established a novel kind of circular mRNA, termed C-RNA, based on Echovirus 29 (E29)-derived internal ribosome entry sites (IRES) and newly designed homology arms and RNA spacers. Our results demonstrated that this kind of circular mRNA is able to mediate strong and durable protein expression, compared to typical linear mRNA. Moreover, for the first time, our study demonstrated that direct intratumoral administration of C-RNA encoding a mixture of cytokines achieved successful modulation of intratumoral and systematic anti-tumor immune responses and finally leading to an enhancement of anti-PD-1 antibody-induced tumor repression in syngeneic mouse model. Additionally, after an optimization of the circular mRNA formulation, a significant improvement of C-RNA mediated protein expression was observed. With this optimized formulation, C-RNA induced enhanced anti-tumor effect via intratumoral administration and elicited significant activation of tumor-infiltrated total T cells and CD8+ T cells. Collectively, we established C-RNA, a novel circular mRNA platform, and demonstrated that it can be applied for direct intratumoral administration for cancer therapy.
Specific Sensitivity to Rare and Extreme Events: Quasi-Complete Black Swan Avoidance vs Partial Jackpot Seeking in Rat Decision-Making*
Authors: Degoulet Mickaël , Willem Louis-Matis , Baunez Christelle , Luchini Stéphane , Pintus Patrick A. 
Published: November 2021

AbstractMost studies assessing animal decision-making under risk rely on probabilities that are typically larger than 10%. To study Decision-Making in uncertain conditions, we explore a novel experimental and modelling approach that aims at measuring the extent to which rats are sensitive - and how they respond - to outcomes that are both rare (probabilities smaller than 1%) and extreme in their consequences (deviations larger than 10 times the standard error). In a four-armed bandit task, stochastic gains (sugar pellets) and losses (time-out punishments) are such that extremely large - but rare - outcomes materialize or not depending on the chosen options. All rats feature both limited diversification, mixing two options out of four, and sensitivity to rare and extreme outcomes despite their infrequent occurrence, by combining options with avoidance of extreme losses (Black Swans) and exposure to extreme gains (Jackpots). Notably, this sensitivity turns out to be one-sided for the main phenotype in our sample: it features a quasi-complete avoidance of Black Swans, so as to escape extreme losses almost completely, which contrasts with an exposure to Jackpots that is partial only. The flip side of observed choices is that they entail smaller gains and larger losses in the frequent domain compared to alternatives. We have introduced sensitivity to Black Swans and Jackpots in a new class of augmented Reinforcement Learning models and we have estimated their parameters using observed choices and outcomes for each rat. Adding such specific sensitivity results in a good fit of the selected model - and simulated behaviors that are close - to behavioral observations, whereas a standard Q-Learning model without sensitivity is rejected for almost all rats. This model reproducing the main phenotype suggests that frequent outcomes are treated separately from rare and extreme ones through different weights in Decision-Making.
An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas
Authors: Falvo David J. , Grimont Adrien , Zumbo Paul , Yang Julie L. , Osterhoudt Alexa , Pan Grace , Rendeiro Andre F. , Wilkinson John E. , Dündar Friederike , Elemento Olivier , Yantiss Rhonda K. , Betel Doron , Koche Richard , Chandwani Rohit 
Published: November 2021

SUMMARYInflammation is essential to the disruption of tissue homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. Herein we employ lineage-traced mouse models to delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and unveil the presence of an epigenetic memory of inflammation in the pancreatic acinar cell compartment. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision. In vivo, this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We demonstrate that both persistent chromatin and transcriptional changes constituting memory are recalled with oncogenic stress. Together, our findings define the dynamics and recall of an epigenetic memory of inflammation that impacts cell fate decisions in a context-dependent manner.
Elexacaftor/Tezacaftor/Ivacaftor alters branching morphogenesis of the mouse embryonic lung
Authors: Lhuillier Mickaël , Aoust Laura , Dreano Elise , Franco-Montoya Marie-Laure , Landry-Truchon Kim , Houde Nicolas , Chhun Stéphanie , Hinzpeter Alexandre , Edelman Aleksander , Delacourt Christophe , Jeannotte Lucie , Sermet-Gaudelus Isabelle , Hadchouel Alice 
Published: November 2021

AbstractIntroductionCFTR modulators triple combo-therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) has proven to clinically benefit homozygous and heterozygous F508del patients. As a result, an increasing number of pregnancies is expected. Studies of the potential impact of these modulators on the development of the foetus are mandatory.MaterialsWe used the early mouse embryonic lung organ culture model to analyse ex vivo the lung branching process and the relative expression of Fgf10, Fgfr2IIIb, Shh, and Hhip development regulator genes in different conditions: standard culture medium, treatment with ETI or with Forskolin ± Inh172. Development of lung branching and distal bud caliber were evaluated in lung explants from heterozygous F508del Cftrtm1Eur/+ and control Cftrtm1Eur+/+ (WT) mouse embryos at E12.5 during pseudo-glandular stage.ResultsExposure to ETI of the Cftrtm1Eur/+ and WT lung explants induced a significant decrease in lung branching after 48h culture and the percentage of terminal bud dilations was significantly increased. These results were recapitulated by cAMP-dependent CFTR continuous activation by Forskolin and reversed by addition of Inh172.ETI induced a significant decrease in Fgf10, Fgfr2IIIb, Shh and Hhip expression in lung explants of both E12.5 Cftrtm1Eur/+ and WT embryos treated with ETI for 72h.ConclusionOur results provide evidence that the triple association Elexacaftor/Tezacaftor/Ivacaftor alters lung branching morphogenesis of WT and heterozygous F508del mouse embryos during the pseudo-glandular stage. Those results argue for a close monitoring of pregnancies in patients treated with these drugs.Plain LanguageIntroductionThe triple combo-therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) improves homozygous and heterozygous F508del patients. As a result, an increasing number of pregnancies is expected. Studies of this treatment on the development of the foetus are lacking. We incubated lungs of murine foetus not carrying CFTR mutation or F508del heterozygous. We show that ETI induces significant defect of lung development and the formation of cysts. These results are at least partly due to CFTR activation. Those results argue for a close monitoring of pregnancies in patients treated with these drugs.
Wheat photosystem II heat tolerance responds dynamically to short and long-term warming
Authors: Posch Bradley C. , Hammer Julia , Atkin Owen K. , Bramley Helen , Ruan Yong-Ling , Trethowan Richard , Coast Onoriode 
Published: November 2021

AbstractHeat-induced inhibition of photosynthesis is a key factor in declining wheat performance and yield. Variation in wheat heat tolerance can be characterised using the critical temperature (Tcrit) above which incipient damage to the photosynthetic machinery occurs. We investigated intraspecies variation and plasticity of wheat Tcrit under elevated temperature in field and controlled environment experiments. We also assessed whether intraspecies variation in wheat Tcrit mirrors patterns of global interspecies variation in heat tolerance reported for mostly wild, woody plants. In the field, wheat Tcrit varied through the course of a day, peaking at noon and lowest at sunrise, and increased as plants developed from heading to anthesis and grain filling. Under controlled temperature conditions, heat stress (36°C) was associated with a rapid rise in wheat Tcrit (i.e. within two hours of heat stress) that peaked after 3–4 days. These peaks in Tcrit indicate a physiological limitation to photosystem II heat tolerance. Analysis of a global dataset (comprising 183 Triticum and wild wheat (Aegilops) species) generated from the current study and a systematic literature review showed that wheat leaf Tcrit varied by up to 20°C (about two-thirds of reported global plant interspecies variation). However, unlike global patterns of interspecies Tcrit variation which has been linked to latitude of genotype origin, intraspecific variation in wheat Tcrit was unrelated to that. Yet, the observed genotypic variation and plasticity of wheat Tcrit suggests that this trait could be a useful tool for high-throughput phenotyping of wheat photosynthetic heat tolerance.
Quality-controlled R-loop meta-analysis reveals the characteristics of R-Loop consensus regions
Authors: Miller H. E. , Montemayor D. , Abdul J. , Vines A. , Levy S. , Hartono S. , Sharma K. , Frost B. , Chedin F. , Bishop A. J. R. 
Published: November 2021

ABSTRACTR-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA during transcription. While the pathological consequences of R-loops have been well-studied to date, the locations, classes, and dynamics of physiological R-loops remain poorly understood. R-loop mapping studies provide insight into R-loop dynamics, but their findings are challenging to generalize. This is due to the narrow biological scope of individual studies, the limitations of each mapping modality, and, in some cases, poor data quality. In this study, we reprocessed 693 R-loop mapping datasets from a wide array of biological conditions and mapping modalities. From this data resource, we developed an accurate method for R-loop data quality control, and we reveal the extent of poor-quality data within previously published studies. We then identified a set of high-confidence R-loop mapping samples and used them to define consensus R-loop sites called “R-loop regions” (RL regions). In the process, we revealed the stark divergence between S9.6 and dRNH-based R-loop mapping methods and identified biologically meaningful subtypes of both constitutive and variable R-loops. Taken together, this work provides a much-needed method to assess R-loop data quality and reveals intriguing aspects of R-loop biology.
Isolation of gametes and zygotes from Setaria viridis
Authors: Toda Erika , Kiba Takatoshi , Kato Norio , Okamoto Takashi 
Published: November 2021

SummarySetaria viridis, the wild ancestor of foxtail millet (Setaria italica), is an effective model plant for larger C4 crops because it has several desirable traits, such as short generation time, prolific seed production and a small genome size. These advantages are well suited for investigating molecular mechanisms in angiosperms, especially C4 crop species. Here, we report a procedure for isolating gametes and zygotes from S. viridis flowers. To isolate egg cells, ovaries were harvested from unpollinated mature flowers and cut transversely, which allowed direct access to the embryo sac. Thereafter, an egg cell was released from the cut end of the basal portion of the dissected ovary. To isolate sperm cells, pollen grains released from anthers were immersed in a mannitol solution, resulting in pollen-grain bursting, which released sperm cells. Additionally, S. viridis zygotes were successfully isolated from freshly pollinated flowers. Isolated zygotes cultured in a liquid medium developed into globular-like embryos and cell masses. Thus, isolated S. viridis gametes, zygotes and embryos are attainable for detailed observations and investigations of fertilization and developmental events in angiosperms.
Exploration and analysis of R-loop mapping data with RLBase
Authors: Miller H. E. , Montemayor D. , Li J. , Levy S. , Pawar R. , Hartono S. , Sharma K. , Frost B. , Chedin F. , Bishop A. J. R. 
Published: November 2021

AbstractR-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA during nascent transcription. In 2012, Ginno et al. introduced the first R-loop mapping method, DNA:RNA immunoprecipitation (DRIP) sequencing. Since that time, dozens of studies have implemented R-loop mapping and new high-resolution techniques have been developed. The resulting datasets have tremendous potential to reveal the causes and consequences of R-loops genome-wide. However, poor quality and variability between mapping approaches pose serious barriers to the meta-analysis of these data. In our recent work, we reprocessed 693 R-loop mapping samples, devising new quality methods, defining a set of high-confidence mapping samples, and then deriving R-loop regions, consensus sites of R-loop formation. This analysis yielded the largest R-loop data resource to date along with novel computational approaches for R-loop mapping analysis. Now, we introduce RLBase, an innovative web server which builds upon those data and software by providing users with the capability to (1) explore hundreds of public R-loop mapping datasets, (2) explore consensus R-loop regions, (3) analyze user-supplied datasets to generate an HTML quality report, and (4) download all the processed data for the 693 samples we previously reprocessed and standardized. In addition to RLBase, we also describe the other software which, along with RLBase, provides a computational framework for R-loop bioinformatics. RLBase, and the rest of these software (termed “RLSuite”), are provided freely under an MIT license and made publicly available: https://gccri.bishop-lab.uthscsa.edu/rlsuite/. RLBase is directly accessible via the following URL: https://gccri.bishop-lab.uthscsa.edu/rlbase/.
Low selectivity index of ivermectin and macrocyclic lactones on SARS-CoV2 replication in vitro argues against their therapeutic use for COVID-19
Authors: Chable-Bessia Christine , Boullé Charlotte , Neyret Aymeric , Swain Jitandrya , Hénaut Mathilde , Merida Peggy , Gros Nathalie , Makinson Alain , Lyonnais Sébastien , Chesnais Cédric B. , Muriaux Delphine 
Published: November 2021

AbstractThere are very limited antiviral therapeutic options for coronavirus infections, therefore global drug re-purposing efforts are paramount to identify available compounds that could provide clinical benefits to patients with COVID-19. Ivermectin was first approved for human use as an endectocide in the 1980s. It remains one of the most important global health medicines in history and has recently been shown to exert in vitro activity against SARS-CoV-2. However, the macrocyclic lactone family of compounds has not previously been evaluated for activity against SARS-CoV-2. The present study aims at comparing their anti-viral activity in relevant pulmonary cell lines in vitro. Here, in vitro antiviral activity of the avermectins (ivermectin and selamectin) and milbemycins (moxidectin and milbemycin oxime) were assessed against a clinical isolate from a CHU Montpellier patient infected with SARS-CoV-2 in 2020. Ivermectin demonstrated anti-SARS-CoV-2 activity in vitro in human pulmonary cells in comparison to VeroE6 (with EC50 of 1-3 μM). Similarly, the other macrocyclic lactones moxidectin, milbemycin oxime and selamectin reduced SARS-CoV-2 replication in vitro (with EC50 of 2-5 μM). Immunofluorescence assays with ivermectin and moxidectin showed a reduction in the number of infected and polynuclear cells suggesting a drug action on viral cell fusion. However, cellular toxicity of the avermectins and milbemycins during infection showed a very low selectivity index <10 for all compounds. In conclusion, none of these agents appears suitable for human use for its anti-SARS-CoV-2 activity per se, due to low selectivity index. This is discussed in regards to recent clinical COVID studies on ivermectin.
The basic reproduction number of COVID-19 across Africa
Authors: Iyaniwura Sarafa A. , Rabiu Musa , David Jummy F. , Kong Jude D. 
Published: November 2021

AbstractThe pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) took the world by surprise. Following the first outbreak of COVID-19 in December 2019, several models have been developed to study and understand its transmission dynamics. Although the spread of COVID-19 is being slowed down by vaccination and other interventions, there is still a need to have a clear understanding of the evolution of the pandemic across countries, states and communities. To this end, there is a need to have a clearer picture of the initial spread of the disease in different regions. In this project, we used a simple SEIR model and a Bayesian inference framework to estimate the basic reproduction number of COVID-19 across Africa. Our estimates vary between 1.98 (Sudan) and 9.66 (Mauritius), with a median of 3.67 (90% CrI: 3.31 - 4.12). The estimates provided in this paper will help to inform COVID-19 modeling in the respective countries/regions.
Generalized Radiograph Representation Learning via Cross-supervision between Images and Free-text Radiology Reports
Authors: Zhou Hong-Yu , Chen Xiaoyu , Zhang Yinghao , Luo Ruibang , Wang Liansheng , Yu Yizhou 
Published: November 2021

AbstractPre-training lays the foundation for recent successes in radiograph analysis supported by deep learning. It learns transferable image representations by conducting large-scale fully-supervised or self-supervised learning on a source domain. However, supervised pre-training requires a complex and labor intensive two-stage human-assisted annotation process while self-supervised learning cannot compete with the supervised paradigm. To tackle these issues, we propose a cross-supervised methodology named REviewing FreE-text Reports for Supervision (REFERS), which acquires free supervision signals from original radiology reports accompanying the radiographs. The proposed approach employs a vision transformer and is designed to learn joint representations from multiple views within every patient study. REFERS outperforms its transfer learning and self-supervised learning counterparts on 4 well-known X-ray datasets under extremely limited supervision. Moreover, REFERS even surpasses methods based on a source domain of radiographs with human-assisted structured labels. Thus REFERS has the potential to replace canonical pre-training methodologies.
Fungal biodiversity in Arctic paleoecosystems assessed by metabarcoding of lake sedimentary ancient DNA
Authors: Seeber PA , von Hippel B , Kauserud H , Löber U , Stoof-Leichsenring KR , Herzschuh U , Epp LS 
Published: November 2021

SummaryFungi are crucial organisms in most ecosystems as they exert ecological key functions and are closely associated with land plants. Fungal community changes may therefore help reveal biodiversity changes in past ecosystems. Lake sediments contain DNA of organisms in the catchment area, which allows reconstructing past biodiversity by using metabarcoding of ancient sedimentary DNA. We developed a novel PCR primer combination for fungal metabarcoding targeting a short amplicon to account for length bias of amplification due to ancient DNA degradation. In-silico PCRs showed higher diversity using this primer combination than using previously established fungal metabarcoding primers. We analyzed existing data from sediment cores from four artic and one boreal lake in Siberia. These cores had been stored for 2–22 years and examined degradation effects of ancient DNA and storage time-related bias in fungal communities. Amplicon size differed between fungal divisions, however, we observed no significant effect of sample age on amplicon length and GC content, suggesting robust results. We also found no indication of post-coring fungal growth during storage distorting ancient fungal communities. Terrestrial soil fungi, including mycorrhizal fungi and saprotrophs, were predominant in all lakes, which supports the use of lake sedimentary ancient DNA for reconstructing terrestrial communities.
Riding into the future on a fly: toward a better understanding of phoresy and avian lice evolution (Phthiraptera) by screening bird carcasses for phoretic lice on hippoboscid flies (Diptera)
Authors: Lee Leshon , Tan David J.X. , Oboňa Jozef , Gustafsson Daniel R. , Yuchen Ang , Meier Rudolf 
Published: November 2021

AbstractMany phoretic relationships between insects are understudied because of taxonomic impediments. We here illustrate for avian lice riding on hippoboscid flies how new natural history data on phoretic relationships can be acquired quickly with NGS barcoding. Most avian lice are host-specific, but some can arrive on new hosts by riding hippoboscid flies that feed on bird blood. Our summary of the literature yielded 254 published records which we here show to belong to two large and 13 small interaction networks for birds, flies, and lice. In order to generate new records, we then developed a new protocol based on screening bird carcasses sourced by citizen scientists. The inspection of 131 carcasses from Singapore lead to the first record of aGuimaraesiellalouse species riding onOrnithoica momiyamaiflies collected from a pitta carcass. Phoresy may explain why this louse species is now known from three phylogenetically disparate hosts (Pitta moluccensis,Ficedula zanthopygia;Pardaliparus elegans). A second new case of phoresy enhances a large interaction network dominated byOrnithophila metallica, a cosmopolitan and polyphagous hippoboscid fly species. Overall, we argue that many other two- and three-way phoretic relationships between arthropods (e.g., mites, pseudoscorpiones, beetles, flies) can be resolved using cost-effective large-scale NGS barcoding, which can be used to pre-sort specimens for taxonomic revision and thus partially overcome some taxonomic impediments.