bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting roles of landscape compositions in shaping functional traits of arthropod community in subtropical vegetable fields
Authors: Zhang Jie , Saqib Hafiz Sohaib Ahmed , Niu Dongsheng , Gavilanez Karla Giovana Guaman , Wang Ao , Yu Deyi , You Minsheng , Pozsgai Gabor , You Shijun
Published: July 2022

Agricultural intensification and land use transformation are among the main driving forces of the unprecedented decline of biodiversity and ecosystem services in croplands. Trait-based approaches provide a unique framework to detect the potential mechanisms of how this intensification affects biodiversity and alter ecosystem services. However, the potential relationship between arthropod traits and various types of habitats is still poorly understood, especially in subtropical vegetable agroecosystems.

Here, we conducted a trait-based approach to evaluate the variable roles of different habitats on functional trait diversity and the structure of the arthropod community in brassica vegetable crops. Twenty-three conventional cruciferous vegetables fields were sampled over two years in three regions in Fujian, China. We found that the increasing proportion of non-brassica vegetable plantations and water bodies negatively affected the functional diversity of arthropods, whereas forest and grassland habitats showed a positive correlation, indicating habitat filtering for certain traits or trait combinations.

This study demonstrates the importance of landscape composition as an ecological filter for vegetable arthropod community, and identifies how the proportion of different habitats selected for or against specific functional traits. Our findings support that increasing forest and grassland areas adjacent to vegetable fields can play a vital role in promoting the functional diversity of arthropod communities. Since the natural enemy assemblages supported by these habitats bear combinations of diverse traits adapted to disturbance, they have the potential to enhance pest suppression in the highly variable environment of vegetable crops.
Multi-omics analyses identify transcription factor interplay in corneal epithelial fate determination and disease
Authors: Smits Jos GA , Cunha Dulce Lima , Amini Maryam , Bertolin Marina , Laberthonnière Camille , Qu Jieqiong , Owen Nicholas , Latta Lorenz , Seitz Berthold , Roux Lauriane N , Stachon Tanja , Ferrari Stefano , Moosajee Mariya , Aberdam Daniel , Szentmary Nora , van Heeringen Simon J. , Zhou Huiqing
Published: July 2022

The transparent corneal epithelium in the eye is maintained through the homeostasis regulated by limbal stem cells, while the non-transparent epidermis relies on epidermal keratinocytes for renewal. Despite their cellular similarities, the precise cell fates of these two types of epithelial stem cells, which give rise to functionally distinct epithelia, remain unknown. We performed a multi-omics analysis of human limbal stem cells from the cornea and keratinocytes from the epidermis, and characterized their molecular signatures, highlighting their similarities and differences. Through gene regulatory network analyses, we identified shared and cell type-specific transcription factors that define specific cell fates, and established their regulatory hierarchy. Single-cell RNA-seq analyses of the cornea and the epidermis confirmed these shared and cell type-specific transcription factors. Notably, the shared and limbal stem cell-specific transcription factors can cooperatively target genes associated with corneal opacity. Importantly, we discovered thatFOSL2, a direct PAX6 target gene, is a novel candidate associated with corneal opacity, and it regulates genes implicated in corneal diseases. By characterizing molecular signatures, our study unveils the regulatory circuitry governing the limbal stem cell fate and its association with corneal opacity.
Single-cell triple-omics uncovers DNA methylation as key feature of stemness in the healthy and ischemic adult brain
Authors: Kremer Lukas PM , Cerrizuela Santiago , Al Shukairi Mohammad Eid , Ellinger Tobias , Straub Jannes , Dehler Sascha , Korkmaz Aylin , Weichenhan Dieter , Plass Christoph , Anders Simon , Martin-Villalba Ana
Published: July 2022

Stem cells in the adult brain are specialized astrocytes capable of generating neurons and glial cells. While neural stem cells (NSCs) and common astrocytes have clearly distinct functions, they share highly similar transcriptome profiles. How stemness is molecularly encoded is therefore unclear. Here we use single-cell NMT-seq to simultaneously characterize the transcriptome, DNA methylome and chromatin accessibility of astrocytes and the NSC lineage in the healthy and ischemic brain. Our data reveal distinct methylation profiles associated with either astrocyte or stem cell function. Stemness is conferred by methylation of astrocyte genes and demethylation of neurogenic genes that are expressed only later. Surprisingly, ischemic injury unlocks the stemness-methylome in common astrocytes enabling generation of neuroblasts. Furthermore, we show that oligodendrocytes employ Tet-mediated demethylation to regulate expression of myelin-related genes, many of which are abnormally methylated in multiple sclerosis. Overall, we show that DNA methylation is a promising target for regenerative medicine.

Abstract Figure
A hybrid approach for predicting transcription factors
Authors: Patiyal Sumeet , Tiwari Palak , Ghai Mohit , Dhapola Aman , Dhall Anjali , Raghava Gajendra P. S.
Published: July 2022

Transcription factors (TFs) are essential DNA-binding proteins that regulate the rate of transcription of several genes and controls the expression of genes inside a cell. The prediction of TFs with high precision is important for understanding number of biological processes such as cell-differentiation, intracellular signaling, cell-cycle control. In this study, we developed a hybrid method that combine alignment-based and alignment-free methods for predicting transcription factors with higher accuracy. All models have been trained, tested and evaluated on a large dataset that contain 19406 TFs and 523560 non-TFs protein sequences. In order to avoid biasness in evaluation, dataset is divided in training and validation/independent dataset, where 80% data was used for training and remaining 20% for external validation. In case of alignment-free methods, models are developed based on machine learning techniques using compositional features of a protein. Our best alignment-free model obtained AUC 0.97 on independent dataset. In case of alignment-based method, we used BLAST at different cut-off to predict transcription factors. Though alignment-based method shows excellent performance but unable to cover all transcription factor due to no-hits. In order to combine power of both, we developed a hybrid method that combine alignment-free and alignment-based method; achieved maximum AUC of 0.99 on independent dataset. The method proposed in this study perform better than existing methods. We incorporated the best models in the webserver/standalone package “TransFacPred” (https://webs.iiitd.edu.in/raghava/transfacpred).

Key Points

Transcription factors (TFs) are vital DNA-binding proteins.

A hybrid method for the prediction of TFs using sequence information.

Computer-aided model were developed using machine-learning algorithm to predict TFs.

Alignment-based and alignment-free approaches were used for the prediction.

A user-friendly webserver, python- and Perl-based standalone package available.
ROR1 plays a critical role in pancreatic tumor-initiating cells with a partial EMT signature
Authors: Yamazaki Masaya , Hino Shinjiro , Usuki Shingo , Miyazaki Yoshihiro , Oda Tatsuya , Nakao Mitsuyoshi , Ito Takaaki , Yamagata Kazuya
Published: July 2022

Tumor-initiating cells are the major drivers of chemoresistance and relapse, making them attractive targets for cancer therapy. However, the identity of tumor- initiating cells in human pancreatic ductal adenocarcinoma (PDAC) and the key molecules underlying their traits remain poorly understood. Here, we show that a partial epithelial-mesenchymal transition (EMT)-like subpopulation marked by high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) is the origin of heterogeneous tumor cells in PDAC. We demonstrate that ROR1 depletion suppresses tumor growth, recurrence after chemotherapy, and metastasis. Mechanistically, ROR1 induces the expression of AURKB by activating E2F to enhance PDAC proliferation. Furthermore, epigenomic analyses reveal that ROR1 is transcriptionally dependent on YAP/BRD4 binding at the enhancer region, and targeting this pathway reduces ROR1 expression and prevents PDAC growth. Collectively, our findings reveal a critical role of ROR1high cells as tumor-initiating cells and the functional importance of ROR1 in PDAC progression, thereby highlighting its therapeutic targetability.

Graphical abstract
Regular geometry and hexagonal structure of honeycomb results from the optimisation of cylindrical cells built in close proximity
Authors: Gallo Vincent , Bridges Alice D. , Woodgate Joseph L. , Chittka Lars
Published: July 2022

The hexagonal structure of honeycomb maximises storage volume while minimising the amount of wax required for its construction. How honeybee builders achieve this geometry, however, remains unclear. Previously, our group identified behavioural patterns that were triggered in builders when they encountered certain sub-scale features associated with partially constructed comb, which resulted in the alignment of new cells to small concavities and the construction of cell walls between two of these stimuli. This caused new cells to be built in the proper locations without the need for explicit instructions . Here, we investigated whether the hexagonal geometry of honeycomb cells resulted from the dense packing of cells that would otherwise have been circular tubes. We hypothesised that the reaction of a builder to a cell that is not fully enclosed by other cells would be an attempt to maximise the internal space by excavating and re-forming the surrounding walls to create a cylindrical interior.

However, the creation of a cylindrical cell would be thwarted by the activities of workers within adjacent cells also acting according to these rules. Eventually an equilibrium will emerge with walls that meet at a junction arranged so that the available angular range (360°) is sub- divided equally between the cells that meet at the junction (typically, internal angles of 120° when three cells meet). To test this hypothesis, we offered wax stimuli to comb-building honeybees, shaped to encourage or to constrain the construction of comb cells, recording the bees’ progress. We found that at an early stage cells could be an irregular shape with curved walls and unequal wall lengths and corner angles, however, when allowed further time and unconstrained access the workers reshaped the cells achieving significantly greater regularity.
Unsupervised machine learning reveals temporal components of gene expression in HeLa cells following release from cell cycle arrest
Authors: Maimon Tom , Trink Yaron , Goldberger Jacob , Kalisky Tomer
Published: July 2022

Gene expression measurements of tissues, tumors, or cell lines taken over multiple time points are valuable for describing dynamic biological phenomena such as the response to growth factors. However, such phenomena typically involve multiple biological processes occurring in parallel, making it difficult to identify and discern their respective contributions at any time point. Here, we demonstrate the use of unsupervised machine learning to deconvolve a series of time-dependent gene expression measurements into its underlying temporal components. We first downloaded publicly available RNAseq data obtained from synchronized HeLa cells at consecutive time points following release from cell cycle arrest. Then, we used Fourier analysis and Topic modeling to reveal three underlying components and their relative contributions at each time point. We identified two temporal components with oscillatory behavior, corresponding to the G1-S and G2-M phases of the cell cycle, and a third component with a transient expression pattern, associated with the immediate-early response gene program, regulation of cell proliferation, and cervical cancer. This study demonstrates the use of unsupervised machine learning to identify hidden temporal components in biological systems, with potential applications to early detection and monitoring of diseases and recovery processes.
Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibilty in a canine model of elite exercise
Authors: Polyák A. , Topal L. , Prorok J. , Tóth N. , Kohajda Zs. , Déri Sz. , Demeter-Haludka V. , Hegyi P. , Venglovecz V. , Sarusi A. , Ágoston G. , Husti Z. , Zombori-Tóth N. , Gazdag P. , Szlovák J. , Árpádffy-Lovas T. , Naveed M. , Jost N. , Virág L. , Nagy N. , Baczkó I. , Farkas A. S. , Varró A.
Published: July 2022

The health benefits of regular physical exercise are well known. Even so, there is increasing evidence that the exercise regimes of elite athletes can evoke cardiac arrhythmias including ventricular fibrillation and even sudden cardiac death (SCD). The mechanism of exercise-induced arrhythmia and SCD is poorly understood. While some studies after endurance training have been performed in small animals these have limited translation value.

Here, we show that chronic training in a canine model (12 sedentary and 12 trained dogs) that mimics the regime of elite athletes induces electrophysiological remodeling (measured by ECG, patch-clamp and immunocytochemical techniques) resulting in increases of both the trigger and the substrate for ventricular arrhythmias. Thus, 4 months sustained training lengthened ventricular repolarization (QTc: 213.6±2.8 ms vs. 237.1±3.4 ms, n=12; APD90: 370.1±32.7 ms vs. 472.8±29.6 ms, n=25 vs. 29), decreased transient outward potassium current (8.8±0.9 pA/pF vs. 6.4±0.5 pA/pF at 50 mV, n=42 vs. 54) and increased the short term variability of repolarization (17.5±4.0 ms vs. 29.5±3.8 ms, n=18 vs. 27). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of extrasystoles: 4/hour vs. 366/hour) in vivo and arrhythmia susceptibility (elicited ventricular fibrillation: 3 of 10 sedentary dogs vs. 6 of 10 trained dogs).

Our findings provide in vivo, cellular electrophysiological and molecular biological evidence for the enhanced susceptibility to ventricular arrhythmia in an experimental large animal model of endurance training.
Fine-scale measurement of the blind spot borders
Authors: Meermeier Annegret , Lappe Markus , Rifai Katharina , Wahl Siegfried , Rucci Michele
Published: July 2022

The blind spot is both a necessity and a nuisance for seeing. It is the portion of the visual field projecting to where the optic nerve crosses the retina, a region devoid of photoreceptors and hence visual input. The precise way in which vision transitions into blindness at the blind spot border is to date unknown. A chief challenge to map this transition is the incessant movement of the eye, which unavoidably smears measurements across space. In this study, we used high-resolution eye-tracking and state-of-the-art retinal stabilization to finely map the blind spot borders. Participants reported the onset of tiny high-contrast probes that were briefly flashed at precise positions around the blind spot. This method has sufficient resolution to enable mapping of blood vessels from psychophysical measurements. Our data show that, even after accounting for eye movements, the transition zones at the edges of the blind spot are considerable. On the horizontal meridian, the regions with detection rates between 80% and 20% span approximately 25% of the overall width of the blind spot. These borders also vary considerably in size across different axes. These data show that the transition from full visibility to blindness at the blind spot border is not abrupt but occurs over a broad area.
”Evolution of ipsilateral breast cancer decoded by proteogenomics”
Authors: Marchi Tommaso De , Pyl Paul Theodor , Sjöström Martin , Reinsbach Susanne Erika , DiLorenzo Sebastian , Nystedt Björn , Tran Lena , Pekar Gyula , Wärnberg Fredrik , Fredriksson Irma , Malmström Per , Fernö Mårten , Malmström Lars , Malmstöm Johan , Niméus Emma
Published: July 2022

Ipsilateral breast tumor recurrence (IBTR) is a clinically important event, where an isolated in-breast recurrence is a potentially curable event but also associated with an increased risk of distant metastases and breast cancer death. It currently remains unclear if IBTRs are associated with molecular changes that can be explored as a resource for precision medicine strategies targeting locally recurring breast cancer. Here, we employed a recently developed proteogenomics workflow to analyze a cohort of 27 primary breast cancers and their matched IBTRs by whole genome sequencing, RNA sequencing, and mass spectrometry-based proteomics to define proteogenomic features of tumor evolution. Analysis of mutational signatures, copy number changes, and cancer specific mutations revealed a relationship with estrogen and progesterone receptor statuses and increased levels of genetic change. This in turn altered the re-programming of the transcriptome and proteome towards a recurring molecular disease phenotype with high replicating capacity and a higher degree of genomic instability possibly enhanced by high expression of APOBEC3B. In conclusion, this study defines how primary breast tumors differentially evolve into different ipsilateral recurrent malignancies depending on their key biomarker status, suggesting that further enhancing the genomic instability in some tumors could serve as an alternative treatment option.
Molecular Evolution of Aryl Hydrocarbon Receptor Signaling Pathway Genes
Authors: Bhalla Diksha , van Noort Vera
Published: July 2022

The Aryl hydrocarbon receptor is an ancient transcriptional factor originally discovered as a sensor of dioxin. In addition to its function as receptor of environmental toxins, it plays an important role in development. Although a significant amount of research has been carried out to understand AHR signal transduction pathway and its involvement in species susceptibility to environmental toxins, none of them to date has comprehensively studied its evolutionary origins. Studying evolutionary origins of molecules can inform ancestral relationships of genes. Vertebrate genome has been shaped by two rounds of whole-genome duplications at the base of vertebrate evolution approximately 600 million years ago (Mya), followed by lineage specific gene losses, which often complicate assignment of functional homology. It is crucial to understand evolutionary origins of this transcription factor and its partners, in order to distinguish orthologs from ancient non-orthologous homologs. In this study, we have investigated evolutionary origins of proteins involved in the AHR pathway. Our results provide evidence of gene loss and duplications, crucial for understanding functional connectivity of human and model species. Multiple studies have shown that 2R-ohnologs (genes and proteins that have survived from the 2R-WGD) are enriched in signaling components relevant to developmental disorders and cancer. Our findings provide a link between AHR pathway’s evolutionary trajectory and its possible mechanistic involvement in pathogenesis.
Insight into the evolutionary assemblage of cranial kinesis from a Cretaceous bird
Authors: Wang Min , Stidham Thomas A. , O’Connor Jingmai K. , Zhou Zhonghe
Published: July 2022

The independent movements and flexibility of various parts of the skull, called cranial kinesis, is an evolutionary innovation that is found in living vertebrates only in some squamates and crown birds, and considered to be a major factor underpinning much of the enormous phenotypic and ecological diversity of living birds, the most diverse group of extant amniotes. Compared to the postcranium, our understanding of the evolutionary assemblage of the characteristic modern bird skull has been hampered by sparse fossil records of early cranial materials, with competing hypotheses regarding the evolutionary development of cranial kinesis among early members of the avialans. Here, a detailed three-dimensional reconstruction of the skull of the Early Cretaceous enantiornithine Yuanchuavis kompsosoura allows for its in depth description, including elements that are poorly known among early diverging avialans but are central to deciphering the mosaic assembly of features required for modern avian cranial kinesis. Our reconstruction of the skull shows evolutionary and functional conservation of the temporal and palatal regions by retaining the ancestral theropod dinosaurian configuration within the skull of this otherwise derived and volant bird. Geometric morphometric analysis of the palatine suggests that loss of the jugal process represents the first step in the structural modifications of this element leading to the kinetic crown bird condition. The mixture of plesiomorphic temporal and palatal structures together with a derived avialan rostrum and postcranial skeleton encapsulated in Yuanchuavis manifests the key role of evolutionary mosaicism and experimentation in early bird diversification.
Identification of circRNAs linked to Alzheimer’s disease and related dementias
Authors: Puri Sambhavi , Hu Junming , Sun Zhuorui , Lin Mintao , Stein Thor , Farrer Lindsay , Wolozin Benjamin , Zhang Xiaoling
Published: July 2022

We conducted a circular-transcriptome-wide analysis and examined circRNA expression patterns associated with AD and clinical and neuropathological AD severity measures in human hippocampus and cortex brain regions. We validated prior studies of circRNA in AD cortex, and demonstrate novel patterns of expression in the AD hippocampus. We also examined circRNA expression across multiple types of dementia and show that circRNA expression differs by dementia subtype. We demonstrate robust circRNA expression in human neuronal precursor cells (NPCs). Then, using NPCs to study qPCR validated circRNA, we show that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in AD brain. These data identify circRNA that are changed with AD, and suggest that treating neuronal cells with oligomeric tau can recapitulate some of these changes.
Multiscale cosimulation design template for neuroscience applications
Authors: Kusch Lionel , Diaz Sandra , Klijn Wouter , Sontheimer Kim , Bernard Christophe , Morrison Abigail , Jirsa Viktor
Published: July 2022

Integration of information across heterogeneous sources creates added scientific value. It is, however, a challenge to progress, often a barrier, to interoperate data, tools and models across spatial and temporal scales. Here we present a design template for coupling simulators operating at different scales and enabling co-simulation. We illustrate its functioning along a neuroscience example, in which individual regions of interest are simulated on the cellular level to address mechanistic questions, while the remaining network is efficiently simulated on the population level. A workflow is illustrated for the use case of The Virtual Brain and NEST, in which the cellular-level hippocampus of the mouse is embedded into a full brain network involving micro and macro electrode recordings. This new tool allows integrating knowledge across scales in the same simulation framework and validate them against multiscale experiments, thereby largely widening the explanatory power of computational models.
Combinatorial microRNA loading into extracellular vesicles for anti-inflammatory therapy
Authors: Pottash Alex Eli , Levy Daniel , Jeyaram Anjana , Kuo Leo , Kronstadt Stephanie M. , Chao Wei , Jay Steven M.
Published: July 2022

Extracellular vesicles (EVs) have emerged as promising therapeutic entities in part due to their potential to regulate multiple signaling pathways in target cells. This potential is derived from the broad array of constituent and/or cargo molecules associated with EVs. Among these, microRNAs (miRNAs) are commonly implicated as important and have been associated with a wide variety of EV-induced biological phenomena. While controlled loading of single miRNAs is a well-documented approach for enhancing EV bioactivity, loading of multiple miRNAs has not been fully leveraged to maximize the potential of EV-based therapies. Here, an established approach to extrinsic nucleic acid loading of EVs, sonication, was utilized to enable controlled loading of multiple miRNAs in HEK293T EVs. Combinations of carefully chosen miRNAs were compared to single miRNAs with respect to anti-inflammatory outcomes in assays of increasing stringency, with the combination of miR-146a, miR-155, and miR-223 found to have the most potential amongst tested groups.
A minimal role for synonymous variation in human disease
Authors: Dhindsa Ryan S. , Wang Quanli , Vitsios Dimitrios , Burren Oliver S. , Hu Fengyuan , DiCarlo James E. , Kruglyak Leonid , MacArthur Daniel G. , Hurles Matthew E. , Petrovski Slavé
Published: July 2022

Synonymous mutations change the DNA sequence of a gene without affecting the amino acid sequence of the encoded protein. Although emerging evidence suggests that synonymous mutations can impact RNA splicing, translational efficiency, and mRNA stability1, studies in human genetics, mutagenesis screens, and other experiments and evolutionary analyses have repeatedly shown that most synonymous variants are neutral or only weakly deleterious, with some notable exceptions. In their recent article, Shen et al. claim to have disproved these well-established findings. They perform mutagenesis experiments in yeast and conclude that synonymous mutations frequently reduce fitness to the same extent as nonsynonymous mutations2. Based on their findings, the authors state that their results “imply that synonymous mutations are nearly as important as nonsynonymous mutations in causing disease.” An accompanying News and Views argues that “revising our expectations about synonymous mutations should expand our view of the genetic underpinnings of human health”3. Considering potential technical concerns with these experiments4 and a large, coherent body of knowledge establishing the predominant neutrality of synonymous variants, we caution against interpreting this study in the context of human disease.
SARS-CoV-2 booster vaccination rescues attenuated IgG1 memory B cell response in primary antibody deficiency patients
Authors: Lin Frank J. , Altman Doss Alexa Michelle , Davis-Adams Hannah G. , Adams Lucas J. , Hanson Christopher H. , VanBlargan Laura A. , Liang Chieh-Yu , Chen Rita. E. , Monroy Jennifer Marie , Wedner H. James , Kulczycki Anthony , Mantia Tarisa L. , O’Shaughnessy Caitlin C. , Raju Saravanan , Zhao Fang R. , Rizzi Elise , Rigell Christopher J. , Dy Tiffany Biason , Kau Andrew L. , Ren Zhen , Turner Jackson , O’Halloran Jane A. , Presti Rachel M. , Fremont Daved H. , Kendall Peggy L. , Ellebedy Ali H. , Mudd Philip A. , Diamond Michael S. , Zimmerman Ofer , Laidlaw Brian J.
Published: July 2022

SARS-CoV-2 vaccines have proven effective in eliciting an immune response capable of providing protective immunity in healthy individuals. However, whether SARS-CoV-2 vaccination induces a long-lived immune response in immunocompromised individuals is poorly understood. Primary antibody deficiency (PAD) syndromes are among the most common immunodeficiency disorders in adults and are characterized by an impaired ability to mount robust antibody responses following infection or vaccination. Here, we present data from a prospective study in which we analyzed the B and T cell response in PAD patients following SARS-COV-2 vaccination. Unexpectedly, individuals with PAD syndromes mounted a SARS-CoV-2 specific B and CD4+ T cell response that was comparable in magnitude to healthy individuals. Many individuals with PAD syndromes displayed reduced IgG1+ and CD11c+ memory B cell responses following the primary vaccination series. However, the IgG1 class-switching defect was largely rescued following mRNA booster vaccination. Boosting also elicited an increase in the SARS-CoV-2-specific B and T cell response and the development of Omicron-specific memory B cells in COVID-19-naïve PAD patients. Together, these data indicate that SARS-CoV-2 vaccines elicit memory B and T cells in PAD patients that may contribute to long-term protective immunity.
Application of Carleman approximants for the estimation of epidemic parameters from incidence data time-series
Authors: Muñoz-Sánchez Juan C. , Elena Santiago F. , Oteo José–Angel
Published: July 2022

We have analyzed the possibility of estimating epidemiological parameters from daily infection incidence data. In particular, we have focused on the determination of the instantaneous reproduction number, the contagion period and the duration of the infectious period using only the reported incidence time-series information. We have developed a data-driven method based on the instantaneous mapping of the infection incidence data on the simplest (two parameter) SIR model, along the progression of an epidemy. The mapping is carried out via Carleman linearization of the non-linear model equations. We concluded that the daily infection incidence series on its own does not carry enough information to provide estimates for the above time scales and hence additional measurements and/or hypotheses must be considered. In contrast, the prevalence time-series does allow for accurate estimates. For the case in which the characteristic infectious period is available, a new algebraic formula for the instantaneous reproduction number has been derived.
Practical application of CO2 as an indicator regarding the risk of infection
Authors: Hartmann Anne , Cetin Yunus Emre , Gastmeier Petra , Kriegel Martin
Published: July 2022

The air quality of enclosed spaces has attracted great attention due to the ongoing Covid-19 pandemic. The infection risk in these spaces can be estimated for various scenarios with different methods so the important parameters and effective infection prevention measures can be compared. Previous studies showed that indoor CO2 concentration could be considered a surrogate for infection risk. In this regard, a generic relation can be established between the CO2 levels and infection probability. Based on this consideration, some practical evaluations between CO2 concentration and infection risk are conducted in this study. The effect of mask efficiency, viral emission rate, and duration of exposure are also included in the assessments. It is shown that continuous CO2 monitoring can be helpful in the evaluation of possible preventive measures. Findings are expected to contribute to the understanding of the simple parameters related to the infection risk.
Estimating waning vaccine effectiveness from population-level surveillance data in multi-variant epidemics
Authors: Murayama Hiroaki , Endo Akira , Yonekura Shouto
Published: July 2022

Monitoring time-varying vaccine effectiveness (e.g., due to waning of immunity and the emergence of novel variants) provides crucial information for outbreak control. Existing studies of time-varying vaccine effectiveness have used individual-level data, most importantly dates of vaccination and variant classification, which are often not available in a timely manner or from a wide range of population groups. We present a novel Bayesian framework for estimating the waning of variant-specific vaccine effectiveness in the presence of multi-variant circulation from population-level surveillance data. Applications to simulated outbreak and COVID-19 epidemic in Japan are also presented. Our results show that variant-specific waning vaccine effectiveness estimated from population-level surveillance data could approximately reproduce the estimates from previous test-negative design studies, allowing for rapid, if crude, assessment of the epidemic situation before fine-scale studies are made available.

Author summary

The emergence of immunity-escaping SARS-CoV-2 variants and the waning of vaccine effectiveness have highlighted the need for near-real-time monitoring of variant-specific protection in the population to guide control efforts. However, standard epidemiological studies to this end typically require access to detailed individual-level dataset, which may not be timely available in an ongoing outbreak. A more convenient and less resource-intensive approach using routinely-collected data could complement such studies by providing tentative estimates of waning vaccine effectiveness until the conclusive evidence becomes available. In this paper, we propose a novel Bayesian framework for estimating waning vaccine effectiveness against multiple co-circulating variants that requires only population-level surveillance data. Using simulated outbreak data of multiple variants,we showed that the proposed method can plausibly recover the ground truth from population-level data. We also applied the proposed method to empirical COVID-19 data in Japan, which yielded estimates that are overall in line with those derived from studies using individual-level data.
Dehydration and infection elicit increased feeding in the western flower thrips,Frankliniella occidentalis, likely triggered by glycogen depletion
Authors: Bailey Samuel T. , Kondragunta Alekhya , Choi Hyojin A. , Han Jinlong , Rotenberg Dorith , Ullman Diane E. , Benoit Joshua B.
Published: July 2022

We examined water balance characteristics and influence of desiccating conditions on adult western flower thrips (Frankliniella occidentalis) physiology and behavior. Western flower thrips are globally invasive and likely to contend with shifts in water availability across their expansive geographic range. Basic water balance characteristics, including water mass and dry mass, were established for adult males and females, revealing a distinct sexual dimorphism wherein females are larger, but males retain a larger percentage of their mass as body water. Males lose relative water mass more quickly and their survival times are shorter when compared to females. RNA-seq analysis identified significant enrichment of factors associated with carbohydrate transport and metabolism in dehydrated males and females. A reduction of glycogen reserves was confirmed during dehydration. The probability of thrips feeding significantly increased when desiccation was a factor. Lastly, infection withTomato spotted wilt orthotospovirus(TSWV), a principal plant-pathogenic virus transmitted byF. occidentalis, did not have a consistent and apparent influence on desiccation tolerance; however, a reduction in glycogen reserves, and an increase in feeding activity in infected thrips, very similar to that observed in dehydrated thrips, was observed. Our results establish the fundamental water balance characteristics of adult thrips, and indicate that dehydration significantly influences the survivorship and feeding behavior of thrips; crucial factors that contribute to their capacity to spread disease.
Structural characterization of human RPA70N association with DNA damage response proteins
Authors: Wu Yeyao , Zang Ning , Fu Wangmi , Zhou Chun
Published: July 2022

The heterotrimeric Replication protein A (RPA) is the ubiquitous eukaryotic single-stranded DNA (ssDNA) binding protein and participates in nearly all aspects of DNA metabolism, especially DNA damage response. The N-terminal OB domain of the RPA70 subunit (RPA70N) is a major protein-protein interaction element for RPA. Previous crystallography studies of RPA70N with p53, DNA2 and PrimPol fragments revealed that RPA70N binds to amphipathic peptides that mimics ssDNA. NMR chemical-shift studies also provided valuable information of RPA70N residues interacting with target sequences. However, it is still not clear how RPA70N recognizes and distinguishes such a diverse group of proteins. Here we present high resolution crystal structures of RPA70N in complex with peptides from HelB, ATRIP, RMI1, WRN and BLM. The structures showed that in addition to the ssDNA mimicry mode of interaction, RPA70N employs multiple ways to bind its partners, some of which may serve to increase the avidity of RPA70N binding.
Adera: A drug repurposing workflow for neuro-immunological investigations using neural networks
Authors: lazarczyk Marzena , Duda Kamila , Mickael Michel-Edwar , Kowalczyk Agnieszka , Sacharczuk Mariusz
Published: July 2022

Drug repurposing in the context of neuro-immunological (NI) investigations is still in its primary stages. Drug repurposing is an important method that bypasses lengthy drug discovery procedures and rather focuses on discovering new usage for known medications. Neuro-immunological diseases such as Alzheimer’s, Parkinson, multiple sclerosis and depression include various pathologies that resulted from the interaction between the central nervous system and the immune system. However, repurposing of medications is hindered by the vast amount of information that needs mining. To challenge the need for repurposing known medications for neuro-immunological diseases, we built a deep neural network named Adera to perform drug repurposing. The model uses two deep learning networks. The first network is an encoder and its main task is to embed text into matrices. The second network we explored the usage of two different loss function, binary cross entropy and means square error (MSE). Furthermore, we investigated the effect of ten different network architecture with each loss function. Our results show that for the binary cross entropy loss function, the best architecture consists of a two layers of convolution neural network and it achieves a loss of less than 0.001. In the case of MSE loss function a shallow network using aRelu activation achieved an accuracy of over 98 % and loss of 0.001. Additionally, Adera was able to predict various drug repurposing targets in agreement with DRUG Repurposing Hub. These results establish the ability of Adera to repurpose with high accuracy drug candidates that can shorten the development of the drug cycle. The software could be downloaded from https://github.com/michel-phylo/ADERA1.
Cryo-EM structure of a RAS/RAF recruitment complex
Authors: Park Eunyoung , Rawson Shaun , Schmoker Anna , Kim Byeong-Won , Oh Sehee , Song KangKang , Jeon Hyesung , Eck Michael
Published: July 2022

Cryo-EM structures of a KRAS/BRAF/MEK1/14-3-3 complex reveal KRAS bound to the flexible Ras-binding domain of BRAF, captured in two orientations. Autoinhibitory interactions are unperturbed by binding of KRAS and in vitro activation studies confirm that KRAS binding is insufficient to activate BRAF, absent membrane recruitment. These structures illustrate the separability of binding and activation of BRAF by Ras and suggest stabilization of this pre-activation intermediate as an alternative to blocking binding of KRAS.
Visual and motor signatures of locomotion dynamically shape a population code for feature detection in Drosophila
Authors: Turner Maxwell H. , Krieger Avery , Pang Michelle M. , Clandinin Thomas R.
Published: July 2022

Natural vision is dynamic: as an animal moves, its visual input changes dramatically. How can the visual system reliably extract local features from an input dominated by self-generated signals? In Drosophila, diverse local visual features are represented by a group of projection neurons with distinct tuning properties. Here we describe a connectome-based volumetric imaging strategy to measure visually evoked neural activity across this population. We show that local visual features are jointly represented across the population, and that a shared gain factor improves trial-to-trial coding fidelity. A subset of these neurons, tuned to small objects, is modulated by two independent signals associated with self-movement, a motor-related signal and a visual motion signal. These two inputs adjust the sensitivity of these feature detectors across the locomotor cycle, selectively reducing their gain during saccades and restoring it during intersaccadic intervals. This work reveals a strategy for reliable feature detection during locomotion.
Conformational and Thermodynamic Differences Underlying Wild-type and Mutant ENL YEATS Domain Specificity for Epigenetic Marks
Authors: Baweja Lokesh , Wereszczynski Jeff
Published: July 2022

Histone post-translational modifications (PTMs) are interpreted by multiple reader domains and proteins to regulate gene expression. The ENL YEATS domain is a prototypical PTM reader that recognizes multiple lysine acetylation marks on the histone H3 tails as a way of recruiting chromatin remodellers. Two ENL YEATS mutations have been identified which have been linked with leukemia, Wilms tumor, and other forms of cancer and result in either an insertion or deletion of residues in the loop connecting beta sheets distant from the protein active site.In vitroexperiments have shown that these mutations modulate the selectivity of YEATS domains for various lysine acetylation marks, although different experiments have provided contrasting views on the ability of the insertion and deletion mutants to discern specific PTMs. Here, we have performed multiple molecular dynamics simulations of wild-type, insertion, and deletion mutant YEATS domains free from and in complex with two PTM peptides: one that is acetylated at K9 of H3 and the other that is acetylated at residue K27 of H3. Results show that these two peptides have distinct flexibilities and binding energetics when bound to YEATS domains, and that these properties are affected by interactions with residues within and outside of the peptide consensus motif. Furthermore, these properties are modulated by the YEATS insertion and deletion mutants, which results in disparate binding effects in these systems. Together, these results suggest that only the partial exposure of histone tails is sufficient in the context of nucleosomes for YEATS-mediated recognition of acetylation marks on histone tails. They also caution against the over-interpretation of results obtained from experiments on reader domainhistone peptide binding in isolation and not in the full-length nucleosome context.
Versatile mapping-by-sequencing with Easymap v.2
Authors: Lup Samuel Daniel , Navarro-Quiles Carla , Micol José Luis
Published: July 2022

Motivation

Mapping-by-sequencing combines Next Generation Sequencing (NGS) with classical genetic mapping by linkage analysis to establish gene-to-phenotype relationships. Although numerous tools have been developed to analyze NGS datasets, only a few are available for mapping-by-sequencing. One such tool is Easymap, a versatile, easy-to-use package that performs automated mapping of point mutations and small insertion/deletions (InDels), as well as large DNA insertions.

Results

Here, we describe Easymap v.2, which includes additional workflows to perform QTL-seq and variant density mapping analyses. Each mapping workflow can accommodate different experimental designs, including outcrossing and backcrossing, F2, M2, and M3mapping populations, chemically induced mutation and natural variant mapping, input files containing single-end or paired-end reads of genomic or complementary DNA sequences, and alternative control sample files in FASTQ and VCF formats. Easymap v.2 can also be used as a variant analyzer in the absence of a mapping algorithm and includes a multi-threading option.

Availability and implementation

Code is available athttp://genetics.edu.umh.es/resources/easymap/

Contact

jlmicol@umh.es
Canalization of genome-wide transcriptional activity in Arabidopsis thaliana accessions by MET1-dependent CG methylation
Authors: Srikant Thanvi , Yuan Wei , Berendzen Kenneth Wayne , Garrido Adrián Contreras , Drost Hajk-Georg , Schwab Rebecca , Weigel Detlef
Published: July 2022

BACKGROUND

Eukaryotes employ epigenetic marks such as DNA methylation at cytosines both for gene regulation and genome defense. In Arabidopsis thaliana, a central role is played by methylation in the CG context, with profound effects on gene expression and transposable element (TE) silencing. Nevertheless, despite its conserved role, genome-wide CG methylation differs substantially between wild A. thaliana accessions.

RESULTS

We hypothesized that global reduction of CG methylation would reduce epigenomic, transcriptomic and phenotypic diversity in A. thaliana accessions. To test our hypothesis, we knocked out MET1, which is required for CG methylation, in 18 early-flowering A. thaliana accessions. Homozygous met1 mutants in all accessions suffered from a range of common developmental defects such as dwarfism and delayed flowering, in addition to accession-specific abnormalities in rosette leaf architecture, silique morphology and fertility. Integrated analysis of genome-wide methylation, chromatin accessibility and transcriptomes confirmed that inactivation of MET1 greatly reduces CG methylation and alters chromatin accessibility at thousands of loci. While the effects on TE activation were similarly drastic in all accessions, the quantitative effects on non-TE genes varied greatly. The expression profiles of accessions became considerably more divergent from each other after genome-wide removal of CG methylation, although the expression of genes with diverse expression profiles across wild-type accessions tended to become more similar in mutants.

CONCLUSIONS

Our systematic analysis of MET1 requirement for genome function in different A. thaliana accessions revealed a dual role for CG methylation: for many genes, CG methylation appears to canalize expression levels, with methylation masking regulatory divergence. However, for a smaller subset of genes, CG methylation increases expression diversity beyond genetically encoded differences.
Systematic comparison of culture media uncovers phenotypic shift of human microglia defined by reduced reliance to CSF1R signaling
Authors: Dorion Marie-France , Yaqubi Moein , Murdoch Hunter J. , Hall Jeffery A. , Dudley Roy , Antel Jack P. , Durcan Thomas M. , Healy Luke M.
Published: July 2022

Efforts to understand microglia function in health and diseases have been hindered by the lack of culture models that recapitulate in situ cellular properties. In recent years, the use of serum-free media with brain-derived growth factors (CSF1R ligands and TGF-β1/2) have been favored for the maintenance of rodent microglia as they promote morphological features observed in situ. Here we study the functional and transcriptomic impacts of such media on human microglia. Media formulation had little impact on microglia transcriptome assessed by RNA sequencing which was sufficient to significantly alter microglia capacity to phagocytose myelin debris and to elicit an inflammatory response to lipopolysaccharide. When compared to immediately ex vivo microglia from the same donors, the addition of fetal bovine serum to culture media, but not growth factors, was found to aid in the maintenance of key signature genes including those involved in phagocytic processes. A phenotypic shift characterized by CSF1R downregulation in culture correlated with a lack of reliance on CSF1R signaling for survival. Consequently, no improvement in cell survival was observed following culture supplementation with CSF1R ligands. Our study provides better understanding of human microglia in culture, with observations that diverge from those previously made in rodent microglia.

Graphical abstract