bluuebunny/crossref_metadata_2025 huggingface dataset:
Tree sequences as a general-purpose tool for population genetic inference
Authors: Whitehouse Logan S. , Ray Dylan , Schrider Daniel R.
Published: February 2024

As population genetics data increases in size new methods have been developed to store genetic information in efficient ways, such as tree sequences. These data structures are computationally and storage efficient, but are not interchangeable with existing data structures used for many population genetic inference methodologies such as the use of convolutional neural networks (CNNs) applied to population genetic alignments. To better utilize these new data structures we propose and implement a graph convolutional network (GCN) to directly learn from tree sequence topology and node data, allowing for the use of neural network applications without an intermediate step of converting tree sequences to population genetic alignment format. We then compare our approach to standard CNN approaches on a set of previously defined benchmarking tasks including recombination rate estimation, positive selection detection, introgression detection, and demographic model parameter inference. We show that tree sequences can be directly learned from using a GCN approach and can be used to perform well on these common population genetics inference tasks with accuracies roughly matching or even exceeding that of a CNN-based method. As tree sequences become more widely used in population genetics research we foresee developments and optimizations of this work to provide a foundation for population genetics inference moving forward.
EasyOmics-A graphical interface for population-scale omics data association, integration and visualization
Authors: Han Yu , Du Qiao , Dai Yifei , Gu Shaobo , Liu Wei , Zhu Mingjia , Feng Landi , Liu Jianquan , Zan Yanjun
Published: February 2024

The rapid growth of population-scale whole genome resequencing, RNA sequencing, bisulfate sequencing, metabolomics and proteomic profiling has led quantitative genetics into a big omics data era. Performing omics data association analysis, such as genome, transcriptome, proteome and methylome wide association analysis, and integrative analysis on multiple omics dataset requires various bioinformatics tools rely on advanced programming skills and command-line environments, which are challenging for most wet-lab biologists. Here, we present EasyOmics a stand-alone R Shiny application with a user-friendly interface for wet-lab biologists to perform population-scale omics data association, integration and visualization. The toolkit incorporates multiple functions designed to meet the increasing demand for big omics data analyses, ranging from data quality control, heritability estimation, genome wide association analysis, conditional association analysis, omics quantitative trait locus mapping, omics wide association analysis, omics data integration and data visualization etc. A wide variety of publication quality graphs can be prepared in EasyOmics using R plot engine with point-and-click. EasyOmics is a platform-independent software that can be run under all operating systems with a docker container for easy installation. It is freely available to non-commercial users at docker hubhttps://hub.docker.com/repository/docker/yuhan2000/gwas/general.
Prior cocaine use diminishes encoding of latent information by orbitofrontal, but not medial, prefrontal ensembles
Authors: Mueller Lauren E. , Konya Caitlin , Sharpe Melissa J. , Wikenheiser Andrew M. , Schoenbaum Geoffrey
Published: February 2024

Maladaptive decision-making is a hallmark of substance use disorders, though how drugs of abuse alter neural representations supporting adaptive behavior remains poorly understood. Past studies show the orbitofrontal (OFC) and prelimbic (PL) cortices are important for decision making, tracking both task-relevant and latent information. However, previous studies have focused on how drugs of abuse impact the firing rates of individual units. More work at the ensemble level is necessary to accurately characterize potential drug-induced changes. Using single-unit recordings in rats during a multidimensional decision-making task and then applying population and ensemble level analyses, we show that prior use of cocaine altered the strength and structure of task-relevant and latent representations in the OFC, changes relatable to suboptimal decision making in this and perhaps other settings. These data expand our understanding of the neuropathological underpinnings of maladaptive decision-making in SUDs, potentially enabling enhanced future treatment strategies.
Fetal brain response to maternal inflammation requires microglia
Authors: Elaine LaMonica Ostrem Bridget , Dominguez Iturza Nuria , Stogsdill Jeffrey , Faits Tyler , Kim Kwanho , Levin Joshua Z. , Arlotta Paola
Published: February 2024

In uteroinfection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal central nervous system infection, is associated with an increased risk of autism and schizophrenia in affected offspring. The cell types mediating the response of the fetal brain to maternal inflammation are largely unknown, hindering the development of therapies to prevent and treat adverse neuropsychiatric outcomes. Here, we show that microglia, the resident phagocytes of the brain, are enriched for expression of receptors for relevant pathogens and cytokines, throughout embryonic development. Using a rodent maternal immune activation (MIA) model in which polyinosinic:polycytidylic acid is injected into pregnant dams, we demonstrate long-lasting transcriptional changes in fetal microglia that persist into postnatal life. We find that MIA induces widespread gene expression changes in neuronal and non-neuronal cells; importantly, these responses are abolished by selective genetic deletion of microglia, indicating that microglia are required for the transcriptional response of other cortical cell types to MIA. These findings demonstrate that microglia play a critical, durable role in fetal response to maternal inflammation, pointing at microglia as a potential therapeutic cell target.
Olive Flowering dependence on winter temperatures - linking empirical results to a dynamic model
Authors: Smoly Ilan , Elbaz Haim , Engelen Chaim , Wechsler Tahel , Elbaz Gal , Ben-Ari Giora , Samach Alon , Friedlander Tamar
Published: February 2024

Increasing winter temperatures jeopardize the yield of fruit trees requiring a prolonged and sufficiently cold winter to flower. Assessing the exact risk to different crop varieties is the first step in mitigating the harmful effect of climate change. Since empirically testing the impacts of many temperature scenarios is very time-consuming, quantitative predictive models could be extremely helpful in reducing the number of experiments needed. Here, we focus on olive (Olea europaea) – a traditional crop in the Mediterranean basin, a region expected to be severely affected by climatic change. Olive flowering and consequently yield depend on the sufficiency of cold periods and the lack of warm ones during the preceding winter. Yet, a satisfactory quantitative model forecasting its expected flowering under natural temperature conditions is still lacking. Previous models simply summed the number of ‘cold hours’ during winter, as a proxy for flowering, but exhibited only mediocre agreement with empirical flowering values, possibly because they overlooked the order of occurrence of different temperatures.

We empirically tested the effect of different temperature regimes on olive flowering intensity and flowering-gene expression. To predict flowering based on winter temperatures, we constructed a dynamic model, describing the response of a putative flowering factor to the temperature signal. The crucial ingredient in the model is an unstable intermediate, produced and degraded at temperature-dependent rates. Our model accounts not only for the number of cold and warm hours but also for their order. We used sets of empirical flowering and temperature data to fit the model parameters, applying numerical constrained optimization techniques, and successfully validated the model outcomes. Our model more accurately predicts flowering under winters with warm periods yielding low-to-moderate flowering and is more robust compared to previous models.

This model is the first step toward a practical predictive tool, applicable under various temperature conditions.
Systematic Identification of UBE2C As a Prognostic Biomarker and Correlated with Immunosuppression and Invasiveness in Glioma
Authors: Feng Hao , Fu Anhui , Yang Rong , Qiao Fei
Published: February 2024

Glioma is one of the common tumors of the central nervous system, which presents difficulties in clinical diagnosis and treatment due to its characteristics of immunosuppression and cell invasion phenotypes. If the condition and prognosis of glioma can be predicted during the process of diagnosis and treatment, it will be more conducive to timely intervention or evaluation of glioma. Therefore, we still need to search for more valuable tumor markers. The differential/risk genes and enrichment analysis based on glioma samples (The Cancer Genome Atlas, TCGA). Target gene UBE2C were obtained by the expression correlation and differential expression analysis for the enrichment results. UBE2C were evaluated by clinical grading, survival prognosis and cell experiments. The correlation of UBE2C with immune invasion, immune checkpoint, network analysis and cell invasiveness of gliomas was analyzed by TCGA-glioma data and STRING, respectively. The results suggests that the high expression and risk of UBE2C in gliomas may be a factor that promotes malignant phenotype of tumor cells. The immune phenotype shows that IL6 and IL10 may be the key nodes affecting the immunosuppressive phenotype of glioma. Further, the tumor cells aggressive genes from the MMP family can be correlated with immunosuppressive phenotypes via UBE2C-IL6/IL10 axis, especially displayed by MMP2/MMP9. The UBE2C may systemic effects the malignant phenotype, immunosuppression and cell invasiveness of tumors systematically, which reflects UBE2C as a potential biomarker of glioma and therapeutic target for this tumor.
Age-related dysregulation of the retinal transcriptome in African turquoise killifish
Authors: Bergmans Steven , Noel Nicole C. L. , Masin Luca , Harding Ellen G. , Krzywańska Aleksandra M. , Schutter Julie D. De , Ayana Rajagopal , Hu Chi-Kuo , Arckens Lut , Ruzycki Philip A. , MacDonald Ryan B. , Clark Brian S. , Moons Lieve
Published: February 2024

Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.

Highlights

The aged killifish retina displays several ageing hallmarks, such as oxidative stress, gliosis and inflammageing, at the transcriptome level.

Risk genes for neurodegenerative disorders show dysregulation in the old killifish retina.

All vertebrate retinal cell types are present in the killifish retina.

Transcriptional dysregulation in the aged killifish retina is observed across cell types.
Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus
Authors: Fernández Ignacio , Saunders Nell , Duquerroy Stéphane , Bolland William H. , Arbabian Atousa , Salazar Eduard Baquero , Blanc Catherine , Lafaye Pierre , Haouz Ahmed , Buchrieser Julian , Schwartz Olivier , Rey Félix A.
Published: February 2024

The human seasonal coronavirus HKU1-CoV, which causes common colds worldwide, relies on the sequential binding to a cell-surface glycan and to TMPRSS2 for entry into target cells. TMPRSS2 is a cell surface protease synthesized as a zymogen that undergoes autolytic activation to process its substrates. Several respiratory viruses - in particular coronaviruses - use TMPRSS2 for proteolytic priming of their surface spike protein to drive membrane fusion upon receptor binding. We describe the crystal structure of the HKU1-CoV receptor binding domain in complex with TMPRSS2, showing that it recognizes residues lining the catalytic groove. Combined mutagenesis of interface residues and comparison across species highlight positions 417 and 469 as determinants of HKU1-CoV host tropism. The structure of a receptor- blocking nanobody in complex with zymogen or activated TMPRSS2 further provides the structural basis of the TMPRSS2 activating conformational change, altering loops recognized by HKU1-CoV and dramatically increasing its binding affinity.
Genetic Stability ofMycobacterium smegmatisunder the Stress of First-Line Antitubercular Agents: Assessing Mutagenic Potential
Authors: Molnár Dániel , Surányi Éva Viola , Trombitás Tamás , Füzesi Dóra , Hirmondó Rita , Tóth Judit
Published: February 2024

The sustained success ofMycobacterium tuberculosisas a pathogen arises from its ability to persist within macrophages for extended periods and its limited responsiveness to antibiotics. Furthermore, the high incidence of resistance to the few available antituberculosis drugs is a significant concern, especially since the driving forces of the emergence of drug resistance are not clear. Drug-resistant strains ofMycobacterium tuberculosiscan emerge throughde novomutations, however, mycobacterial mutation rates are low. To unravel the effects of antibiotic pressure on genome stability, we determined the genetic variability, phenotypic tolerance, DNA repair system activation, and dNTP pool upon treatment with current antibiotics usingMycobacterium smegmatis.Whole-genome sequencing revealed no significant increase in mutation rates after prolonged exposure to first-line antibiotics. However, the phenotypic fluctuation assay indicated rapid adaptation to antibiotics mediated by non-genetic factors. The upregulation of DNA repair genes, measured using qPCR, suggests that genomic integrity may be maintained through the activation of specific DNA repair pathways. Our results, indicating that antibiotic exposure does not result inde novoadaptive mutagenesis under laboratory conditions, do not lend support to the model suggesting antibiotic resistance development through drug pressure-induced microevolution.
Spatial context non-uniformly modulates inter-laminar communication in the primary visual cortex
Authors: Xu Xize , Morton Mitchell P. , Hudson Nyomi V. , Nandy Anirvan S. , Jadi Monika P.
Published: February 2024

Our visual experience is a result of the concerted activity of neuronal ensembles in the sensory hierarchy. Yet how the spatial organization of objects influences neural activity in this hierarchy remains poorly understood. We investigate how the inter-laminar interactions in the primary visual cortex (V1) are affected by visual stimuli in isolation or with flanking stimuli at various spatial configurations that are known to cause non-uniform degradation of perception. By employing dimensionality reduction approaches to simultaneous layer-specific population recordings, we establish that cortical layers interact through a structurally stable communication subspace. Spatial configuration of contextual stimuli differentially modulates inter-laminar communication efficacy, the balance between feedforward and feedback signaling, and contextual signaling in the superficial layers. Remarkably, these modulations mirror the spatially non-uniform aspects of perceptual degradation. Our results suggest a model of retinotopically non-uniform cortical connectivity in the output layers of V1 that influences communication in the sensory hierarchy.
Rapid generation and screening of transgenic black soldier fly (Hermetia illucens)
Authors: Pfitzner Chandran , Tepper Kate , Kumar Sheemal , Retief Carly , McNab Justin M , Harrell Robert A , Maselko Maciej
Published: February 2024

Background

The black soldier fly (BSF),Hermetia illucensis a widely used, and mass-produced insect that fulfils an important role in both the management of organic waste and as a component of animal feed formulations. They also have significant potential as a platform for converting organic waste into high-value proteins, and lipids for the production of biofuels. Applying synthetic biology to BSF provides even more potential for improvement through the generation of transgenic BSF to enhance animal feed, produce and fine tune high-value industrial biomolecules, and to expand their waste conversion capabilities.

Results

To enable the rapid generation and screening of transgenic BSF, we utilised microinjections of piggyBac mRNA with donor plasmids. We have found preliminary screening of G0 BSF to identify mosaics for outcrossing can be completed less than 2 weeks after microinjection. Stable transgenic lines were reliably generated with effective transformation rates of 30-33%, and transmission of the transgene could be confirmed 3 days after outcrossing the G0 adults. We also present a protocol for identifying the location of integrated transgenes.

Conclusions

The methods presented here expedite the screening process for BSF transgenesis and further expand the toolkit for BSF synthetic biology.
The ZmHSF20–ZmHSF4–ZmCesA2 module regulates heat stress tolerance in maize
Authors: Li Ze , Li Zerui , Ji Yulong , Wang Chunyu , Wang Shufang , Shi Yiting , Le Jie , Zhang Mei
Published: February 2024

Temperature shapes the geographical distribution and behavior of plants. Understanding the regulatory mechanisms behind plant heat response is important for developing climate-resilient crops, including maize (Zea mays). To identify transcription factors that may contribute to heat response, we generated a dataset of short- and long-term transcriptome changes following a heat treatment time course in the maize inbred line B73. Co-expression network analysis highlighted several transcription factors, including the class B2a heat shock factor ZmHSF20.ZmHsf20mutant seedlings exhibited enhanced tolerance of heat stress. Furthermore, DNA affinity purification sequencing and CUT&Tag assays demonstrated that ZmHSF20 binds the promoters ofCellulose synthase A2(ZmCesA2) and three class AHSFgenes, includingZmHSF4, repressing their transcription. We showed that ZmCesA2 and ZmHSF4 positively regulate heat response, with ZmHSF4 directly activatingZmCesA2transcription. In agreement with the transcriptome analysis, ZmHSF20 negatively modulated cellulose accumulation and repressed the expression of cell wall–related genes. Importantly, theZmHsf20 ZmHsf4double mutant exhibited decreased thermotolerance, placing ZmHSF4 downstream of ZmHSF20. Based on our results, we propose an expanded model of the heat stress response in maize, whereby ZmHSF20 lowers heat tolerance of seedlings by repressingZmHSF4andZmCesA2, thus balancing growth and defense at the seedling stage.

One-sentence summary

ZmHSF20, as a negative factor, acts upstream ofZmHSF4andZmCesA2, which are involved in positively regulating the cell wall development under heat stress, thereby improving maize heat tolerance.
Expectations about presence enhance the influence of content-specific expectations on low-level orientation judgements
Authors: Haarsma Joost , Kaltenmaier Aaron , Fleming Stephen M , Kok Peter
Published: February 2024

Will something appear and if so, what will it be? Perceptual expectations can concern both the presence and content of a stimulus. However, it is unclear how these different types of expectations interact with each other in biasing perception. Here, we tested how expectations about stimulus presence and content differently affect perceptual inference. Across separate online discovery (N=110) and replication samples (N=218), participants were asked to judge both the presence and content (orientation) of noisy grating stimuli. Crucially, preceding compound cues simultaneously and orthogonally predicted both whether a grating was likely to appear as well as what its orientation would be. We found that expectations of presence interacted with expectations of content, such that the latter’s effect on discrimination was larger when a stimulus was expected to appear than when it was not. This interaction was observed both when a grating was truly presented and when participants falsely perceived one. Confidence in having seen a grating on the other hand was independently affected by presence and content expectations. Further, modelling revealed higher sensitivity in distinguishing between grating presence and absence following absence cues than presence cues, demonstrating an asymmetry between gathering evidence in favour of stimulus presence and absence. Finally, evidence for overweighted predictions being associated with hallucination-like perception was inconclusive. In sum, our results provide nuance to popular predictive processing accounts of perception by showing that expectations of presence and content have distinct but interacting roles in shaping conscious perception.
High-Performance Wide-Band Open-Source System for Acoustic Stimulation
Authors: Silva Artur , Carvalho Filipe , Cruz Bruno F.
Published: February 2024

The design and characterization of a low-cost, open-source auditory delivery system to deliver high performance auditory stimuli is presented. The system includes a high-fidelity sound card and audio amplifier devices with low-latency and wide bandwidth targeted for behavioral neuroscience research. The characterization of the individual devices and the entire system is performed, providing a thorough audio characterization data for varying frequencies and sound levels. The system implements the open-source Harp protocol, enabling the hardware timestamping of devices and seamless synchronization with other Harp devices.

Specifications table
An egg sabotaging mechanism drives non-Mendelian transmission in mice
Authors: Clark Frances E. , Greenberg Naomi L. , Silva Duilio M.Z.A. , Trimm Emily , Skinner Morgan , Walton R Zaak , Rosin Leah F. , Lampson Michael A. , Akera Takashi
Published: February 2024

During meiosis, homologous chromosomes segregate so that alleles are transmitted equally to haploid gametes, following Mendel’s Law of Segregation. However, some selfish genetic elements drive in meiosis to distort the transmission ratio and increase their representation in gametes. The established paradigms for drive are fundamentally different for female vs male meiosis. In male meiosis, selfish elements typically kill gametes that do not contain them. In female meiosis, killing is predetermined, and selfish elements bias their segregation to the single surviving gamete (i.e., the egg in animal meiosis). Here we show that a selfish element on mouse chromosome 2,R2d2, drives using a hybrid mechanism in female meiosis, incorporating elements of both male and female drivers. IfR2d2is destined for the polar body, it manipulates segregation to sabotage the egg by causing aneuploidy that is subsequently lethal in the embryo, so that surviving progeny preferentially containR2d2. In heterozygous females,R2d2orients randomly on the metaphase spindle but lags during anaphase and preferentially remains in the egg, regardless of its initial orientation. Thus, the egg genotype is either euploid withR2d2or aneuploid with both homologs of chromosome 2, with only the former generating viable embryos. Consistent with this model,R2d2heterozygous females produce eggs with increased aneuploidy for chromosome 2, increased embryonic lethality, and increased transmission ofR2d2. In contrast to a male meiotic driver, which kills its sister gametes produced as daughter cells in the same meiosis,R2d2eliminates “cousins” produced from meioses in which it should have been excluded from the egg.
UnconventionalIFNω-like genes dominate the type I IFN locus and the constitutive antiviral responses in bats
Authors: Geng Rong , Wang Qi , Yao Yu-Lin , Shen Xu-Rui , Jia Jing-Kun , Wang Xi , Zhu Yan , Li Qian , Shi Zheng-Li , Zhou Peng
Published: February 2024

Bats are the natural reservoir hosts of some viruses, some of which may spillover to humans and cause global-scale pandemics. Different to humans, bats may coexist with high pathogenic viruses without showing symptoms of diseases. As one of the most important first defenses, bat type I interferon (IFN-Is) were thought to play a role during this virus coexistence and thus were studied in recent years. However, there are arguments that whether bats have a contracted genome locus or constitutive expressed IFNs, mainly due to species-specific findings. We hypothesized that because of the lacking of pan-bat analysis, the common characters for bat IFN-Is have not been revealed yet. Here, we characterized the IFN-I locus for 9 Yangochiroptera bats and 3 Yinpterochiroptera based on the their high quality bat genomes. We also compared the basal expression for 6 bats and compared the antiviral, anti-proliferative activity and thermo-stability of a representativeRhinolophusbat IFNs. We found a dominance of unconventionalIFNω-like responses in the IFN-I system, which is unique to bats. In contrast toIFNa-dominated IFN-I loci in the majority of other mammals, bats generally have shorter IFN-I loci with more unconventionalIFNω-like genes (IFNωor relatedIFNaω), but with less or even noIFNagenes. In addition, bats generally have constitutively expressed IFNs, the highest expressed of which is more likely anIFNω-like gene. Likewise, the highly expressed IFNω-like protein also demonstrated the best antiviral activity, anti-proliferative activity or thermo-stability, as shown in a representativeRhinolophusbat species. Overall, we revealed pan-bat unique characteristics in IFN-I system, which provide insights into our understanding of the innate immunity that contribute to a special coexistence between bats and viruses.
ASTROGLIOSIS AND NEUROINFLAMMATION UNDERLIE SCOLIOSIS UPON CILIA DYSFUNCTION
Authors: Djebar Morgane , Anselme Isabelle , Pezeron Guillaume , Bardet Pierre-Luc , Cantaut-Belarif Yasmine , Eschstruth Alexis , Santos Diego López , Ribeuz Hélène Le , Jenett Arnim , Khoury Hanane , Véziers Joelle , Parmentier Caroline , Hirschler Aurélie , Carapito Christine , Bachmann-Gagescu Ruxandra , Schneider-Maunoury Sylvie , Vesque Christine
Published: February 2024

Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene. Here, we dissected the mechanisms of scoliosis onset in a zebrafish mutant for therpgrip1lgene encoding a ciliary transition zone protein.rpgrip1lmutant fish developed scoliosis with near-total penetrance but asynchronous onset in juveniles. Taking advantage of this asynchrony, we found that curvature onset was preceded by ventricle dilations and was concomitant to the perturbation of Reissner fiber polymerization and to the loss of multiciliated tufts around the subcommissural organ. Rescue experiments showed that Rpgrip1l was exclusively required infoxj1a-expressing cells to prevent axis curvature. Genetic interactions investigations ruled out Urp1/2 levels as a main driver of scoliosis inrpgrip1mutants. Transcriptomic and proteomic studies identified neuroinflammation associated with increased Annexin levels as a potential mechanism of scoliosis development inrpgrip1ljuveniles. Investigating the cell types associated withannexin2over-expression, we uncovered astrogliosis, arising in glial cells surrounding the diencephalic and rhombencephalic ventricles just before scoliosis onset and increasing with time in severity. Anti-inflammatory drug treatment reduced scoliosis penetrance and severity and this correlated with reduced astrogliosis and macrophage/microglia enrichment around the diencephalic ventricle. Mutation of thecep290gene encoding another transition zone protein also associated astrogliosis with scoliosis. Thus, we propose astrogliosis induced by perturbed ventricular homeostasis and associated with immune cell activation as a novel pathogenic mechanism of zebrafish scoliosis caused by cilia dysfunction.
Chromatin structure around long non-coding RNA (lncRNA) genes inSchistosoma mansonigonads
Authors: de Carvalho Augusto Ronaldo , Quack Thomas , Grevelding Christoph G. , Grunau Christoph
Published: February 2024

In this study, we employed a total of eight distinct modifications of histone proteins (H3K23ac, H3K27me3, H3K36me3, H3K4me3, H3K9ac, H3K9me3, H4K12ac, and H4K20me1) to discern the various chromatin colors encompassing lncRNA genes in both mature and immature gonads of the human parasiteSchistosoma mansoni. Our investigation revealed that these chromatin colors exhibit a tendency to aggregate based on the similarities in their metagene shapes, leading to the formation of less than six distinct clusters. Moreover, these clusters can be further grouped according to their resemblances by shape, which are co-linear with specific regions of the genes and potentially associated with transcriptional stages.
Evolutionary approaches predicted changes in transcription factors andcis-elements that associate with Kranz anatomy development in maize
Authors: Saji Angeo , Bijukumar Gopikrishnan , Nikhitha R , Thakur Vivek
Published: February 2024

C4plants are more efficient in high temperatures and less water due to unique anatomy and biochemical modifications, but critical regulator genes controlling Kranz anatomy remain undiscovered. This study aims to investigate the genes andcis-motifs that may be critical regulators in establishing and maintaining Kranz anatomy features in leaves of C4grasses by investigating candidate genes and their upstream regions fromZea maysby looking for genes with adaptive evolution in solely C4orthologs and motifs present uniquely in C4plants. Three genes out of 70 genes analyzed, namelymyb89,spb21,andereb80were observed from Maize with adaptive evolution uniquely present in multiple C4species, with the first two supported by expression data from different studies to be possibly involved in Kranz regulation, with further experimental validation required to investigate their exact roles in Kranz development. 12 motifs were found upstream of gene orthologs specific to or enriched in C4species. Three motifs upstream of IDP8537 and gras19 were found in a subset of their coexpression cluster, further suggesting their potential involvement in Kranz anatomy regulation. These novel motifs are potential additions to the limited Kranz-specific motifs and can aid in predicting new regulators after experimental validation.

HIGHLIGHT

In this paper, we analyze the putative regulator sets of Kranz anatomy to discover important regulators and novelcis-regulatory elements that possibly regulate Kranz anatomy using evolutionary approaches.
Post-transcriptional control drives Aurora kinase A expression in human cancers
Authors: Cacioppo Roberta , Rad Deniz , Pagani Giulia , Gandellini Paolo , Lindon Catherine
Published: February 2024

Aurora kinase A (AURKA) is a major regulator of the cell cycle. A prominent association exists between high expression of AURKA and cancer, and impairment of AURKA levels can trigger its oncogenic activity. In order to explore the contribution of post-transcriptional regulation to AURKA expression in different cancers, we carried out a meta-analysis of -omics data of 18 cancer types from The Cancer Genome Atlas (TCGA). Our study confirmed a general trend for increased AURKA mRNA in cancer compared to normal tissues and revealed that AURKA expression is highly dependent on post-transcriptional control in several cancers. Correlation and clustering analyses of AURKA mRNA and protein expression, and expression of AURKA-targetinghsa-let-7amiRNA, unveiled thathsa-let-7ais likely involved to varying extents in controlling AURKA expression in cancers. We then measured differences in the short/long ratio (SLR) of the two alternative cleavage and polyadenylation (APA) isoforms of AURKA mRNA across cancers compared to the respective healthy counterparts. We suggest that the interplay between APA andhsa-let-7atargeting of AURKA mRNA may influence AURKA expression in some cancers.hsa-let-7aand APA may also independently contribute to altered AURKA levels. Therefore, we argue that AURKA mRNA and protein expression are often discordant in cancer as a result of dynamic post-transcriptional regulation.
Predicting the direction of phenotypic difference
Authors: Gokhman David , Harris Keith D. , Carmi Shai , Greenbaum Gili
Published: February 2024

Predicting phenotypes from genomic data is a key goal in genetics, but for most complex phenotypes, predictions are hampered by incomplete genotype-to-phenotype mapping. Here, we describe a more attainable approach than quantitative predictions, which is aimed at qualitatively predicting phenotypic differences. Despite incomplete genotype-to-phenotype mapping, we show that it is relatively easy to determine which of two individuals has a greater phenotypic value. This question is central in many scenarios, e.g., comparing disease risk between individuals, the yield of crop strains, or the anatomy of extinct vs extant species. To evaluate prediction accuracy, i.e., the probability that the individual with the greater predicted phenotype indeed has a greater phenotypic value, we developed an estimator of the ratio between known and unknown effects on the phenotype. We evaluated prediction accuracy using human data from tens of thousands of individuals from either the same family or the same population, as well as data from different species. We found that, in many cases, even when only a small fraction of the loci affecting a phenotype is known, the individual with the greater phenotypic value can be identified with over 90% accuracy. Our approach also circumvents some of the limitations in transferring genetic association results across populations. Overall, we introduce an approach that enables accurate predictions of key information on phenotypes — the direction of phenotypic difference — and suggest that more phenotypic information can be extracted from genomic data than previously appreciated.
Graphene microelectrode arrays, 4D structured illumination microscopy, and a machine learning-based spike sorting algorithm permit the analysis of ultrastructural neuronal changes during neuronal signalling in a model of Niemann-Pick disease type C
Authors: Lu Meng , Hui Ernestine , Brockhoff Marius , Trauble Jakob , Fernandez-Villegas Ana , Burton Oliver J , Lamb Jacob , Ward Edward , Hooper Philippa J , Tadbier Wadood , Laubli Nino F , Hofmann Stephan , Kaminski Clemens F , Lombardo Antonio , Kaminski Schierle Gabriele S
Published: February 2024

Simultaneously recording network activity and ultrastructural changes of the synapse is essential for advancing our understanding of the basis of neuronal functions. However, the rapid millisecond-scale fluctuations in neuronal activity and the subtle sub-diffraction resolution changes of synaptic morphology pose significant challenges to this endeavour. Here, we use graphene microelectrode arrays (G-MEAs) to address these challenges, as they are compatible with high spatial resolution imaging across various scales as well as high temporal resolution electrophysiological recordings. Furthermore, alongside G-MEAs, we deploy an easy-to-implement machine learning-based algorithm to efficiently process the large datasets collected from MEA recordings. We demonstrate that the combined use of G-MEAs, machine learning (ML)-based spike analysis, and four-dimensional (4D) structured illumination microscopy (SIM) enables the monitoring of the impact of disease progression on hippocampal neurons which have been treated with an intracellular cholesterol transport inhibitor mimicking Niemann-Pick disease type C (NPC) and show that synaptic boutons, compared to untreated controls, significantly increase in size, which leads to a loss in neuronal signalling capacity.
Code Multiplexed Nanocapacitor Arrays for Scalable Neural Recordings
Authors: Weaver Sean , Chen Yiyang , Renz Aline , Choi Woojun , Vyza Yashwanth , Schlotter Tilman , Vulić Katarina , Kim Donghwan , Atzeni Gabriele , Momotenko Dmitry , Nakatsuka Nako , Jang Taekwang , Vörös János
Published: February 2024

Large scale neural recordings are redefining our understanding of the brain. However, simultaneously recording potentials from thousands of microelectrodes remains challenging. We overcome this limitation by measuring activity-induced changes in mutual capacitance. Code division multiplexing enabled simultaneous recordings of neural activity from 1,024 nanocapacitor electrodes at a density of 10k electrodes/mm.2Features of neural activityi.e., action potentials, bursts, and local field potentials were measured in recordings, benchmarking our device against the state-of-the-art.

Capacitive sensing of neural activity improves the scalability, fabrication, and miniaturization of microelectrode arrays.
The assembly and efflux processes revealed byin situstructures of the ABC-type tripartite pump MacAB-TolC
Authors: Huo Tong , Zheng Wei , Yu Zhili , Wu Yaoming , Ren Qiuyu , Cao Junli , Wang Zhao , Shi Xiaodong
Published: February 2024

The MacAB-TolC tripartite efflux pump is widely distributed in Gram-negative bacteria, extruding antibiotics and virulence factors that lead to multidrug resistance and pathogenicity. This pump spans the cell envelope through its three components, an inner membrane ATP-binding cassette (ABC) transporter MacB, a periplasmic adaptor protein MacA, and an outer membrane protein TolC. However, the assembly process and efflux mechanism of the MacAB-TolC in cells remain unclear. Here, we resolve thein situstructures ofEscherichia coli(E. coli) MacAB-TolC efflux pump by electron cryo-tomography and subtomogram averaging. InE. coliwithout antibiotic treatment, we observe a fully assembled MacAB-TolC pump with a weak constriction density in the middle of the MacA region. WhenE. colicells were treated with erythromycin, we discovered the emergence of MacA-TolC subcomplexes, indicating flexible binding of MacB in the presence of an antibiotic substrate. This finding was further validated byin vivocrosslinking results. Together, our data present thein situassembly process of the MacAB-TolC and derive a substrate-driven working model for ABC-type tripartite pump.
AI-driven Classification of Cancer-Associated Fibroblasts Using Morphodynamic and Motile Features
Authors: Kang Minwoo , Min Chanhong , Somayadineshraj D. , Shin Jennifer H.
Published: February 2024

The heterogeneous natures of cancer-associated fibroblasts (CAFs) play critical roles in cancer progression, with some promoting tumor growth while others inhibit it. To utilize CAFs as a target for cancer treatment, issues with subtypes of CAFs must be resolved such that specific pro-tumorigenic subtypes can be suppressed or reprogrammed into anti-tumorigenic ones. Currently, single-cell RNA sequencing (scRNA-Seq) is a prevalent strategy for classifying CAFs, primarily based on their biomolecular features.

Alternatively, this study proposes assessing CAFs on a larger biophysical scale, focusing on cell morphological and motile features. Since these features are downstream effectors of differential gene expression combinations, they can serve as holistic descriptors for CAFs, offering a complementary strategy for classifying CAF subtypes. Here, we propose an artificial intelligence (AI) classification framework to comprehensively characterize CAF subtypes using morphodynamic and motile features. This framework extracts these features from label-free live-cell imaging data of CAFs employing advanced deep learning and machine learning algorithms.

The results of this study highlight the ability of morphodynamic and motile features to complement biomolecular features in accurately reflecting CAF subtype characteristics. In essence, our AI-based classification framework not only provides valuable insights into CAF biology but also introduces a novel approach for comprehensively describing and targeting heterogeneous CAF subtypes based on biophysical features.
Extracellular electron transfer genes expressed by candidate flocking bacteria in cable bacteria sediment
Authors: Lustermans Jamie JM , Sereika Mantas , Burdorf Laurine DW , Albertsen Mads , Schramm Andreas , Marshall Ian PG
Published: February 2024

Cable bacteria, filamentous sulfide oxidizers that live in sediments, are at times associated with large flocks of swimming bacteria. It has been proposed that these flocks of bacteria transport electrons extracellularly to cable bacteria via an electron shuttle intermediate, but the identity and activity of these bacteria in freshwater sediment remains mostly uninvestigated. We coupled metagenomics and metatranscriptomics to 16S rRNA amplicon-based correlations with cable bacteria from two time series experiments up to 155 days. We identified bacteria expressing genes for extracellular electron transfer and motility, including synthesis genes for potential extracellular electron shuttles: phenazines and flavins. Of the 85 high quality MAGs (Metagenome Assembled Genomes >90% complete and <5% contaminated), 56 had genes encoding flagellar proteins, and of these 22 had genes encoding extracellular electron transport proteins. The candidate flockers constituted 21.4% of all MAGs and 42.1% of the proposed flocking bacteria expressed extracellular electron transfer genes. The proposed flockers belonged to a large variety of taxonomic groups: 18 genera spread across 9 phyla. Our data suggest that electric relationships in freshwater sediments between cable bacteria and other microbes likely help to generate and/or sustain cryptic element cycling and ‘deep oxygen breathing’, affecting more element cycles than sulfur, like metal– and in particular iron– and carbon cycles.
Red blood cell passage through deformable interendothelial slits in the spleen: Insights into splenic filtration and hemodynamics
Authors: Li Guansheng , Li He , Ndou Papa Alioune , Franco Mélanie , Qiang Yuhao , Li Xuejin , Buffet Pierre A. , Dao Ming , Karniadakis George Em
Published: February 2024

The spleen constantly clears altered red blood cells (RBCs) from the circulation, tuning the balance between RBC formation (erythropoiesis) and removal. The retention and elimination of RBCs occur predominantly in the open circulation of the spleen, where RBCs must cross submicron-wide inter-endothelial slits (IES). Several experimental and computational studies have illustrated the role of IES in filtrating the biomechanically and morphologically altered RBCs based on a rigid wall assumption. However, these studies also reported that when the size of IES is close to the lower end of clinically observed sizes (less than 0.5μm), an unphysiologically large pressure difference across the IES is required to drive the passage of normal RBCs, sparking debates on the feasibility of the rigid wall assumption. In this work, we perform a computational investigation based on dissipative particle dynamics (DPD) to explore the impact of the deformability of IES on the filtration function of the spleen. We simulate two deformable IES models, namely the passive model and the active model. In the passive model, we implement the worm-like string model to depict the IES’s deformation as it interacts with blood plasma and allows RBC to traverse. In contrast, the active model involved regulating the IES deformation based on the local pressure surrounding the slit. To demonstrate the validity of the deformable model, we simulate the filtration of RBCs with varied size and stiffness by IES under three scenarios: 1) a single RBC traversing a single slit; 2) a suspension of RBCs traversing an array of slits, mimickingin vitrospleen-on-a-chip experiments; 3) RBC suspension passing through the 3D spleen filtration unit known as ‘the splenon’. Our simulation results of RBC passing through a single slit show that the deformable IES model offers more accurate predictions of the critical cell surface area to volume ratio that dictate the removal of aged RBCs from circulation compared to prior rigid-wall models. Our biophysical models of the spleen-on-a-chip indicates a hierarchy of filtration function stringency: rigid model > passive model > active model, providing a possible explanation of why the spleen-on-a-chip could overestimate the filtration function of IES. We also illustrate that the biophysical model of ‘the splenon’ enables us to replicate theex vivoexperiments involving spleen filtration of malaria-infected RBCs. Taken together, our simulation findings indicate that the deformable IES model could serve as a mesoscopic representation of spleen filtration function closer to physiological reality, addressing questions beyond the scope of current experimental and computational models and enhancing our understanding of the fundamental flow dynamics and mechanical clearance processes within in the human spleen.