bluuebunny/crossref_metadata_2025 huggingface dataset:
The embryonic DNA methylation program modulates thecis-regulatory landscape via CTCF antagonism
Authors: Monteagudo-Sánchez Ana , Richard Albert Julien , Scarpa Margherita , Noordermeer Daan , Greenberg Maxim V.C.
Published: November 2023

During mammalian embryogenesis, both the 5-cytosine DNA methylation (5meC) landscape and three-dimensional (3D) chromatin architecture are profoundly remodeled during a process known as “epigenetic reprogramming.” An understudied aspect of epigenetic reprogramming is how the 5meC flux,per se, affects the 3D genome. This is pertinent given the 5meC-sensitivity of DNA binding for a key regulator of chromosome folding: CTCF. We profiled the CTCF binding landscape using a mouse embryonic stem cell (ESC) differentiation protocol that models the exit of naïve pluripotency, wherein global DNA methylation levels start low and increase to somatic levels within four days. We took advantage of the fact that mouse ESCs lacking DNA methylation machinery exhibit globally similar differentiation dynamics, thus allowing for dissection of more subtle effects of CTCF misregulation on gene expression. We carried this out by performing CTCF HiChIP in both wild-type and mutant conditions to assess aberrant CTCF-CTCF contacts in the absence of 5meC. We went on to assess the impact that misregulated CTCF binding has oncis-regulatory contacts by performing H3K27ac HiChIP, given that H3K27ac is enriched on active promoters and enhancers. Using DNA methylation epigenome editing, we were able to directly demonstrate that the DNA methyl-mark is able to impact CTCF binding. Finally, a detailed dissection of the imprintedZdbf2gene showed how 5meC-antagonism of CTCF allows for proper gene regulation during differentiation. This work provides a comprehensive overview of how DNA methylation impacts the 3D genome in a relevant model for early embryonic events.
Fine-grained modelling of ATP dependence of decision-making capacity in genetic regulatory networks
Authors: Kumar Rajneesh , Johnston Iain G.
Published: November 2023

Cellular decision-making is fundamental to life, from developmental biology to environmental responses and antimicrobial resistance. Many regulatory processes that drive cellular decisions rely on gene expression, which requires energy in the form of ATP. As even genetically identical cells can have dramatically different ATP levels, bioenergetic status can be an important source of variability in cellular decision-making. Existing studies have investigated this energy dependence but often use coarse-grained modelling approaches (which are not always readily connected to the underlying molecular processes of gene regulation). Here we use a fine-grained mathematical model of gene expression in a two-gene decision-making regulatory network to explore cellular decision-making capacity as energy availability varies. We simulate both a deterministic model, to explore the emergence of different cell fate attractors as ATP levels vary, and a stochastic case to explore how ATP influences the noisy dynamics of stochastic cell decision-making. Higher energy levels typically support increased decision-making capacity (higher numbers of, and more separated, cell states that can be selected), and the fine-grained modelling reveals some differences in behaviour from previous coarse-grained modelling approaches.
Contrasting segregation patterns among endogenous retroviruses across the koala population
Authors: Lillie Mette , Pettersson Mats , Jern Patric
Published: November 2023

Koalas (Phascolarctos cinereus) are subject to retroviral infections by the koala retrovirus (KoRV), resulting in accumulation of heritable endogenous KoRV in the koala germline. Like other vertebrates, koalas have experienced a history of retroviral epidemics leaving marks as endogenous retroviruses (ERVs) in their genomes; another recently identified ERV lineage, namedphaCin-β, shows a pattern of recent, possibly current, activity with high insertional polymorphism in the koala population that predates the establishment of endogenous KoRV. We investigate geographic patterns of retrovirus activity, focusing on three distinct ERV lineages of increasing estimated ages from KoRV tophaCin-βand tophaCin-β-like, using a whole-genome sequencing dataset of 430 koalas produced by the Koala Genome Survey. We find thousands of ERV loci across the koala population and identify contrasting patterns of polymorphism. In the youngest established ERV-lineage (KoRV), we identify thousands of integrations among northern individuals. In thephaCin-βERV lineage, which is slightly older yet with overlapping time of activity with KoRV, we observe hundreds of integrations in northern individuals. In southern koalas, however,phaCin-βloci are found at higher frequencies possibly reflecting a bottleneck effect. Overall, the findings suggest high ERV burden in koalas that represent historic retrovirus-host interactions. Importantly, the ERV catalogue supplies improved markers for population conservation genetics of this endangered species.
Autapses enable temporal pattern recognition in spiking neural networks
Authors: Yaqoob Muhammad , Steuber Volker , Wróbel Borys
Published: November 2023

Most sensory stimuli are temporal in structure. How action potentials encode the information incoming from sensory stimuli remains one of the central research questions in neuroscience. Although there is evidence that the precise timing of spikes represents information in spiking neuronal networks, information processing in spiking networks is still not fully understood. One feasible way to understand the working mechanism of a spiking network is to associate the structural connectivity of the network with the corresponding functional behaviour. This work demonstrates the structure-function mapping of spiking networks evolved (or handcrafted) for a temporal pattern recognition task. The task is to recognise a specific order of the input signals so that theOut putneurone of the network spikes only for the correct placement and remains silent for all others. The minimal networks obtained for this task revealed the twofold importance of autapses in recognition; first, autapses simplify the switching among different network states. Second, autapses enable a network to maintain a network state, a form of memory. To show that the recognition task is accomplished by transitions between network states, we map the network states of a functional spiking neural network (SNN) onto the states of a finite-state transducer (FST, a formal model of computation that generates output symbols, here: spikes or no spikes at specific times, in response to input, here: a series of input signals). Finally, based on our understanding, we define rules for constructing the topology of a network handcrafted for recognising a subsequence of signals (pattern) in a particular order. The analysis of minimal networks recognising patterns of different lengths (two to six) revealed a positive correlation between the pattern length and the number of autaptic connections in the network. Furthermore, in agreement with the behaviour of neurones in the network, we were able to associate specific functional roles of ‘locking,’ ‘switching,’ and ‘accepting’ to neurones.
oncotree2vec – A method for embedding and clustering of tumor phylogenetic trees
Authors: Baciu-Drăgan Monica-Andreea , Beerenwinkel Niko
Published: November 2023

Understanding the genomic heterogeneity of tumors is an important task in computational oncology, especially in the context of finding personalized treatments based on the genetic profile of each patient’s tumor. Tumor clustering that takes into account the temporal order of genetic events, as represented by tumor mutation trees, is a powerful approach for grouping together patients with genetically and evolutionarily similar tumors and can provide insights into discovering tumor sub-types, for more accurate clinical diagnosis and prognosis. Here, we propose oncotree2vec, a method for clustering tumor mutation trees by learning vector representations of mutation trees that capture the different relationships between subclones in an unsupervised manner. Learning low-dimensional tree embeddings facilitates the visualization of relations between trees in large cohorts and can be used for downstream analyses, such as deep learning approaches for single-cell multi-omics data integration. We assessed the performance and the usefulness of our method in three simulation studies, and on two real datasets: a cohort of 43 trees from six cancer types with different branching patterns corresponding to different modes of spatial tumor evolution and a cohort of 123 AML mutation trees.
Live-cell imaging reveals the trade-off between target search flexibility and efficiency for Cas9 and Cas12a
Authors: Olivi Lorenzo , Bagchus Cleo , Pool Victor , Bekkering Ezra , Speckner Konstantin , Wu Wen , Martens Koen , van der Oost John , Staals Raymond , Hohlbein Johannes
Published: November 2023

CRISPR-Cas systems have widely been adopted as genome editing tools, with two frequently employed Cas nucleases beingSpyCas9 andLbCas12a. Although both nucleases use RNA guides to find and cleave target DNA sites, the two enzymes differ in terms of protospacer-adjacent motif (PAM) requirements, guide architecture and cleavage mechanism. In the last years, rational engineering led to the creation of PAM-relaxed variantsSpRYCas9 and impLbCas12a to broaden the targetable DNA space. By employing their catalytically inactive variants (dCas9/dCas12a), we quantified how the protein-specific characteristics impact the target search process. To allow quantification, we fused these nucleases to the photoactivatable fluorescent protein PAmCherry2.1 and performed single-particle tracking in cells ofEscherichia coli. From our tracking analysis, we derived kinetic parameters for each nuclease with a non-targeting RNA guide, strongly suggesting that interrogation of DNA byLbdCas12a variants proceeds faster than that ofSpydCas9. In the presence of a targeting RNA guide, both simulations and imaging of cells confirmed thatLbdCas12a variants are faster and more efficient in finding a specific target site. Our work demonstrates the trade-off of relaxing PAM requirements inSpydCas9 andLbdCas12a using a powerful framework, which can be applied to other nucleases to quantify their DNA target search.
Presaccadic attention enhances and reshapes the Contrast Sensitivity Function differentially around the visual field
Authors: Kwak Y. , Zhao Y. , Lu Z-L. , Hanning N.M. , Carrasco M.
Published: November 2023

Contrast sensitivity, which constrains our vision, decreases from fovea to periphery, from the horizontal to the vertical meridian, and from the lower vertical to the upper vertical meridian. The Contrast Sensitivity Function (CSF) depicts how contrast sensitivity varies with spatial frequency (SF). To overcome these visual constraints, we constantly make saccadic eye movements to foveate on relevant objects in the scene. Already before saccade onset,presaccadic attentionshifts to the saccade target and enhances perception. However, it is unknown whether and how it modulates the interplay between contrast sensitivity and SF, and if this effect varies around polar angle locations. Contrast sensitivity enhancement may result from a horizontal or vertical shift of the CSF, increase in bandwidth, or any combination. Here, we investigated these possibilities by extracting key attributes of the CSF using Hierarchical Bayesian Modeling, which enables precise estimation of the CSF parameters by decomposing the variability of the dataset into multiple levels. The results reveal that presaccadic attention (1) enhances contrast sensitivity across SF, (2) increases the most preferred and the highest discernable SF, and (3) narrows the bandwidth. Therefore, presaccadic attention bridges the gap between presaccadic and post-saccadic input by increasing visibility at the saccade target. Counterintuitively, the presaccadic enhancement in contrast sensitivity was more pronounced where perception is better –along the horizontal than the vertical meridian– exacerbating polar angle asymmetries. Our results call for an investigation of the differential neural modulations underlying presaccadic perceptual changes for different saccade directions.

Significance statement

The contrast sensitivity function (CSF) describes how our ability to perceive contrast depends on spatial frequency. Contrast sensitivity is highest at the fovea and decreases in the periphery, especially at vertical locations. We thus make saccadic eye movements to view objects in detail. Already before moving our eyes,presaccadic attentionenhances perception at the target location. But how does it influence the interplay between spatial frequency and contrast sensitivity, and does its effect vary around the visual field? Using Hierarchical Bayesian Modeling, we show that presaccadic attention enhances and reshapes the CSF to prepare the periphery for upcoming fixation. Counterintuitively, it does so more at horizontal locations where vision is stronger, suggesting smoother perception across horizontal than vertical eye movements.
Post-stroke rapamycin treatment improves post-recanalization cerebral blood flow and outcome in rats
Authors: Schneider Anna M , Couch Yvonne , Larkin James , Buchan Alastair M , Beard Daniel J
Published: November 2023

Ischaemic stroke treatment is limited to recanalizing the occluded vessel, while there is no approved adjunctive cerebroprotective therapy to protect either the neurons and parenchyma or the neurovascular unit. Pharmacological inhibition of mammalian target of rapamycin-1 (mTORC1) with rapamycin has shown promise in reducing infarct volume and improving functional outcomes. However, previous studies that investigated the effects of rapamycin on the vasculature and cerebral blood flow (CBF), administered rapamycin prior to or during stroke induction, thus limiting the potential for clinical translation. Therefore we investigated whether rapamycin maintains its cerebrovascular protective effect when administered immediately after recanalization following 90 minutes stroke in Wistar rats. We show, that rapamycin significantly improved post-recanalization cerebral blood flow (CBF), suggesting a beneficial neurovascular effect of rapamycin. Rats treated with rapamycin had smaller infarct volumes and improved functional outcomes compared to the control animals at three days post-stroke. The mechanisms of the overall positive effects seen in this study are likely due to rapamycin’s hyperacute effects on the neurovasculature, as shown with increased CBF during this phase. This paper shows that rapamycin treatment is a promising adjunct cerebroprotective therapy option for ischemic stroke.
Natural killer cell cytotoxicity shapes the clonal evolution of B cell leukaemia
Authors: Buri Michelle C. , Shoeb Mohamed R. , Bykov Aleksandr , Repiscak Peter , Baik Hayeon , Dupanovic Alma , David Faith O. , Kovacic Boris , Hall-Glenn Faith , Dopa Sara , Urbanus Jos , Sippl Lisa , Stofner Susanne , Emminger Dominik , Cosgrove Jason , Schinnerl Dagmar , Poetsch Anna R. , Lehner Manfred , Koenig Xaver , Perié Leïla , Schumacher Ton N. , Gotthardt Dagmar , Halbritter Florian , Putz Eva M.
Published: November 2023

The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA barcoded mouse BCR/ABLp185+B acute lymphoblastic leukaemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Whereas most tumour cell clones were efficiently eliminated by NK cells, a certain fraction of tumour cells harboured an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumour cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumour cell clones, which were characterised by an IFN-γ signature. Besides well-known regulators of immune evasion, our analysis of NK cell resistant tumour cells revealed the upregulation of genes, includingLy6a, which we found to promote NK cell resistance in leukaemic cells. Translation of our findings to the human system showed that high expression ofLY6Eon tumour cells impaired the physical interaction with NK cells and led to worse prognosis in leukaemia patients. Our results demonstrate that tumour cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.
Truly the best of both worlds: merging lineage-specific and universal baiting kits to maximize phylogenomic inference
Authors: Fonseca Luiz Henrique M. , Asselman Pieter , Goodrich Katherine R. , Nge Francis J. , Soulé Vincent , Mercier Kathryn , Couvreur Thomas L. P. , Chatrou Lars W.
Published: November 2023

PREMISE

The development of RNA baiting kits for reduced representation approaches of genomic sequencing is popularized, with universal and clade-specific kits for flowering plants available. Here, we provided an updated version of the Annonaceae bait kit targeting 799 low copy genes, known as Annonaceae799.

METHODS

This new version of the kit combines the original 469 genes from the previous version of the Annonaceae kit with 334 genes from the universal Angiosperms353 kit. We also compared the results obtained using the Original Angiosperms353 kit with our custom approach. Parsimony informative sites (pis) were evaluated for all genes and combined matrices.

RESULTS

The new version of the kit has extremely high rates of gene recovery. On average, 796 genes were recovered per sample, and 777.5 genes recovered with at least 50% of their size. Off-target reads were also obtained. Evaluating size, the proportion of on- and off-target regions, and the number of pis, the genes from the Angiosperms353 usually outperform the genes from the original Annonaceae bait kit.

DISCUSSION

The results obtained show that the new sequences from the Angiosperms353 aggregate variable and putative relevant bases for future studies on species-level phylogenomics, and within species studies. The merging of kits also creates a link between projects and makes available new genes for phylogenetic and populational studies.
Enhanced efficiency in the bilingual brain through the inter-hemispheric cortico-cerebellar pathway in early second language acquisition
Authors: Gracia-Tabuenca Zeus , Barbeau Elise B. , Kousaie Shanna , Chen Jen-Kai , Chai Xiaoqian , Klein Denise
Published: November 2023

The bilingual experience has a profound impact on the functional and structural organization of the brain, but it is not yet well known how this experience influences whole-brain functional network connectivity. We examined a well-characterized large sample (151 participants) of monolinguals and bilinguals with varied age of second language acquisition, who underwent resting-state functional magnetic brain imaging. We constructed comprehensive functional brain networks for each participant, encompassing cortical, subcortical, and cerebellar regions of interest. Whole-brain analyses revealed that bilingual individuals exhibit higher global efficiency than monolinguals, indicating enhanced functional integration in the brain. Moreover, the age at which the second language was acquired correlated with this increased efficiency, suggesting that earlier exposure to a second language has lasting positive effects on brain functional organization. Further investigation through the network-based statistics (NBS) approach indicates that this effect is primarily driven by heightened functional connectivity between association networks and the cerebellum. This work shows that early learning enhances global whole-brain efficiency and that the timing of learning of two languages has an impact on functional brain organization.

Significance statement

Long-term learning impacts brain organization at different spatial scales, and this may be particularly enhanced during early stages of life. Bilingualism offers a unique opportunity to test long-term learning effects in the human brain, given that exposure to a second language can occur from birth or later in life, and can be maintained over long periods of time. We found that second language acquisition in early childhood (before five years of age) enhances brain network efficiency, and that this effect goes beyond the language and cognitive control regions, in fact, the interhemispheric cortico-cerebellar circuit plays a key role. This work shows that the timing of bilingual learning experience alters the brain functional organization at the global and local levels.
Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment
Authors: Soupir Alex C , Hayes Mitchell T , Peak Taylor C , Ospina Oscar , Chakiryan Nicholas H , Berglund Anders E , Stewart Paul A , Nguyen Jonathan , Segura Carlos Moran , Francis Natasha L. , Echevarria Paola M. Ramos , Chahoud Jad , Li Roger , Tsai Kenneth Y. , Balasi Jodi A. , Peres Yamila Caraballo , Dhillon Jasreman , Martinez Lindsey A. , Gloria Warren E. , Schurman Nathan , Kim Sean , Gregory Mark , Mulé James , Fridley Brooke L , Manley Brandon J
Published: November 2023

Background

Immunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates.

Results

21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors.YES1was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pairCOL4A1-ITGAVhad significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of bothCOL4A1andITGAV. In CPTAC, collagen IV protein was more abundant in advanced stages of disease.

Conclusions

On spatial transcriptomics,COL4A1andITGAVwere more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC.
Video diffusion for early cellular apoptosis forecasting
Authors: Awasthi Akash , Nizam Jaer , Zare Samira , Ahmad Safwan , Montalvo Melisa J. , Varadarajan Navin , Roysam Badri , Nguyen Hien
Published: November 2023

Reliable and early prediction of cell death (apoptosis) is critically important in various areas of biology, particularly in characterizing the effectiveness of cell-based infusion products utilized for cancer immunotherapy. While deep Convolutional Neural Networks (CNNs) are often used in state-of-the-art approaches for apoptosis classification, they typically focus solely on individual cells and ignore cell-cell interaction. To address this limitation, we propose a novel generative approach based on a video diffusion model, which predicts future cellular behaviors for early detection of apoptosis events, even before molecular markers like Annexin-V or visual indications like membrane blebbing become apparent. Our approach accounts for the interactions of multiple target cells and their spatial and temporal relationships at each time frame. We condition our generative model on two starting frames and utilize an auto-regressive framework to predict the subsequent five frames. Our model achieves a 0.88 F1 score on the cell death event classification and 2.11 mean absolute death-time error, significantly outperforming state-of-the-art methods.
Firefighter Helmets and Cervical Intervertebral Kinematics: An OpenSim-Based Biomechanical Study
Authors: Paulon Gustavo , Subramanian Sudeesh , Chowdhury Suman
Published: November 2023

The assessment of cervical intervertebral kinematics can serve as the basis for understanding any degenerative changes in the cervical spine due to the prolonged wear of a heavyweight, imbalanced firefighting helmet. Therefore, this study aimed to analyze cervical intervertebral kinematics using OpenSim musculoskeletal modeling platform in order to provide much-needed insights of how the inertial properties of firefighter helmet affect cervical spinal mobility. A total of 36 firefighters (18 males and 18 females) were recruited to perform static and dynamic neck flexion, extension, and left and right lateral bending tasks for three conditions: 1) no-helmet, 2) US-style helmet with a comparatively superior center of mass (COM), and 3) European-style helmet with relatively higher mass but an inferior COM. Three custom-made OpenSim head-neck models were created to calculate cervical intervertebral kinematics for each helmet condition. Results showed that the helmet use significantly (p<0.001) affects neck and cervical spinal kinematics. Especially, the superior COM placement in the US-style helmet, despite its lighter weight, caused more pronounced kinematic changes and quicker attainment of peak flexion and extension angles compared to the European-style helmet across all cervical joints. Moreover, results also revealed discrepancies between OpenSim-derived neck and cervical range-of-motion and those reported in previous in-vivo studies. In conclusion, the present study underscores the importance of designing firefighter helmets with a lower profile (less superior COM) to enhance neck range of motion and minimize potential neck injuries.
Identification ofavaCfrom infant gut microbial isolates that convert 5AVA to 2-piperidone with high efficiency
Authors: Zhou Qiudi , Feng Lihui
Published: November 2023

2-Piperidone has been identified as a biomarker for various human diseases, but its originin vivoremains poorly understood. Furthermore, 2-piperidone is a crucial industrial raw material, and thus the discovery of novel efficient 2-piperidone synthases may have an important application in its biosynthesis. In this study, we aimed to identify the bacterial source and metabolic mechanism of 2-piperidone from a previously generated infant gut microbial culture collection. We found that 2-piperidone could be produced from 5AVA by four bacterial strains, includingCollinsella aerofaciensLFYP39,Collinsella intestinalisLFYP54,Clostridium bolteaeLFYP116, andClostridium hathewayiLFYP18 from 51 bacterial strains. Furthermore, 2-piperidone could be synthesized from proline by cross-feeding betweenClostridium difficileLFYP43 andCollinsella intestinalisLFYP54. We employed a gain-of-function library to identify the geneavaC(5-aminovaleric acid cyclase) which can catalyze 5AVA to produce 2-piperidone inC. intestinalisLFYP54. Homologous genes ofavaCwere also identified and validated in the other three bacterial strains. GeneavaCexhibits a broad distribution in the natural environmental bacteria. Overall, our research identified the gut bacterial strains and the genes that are responsible for the production of 2-piperidone. This study may facilitate the prediction of 2-piperidone-related disease risks through the analysis of gut bacterial community composition, and enhance the efficiency of 2-piperidone in its biosynthesis in industry.

Importance

In recent decades, it has become a consensus that gut microbiota can affect host health through producing metabolites. However, the complexity of gut flora composition makes finding the sources of the particular metabolite challenging. 2-piperidone is a biomarker for various diseases and a highly valued raw material for nylons. In this study, we identified the gut bacterial strains that can transform 5AVA to 2-piperidone. A novel 2-piperidone synthase gene,avaC, was also identified and characterized. These findings provided new insights into the potential connection between 2-piperidone related diseases and the intestinal flora, as well as a possible novel approach for more efficient biosynthesis of 2-piperidone in industry.
The T Cell Receptor β Chain Repertoire of Tumor Infiltrating Lymphocytes Improves Neoantigen Prediction and Prioritization
Authors: Pham Thi Mong Quynh , Nguyen Thanh Nhan , Nguyen Bui Que Tran , Tran Thi Phuong Diem , Pham Nguyen My Diem , Nguyen Hoang Thien Phuc , Ho Thi Kim Cuong , Nguyen Dinh Viet Linh , Nguyen Huu Thinh , Tran Duc Huy , Tran Thanh Sang , Pham Truong-Vinh Ngoc , Le Minh-Triet , Nguyen Thi Tuong Vy , Phan Minh-Duy , Giang Hoa , Nguyen Hoai-Nghia , Tran Le Son
Published: November 2023

In the realm of cancer immunotherapy, the meticulous selection of neoantigens plays a fundamental role in enhancing personalized treatments. Traditionally, this selection process has heavily relied on predicting the binding of peptides to human leukocyte antigens (pHLA). Nevertheless, this approach often overlooks the dynamic interaction between tumor cells and the immune system. In response to this limitation, we have developed an innovative prediction algorithm rooted in machine learning, integrating T cell receptor β chain (TCRβ) profiling data from colorectal cancer (CRC) patients for a more precise neoantigen prioritization. TCRβ sequencing was conducted to profile the TCR repertoire of tumor-infiltrating lymphocytes (TILs) from 28 CRC patients. The data unveiled both intra-tumor and inter-patient heterogeneity in the TCRβ repertoires of CRC patients, likely resulting from the stochastic utilization of V and J segments in response to neoantigens. Our novel combined model integrates pHLA binding information with pHLA-TCR binding to prioritize neoantigens, resulting in heightened specificity and sensitivity compared to models using individual features alone. The efficacy of our proposed model was corroborated through ELISpot assays on long peptides, performed on four CRC patients. These assays demonstrated that neoantigen candidates prioritized by our combined model outperformed predictions made by the established tool NetMHCpan. This comprehensive assessment underscores the significance of integrating pHLA binding with pHLA-TCR binding analysis for more effective immunotherapeutic strategies.
Phylogenomics and phylodynamics of Zika Virus from Asia
Authors: Baig Kamil , Farah Shazia , Atkulwar Ashwin
Published: November 2023

The current study analyzes the Zika virus from Asia from a phylogenomic and phylodynamic perspective. To perform this study, 68 genomes from Asia were analyzed. A similar dataset was used to perform phylogenomics using Median Joining Network (MJN). MJN reconfirms African origin of Zika virus along with few notable instances of common origin of infection in some Asian countries. We investigated population dynamics using SkyGrid, Exponential Growth, and Constant Coalescence models. According to our phylodynamic analysis, effective population sizes throughout Asia reached higher peaks during the outbreak of 2016-2017. Zika virus population size increased exponentially during 2016-2017. From 1966 to 2021, there was a high and low peak in effective population size except for the outbreak of 2016-2017. To counter the outbreak of Zika Virus in Asian Countries in future, we recommend continuous genomic surveillance.
The stress history of soil bacteria under organic farming enhances the growth of wheat seedlings
Authors: Ornik Muriel , Salinas Renata , Antonacci Giona , Schädler Martin , Azarbad Hamed
Published: November 2023

The effects of stress factors associated with climate change and agricultural management practices on microorganisms are often studied separately, and it remains to be determined how these factors impact the soil microbiome and, subsequently, plant growth characteristics. The aim of this study was to understand how the historical climate and agriculture to which soil microbes have been exposed can influence the growth characteristics of wheat seedlings and their associated bacterial communities. We collected soil from organic and conventional fields with different histories of climate conditions to extract microbes to inoculate wheat seeds. The results showed a positive interaction between conventional farming practices and an ambient climate for faster and higher germination rates. We demonstrate that soil microbial extracts from organic farming with experience of the future climate significantly enhanced above-ground biomass along with bacterial diversity in the seedlings compared to the soil from conventional farming. Our data suggest that soil microbiomes selected by organic farming with a history of future climates can positively impact the aboveground biomass of wheat seedlings and their bacterial assemblages, emphasizing the potential benefits of organic farming practices under changing climate conditions.
Plant-based natural products for symptomatic relief of Parkinson’s disease: prevalence, interest, awareness and determinants
Authors: Diadhiou Sandra , Maas Bart R. , Schootemeijer Sabine , Bloem Bastiaan R. , de Vries Nienke M. , Calon Frédéric , Darweesh Sirwan K.L. , de Rus Jacquet Aurelie
Published: November 2023

Natural health products (NHP) have emerged as a potential symptomatic therapeutic approach for persons with Parkinson’s disease (PwP). The objective of this study was to quantify the prevalence of ever use of NHP, interest in plant-based NHP, awareness of potential herb-drug interactions, and how often NHP use was discussed by PwP with their healthcare professionals. We addressed these objectives by embedding a cross-sectional 4-item survey within a large population-based cohort of PwP (PRIME-NL study). Sixty-five percent (n=367) of the 566 participants who were contacted completed the survey. Of those participants, 132 (36%) reported having used NHP to alleviate Parkinson’s disease (PD)-related symptoms, with coffee, cannabis and turmeric being the most popular. Overall, 12% (n=44) of PwP had used at least one NHP other than coffee or cannabis. Furthermore, 71% (n=259) participants expressed an interest in exploring the use of NHP, but only 39% (n=51) of NHP users were aware that these products could interact with PD medication. Finally, only 39% (n=51) of NHP users had discussed the use of NHP with their neurologist or PD nurse specialist. In a sensitivity analysis, we conservatively assumed that all non-responders to the survey had never used NHP and had no interest in exploring NHP. This rendered an estimated prevalence of NHP use of 23% and an estimated interest in exploring NHP of 46%. In conclusion, over one in three PwP has used NHP to alleviate symptoms of PD and the majority of PwP is interested in exploring the use of plant-based NHP. Most users had not discussed the intake of NHP with their PD healthcare professional and were unaware that these products could interact with PD medication. This study supports the need for evidence-based research on the properties of plant-derived therapeutics.
Enhancer landscape of lung neuroendocrine tumors reveals regulatory and developmental signatures with potential theranostic implications
Authors: Davis Ester , Avniel-Polak Shani , Abu-Kamel Shahd , Antman Israel , Saadoun Tsipora , Brim Chava , Bel-Ange Anat , Atlan Karine , Tzur Tomer , Akar Firas Abu , Wald Ori , Izhar Uzi , Hecht Merav , Grozinsky-Glasberg Simona , Drier Yotam
Published: November 2023

Well-differentiated low-grade lung neuroendocrine tumors (lung carcinoids or LNETs) are histopathologically classified as typical and atypical LNETs, but each subtype is still heterogeneous at both the molecular level and its clinical manifestation. Here, we report the first genome-wide profiles of primary LNETs cis-regulatory elements by H3K27ac ChIP-seq with matching RNA-seq profiles. Analysis of these regulatory landscapes revealed three regulatory subtypes, independent of the typical / atypical classification. We identified unique differentiation signals that delineate each subtype. The ‘proneuronal subtype’ emerges under the influence of ASCL1, TCF4, and SOX4 transcription factors, embodying a pronounced proneuronal signature. The ‘luminal subtype’ is characterized by gain of acetylation at markers of luminal cells and GATA2 activation, and loss of LRP5 and OTP. The ‘HNF+ subtype’ is characterized by a robust enhancer landscape driven by HNF1A, HNF4A, and FOXA3, with a notable acetylation and expression of FGF signaling genes, especially FGFR3 and FGFR4 genes, pivotal components of the FGF pathway. Our findings not only deepen the understanding of LNETs’ regulatory and developmental diversity but also spotlight the HNF+ subtype’s reliance on FGFR signaling. We demonstrate that targeting this pathway with FGF inhibitors curtails tumor growth both in vitro and in xenograft models, unveiling a potential vulnerability and paving the way for targeted therapies. Overall, our work provides an important resource for studying LNETs to uncover regulatory networks, differentiation signals and therapeutically relevant dependences.
Pooled optical screening in bacteria using chromosomally expressed barcodes
Authors: Soares Ruben R. G. , García-Soriano Daniela A. , Larsson Jimmy , Fange David , Schirman Dvir , Grillo Marco , Knöppel Anna , Sen Beer Chakra , Svahn Fabian , Zikrin Spartak , Nilsson Mats , Elf Johan
Published: November 2023

Optical pooled screening is an important tool to study dynamic phenotypes for libraries of genetically engineered cells. However, the desired engineering often requires that the barcodes used forin situgenotyping are expressed from the chromosome. This has not been possible in bacteria. Here we describe a method forin situgenotyping of libraries with genomic barcodes inEscherichia. coli. The method is applied to measure the intracellular maturation time of 81 red fluorescent proteins.
Electrical Signalling in Three Dimensional Bacterial Biofilms Using an Agent Based Fire-Diffuse-Fire Model
Authors: Carneiro da Cunha Martorelli Victor , Akabuogu Emmanuel , Krašovec Rok , Roberts Ian S. , Waigh Thomas A.
Published: November 2023

Agent based models were used to describe electrical signalling in bacterial biofilms in three dimensions. Specifically, wavefronts of potassium ions inE. colibiofilms subjected to stress from blue light were modelled from experimental data. Electrical signalling only occurs when the biofilms grow beyond a threshold size, which we have shown to vary with theK+ion diffusivity and theK+ion threshold concentration which triggered firing in thefire-diffuse-fire model. The transport of the propagating wavefronts shows super-diffusive scaling on time.K+ion diffusivity is the main factor that affects the wavefront velocity. TheK+ion diffusivity and the firing threshold also affect the anomalous exponent for the propagation of the wavefront determining whether the wavefront is sub-diffusive or super-diffusive. The geometry of the biofilm and its relation to the mean square displacement (MSD) of the wavefront as a function of time was investigated for spherical, cylindrical, cubical and mushroom-like structures. The MSD varied significantly with geometry; an additional regime to the kinetics occurred when the potassium wavefront leaves the biofilm. Adding cylindrical defects to the biofilm, which are known to occur inE. colibiofilms, the wavefront MSD also had an extra kinetic regime for the propagation through the defect.
Co-habiting ants and silverfish display a converging feeding ecology
Authors: Parmentier Thomas , Molero-Baltanás Rafael , Valdivia Catalina , Gaju-Ricart Miquel , Boeckx Pascal , Łukasik Piotr , Wybouw Nicky
Published: November 2023

Species from a great number of animal taxa have specialized to living with social hosts. Depending on their level of specialization, these symbiotic animals are characterized by distinct behavioural, chemical, and morphological traits that enable close heterospecific interactions. Despite its functional importance, our understanding of the feeding ecology of specialized animals living with social hosts remains limited.

In this study, we examined how host specialization of silverfish co-habiting with ants affects several components of their feeding ecology. We combined stable isotope profiling, feeding assays, phylogenetic reconstruction, and microbial community characterization of theNeoasterolepismasilverfish genus and a wider nicoletiid and lepismatid silverfish panel where divergent myrmecophilous lifestyles are observed.

Stable isotope profiling (δ13C and δ15N) showed that the isotopic niches (proxy for trophic niches) of granivorousMessorants andMessor-specializedNeoasterolepismaexhibit a remarkable overlap within an ant nest. Trophic experiments and gut dissections further supported that these specializedNeoasterolepismasilverfish transitioned to a diet that includes plant seeds. In contrast, the isotopic niches of generalistNeoasterolepismasilverfish and generalist nicoletiid silverfish were clearly different from their ant hosts within the shared nest environment.

The impact of the myrmecophilous lifestyle on feeding ecology was also evident in the internal silverfish microbiome. Compared to generalists,Messor-specialists exhibited a higher bacterial density and a higher proportion of heterofermentative lactic acid bacteria. Moreover, the nest environment explained the infection profile (or the 16S rRNA genotypes) ofWeissellabacteria inMessor-specialized silverfish and the ant hosts.

Together, we show that social hosts are important determinants for the feeding ecology of symbiotic animals, and can induce diet convergence.
Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice
Authors: Brito David V.C. , Kupke Janina , Sokolov Rostilav , Cambridge Sidney , Both Martin , Bengtson C. Peter , Rozov Andrei , Oliveira Ana M.M.
Published: November 2023

Long-term memories are believed to be encoded by unique transcriptional signatures in the brain. The expression of immediate early genes (IEG) promotes structural and molecular changes required for memory consolidation. Recent evidence has shown that the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. However, it remains unknown whether IEG expression may play a role in memory suppression. Here we uncovered a novel function of the IEG neuronal PAS domain protein 4 (Npas4), as an inducible memory suppressor gene of highly salient aversive experiences. Using a contextual fear conditioning paradigm, we found that low stimulus salience leads to monophasic Npas4 expression, while highly salient learning induces a biphasic expression of Npas4 in the hippocampus. The later phase requires NMDA receptor activity and is independent of dopaminergic neurotransmission. Ourin vivopharmacological and genetic manipulation experiments suggested that the later phase of Npas4 expression restricts the consolidation of a fear memory and promote behavioral flexibility, by facilitating fear extinction and the contextual specificity of fear responses. Moreover, immunofluorescence and electrophysiological analysis revealed a concomitant increase in synaptic input from cholecystokinin (CCK)-expressing interneurons. Our results demonstrate how salient experiences evoke unique temporal patterns of IEG expression that fine-tune memory consolidation. Moreover, our study provides evidence for inducible gene expression associated with memory suppression as a possible mechanism to balance the consolidation of highly salient memories, and thereby to evade the formation of maladaptive behavior.
Towards the accurate modelling of antibody-antigen complexes from sequence using machine learning and information-driven docking
Authors: Giulini Marco , Schneider Constantin , Cutting Daniel , Desai Nikita , Deane Charlotte M. , Bonvin Alexandre M.J.J.
Published: November 2023

Antibody-antigen complex modelling is an important step in computational workflows for therapeutic antibody design. While experimentally determined structures of both antibody and the cognate antigen are often not available, recent advances in machine learning-driven protein modelling have enabled accurate prediction of both antibody and antigen structures. Here, we analyse the ability of protein-protein docking tools to use machine learning generated input structures for information-driven docking. We find that HADDOCK can generate accurate models of antibodyantigen complexes using an ensemble of antibody structures generated by machine learning tools and AlphaFold2 predicted antigen structures. Targeted docking using knowledge of the complementary determining regions on the antibody and some information about the targeted epitope allows the generation of high quality models of the complex with reduced sampling, resulting in a computationally cheap protocol that outperforms the ZDOCK baseline. The data set used to benchmark the docking protocols in this study is available at github.com/haddocking/ai-antibodies. The docking models will be deposited at data.sbgrid.org/labs/32/ upon acceptance.
Individual recognition in a jumping spider (Phidippus regius)
Authors: Dahl Christoph D. , Cheng Yaling
Published: November 2023

Individual recognition is conceptually complex and computationally intense, leading to the general assumption that this social knowledge is solely present in vertebrates with larger brains, while miniature-brained animals in differentiating societies eschew the evolutionary pressure for individual recognition by evolving computationally less demanding class-level recognition, such as kin, social rank, or mate recognition. Arguably, this social knowledge is restricted to species with a degree of sociality (sensu [1], for a review [2]). Here we show the exception to this rule in an asocial arthropod species, the jumping spider (Phidippus regius). Using a habituation - dishabituation paradigm, we visually confronted pairs of spatially separated spiders with each other and measured the ‘interest’ of one spider towards the other. The spiders exhibited high interest upon initial encounter of an individual, reflected in mutual approach behaviour, but adapted towards that individual when it reoccurred in the subsequent trial, indicated by their preference of staying farther apart. In contrast, spiders exhibited a rebound from habituation, reflected in mutual approach behaviour, when a different individual occurred in the subsequent trial, indicating the ability to tell apart spiders’ identities. These results suggest thatP. regiusis capable of individual recognition based on long-term social memory.