bluuebunny/crossref_metadata_2025 huggingface dataset:
A network model of the modulation of gamma oscillations by NMDA receptors in cerebral cortex
Authors: Susin Eduarda , Destexhe Alain
Published: December 2021

Psychotic drugs such as ketamine induce symptoms close to schizophrenia, and stimulate the production of gamma oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating gamma oscillations, and have integrated the action of drugs such as ketamine to partially block n-methyl-d-Aspartate (NMDA) receptors. The model can reproduce the paradoxical increase of gamma oscillations by NMDA-receptor antagonists, assuming that antagonists affect NMDA receptors with higher affinity on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channnels are diminished, an increase of gamma power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to gamma states, but was also present in asynchronous states with no apparent gamma. We conclude that NMDA antagonists induce an increased excitability state, which may or may not produce gamma oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations.

Significance Statement

n-methyl-d-Aspartate (NMDA) synaptic receptors mediate excitatory interactions using the neurotransmitter glutamate. NMDA receptors have been implicated in psychosis such as schizophrenia and are also targeted by hallucinogenic drugs like Ketamine. However, the exact mechanisms of action are sill unclear. Furthermore, Ketamine paradoxially leads to and excited state, while it is a blocker of NMDA receptors, therefore in principle diminishing excitation. Here, we use models of cortical networks generating gamma oscillations, and show that this model can explain the paradoxical exciting effect of Ketamine if one assumes a higher affinity on NMDA receptors of inhibitory interneurons. The simulated Ketamine effect reproduces known symptoms of psychosis such as increased gamma oscillations and exacerbated responses to external inputs, compatible with hallucinations.
Hemicentin mediated type IV collagen assembly strengthens juxtaposed basement membrane linkage
Authors: Gianakas Claire A. , Keeley Daniel P. , Ramos-Lewis William , Park Kieop , Jayadev Ranjay , Chi Qiuyi , Sherwood David R.
Published: December 2021

Basement membrane (BM) matrices surround and separate most tissues. However, through poorly understood mechanisms, BMs of adjacent tissues can also stably link to support organ structure and function. Using endogenous knock-in fluorescent proteins, conditional RNAi, optogenetics, and quantitative live imaging, we identified matrix proteins mediating a BM linkage (B-LINK) between the uterine utse and epidermal seam cell BMs in Caenorhabditis elegans that supports the uterus during egg-laying. We found that hemicentin is secreted by the utse and promotes fibulin-1 assembly to jointly initiate the B-LINK. During egg-laying, however, both proteins decline in levels and are not required for B-LINK maintenance. Instead, we discovered that hemicentin also promotes type IV collagen assembly, which accumulates to high levels during egg-laying and sustains the B-LINK during the mechanically active egg-laying period. This work reveals mechanisms underlying BM-BM connection maturation and identifies a crucial function for hemicentin and fibulin-1 in initiating attachment and type IV collagen in strengthening this specialized form of tissue linkage.

Tissue attachment through linking juxtaposed basement membranes (BMs) is crucial for the structure and function of many organs. Gianakas et al. identify a key role for hemicentin and fibulin-1 in initiating BM-BM attachment and type IV collagen in stabilizing this linkage and allowing it to resist high mechanical loads.
User-friendly analysis of droplet array images
Authors: Sanka Immanuel , Bartkova Simona , Pata Pille , Ernits Mart , Meinberg Monika , Agu Natali , Aruoja Villem , Smolander Olli-Pekka , Scheler Ott
Published: December 2021

Water-in-oil droplets allow researchers to perform massive experimental parallelization and high-throughput studies, such as single-cell experiments. However, the analysis of such vast arrays of droplets usually requires advanced expertise and sophisticated workflow tools, which limits the accessibility for wider user base in chemistry and biology. Thus, there is a need for more user-friendly tools for droplet analysis. In this article, we deliver a set of analytical pipelines for user-friendly analysis of typical scenarios in droplet-based experiments. We build the pipelines combining different open-source image-analysis software with the custom-developed data visualization tool “EasyFlow”. Our pipelines are designed to be applicable for the typical experimental scenarios users encounter with droplets: i) mono- and polydisperse droplets, ii) brightfield and fluorescent images, iii) droplet and object detection, iv) signal profile of droplets and objects (e.g., fluorescence).
A deep learning framework for predicting human essential genes from population and functional genomic data
Authors: LaPolice Troy M. , Huang Yi-Fei
Published: December 2021

Being able to predict essential genes intolerant to loss-of-function (LOF) mutations can dramatically improve our ability to identify genes associated with genetic disorders. Numerous computational methods have recently been developed to predict human essential genes from population genomic data; however, the existing methods have limited power in pinpointing short essential genes due to the sparsity of polymorphisms in the human genome. Here we present an evolution-based deep learning model, DeepLOF, which integrates population and functional genomic data to improve gene essentiality prediction. Compared to previous methods, DeepLOF shows unmatched performance in predicting ClinGen haploinsufficient genes, mouse essential genes, and essential genes in human cell lines. Furthermore, DeepLOF discovers 109 potentially essential genes that are too short to be identified by previous methods. Altogether, DeepLOF is a powerful computational method to aid in the discovery of essential genes.
The class I TCP transcription factor AtTCP8 is a modulator of phytohormone-responsive signaling networks
Authors: Spears Benjamin J. , McInturf Samuel A. , Chlebowski Meghann , Su Jianbin , Mendoza-Cózatl David G. , Gassmann Walter
Published: December 2021

The plant-specific TEOSINTE BRANCHED1/ CYCLOIDEA/ PROLIFERATING CELL FACTOR (TCP) transcription factor family is most closely associated with regulating plant developmental programs. Recently, TCPs were also shown to mediate host immune signaling, both as targets of pathogen virulence factors and regulators of plant defense genes. However, any comprehensive characterization of TCP gene targets is still lacking. Loss of the class I TCP AtTCP8 attenuates early immune signaling, and when combined with mutations in AtTCP14 and AtTCP15, additional layers of defense signaling in Arabidopsis thaliana. Here we focus on TCP8, the most poorly characterized of the three to date. We use chIP and RNA-sequencing to identify TCP8-bound gene promoters and differentially regulated genes in the tcp8 mutant, data sets that are heavily enriched in signaling components for multiple phytohormone pathways, including brassinosteroids (BRs), auxin, and jasmonic acid (JA). Using BR signaling as a representative example, we show that TCP8 directly binds and activates the promoters of the key BR transcriptional regulators BZR1 and BZR2/BES1. Furthermore, tcp8 mutant seedlings exhibit altered BR-responsive growth patterns and complementary reductions in BZR2 transcript levels, while the expressed protein demonstrates BR-responsive changes in subnuclear localization and transcriptional activity. We conclude that one explanation for the significant targeting of TCP8 alongside other TCP family members by pathogen effectors may lie in its role as a modulator of brassinosteroid and other plant hormone signaling pathways.

One Sentence Summary

One member of a pathogen-targeted transcription factor family modulates phytohormone response networks and displays brassinosteroid-dependent cellular location and activity.
Isolating salient variations of interest in single-cell data with contrastiveVI
Authors: Weinberger Ethan , Lin Chris , Lee Su-In
Published: December 2021

Single-cell datasets are routinely collected to investigate changes in cellular state between control cells and corresponding cells in a treatment condition, such as exposure to a drug or infection by a pathogen. To better understand heterogeneity in treatment response, it is desirable to disentangle latent structures and variations uniquely enriched in treated cells from those shared with controls. However, standard computational models of single-cell data are not designed to explicitly separate these variations. Here, we introduce Contrastive Variational Inference (contrastiveVI; https://github.com/suinleelab/contrastiveVI), a framework for analyzing treatment-control scRNA-seq datasets that explicitly disentangles the data into shared and treatment-specific latent variables. Using four treatment-control scRNA-seq dataset pairs, we apply contrastiveVI to perform a broad set of standard analysis tasks, including visualization, clustering, and differential expression testing. In each case, we find that our method consistently achieves results that agree with known biological ground truths, while previously proposed methods often fail to do so. We conclude by generalizing our framework to multimodal measurements and applying it to analyze a single-cell dataset with joint transcriptome and surface protein measurements.
Opioid withdrawal abruptly disrupts amygdala circuit function by reducing peptide actions
Authors: Gregoriou Gabrielle C. , Patel Sahil D. , Pyne Sebastian , Winters Bryony L. , Bagley Elena E.
Published: December 2021

Opioid withdrawal drives relapse and contributes to compulsive drug use through disruption of endogenous opioid dependent learning circuits in the amygdala. Normally, endogenous opioids control these circuits by inhibiting glutamate release from basolateral amygdala principal neurons onto GABAergic intercalated cells. Using patch-clamp electrophysiology in rat brain slices, we reveal that opioid withdrawal dials down this endogenous opioid inhibition of synaptic transmission. Peptide activity is dialled down due to a protein kinase A dependent increase in the activity of the peptidase, neprilysin. This disrupts peptidergic control of both GABAergic and glutamatergic transmission through multiple amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent learning processes in the amygdala during withdrawal. and may direct behaviour towards compulsive drug use. Restoration of endogenous peptide activity during withdrawal may be a viable option to normalise synaptic transmission in the amygdala and restore normal reward learning.

In Brief

We find that opioid withdrawal dials down inhibitory neuropeptide activity in the amygdala. This disrupts both GABAergic and glutamatergic transmission through amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent learning processes in the amygdala during withdrawal and may direct behaviour towards compulsive drug use.

Highlights

During opioid withdrawal, peptidase activity is upregulated in an amygdala circuit

Peptidase upregulation occurs via a PKA-dependent mechanism

Increased peptidase activity limits peptidergic control of synaptic transmission

Opioid withdrawal disrupts the balance of excitation and inhibition in the amygdala
In vivo reprogramming and epigenetic rejuvenation of adult cardiomyocytes ameliorate heart failure in mice
Authors: de Lázaro Irene , Zhang Bohan , Makarova Nadezhda E , Mariotti Marco , Orejón-Sánchez Tiara L , Tringides Christina M , Gladyshev Vadim N , Mooney David J
Published: December 2021

Partial cell reprogramming has been demonstrated in certain mouse tissues by in situ overexpression ofOct3/4,Klf4,Sox2andcMyc(OKSM) transcription factors, and can induce rejuvenation and/or augment regeneration. Reprogramming of adult cardiomyocytes has been elusive until recently, but its success could help overcome the lack of endogenous regenerative capacity of the mammalian myocardium. Here, we generated cardiomyocyte-specific, doxycycline-inducible, reprogrammable mice and demonstrated that sustained OKSM induction reprograms cardiomyocytes fully into teratoma-forming pluripotent cells. However, we also showed that cyclic OKSM upregulation induces significant decrease of epigenetic age in the cardiomyocytes without de-differentiation or reacquisition of pluripotency. In mice with progressive heart failure, cardiomyocyte epigenetic rejuvenation correlated with stabilization of systolic heart function. These findings confirm that OKSM can reprogram adult mouse cardiomyocytes to different states depending on the duration of their expression, and provide further evidence that partially reprogrammed cardiomyocytes may contribute to ameliorate cardiac disease.
Dissociable roles for the striatal cholinergic system in different flexibility contexts
Authors: Williams Brendan , Christakou Anastasia
Published: December 2021

The production of behavioural flexibility requires the coordination and integration of information from across the brain, by the dorsal striatum. In particular, the striatal cholinergic system is thought to be important for the modulation of striatal activity. Research from animal literature has shown that chemical inactivation of the dorsal striatum leads to impairments in reversal learning. Furthermore, proton magnetic resonance spectroscopy work has shown that the striatal cholinergic system is also important for reversal learning in humans. Here, we aim to assess whether the state of the dorsal striatal cholinergic system at rest is related to flexible behaviour in reversal learning. We provide preliminary results showing that variability in choline in the dorsal striatum is significantly related to both the number perseverative and regressive errors that participants make, and their rate of learning from positive and negative prediction errors. These findings, in line with previous work, suggest the resting state of dorsal striatal cholinergic system has important implications for producing flexible behaviour. However, these results also suggest the system may have heterogeneous functionality across different types of tasks measuring behavioural flexibility. These findings provide a starting point for further interrogation into understanding the functional role of the striatal cholinergic system in flexibility.
Super-resolution vibrational imaging using expansion stimulated Raman scattering microscopy
Authors: Shi Lixue , Klimas Aleksandra , Gallagher Brendan , Cheng Zhangyu , Fu Feifei , Wijesekara Piyumi , Miao Yupeng , Ren Xi , Zhao Yongxin , Min Wei
Published: December 2021

Stimulated Raman scattering (SRS) microscopy is an emerging technology that provides high chemical specificity for endogenous biomolecules and can circumvent common constraints of fluorescence microscopy including limited capabilities to probe small biomolecules and difficulty resolving many colors simultaneously due to spectral overlap. However, the resolution of SRS microscopy remains governed by the diffraction limit. To overcome this, we describe a new technique called Molecule Anchorable Gel-enabled Nanoscale Imaging of Fluorescence and stImulatEd Raman Scattering microscopy (MAGNIFIERS), that integrates SRS microscopy with expansion microscopy (ExM). ExM is a powerful strategy providing significant improvement in imaging resolution by physical magnification of hydrogel-embedded preserved biological specimens. MAGNIFIERS offers chemical-specific nanoscale imaging with sub-50 nm resolution and has scalable multiplexity when combined with multiplex Raman probes and fluorescent labels. We used MAGNIFIERS to visualize nanoscale features in a label-free manner with C-H vibration of proteins, lipids and DNA in a broad range of biological specimens, from mouse brain, liver and kidney to human lung organoid. In addition, we applied MAGNIFIERS to track nanoscale features of protein synthesis in protein aggregates using metabolic labeling of small metabolites. Finally, we used MAGNIFIERS to demonstrate 8-color nanoscale imaging in an expanded mouse brain section. Overall, MAGNIFIERS is a valuable platform for super-resolution label-free chemical imaging, high-resolution metabolic imaging, and highly multiplexed nanoscale imaging, thus bringing SRS to nanoscopy.
Experimental platform for the functional investigation of membrane proteins in giant unilamellar vesicles
Authors: Dolder Nicolas , Müller Philipp , von Ballmoos Christoph
Published: December 2021

Giant unilamellar vesicles (GUVs) are micrometer-sized model membrane systems that can be viewed directly under the microscope. They serve as scaffolds for the bottom-up creation of synthetic cells, targeted drug delivery and have been used in many in vitro studies of membrane related phenomena. GUVs are also of interest for the functional investigation of membrane proteins that carry out many key cellular functions. A major hurdle to a wider application of GUVs in this field is the diversity of existing protocols that are optimized for individual proteins. Here, we compare PVA assisted and electroformation techniques for GUV formation under physiologically relevant conditions, and analyze the effect of immobilization on vesicle structure and membrane tightness towards small substrates and protons. There, differences in terms of yield, size, and leakage of GUVs produced by PVA assisted swelling and electroformation were found, dependent on salt and buffer composition. Using fusion of oppositely charged membranes to reconstitute a model membrane protein, we find that empty vesicles and proteoliposomes show similar fusion behavior, which allows for a rapid estimation of protein incorporation using fluorescent lipids.
Exploratory growth in Streptomyces venezuelae involves a unique transcriptional program, enhanced oxidative stress response, and profound acceleration in response to glycerol
Authors: Shepherdson Evan M. F. , Netzker Tina , Stoyanov Yordan , Elliot Marie A.
Published: December 2021

Exploration is a recently discovered mode of growth and behaviour exhibited by some Streptomyces species that is distinct from their classical sporulating life cycle. While much has been uncovered regarding initiating environmental conditions and the phenotypic outcomes of exploratory growth, how this process is coordinated at a genetic level remains unclear. We used RNA-sequencing to survey global changes in the transcriptional profile of exploring cultures over time in the model organism Streptomyces venezuelae. Transcriptomic analyses revealed widespread changes in gene expression impacting diverse cellular functions. Investigations into differentially expressed regulatory elements revealed specific groups of regulatory factors to be impacted, including the expression of several extracytoplasmic function (ECF) sigma factors, second messenger signalling pathways, and members of the whiB-like (wbl) family of transcription factors. Dramatic changes were observed among primary metabolic pathways, especially among respiration-associated genes and the oxidative stress response; enzyme assays confirmed that exploring cultures exhibit an enhanced oxidative stress response compared with classically growing cultures. Changes in expression of the glycerol catabolic genes in S. venezuelae led to the discovery that glycerol supplementation of the growth medium promotes a dramatic acceleration of exploration. This effect appears to be unique to glycerol as an alternative carbon source and this response is broadly conserved across other exploration-competent species.
Taking stock of the past: A psychometric evaluation of the Autobiographical Interview
Authors: Lockrow Amber W. , Setton Roni , Spreng Karen A.P. , Sheldon Signy , Turner Gary R. , Spreng R. Nathan
Published: December 2021

Autobiographical memory (AM) involves a rich phenomenological re-experiencing of a spatio-temporal event from the past, which is challenging to objectively quantify. The Autobiographical Interview (AI; Levine etal., 2002,Psychology & Aging) is a manualized performance-based assessment designed to quantify episodic (internal) and semantic (external) features of recalled and verbally conveyed prior experiences. The AI has been widely adopted yet has not undergone a comprehensive psychometric validation. We investigated the reliability, validity, association to individual differences measures, and factor structure in healthy younger and older adults (N=352). Evidence for the AI’s reliability was strong: the subjective scoring protocol showed high inter-rater reliability and previously identified age effects were replicated. Internal consistency across timepoints was robust, suggesting stability in recollection. Central to our validation, internal AI scores were positively correlated with standard, performance-based measures of episodic memory, demonstrating convergent validity. The two-factor structure for the AI was not well-supported by confirmatory factor analysis. Adjusting internal and external detail scores for the number of words spoken (detail density) improved trait estimation of AM performance. Overall, the AI demonstrated sound psychometric properties for inquiry into the qualities of autobiographical remembering.
Post-error slowing reflects the joint impact of adaptive and maladaptive processes during decision making
Authors: Fievez Fanny , Derosiere Gerard , Verbruggen Frederick , Duque Julie
Published: December 2021

Errors and their consequences are typically studied by investigating changes in decision speed and accuracy in trials that follow an error, commonly referred to as “post-error adjustments”. Many studies have reported that subjects slow down following an error, a phenomenon called “post-error slowing” (PES). However, the functional significance of PES is still a matter of debate as it is not always adaptive. That is, it is not always associated with a gain in performance and can even occur with a decline in accuracy. Here, we hypothesized that the nature of PES is influenced by one’s speed-accuracy tradeoff policy, which determines the overall level of choice accuracy in the task at hand. To test this hypothesis, we investigated post-error adjustments in subjects performing the same task while they were required to either emphasize speed (low accuracy) or cautiousness (high accuracy) in two distinct contexts (hasty and cautious contexts, respectively) experienced on separate days. Accordingly, our data indicate that post-error adjustments varied according to the context in which subjects performed the task, with PES being solely significant in the hasty context. In addition, we only observed a gain in performance after errors in a specific trial type, suggesting that post-error adjustments depend on a complex combination of processes that affect the speed of ensuing actions as well as the degree to which such PES comes with a gain in performance.
Theta oscillations in the prefrontal-hippocampal circuit do not couple to respiration-related oscillations
Authors: Srikanth Sunandha , Le Dylan , Hu Yudi , Leutgeb Jill K. , Leutgeb Stefan
Published: December 2021

Oscillatory activity is thought to coordinate neural computations across brain regions, and theta oscillations are critical for learning and memory. Because the frequency of respiratory-related oscillations (RROs) in rodents can overlap with the frequency of theta in the prefrontal cortex (PFC) and the hippocampus, we asked whether odor-cued working memory may be supported by coupling between these two oscillations. We first confirmed that RROs are propagated to the hippocampus and PFC and that RRO frequency overlaps with canonical theta frequency. However, we found low coherence between RROs and local theta oscillations in the hippocampus-PFC network when the two types of oscillations overlapped in frequency. This effect was observed during all behavioral phases including during movement and while odors were actively sampled when stationary. Despite the similarity in frequency, RROs and theta oscillations therefore appear to be limited to supporting computation in distinct networks, which suggests that sustained long-range coordination between oscillation patterns that depend on separate pacemakers is not necessary to support at least one type of working memory.
Network design principle for robust oscillatory behaviors with respect to biological noise
Authors: Qiao Lingxia , Zhang Zhi-Bo , Zhao Wei , Wei Ping , Zhang Lei
Published: December 2021

Oscillatory behaviors, which are ubiquitous in transcriptional regulatory networks, are often subject to inevitable biological noise. Thus a natural question is how transcriptional regulatory networks can robustly achieve accurate oscillation in the presence of biological noise. Here, we search all two- and three-node transcriptional regulatory network topologies for those robustly capable of accurate oscillation against the parameter variability (extrinsic noise) or stochasticity of chemical reactions (intrinsic noise). We find that, no matter what source of the noise is applied, the topologies containing the repressilator with positive auto-regulation show higher robustness of accurate oscillation than those containing the activator-inhibitor oscillator, and additional positive auto-regulation enhances the robustness against noise. Nevertheless, the attenuation of different sources of noise is governed by distinct mechanisms: the parameter variability is buffered by the long period, while the stochasticity of chemical reactions is filtered by the high amplitude. Furthermore, we analyze the noise of a synthetic human nuclear factor κB (NF-κB) signaling network by varying three different topologies, and verify that the addition of a repressilator to the activator-inhibitor oscillator, which leads to the emergence of high-robustness motif—the repressilator with positive auto-regulation, improves the oscillation accuracy in comparison to the topology with only an activator-inhibitor oscillator. These design principles may be applicable to other oscillatory circuits.
Antibody-Independent Antitumor Effects of Cd32A-Chimeric Receptor T Cells: Implications for Breast Cancer Prognosis and Treatment
Authors: Sconocchia Giuseppe , Lanzilli Giulia , Cesarini Valeriana , Silvestris Domenico Alessandro , Arriga Roberto , Rezvani Katayoun , Caratelli Sara , Chen Ken , Dou Jinzhuang , Cenciarelli Carlo , Toietta Gabriele , Baldari Silvia , Sconocchia Tommaso , Paolis Francesca De , Aureli Anna , Iezzi Giandomenica , del Principe Maria Ilaria , Venditti Adriano , Ottaviani Alessio , Spagnoli Giulio Cesare
Published: December 2021

Fcγ RIIA (CD32A) and their ligands, including the immunoglobulin Fc fragment and pentraxins, are key players in a variety of innate immune responses. Still unclear is whether additional ligands of CD32A do exist. The objective of this study is to demonstrate that CD32A-chimeric receptor (CR) can be utilized for the identification of CD32A cell surface ligand(s). Among fifteen cancer cell lines tested, CD32A-CR T cells recognized three of breast cancer (BC) including the MDA-MB-468 and one colorectal carcinoma (HT29) in the absence of targeting antibodies. Conjugation of sensitive BC cells with CD32A-CR T cells induced CD32A polarization and down-regulation, CD107 release, and mutual cell eliminationin vitro. Conversely, normal fibroblasts and myoblasts were not affected while normal HUVEC cells promoted CD32A down-regulation. CD32A-CR T cell activity was not inhibited by human IgGs or human serum, but; it was rather enhanced by cetuximab antibody. RNAseq analysis of sensitive vs resistant BC cells identified a fingerprint of 42 genes predicting the sensitivity of BC cells to CD32A-CR T cells and their association with favorable prognostic significance in advanced BC patients. Our data also identify ICAM 1 as a major regulator of CD32A-CR T cell-mediated cytotoxicity. Finally, CD32A-CR T cell administration protected immunodeficient mice from subcutaneous growth of MDA-MB-468 cells in the absence of tumor-specific antibodies. These data indicate that CD32A-CR can be utilized for the identification of (1) cell surface CD32A ligand(s); (2) rational therapeutic strategies to target BC; and (3) novel transcriptomic signatures prognostically relevant for advanced BC patients.
Multi-omics Topic Modeling for Breast Cancer Classification
Authors: Valle Filippo , Osella Matteo , Caselle Michele
Published: December 2021

The integration of transcriptional data with other layers of information, such as the post-transcriptional regulation mediated by microRNAs, can be crucial to identify the driver genes and the subtypes of complex and heterogeneous diseases such as cancer. This paper presents an approach based on topic modeling to accomplish this integration task. More specifically, we show how an algorithm based on a hierarchical version of stochastic block modeling can be naturally extended to integrate any combination of ‘omics data. We test this approach on breast cancer samples from the TCGA database, integrating data on messenger RNA, microRNAs and copy number variations. We show that the inclusion of the microRNA layer significantly improves the accuracy of subtype classification. Moreover, some of the hidden structures or “topics” that the algorithm extracts actually correspond to genes and microRNAs involved in breast cancer development, and are associated to the survival probability.

Simple Summary

Topic models are algorithms introduced for discovering hidden topics or latent variables in large unstructured text corpora. Leveraging on analogies between texts and gene expression profiles, these algorithms can be used to find structures in expression data. This work presents an application of topic modeling techniques to the identification of breast cancer subtypes. In particular, we extended a specific class of topic models to allow a multi-omics approach. As an illustrative example, considering both messenger RNA and microRNA expression levels, we were able to clearly distinguish healthy from tumor samples, as well as the different breast cancer subtypes. The integration of different layers of information is crucial for the observed classification accuracy. Our approach naturally provides the genes and the microRNAs associated to the specific topics that are used for the sample organization. We show that indeed these topics often contain genes involved in breast cancer development, and are associated to different survival probabilities.
Metal transporter SLC39A14/ZIP14 modulates regulation between the gut microbiome and host metabolism
Authors: Thorn Trista L. , Mitchell Samuel B. , Kim Yongeun , Lee Min-Ting , Comrie Janine M. C. , Johnson Elizabeth L. , Aydemir Tolunay B.
Published: December 2021

Zinc (Zn) plays a critical role in maintaining intestinal homeostasis by regulating intestinal epithelial cells, host immune cells, and gut microbiome community composition. Deletion of metal transporter Slc39a14/Zip14 causes spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose, suggesting a role for ZIP14-mediated intestinal metal transport in regulating both intestinal homeostasis and systemic metabolism. Here, we showed the function of ZIP14-mediated Zn transport in the gut microbiome composition and how ZIP14-linked changes to gut microbiome community composition are correlated with changes in host metabolism. Deletion of Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract; reduced bacterial diversity and Saccharomyces cerevisiae (S. cerevisiae) overgrowth; altered host metabolome; and shifted host energy metabolism toward glucose utilization. This work provides evidence for the regulation of gut microbiome composition, host metabolome, and energy metabolism by metal transporter ZIP14.

Significance

Intestinal permeability, gut dysbiosis, and Zn dyshomeostasis are emerging signatures of inflammatory bowel diseases and metabolic disorders such as type-2-diabetes and obesity. Zn deficiency is a common clinical finding among these diseases. Zn is essential for the regulation of the intestinal epithelial cells, host immune cells, and the gut microbiome. Transporter-mediated mobilization of Zn plays a critical role in maintaining intestinal homeostasis by facilitating the targeted tissue/cell-specific function. However, studies are lacking in linking transporter-mediated Zn mobilization, gut microbiome, host’s intestinal health, and metabolism. Using the systems-level approach, this study revealed novel findings that deletion of Slc39a14/Zip14 resulted in altered intestinal Zn homeostasis, gut microbiome composition, host metabolome and energy metabolism.
Heterogeneity of network and coding states in CA1
Authors: Guardamagna Matteo , Stella Federico , Battaglia Francesco P.
Published: December 2021

Theta sequences and phase precession shape the activity time course of hippocampal place cells. Theta sequences are rapid sweeps of spikes from multiple cells, tracing trajectories from past to future. Phase precession is the correlation between a place cell’s theta firing phase and animal position. Here we present an analysis of the strongly variable character of these features in CA1. We identify a cell group that do not phase precess but reliably express theta sequences. The cells that do phase precess only do so when the medium gamma oscillations (60-90 Hz, linked to Entorhinal inputs) dominates but then they show less theta sequences. The same cells express more sequences but not precession when slow gamma (20-45 Hz, linked to CA3 inputs) dominates. Moreover, sequences occur independently in the two groups. Our results challenge a causal relationship between precession and sequences and highlights the highly heterogeneous character of the hippocampal output.
Single-cell RNA-seq analysis reveals lung epithelial cell-specific contributions of Tet1 to allergic inflammation
Authors: Zhu Tao , Brown Anthony P. , Cai Lucy , Quon Gerald , Ji Hong
Published: December 2021

Tet1 protects against house dust mite (HDM)-induced lung inflammation in mice and alters the lung methylome and transcriptome. In order to explore the role of Tet1 in individual lung epithelial cell types in HDM-induced inflammation, we established a model of HDM-induced lung inflammation in Tet1 knockout and littermate wildtype mice and studied EpCAM+ lung epithelial cells using single-cell RNA-seq analysis. We identified eight EpCAM+ lung epithelial cell types, among which AT2 cells were the most abundant. HDM challenge increased the percentage of alveolar progenitor cells (AP), broncho alveolar stem cells (BAS), and goblet cells, and decreased the percentage of AT2 and ciliated cells. Bulk and cell-type-specific analysis identified genes subject to Tet1 regulation and linked to augmented lung inflammation, including alarms, detoxification enzymes, oxidative stress response genes, and genes in tissue repair. The transcriptomic regulation was accompanied by alterations in TF activities. Trajectory analysis supports that HDM may enhance the differentiation of AP and BAS cells into AT2 cells, independent of Tet1. Collectively, our data showed that lung epithelial cells had common and unique transcriptomic signatures of allergic lung inflammation. Tet1 deletion altered transcriptomic networks in various lung epithelial cells, with an overall effect of promoting allergen-induced lung inflammation.
Vicia faba TPC1, a genetically encoded variant of the vacuole Two Pore Channel 1, is hyperexcitable
Authors: Lu Jinping , Dreyer Ingo , Dickinson Miles Sasha , Panzer Sabine , Jaslan Dawid , Navarro-Retamal Carlos , Geiger Dietmar , Terpitz Ulrich , Becker Dirk , Stroud Robert M. , Marten Irene , Hedrich Rainer
Published: December 2021

To fire action-potential-like electrical signals, the vacuole membrane requires the depolarization-activated two-pore channel TPC1, also called Slowly activating Vacuolar SV channel. The TPC1/SV channel, encoded by the TPC1 gene, functions as a voltage-dependent and Ca2+-regulated potassium channel. TPC1 currents are activated by a rise in cytoplasmic Ca2+ but inhibited by luminal Ca2+. In search for species-dependent functional TPC1 channel variants, we studied polymorphic amino acids contributing to luminal Ca2+ sensitivity. We found that the acidic residues E457, E605 and D606 of the Ca2+-sensitive Arabidopsis AtTPC1 channel were neutralized by either asparagine or alanine in Vicia faba and many other Fabaceae as well. When expressed in the Arabidopsis loss-of-AtTPC1 function background, the wild type VfTPC1 was hypersensitive to vacuole depolarization and insensitive to blocking luminal Ca2+. When AtTPC1 was mutated for the three VfTPC1-homologous polymorphic site residues, the Arabidopsis At-VfTPC1 channel mutant gained VfTPC1-like voltage and luminal Ca2+ insensitivity that together made vacuoles hyperexcitable. These findings indicate that natural TPC1 channel variants in plant families exist which differ in vacuole excitability and very likely respond to changes in environmental settings of their ecological niche.

Significance statement

Vacuolar electrical excitability and stress-related Ca2+ signaling depends on the activity of the vacuolar cation channel TPC1. Until now, the regulatory features of AtTPC1 from the model plant Arabidopsis thaliana was believed to apply to the TPC1 channels of other species. However, here we now show that, surprisingly, the VfTPC1 channel of the economic broad bean, in contrast to AtTPC1, proves to be hyperactive and confers hyperexcitability to the vacuole. The different gating behavior is most likely related to an impaired Ca2+ sensor site in the vacuolar pore vestibule, rising the probability to open at more negative membrane voltages. These natural variants of the TPC1 channel could help the plant adapt and respond to environmental challenges.
Multimodal fusion analysis of functional, cerebrovascular and structural neuroimaging in healthy ageing subjects
Authors: Liu Xulin , Tyler Lorraine K ,   Cam-CAN, Rowe James B , Tsvetanov Kamen A
Published: December 2021

Brain ageing is a complex process which requires a multimodal approach. Neuroimaging can provide insights into brain morphology, functional organization and vascular dynamics. However, most neuroimaging studies of ageing have focused on each imaging modality separately, limiting the understanding of interrelations between processes identified by different modalities and their relevance to cognitive decline in ageing. Here, we used a data-driven multimodal approach, linked independent component analysis (ICA), to jointly analyze magnetic resonance imaging of grey matter volume, cerebrovascular, and functional network topographies in relation to measures of fluid intelligence. Neuroimaging and cognitive data from the Cambridge Centre for Ageing and Neuroscience study were used, with healthy participants aged 18 to 88 years (main dataset n = 215; secondary dataset n = 433). Using linked ICA, functional network activities were characterized in independent components but not captured in the same component as structural and cerebrovascular patterns. Split-sample (n = 108/107) and out-of-sample (n = 433) validation analyses using linked ICA were also performed. Global grey matter volume with regional cerebrovascular changes and the right frontoparietal network activity were correlated with age-related and individual differences in fluid intelligence. This study presents the insights from linked ICA to bring together measurements from multiple imaging modalities, with independent and additive information. We propose that integrating multiple neuroimaging modalities allows better characterization of brain pattern variability and changes associated with healthy ageing.
The nonlinearity of regulation in biological networks
Authors: Manicka Santosh , Johnson Kathleen , Levin Michael , Murrugarra David
Published: December 2021

The extent to which the components of a biological system are (non)linearly regulated determines how amenable they are to therapy and control. To better understand this property termed ‘regulatory nonlinearity’, we analyzed a suite of 137 published Boolean network models, containing a variety of complex nonlinear regulatory interactions, using a probabilistic generalization of Boolean logic that George Boole himself had proposed. Leveraging the continuous-nature of this formulation, we used Taylor decomposition to approximate the models with various levels of regulatory nonlinearity. A comparison of the resulting series of approximations of the biological models with appropriate random ensembles revealed that biological regulation tends to be less nonlinear than expected, meaning that higher-order interactions among the regulatory inputs tend to be less pronounced. A further categorical analysis of the biological models revealed that the regulatory nonlinearity of cancer and disease networks could not only be sometimes higher than expected but also relatively more variable. We show that this variation is caused by differences in the apportioning of information among the various orders of regulatory nonlinearity. Our results suggest that there may have been a weak but discernible selection pressure for biological systems to evolve linear regulation on average, but for certain systems such as cancer, on the other hand, to also evolve more nonlinear rules.
Intramolecular interactions enhance the potency of gallinamide A analogs againstTrypanosoma cruzi
Authors: Da Silva Elany Barbosa , Sharma Vandna , Hernandez-Alvarez Lilian , Tang Arthur H. , Stoye Alexander , O’Donoghue Anthony J. , Gerwick William H. , Payne Richard J. , McKerrow James H. , Podust Larissa M.
Published: December 2021

Gallinamide A, a metabolite of the marine cyanobacteriumSchizothrixsp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated potency of gallinamide A and 23 synthetic analogs against intracellularTrypanosoma cruziamastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogs at ∼2Å. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular π−π stacking interactions between the aromatic substituents at P1’ and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1’ interacts with tryptophan-184. The P1-P1’ interactions had no effect on anti-cruzain activity whereas anti-T. cruzipotency increased by ∼5-fold, likely due to an increase in solubility/permeability of the analogs.
Weakly deleterious natural genetic variation greatly amplifies probability of resistance in multiplexed gene drive systems
Authors: Khatri Bhavin S. , Burt Austin
Published: December 2021

Evolution of resistance is a major barrier to successful deployment of gene drive systems to suppress natural populations, which could greatly reduce the burden of many vector borne diseases. Multiplexed guide RNAs that require resistance mutations in all target cut sites is a promising anti-resistance strategy, since in principle resistance would only arise in unrealistically large populations. Using novel stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) non-homologous end-joining mutations, 2) single nucleotide mutants arising de novo or, 3) single nucleotide polymorphisms pre-existing as standing variation. Our results explore the relative importance of these mechanisms and highlight a complexity of the mutation-selection-drift balance between haplotypes with complete resistance and those with an incomplete number of resistant alleles. We find this leads to a qualitatively new phenomenon where weakly deleterious naturally occurring variants greatly amplify the probability of multi-site resistance. This challenges the intuition that many target sites would guarantee prevention of resistance, where in the face of standing genetic variation, it can be probable even in not very large populations. This result has broad application to resistance arising in many multi-site evolutionary scenarios including multi-drug resistance to antibiotics, antivirals and cancer treatments, as well as the evolution of vaccine escape mutations in large populations.
Lack of pulmonary fibrogenicity and carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model
Authors: Yamano Shotaro , Takeda Tomoki , Goto Yuko , Hirai Shigeyuki , Furukawa Yusuke , Kikuchi Yoshinori , Kasai Tatsuya , Misumi Kyohei , Suzuki Masaaki , Takanobu Kenji , Senoh Hideki , Saito Misae , Kondo Hitomi , Umeda Yumi
Published: December 2021

Background

With the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. There have been no systemic inhalation exposure studies of titanium dioxide nanoparticles (TiO2 NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) 26-week study mice model for detecting carcinogenicity.

Methods

Male and female rasH2 mice were exposed to 2, 8 or 32 mg/m3 of TiO2 NPs for 6 hours/day, 5 days/week for 26 weeks using a whole-body inhalation exposure system, with reference to the Organization for Economic Co-operation and Development principles of Good Laboratory Practice. All tissues including lungs, and blood were collected and subjected to biological and histopathological analyses. Additionally, Ki67 positive index were evaluated in mice lung alveolar epithelial type 2 cell (AEC2).

Results

This study established a stable method for generating and exposing TiO2 NPs aerosol, and clarified the dose-response relationship by TiO2 NPs inhalation to rasH2 mice. TiO2 NPs exposure induced deposition of particles in lungs and mediastinal lymph nodes in a dose-dependent manner in each exposure group. Additionally, alveolar inflammation was only observed in 32 mg/m3 exposure group in both the sexes. Exposure to TiO2 NPs, as well as other organs, did not increase the incidence of lung tumors in any group, and pulmonary fibrosis and pre-neoplastic lesions were not observed in all groups. Finally, the cell proliferative activity of AEC2 was examined, and it was not increased by exposure to TiO2 NPs.

Conclusions

This is the first report showing the lack of pulmonary fibrogenicity and carcinogenicity (no evidence of carcinogenic activity) of TiO2 NPs in 26-week inhalation study in rasH2 mice exposed up to 32 mg/m3, which is considered to be a high concentration. Macrophages undergoing phagocytosis due to TiO2 NPs exposure formed inflammatory foci in the alveolar regions of exposed mice but did not develop fibrosis or hyperplasia or tumors. Moreover, the cell proliferative ability of AEC2 in lesions was not increased. In addition, no carcinogenicity was observed for any organs other than the lungs in this study.