bluuebunny/crossref_metadata_2025 huggingface dataset:
Food odours associated with conspecific corpses cause food avoidance in an invasive ant
Authors: Wagner Thomas , Czaczkes Tomer J.
Published: May 2023

Invasive ants, such asLinepithema humile(the Argentine ant), pose a global threat, necessitating a better understanding of their behaviour in order to improve management strategies. Traditional eradication methods, including baiting, have had limited success, but the causes of control failure are not always clear. Here we propose that ants may learn to avoid toxic baits in part due to their association with ant corpses. Ants were tested on a Y-maze after exposure to scented corpses or dummies. 69% (n = 64) of ants avoided branches bearing the scent of scented corpses. At a collective level, colonies neglected food sources associated with scented ant corpses in favour of a food source with a novel odour, with only 42% (n = 273) of foragers feeding from the corpse-scent associated food source. However, if corpses were produced by feeding ants scented toxicant, focal ants encountering these corpses did not avoid the corpse-associated scent on a Y maze (53%, n = 65). Moreover, in a dual-feeder test, ants did not avoid feeding at food sources scented with an odour associated with conspecific corpses. The study demonstrates that conspecific corpses can act as a negative stimulus forLinepithema humile, leading to avoidance of odours associated with corpses, which can lead to potential avoidance of toxic baits. Why the more realistic Y-maze trial with corpses of ants that had ingested the toxicant elicited no avoidance is unclear: it may be due to weaker odour cues from ingested food, or a counterbalancing of the negative corpse stimulus by the positive presence of food remains on the corpse. Nonetheless, this study demonstrates that conspecific corpses act as a negative stimulus for ants, and this should be kept in mind when planning control efforts. A simple solution to this issue would be adding odours to baits, and cycling baits between treatments. This would disrupt the association between bait odour and corpses.
Identification of Novel Allosteric Sites of SARS-CoV-2 Papain-Like Protease (PLpro) for the Development of COVID-19 Antivirals
Authors: Ferreira Juliana C. , Villanueva Adrian J. , Al Adem Kenana , Fadl Samar , Alzyoud Lara , Ghattas Mohammad A , Rabeh Wael M.
Published: May 2023

Coronaviruses such as SARS-CoV-2 encode a conserved papain-like protease (PLpro) that is crucial for viral replication and immune evasion, making it a prime target for antiviral drug development. In this study, three surface pockets on SARS-CoV-2 PLpro that may function as sites for allosteric inhibition were computationally identified. To evaluate the effects of these pockets on proteolytic activity, 52 residues were separately mutated to alanine. In Pocket 1, located between the Ubl and thumb domains, the introduction of alanine at T10, D12, T54, Y72, or Y83 reduced PLpro activity to <12% of that of WT. In Pocket 2, situated at the interface of the thumb, fingers, and palm domains, Q237A, S239A, H275A, and S278A inactivated PLpro. Finally, introducing alanine at five residues in Pocket 3, between the fingers and palm domains, inactivated PLpro: S212, Y213, Y251, K254, and Y305. Pocket 1 has a higher druggability score than Pockets 2 and 3. MD simulations showed that interactions within and between domains play critical roles in PLpro activity and thermal stability. The essential residues in Pockets 1 and 2 participate in a combination of intra- and inter-domain interactions. By contrast, the essential residues in Pocket 3 predominantly participate in inter-domain interactions. The most promising targets for therapeutic development are Pockets 1 and 3, which have the highest druggability score and the largest number of essential residues, respectively. Non-competitive inhibitors targeting these pockets may be antiviral agents against COVID-19 and related coronaviruses.
Microtubule-mediated cell shape regulation contributes to efficient cell packing inArabidopsis thalianacotyledons
Authors: Matz Timon W. , Eng Ryan C. , Sampathkumar Arun , Nikoloski Zoran
Published: May 2023

Recent advances have started to uncover the mechanisms involved in organ and cell shape regulation. However, organizational principles of epidermal cells in different tissues remain poorly understood. Here, we show that polygonal representations of cotyledon pavement cells (PCs) inArabidopsis thalianaexhibit increasing irregularity in side lengths and internal vertex angles during early stages of development. While the shape of PCs in cotyledons is more complex than that of cells in the shoot apical meristem (SAM), the polygonal representations of these cells share similar irregularity of side length. Comparison of the surface cell area with the area of the regular polygons, having optimally spaced tri-cellular junctions, reveals suboptimal junction placement for coverage in cotyledons and SAM. We also found that cotyledons show increased packing density compared to the SAM, indicating that PCs forgo coverage of larger areas to potentially increase tissue stability. The identified shape irregularity and cell packing is associated with microtubule cytoskeleton. Our study provides a framework to analyze reasons and consequences of irregularity of polygonal shapes for biological as well as artificial shapes in larger organizational context.

We provide a polygonal cell representation in a tissue context and use it to draw conclusions about cell packing in epidermis ofA. thalianacotyledon.
Specific attributes of the VLdomain influence both the structure and structural variability of CDR-H3 through steric effects
Authors: Guloglu Bora , Deane Charlotte M.
Published: May 2023

Antibodies, through their ability to target virtually any epitope, play a key role in driving the adaptive immune response in jawed vertebrates. The binding domains of standard antibodies are their variable light (VL) and heavy (VH) domains, both of which present analogous complementarity-determining region (CDR) loops. It has long been known that the VHCDRs contribute more heavily to the antigen-binding surface (paratope), with the CDR-H3 loop providing a major modality for the generation of diverse paratopes. Here, we provide evidence for an additional role of the VLdomain as a modulator of CDR-H3 structure, using a diverse set of antibody crystal structures and a large set of molecular dynamics simulations. We show that specific attributes of the VLdomain such as CDR canonical forms and genes can influence the structural diversity of the CDR-H3 loop, and provide a physical model for how this effect occurs through inter-loop contacts and packing of CDRs against each other. Our study provides insights into the interdependent nature of CDR conformations, an understanding of which is important for the rational antibody design process.
Unravelling a novel role for Cannabidivarin in the modulation of subventricular zone postnatal neurogenesis
Authors: Lourenço Diogo M. , Soares Rita , Santos Sónia Sá , Mateus Joana M. , Rodrigues Rui S. , Moreira João B. , Vaz Sandra H. , Sebastião Ana M. , Solá Susana , Xapelli Sara
Published: May 2023

Postnatal neurogenesis has been shown to rely on the endocannabinoid system. Here we aimed at unravelling the role of Cannabidivarin (CBDV), a non-psychoactive cannabinoid, with high affinity for the non-classical cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis. Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs) were incubated with CBDV and/or 5’-Iodoresinferotoxin (TRPV1 antagonist), and their role on cell viability, proliferation, and differentiation were dissected. CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival, cell proliferation and neuronal differentiation. Furthermore, pulse-chase experiments revealed that CBDV-induced neuronal differentiation was a result of cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV inhibited oligodendrocyte differentiation and maturation. Since our data suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a sodium-calcium channel, and that intracellular calcium levels are known regulators of NSPCs fate and neuronal maturation, single cell calcium imaging was performed to evaluate the functional response of SVZ-derived cells. We observed that CBDV-responsive cells displayed a two-phase calcium influx profile, being the initial phase dependent on TRPV1 activation. Taken together, this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1 modulation. These findings pave the way to future neural stem cell biological studies and repair strategies by repurposing this non-psychoactive cannabinoid as a valuable therapeutic target.
Quantifying network behavior in the rat prefrontal cortex: a reproducibility crisis
Authors: Sha Congzhou M. , Wang Jian , Mailman Richard B. , Yang Yang , Dokholyan Nikolay V.
Published: May 2023

The question of how consciousness and behavior arise from neural activity is fundamental to understanding the brain, and to improving the diagnosis and treatment of neurological and psychiatric disorders. There is significant murine and primate literature on how behavior is related to the electrophysiological activity of the medial prefrontal cortex and its role in working memory processes such as planning and decision-making. Existing experimental designs, however, have insufficient statistical power to unravel the complex processes of the prefrontal cortex. We therefore examined the theoretical limitations of such experiments, providing concrete guidelines for robust and reproducible science. We piloted the use of dynamic time warping and associated statistical tests to data from neuron spike trains and local field potentials, to quantify neural network synchronicity and correlate neuroelectrophysiology with rat behavior. Our results indicate the statistical limitations of existing data, making meaningful comparison between dynamic time warping with traditional Fourier and wavelet analysis currently impossible until larger and cleaner datasets are available.

Significance Statement

The prefrontal cortex is important in decision-making, yet no robust method currently exists to correlate neuron firing in the PFC to behavior. We argue that existing experimental designs are ill-suited to addressing these scientific questions, and we propose a potential method using dynamic time warping to analyze PFC neural electrical activity. We conclude that careful curation of experimental controls is needed to separate true neural signals from noise accurately.
CENTRE: A gradient boosting algorithm for Cell-type-specific ENhancer-Target pREdiction
Authors: Rapakoulia Trisevgeni , Lopez Ruiz De Vargas Sara , Omgba Persia Akbari , Laupert Verena , Ulitsky Igor , Vingron Martin
Published: May 2023

Motivation

Identifying target promoters of active enhancers is a crucial step for realizing gene regulation and deciphering phenotypes and diseases. Up to now, several computational methods were developed to predict enhancer gene interactions but they require either many epigenomic and transcriptomic experimental assays to generate cell-type-specific predictions or a single experiment applied to a large cohort of cell types to extract correlations between activities of regulatory elements. Thus, inferring cell-type-specific enhancer gene interactions in unstudied or poorly annotated cell types becomes a laborious and costly task.

Results

Here, we aim to infer cell-type-specific enhancer target interactions, using minimal experimental input. We introduce CENTRE, a machine learning framework that predicts enhancer target interactions in a cell-type-specific manner, using only gene expression and ChIP-seq data for three histone modifications for the cell type of interest. CENTRE exploits the wealth of available datasets and extracts cell-type agnostic statistics to complement the cell-type specific information. CENTRE is thoroughly tested across many datasets and cell types and achieves equivalent or superior performance than existing algorithms that require massive experimental data.

Availability

CENTRE’s open source code is available at GitHub viahttps://github.com/slrvv/CENTRE
Tractable and Expressive Generative Models of Genetic Variation Data
Authors: Dang Meihua , Liu Anji , Wei Xinzhu , Sankararaman Sriram , Van den Broeck Guy
Published: May 2023

Population genetic studies often rely on artificial genomes (AGs) simulated by generative models of genetic data. In recent years, unsupervised learning models, based on hidden Markov models, deep generative adversarial networks, restricted Boltzmann machines, and variational autoencoders, have gained popularity due to their ability to generate AGs closely resembling empirical data. These models, however, present a tradeoff between expressivity and tractability. Here, we propose to use hidden Chow-Liu trees (HCLTs) and their representation as probabilistic circuits (PCs) as a solution to this tradeoff. We first learn an HCLT structure that captures the long-range dependencies among SNPs in the training data set. We then convert the HCLT to its equivalent PC as a means of supporting tractable and efficient probabilistic inference. The parameters in these PCs are inferred with an expectation-maximization algorithm using the training data. Compared to other models for generating AGs, HCLT obtains the largest log-likelihood on test genomes across SNPs chosen across the genome and from a contiguous genomic region. Moreover, the AGs generated by HCLT more accurately resemble the source data set in their patterns of allele frequencies, linkage disequilibrium, pairwise haplotype distances, and population structure. This work not only presents a new and robust AG simulator but also manifests the potential of PCs in population genetics.
Ranked Subtree Prune and Regraft
Authors: Collienne Lena , Whidden Chris , Gavryushkin Alex
Published: May 2023

Phylogenetic trees are a mathematical formalisation of evolutionary histories between organisms, species, genes, cancer cells, etc. For many applications, e.g. when analysing virus transmission trees or cancer evolution, (phylogenetic) time trees are of interest, where branch lengths represent times. Computational methods for reconstructing time trees from (typically molecular) sequence data, for example Bayesian phylogenetic inference using Markov Chain Monte Carlo (MCMC) methods, rely on algorithms that sample the treespace. They employ tree rearrangement operations such as SPR (Subtree Prune and Regraft) and NNI (Nearest Neighbour Interchange) or, in the case of time tree inference, versions of these that take times of internal nodes into account. While the classic SPR tree rearrangement is well-studied, its variants for time trees are less understood, limiting comparative analysis for time tree methods.

In this paper we consider a modification of the classical SPR rearrangement on the space of ranked phylogenetic trees, which are trees equipped with a ranking of all internal nodes. This modification results in two novel treespaces, which we propose to study. We begin this study by discussing algorithmic properties of these treespaces, focusing on those relating to the complexity of computing distances under the ranked SPR operations as well as similarities and differences to known tree rearrangement based treespaces. Surprisingly, we show the counterintuitive result that adding leaves to trees can actually decrease their ranked SPR distance, which may have an impact on the results of time tree sampling algorithms given uncertain “rogue taxa”.
Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice
Authors: Baudo Gherardo , Flinn Hannah , Holcomb Morgan , Tiwari Anjana , Soriano Sirena , Taraballi Francesca , Godin Biana , Zinger Assaf , Villapol Sonia
Published: May 2023

Traumatic Brain Injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after a controlled cortical impact injury. Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of proinflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.
What can Ribo-seq and proteomics tell us about the non-canonical proteome?
Authors: Prensner John R. , Abelin Jennifer G. , Kok Leron W. , Clauser Karl R. , Mudge Jonathan M. , Ruiz-Orera Jorge , Bassani-Sternberg Michal , Deutsch Eric W. , van Heesch Sebastiaan
Published: May 2023

Ribosome profiling (Ribo-seq) has proven transformative for our understanding of the human genome and proteome by illuminating thousands of non-canonical sites of ribosome translation outside of the currently annotated coding sequences (CDSs). A conservative estimate suggests that at least 7,000 non-canonical open reading frames (ORFs) are translated, which, at first glance, has the potential to expand the number of human protein-coding sequences by 30%, from ∼19,500 annotated CDSs to over 26,000. Yet, additional scrutiny of these ORFs has raised numerous questions about what fraction of them truly produce a protein product and what fraction of those can be understood as proteins according to conventional understanding of the term. Adding further complication is the fact that published estimates of non-canonical ORFs vary widely by around 30-fold, from several thousand to several hundred thousand. The summation of this research has left the genomics and proteomics communities both excited by the prospect of new coding regions in the human genome, but searching for guidance on how to proceed. Here, we discuss the current state of non-canonical ORF research, databases, and interpretation, focusing on how to assess whether a given ORF can be said to be “protein-coding”.

In brief

The human genome encodes thousands of non-canonical open reading frames (ORFs) in addition to protein-coding genes. As a nascent field, many questions remain regarding non-canonical ORFs. How many exist? Do they encode proteins? What level of evidence is needed for their verification? Central to these debates has been the advent of ribosome profiling (Ribo-seq) as a method to discern genome-wide ribosome occupancy, and immunopeptidomics as a method to detect peptides that are processed and presented by MHC molecules and not observed in traditional proteomics experiments. This article provides a synthesis of the current state of non-canonical ORF research and proposes standards for their future investigation and reporting.

Highlights

Combined use of Ribo-seq and proteomics-based methods enables optimal confidence in detecting non-canonical ORFs and their protein products.

Ribo-seq can provide more sensitive detection of non-canonical ORFs, but data quality and analytical pipelines will impact results.

Non-canonical ORF catalogs are diverse and span both high-stringency and low-stringency ORF nominations.

A framework for standardized non-canonical ORF evidence will advance the research field.

Graphical Abstract
Chronic activation of the aryl hydrocarbon receptor in muscle exacerbates ischemic pathology in chronic kidney disease
Authors: Balestrieri Nicholas , Palzkill Victoria , Pass Caroline , Tan Jianna , Salyers Zachary R. , Moparthy Chatick , Murillo Ania , Kim Kyoungrae , Thome Trace , Yang Qingping , O’Malley Kerri A. , Berceli Scott A. , Yue Feng , Scali Salvatore T. , Ferreira Leonardo F. , Ryan Terence E.
Published: May 2023

Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the cellular and physiological mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic toxins, many of which are ligands for the aryl hydrocarbon receptor (AHR), are associated with adverse limb outcomes in PAD. We hypothesized that chronic AHR activation, driven by the accumulation of tryptophan-derived uremic metabolites, may mediate the myopathic condition in the presence of CKD and PAD. Both PAD patients with CKD and mice with CKD subjected to femoral artery ligation (FAL) displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1,Cyp1b1, andAldh3a1) when compared to either muscle from the PAD condition with normal renal function (P<0.05 for all three genes) or non-ischemic controls. Skeletal-muscle-specific AHR deletion in mice (AHRmKO) significantly improved limb muscle perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and contractile function, as well as enhanced mitochondrial oxidative phosphorylation and respiratory capacity in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. These findings establish chronic AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in PAD. Further, the totality of the results provide support for testing of clinical interventions that diminish AHR signaling in these conditions.
Association of Muscle Strength to Body Composition Measures using DXA, D3Cr, and BIA in Collegiate Athletes
Authors: Cataldi Devon , Bennett Jonathan P. , Quon Brandon K. , Leong Lambert , Kelly Thomas L , Evans William J , Prado Carla M. , Heymsfield Steven B. , Shepherd John A
Published: May 2023

Background

Measurements of body composition are helpful indicators of health outcomes, but muscle strength has a greater correlation with disease risk and long-term health outcomes, particularly among older adults. Whole-body DXA scans uniquely parse out total and regional lean soft tissue (LST) and appendicular (ALST), primarily composed of skeletal muscle and often used to diagnose sarcopenia and frailty. An alternative approach measures the enrichment of deuterated Creatinine (D3Crn) in urine after ingesting a tracer dose of deuterated creatine (D3Cr) to determine creatine pool size and estimate whole-body muscle mass. The utility of D3Cr relationships between strength and body composition in young athletes has yet to be established. In this study, we investigated the association of muscle strength and body composition using multiple methods including DXA, D3Cr, and bioelectrical impedance (BIA), in a collegiate athletic population.

Methods

TheDa KineStudy enrolled 80 multi-sport collegiate athletes. Each subject consumed a 60 mg dose of D3Cr and completed whole-body DXA, BIA, and strength tests of the leg and trunk using an isokinetic dynamometer. The analysis was stratified by sex. Pearson’s correlations, forward stepwise linear regression and quartileptrend significance were used to show the associations of body composition measures to muscle strength.

Results

The mean (SD) age of the 80 (40M/40F) athletes was 21.8 (4.2) years. Raw whole-body values had higher correlations with muscle strength in both sexes compared to the normalized values by height, body mass (BM), and BMI. DXA LST had the highest leg (R2=0.36, 0.37) and trunk (R2=0.53, 0.61) strength in both males and females. Trunk strength was more highly associated with body composition measures than leg strength in both sexes and all measurement techniques. One or more DXA LST measures (total, leg, and ALST) were consistently more highly associated with leg and trunk strengths for both sexes than BIA and D3Cr measures. Adjusting all body composition values by age, BMI, and BIA variables did not improve the associations. A significantptrend across quartiles was observed for DXA LST and ALST for all measures of strength in both sexes.

Conclusion

Although statistical significance was not reached between devices, DXA body composition output variables, especially LST, showed the highest associations with both sexes’ leg and trunk muscle strength. Furthermore, without adjustment for demographic information or BIA variables, whole-body values show stronger associations with muscle strength. Future research should investigate the impact of muscle mass changes on LST and functional measures.
Neo-functionalization inSaccharomyces cerevisiae: A Novel Nrg1-Rtg3 chimeric transcriptional modulator is essential to maintain mitochondrial DNA integrity
Authors: Campero-Basaldua Carlos , González James , García-Rodriguez Janeth , Ramírez Edgar , Hernández Hugo , Aguirre Beatriz , Torres-Ramírez Nayeli , Márquez Dariel , Sánchez Norma , Gómez-Hernández Nicolás , Riego-Ruiz Lina , Scazzocchio Claudio , González Alicia
Published: May 2023

InSaccharomyces cerevisiae, the transcriptional repressor Nrg1 (Negative Regulator of Glucose-repressed genes) and the b/Zip transcription factor Rtg3 (ReTroGrade regulation) mediate glucose repression and mitochondria to nucleus signaling, respectively. Here we show a novel function for these two proteins, in which alanine promotes the formation of a chimeric Nrg1/Rtg3 regulator that represses theALT2gene (encoding an alanine transaminase paralogue of unknown function) expression. ANRG1/NRG2paralogous pair, resulting from a post-wide genome, small scale duplication event, is extant in theSaccharomycesgenus. Neo-functionalization of only one paralogue resulted in Nrg1, able to interact with Rtg3. Eithernrg1Δ orrtg3Δ single mutant strains are unable to utilize ethanol and show a typical petite (small) phenotype on glucose. Neither of the WT genes complemented the petite phenotype, suggesting irreversible mitochondrial DNA damage in these mutants. Neithernrg1Δ norrtg3Δ mutant strains express genes encoded by any of five polycistronic units transcribed from mitochondrial DNA inS. cerevisiae. This, and the direct measure of the mitochondrial DNA gene complement confirms that irreversible damage of the mitochondrial DNA occurred in both mutant strains and is consistent with an essential role of the chimeric Nrg1/Rtg3 regulator in mitochondrial DNA maintenance.
Resilience of A Learned Motor Behavior After Chronic Disruption of Inhibitory Circuits
Authors: Torok Zsofia , Luebbert Laura , Feldman Jordan , Duffy Alison , Nevue Alexander A. , Wongso Shelyn , Mello Claudio V. , Fairhall Adrienne , Pachter Lior , Gonzalez Walter G. , Lois Carlos
Published: May 2023

Maintaining motor behaviors throughout life is crucial for an individual’s survival and reproductive success. The neuronal mechanisms that preserve behavior are poorly understood. To address this question, we focused on the zebra finch, a bird that produces a highly stereotypical song after learning it as a juvenile. Using cell-specific viral vectors, we chronically silenced inhibitory neurons in the pre-motor song nucleus called the high vocal center (HVC), which caused drastic song degradation. However, after producing severely degraded vocalizations for around 2 months, the song rapidly improved, and animals could sing songs that highly resembled the original. In adult birds, single-cell RNA sequencing of HVC revealed that silencing interneurons elevated markers for microglia and increased expression of the Major Histocompatibility Complex I (MHC I), mirroring changes observed in juveniles during song learning. Interestingly, adults could restore their songs despite lesioning the lateral magnocellular nucleus of the anterior neostriatum (LMAN), a brain nucleus crucial for juvenile song learning. This suggests that while molecular mechanisms may overlap, adults utilize different neuronal mechanisms for song recovery. Chronic and acute electrophysiological recordings within HVC and its downstream target, the robust nucleus of the archistriatum (RA), revealed that neuronal activity in the circuit permanently altered with higher spontaneous firing in RA and lower in HVC compared to control even after the song had fully recovered. Together, our findings show that a complex learned behavior can recover despite extended periods of perturbed behavior and permanently altered neuronal dynamics. These results show that loss of inhibitory tone can be compensated for by recovery mechanisms partly local to the perturbed nucleus and do not require circuits necessary for learning.
SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration
Authors: Thumu Surya Chandra Rao , Jain Monika , Soman Sumitha , Das Soumen , Verma Vijaya , Nandi Arnab , Gutmann David H. , Jayaprakash Balaji , Nair Deepak , Clement James Premdoss , Marathe Swananda , Ramanan Narendrakumar
Published: May 2023

Reactive astrogliosis is a common pathological hallmark of central nervous system (CNS) injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. TheseSrfGFAP-ERCKO astrocytes do not affect neuron survival, synapse numbers, synaptic plasticity or learning and memory. However, the brains ofSrfknockout mice exhibited neuroprotection against kainic-acid induced excitotoxic cell death. Relevant to human neurodegenerative diseases,SrfGFAP-ERCKO astrocytes abrogate nigral dopaminergic neuron death and reduce β-amyloid plaques in mouse models of Parkinson’s and Alzheimer’s disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases.
Extending PROXIMAL to predict degradation pathways of phenolic compounds in the human gut microbiota
Authors: Balzerani Francesco , Blasco Telmo , Pérez-Burillo Sergio , Valcarcel Luis , Planes Francisco J. , Hassoun Soha
Published: May 2023

Despite significant advances in reconstructing genome-scale metabolic networks, the understanding of cellular metabolism remains incomplete for many organisms. A promising approach for elucidating cellular metabolism is analysing the full scope of enzyme promiscuity, which exploits the capacity of enzymes to bind to non-annotated substrates and generate novel reactions. To guide time-consuming costly experimentation, different computational methods have been proposed for exploring enzyme promiscuity. One relevant algorithm is PROXIMAL, which strongly relies on KEGG to define generic reaction rules and link specific molecular substructures with associated chemical transformations. Here, we present a completely new pipeline, PROXIMAL2, which overcomes the dependency on KEGG data. In addition, PROXIMAL2 introduces two relevant improvements with respect to the former version: i) correct treatment of multi-step reactions and ii) tracking of electric charges in the transformations. We compare PROXIMAL and PROXIMAL2 in recovering annotated products from substrates in KEGG reactions, finding a highly significant improvement in the level of accuracy. We then applied PROXIMAL2 to predict degradation reactions of phenolic compounds in the human gut microbiota. The results were compared to RetroPath RL, a different and relevant enzyme promiscuity method. We found a significant overlap between these two methods but also complementary results, which open new research directions into this relevant question in nutrition.
TheAzotobacter vinelandiiAlgU Regulon During Vegetative Growth and Encysting Conditions: A Proteomic Approach
Authors: Chowdhury-Paul Sangita , Martínez-Ortíz Iliana C. , Pando-Robles Victoria , Moreno Soledad , Espín Guadalupe , Merino Enrique , Núñez Cinthia
Published: May 2023

In thePseduomonadaceafamily, the extracytoplasmic function sigma factor AlgU is crucial to withstand adverse conditions.Azotobacter vinelandii,a closed relative ofPseudomonas aeruginosa, has been a model for cellular differentiation in Gram-negative bacteria since it forms desiccation-resistant cysts. Previous work demonstrated the essential role of AlgU to withstand oxidative stress and onA. vinelandiidifferentiation, particularly for the positive control of alginate production. In this study, the AlgU regulon was dissected by a proteomic approach under vegetative growing conditions and upon encystment induction. Our results revealed several molecular targets that explained the requirement of this sigma factor during oxidative stress and extended its role in alginate production. Furthermore, we demonstrate that AlgU was necessary to produce alkyl resorcinols, a type of aromatic lipids that conform the cell membrane of the differentiated cell. AlgU was also found to positively regulate stress resistance proteins such as OsmC, LEA-1, or proteins involved in trehalose synthesis. A position-specific scoring-matrix (PSSM) was generated based on the consensus sequence recognized by AlgU inP. aeruginosa, which allowed the identification of direct AlgU targets in theA. vinelandiigenome. This work further expands our knowledge about the function of the ECF sigma factor AlgU inA. vinelandiiand contributes to explains its key regulatory role under adverse conditions.
The mature N termini ofPlasmodiumeffector proteins confer specificity of export
Authors: Hasan Muhammad M. , Polino Alexander J. , Mukherjee Sumit , Vaupel Barbara , Goldberg Daniel E.
Published: May 2023

The intraerythrocytic malaria parasitePlasmodium falciparumexports hundreds of proteins into the host red blood cell (RBC). Most are targeted to the ER by a stretch of hydrophobic amino acids and cleaved further downstream at a conserved motif called the Protein Export Element (PEXEL) by the ER protease plasmepsin V (PM V). The mature effectors then travel through the secretory pathway to the parasitophorous vacuole (PV) that surrounds the parasite. There, PEXEL proteins are somehow recognized as export-destined proteins, as opposed to PV- resident proteins, and are selectively translocated out into the RBC. The mature N terminus appears to be important for export. There is conflicting data on whether PM V cleavage is needed for proper export, or whether any means of generating the mature N terminus would suffice. We replaced the PEXEL-containing N-terminal sequence of an exported GFP reporter with a signal peptide sequence and showed that precise cleavage by signal peptidase, generating the proper mature N terminus, yields export competence. Expressing a construct with only the native ER targeting signal without the PM V cleavage site dramatically decreased the amount of a mature PEXEL reporter, indicating that the hydrophobic stretch lacks an efficient cleavage signal. Therefore, the PEXEL motif functions as a specialized signal cleavage site when appropriately located after an ER targeting sequence. Our data suggest that PM V cleavage and RBC export are two independent events for PEXEL proteins. We also tested and rejected the hypothesis that an alpha-helical mature N terminus is necessary for export.

Importance

Malaria parasites export hundreds of proteins to the cytoplasm of the host red blood cells for their survival. A five amino acid sequence, called the PEXEL motif, is conserved among many exported proteins and is thought to be a signal for export. However, the motif is cleaved inside the endoplasmic reticulum of the parasite and mature proteins starting from the fourth PEXEL residue travel to the parasite periphery for export. We showed that the PEXEL motif is dispensable for export as long as identical mature proteins can be efficiently produced via alternative means in the ER. We also showed that the exported and non-exported proteins are differentiated at the parasite periphery based on their mature N termini, however, any discernible export signal within that region remained cryptic. Our study resolves a longstanding paradox in PEXEL protein trafficking.
Behavioral Consequences of Velocity Commands: Brownian Processes in Human Motor Tasks
Authors: Tessari Federico , Hermus James , Sugimoto-Dimitrova Rika , Hogan Neville
Published: May 2023

The motor neuroscience literature suggests that the central nervous system may encode some motor commands in terms of velocity. In this work, we tackle the question: what consequences would velocity commands produce at the behavioral level? Considering the ubiquitous presence of noise in the neuromusculoskeletal system, we predict that velocity commands affected by stationary noise would produce “random walks”, also known as Brownian processes, in position. Brownian motions are distinctively characterized by a linearly growing variance and a power spectral density that declines in inverse proportion to frequency. This work first shows that these Brownian processes are indeed observed in unbounded motion tasks e.g., rotating a crank. We further predict that such growing variance would still be present, but bounded, in tasks requiring a constant posture e.g., maintaining a static hand position or quietly standing. This hypothesis was also confirmed by experimental observations. A series of descriptive models are investigated to justify the observed behavior. Interestingly, one of the models capable of accounting for all the experimental results must feature forward-path velocity commands corrupted by stationary noise. The results of this work provide behavioral support for the hypothesis that humans plan the motion components of their actions in terms of velocity.
Are circadian amplitudes and periods correlated? A newtwistin the story
Authors: Olmo Marta del , Schmal Christoph , Mizaikoff Camillo , Grabe Saskia , Gabriel Christian , Kramer Achim , Herzel Hanspeter
Published: May 2023

Three parameters are important to characterize a circadian and in general any biological clock: period, phase and amplitude. While circadian periods have been shown to correlate with entrainment phases, and clock amplitude influences the phase response of an oscillator to pulse-like zeitgeber signals, the co-modulations of amplitude and periods, which we term twist, have not been studied in detail. In this paper we define two concepts: parametric twist refers to amplitude-period correlations arising in ensembles of self-sustained clocks in the absence of external inputs, and phase space twist refers to the co-modulation of an individual clock’s amplitude and period in response to external zeitgebers. Our findings show that twist influences the interaction of oscillators with the environment, facilitating entrainment, fastening recovery to pulse-like perturbations or modifying the response of an individual clock to coupling. This theoretical framework might be applied to understand the emerging properties of other oscillating systems.
Effects of lithium on locomotor activity and circadian rhythm of honey bees
Authors: Erdem Babur , Arslan Okan Can , Sevin Sedat , Gozen Ayse Gul , Agosto Jose L. , Giray Tugrul , Alemdar Hande
Published: May 2023

The miticide effect of lithium on the honey bee (Apis mellifera) parasiteVarroahas been discovered.Varroamite is considered the principal threat to bee health and, as a result, to pollination and food security. In this study, we investigated the behavioral effects of lithium on honey bees, specifically locomotor activity (LMA) level and circadian patterns of LMA, such as rhythmicity, and periodicity. Any effects of lithium on activity may be important for bee health since timing and daylight are critical for bee foraging and bee’s use of the sun compass for navigation and communication. Both acute and chronic lithium treatments affected the LMA of honey bees. The effect varies depending on light and dark conditions. Chronic treatment with lithium disrupted the rhythmicity and altered the period of the circadian rhythm. While the circadian period was not affected by the light condition in the control group, lithium treatment lengthened the period in constant light condition. Lithium decreased total LMA in a constant light condition where typically activity is increased and not under the dark condition, both in acute and chronic treatments. However, mortality in the high-dose lithium treatment group is higher in the dark environment in the acute experiment. Lithium is also the first-line therapy for bipolar disorder. This disorder causes excessively elevated activity called mania and circadian rhythm abnormalities. The effects of lithium on reducing light-induced activity and the circadian rhythm of bees are reminiscent of its stabilizing effect on activity and circadian rhythms in bipolar disorder treatment.
Epigenetic reprogramming of imprinting at meiosis
Authors: Montgomery Sean A. , Berger Frédéric
Published: May 2023

In mammals, genomic imprinting results from different sets of epigenetic marks that distinguish the parental origins of loci in the progeny. Epigenetic reprogramming of genomic imprinting is necessary to establish a totipotent cell state. The consecutive erasure of parental epigenetic marks and the deposition of new marks occurs alongside major life stage transitions including gametogenesis and fertilization. However, despite occurring concomitantly with gametogenesis, the role of meiosis in epigenetic reprogramming has received little attention. To address this question, we use the model bryophyteMarchantia polymorpha. Following the haploid reproductive phase of this land plant, the expression of the paternal genome is silenced by the histone modification H3K27me3 in the short-lived diploid embryo. We show that imprinting is erased during meiosis, which occurs separately from gametogenesis and fertilization in Marchantia. The epigenetic reprogramming initiated during meiosis is completed in the meiotic spores where the chromatin landscape of the next haploid generation is establishedde novo. Hence, our findings illustrate a potential role for meiosis in epigenetic reprogramming that may be generalized to other sexually reproducing species.
Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology
Authors: Goralski Thomas , Meyerdirk Lindsay , Breton Libby , Brasseur Laura , Kurgat Kevin , DeWeerd Daniella , Turner Lisa , Becker Katelyn , Adams Marie , Newhouse Daniel , Henderson Michael X.
Published: May 2023

Lewy pathology composed of α-synuclein is the key pathological hallmark of Parkinson’s disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains. We find, both in PD and in a mouse model of PD, that there are specific classes of excitatory neurons that are vulnerable to developing Lewy pathology in the cortex. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. This gene signature indicates that neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. However, beyond DNA repair gene upregulation, we find that neurons also activate apoptotic pathways, suggesting that if DNA repair fails, neurons undergo programmed cell death. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.
Endocytic down-regulation of the striatal dopamine transporter by amphetamine in sensitized mice in sex-dependent manner
Authors: Bagalkot Tarique , Sorkin Alexander
Published: May 2023

Dopamine transporter (DAT) controls dopamine signaling in the brain through the reuptake of synaptically released dopamine. DAT is a target of abused psychostimulants such as amphetamine (Amph). Acute Amph is proposed to cause transient DAT endocytosis which among other Amph effects on dopaminergic neurons elevates extracellular dopamine. However, the effects of repeated Amph abuse, leading to behavioral sensitization and drug addiction, on DAT traffic are unknown. Hence, we developed a 14-day Amph-sensitization protocol in knock-in mice expressing HA-epitope tagged DAT (HA-DAT) and investigated effects of Amph challenge on HA-DAT in sensitized animals. Amph challenge resulted in the highest locomotor activity on day 14 in both sexes, which was however sustained for 1 hour in male but not female mice. Strikingly, significant (by 30-60%) reduction in the amount of the HA-DAT protein in striatum was observed in response to Amph challenge of sensitized males but not females. Amph reduced Vmax of dopamine transport in striatal synaptosomes of males without changing Km values. Consistently, immunofluorescence microscopy revealed a significant increase of HA-DAT co-localization with the endosomal protein VPS35 only in males. Amph-induced HA-DAT down-regulation in the striatum of sensitized mice was blocked by chloroquine, vacuolin-1 (inhibitor of PIKfive kinase), and inhibitor of Rho-associated kinases (ROCK1/2), indicative of the involvement of endocytic trafficking in DAT down-regulation. Interestingly, HA-DAT protein down-regulation was observed in nucleus accumbens and not in dorsal striatum. We propose that Amph challenge in sensitized mice leads to ROCK-dependent endocytosis and post-endocytic traffic of DAT in a brain-region-specific and sex-dependent manner.