bluuebunny/crossref_metadata_2025 huggingface dataset:
MalKinID: A Likelihood-Based Model for Identifying Malaria Parasite Genealogical Relationships Using Identity-by-Descent
Authors: Wong Wesley , Wang Lea , Schaffner Stephen S , Li Xue , Cheeseman Ian , Anderson Timothy J.C. , Vaughan Ashley , Ferdig Michael , Volkman Sarah K , Hartl Daniel L , Wirth Dyann F
Published: July 2024

Pathogen genomics is a powerful tool for tracking infectious disease transmission. In malaria, identity-by-descent (IBD) is used to assess the genetic relatedness between parasites and has been used to study transmission and importation. In theory, IBD can be used to distinguish genealogical relationships to reconstruct transmission history or identify parasites for genotype- to-phenotype quantitative-trait-locus experiments.MalKinID(Malaria Kinship Identifier) is a new likelihood-based classification model designed to identify genealogical relationships among malaria parasites based on genome-wide IBD proportions and IBD segment distributions.

MalKinIDwas calibrated to the genomic data from three laboratory-based genetic crosses (yielding 440 parent-child and 9060 full-sibling comparisons).MalKinIDidentified lab generated F1 progeny with >80% sensitivity and showed that 0.39 (95% CI 0.28, 0.49) of the second- generation progeny of a NF54 and NHP4026 cross were F1s and 0.56 (0.45, 0.67) were backcrosses of an F1 with the parental NF54 strain. In simulated outcrossed importations,MalKinIDaccurately reconstructs genealogy history with high precision and sensitivity, with F1- scores exceeding 0.84. However, when importation involves inbreeding, such as during serial co-transmission, the precision and sensitivity ofMalKinIDdeclined, with F1-scores of 0.76 (0.56, 0.92) and 0.23 (0.0, 0.4) for PC and FS and <0.05 for second-degree and third-degree relatives. Genealogical inference is most powered 1) when outcrossing is the norm or 2) when multi- sample comparisons based on a predefined pedigree are used.MalKinIDlays the foundations for using IBD to track parasite transmission history and for separating progeny for quantitative- trait-locus experiments.
Mangrove endophytes shorten the life cycle of rice while enhancing yield and salt tolerance
Authors: Alghamdy Amal , Rawat Anamika , Parween Sabiha , Nagarajan Arun Prasanna , Saad Maged M. , Hirt Heribert
Published: July 2024

Global climate change increasingly challenges agriculture with flooding and salinity. Among strategies to enhance crop resilience to these stresses, we tested several endophytic bacterial strains from mangroves, which are permanently exposed to flooding and high salinity. We show several strains that can enhance flooding and salinity tolerance in Arabidopsis and rice plants. Two strains and their combination massively enhanced the growth and yield ofOryza sativacv. Nipponbare under both soil and hydroponic growth conditions with and without salt treatment. The bacteria-induced transcriptome changes in O. sativa roots related to ABA-signaling with lignin and suberin deposition in root tissues explain the altered responses of colonized rice plants to hypoxic and saline stress conditions. While enhancing yield and grain quality, bacterially colonized rice plants also show much earlier flowering, thereby massively shortening the life cycle of rice plants and opening the possibility for an additional harvest per year. These results show that microbes can be a powerful tool for enhancing the yield and resilience of rice to hypoxic and saline stress conditions.
Mathematical Modelling of Reoviruses in Cancer Cell Cultures
Authors: Baabdulla Arwa Abdulla , Cristi Francisca , Shmulevitz Maya , Hillen Thomas
Published: July 2024

Oncolytic virotherapy has emerged as a potential cancer therapy, utilizing viruses to selectively target and replicate within cancer cells while preserving normal cells. In this paper, we investigate the oncolytic potential of unmodified reovirus T3wt relative to a mutated variant SV5. In animal cancer cell monolayer experiments it was found that SV5 was more oncolytic relative to T3wt. SV5 forms larger sized plaques on cancer cell monolayers and spreads to farther distances from the initial site of infection as compared to T3wt. Paradoxically, SV5 attaches to cancer cells less efficiently than T3wt, which lead us to hypothesize that there might be an optimal binding affinity with maximal oncolytic activity. To understand the relationship between the binding process and virus spread for T3wt and SV5, we employ mathematical modelling. A reaction-diffusion model is applied, which is fit to the available data and then validated on data that were not used for the fit. Analysis of our model shows that there is an optimal binding rate that leads to maximum viral infection of the cancer monolayer, and we estimate this value for T3wt and SV5. Moreover, we find that the viral burst size is an important parameter for viral spread, and that a combination of efficient binding and large burst sizes is a promising direction to further develop anti-cancer viruses.
B cell receptor silencing reveals the origin of high-grade B cell lymphomas withMYCandBCL2rearrangements
Authors: Sindaco Paola , Lonardi Silvia , Varano Gabriele , Pietrini Ilaria , Morello Gaia , Balzarini Piera , Neuman Hadas , Vit Filippo , Bertolazzi Giorgio , Arima Hiroshi , Chiarini Marco , Lorenzi Luisa , Pellegrini Vilma , Giampaolo Sabrina , Garzon Daniel , Ranise Cecilia , Bugatti Mattia , Pagani Chiara , Daffini Rosa , Mainoldi Federica , Selvarasa Viveka , Sivacegaram Anojan , Yang Henry , Ying Li , Cancila Valeria , Bonnal Raoul , Visco Euplio , Gonzalez Cristina Lopez , Capaccio Pasquale , Ferreri Andres J. M. , Tucci Alessandra , Cabras Antonello D. , Pruneri Giancarlo , di Napoli Arianna , Siebert Reiner , Bomben Riccardo , Falini Brunangelo , Pizzi Marco , Song Joo Y. , Chan Wing C. , Ponzoni Maurilio , Mehr Ramit , Tripodo Claudio , Facchetti Fabio , Casola Stefano
Published: July 2024

The B cell receptor (BCR) is essential for mature B cell lymphomas, serving as therapeutic target. Here, we show that high-grade B cell lymphomas withMYCandBCL2rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. HGBCL-DH-BCL2with undetectable IGH (IGHUND) differ from IGH-expressing counterparts for germinal center-zone gene programs,MYCexpression and T cell infiltration. While IGH+HGBCL-DH-BCL2prefer IGM/IG-Kappa expression, IGHUNDcounterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGHUNDHGBCL-DH-BCL2preserveIGHVgene integrity, overcoming antigen-driven selection. IGH silencing precedes onset and shapes evolution of HGBCL-DH-BCL2from Follicular Lymphoma (FL) or FL/HGBCL-DH-BCL2common precursor. In FL/HGBCL-DH-BCL2pairs and HGBCL-DH-BCL2models, BCR silencing promoted RAG1/2-dependent IG light chain editing, causing t(8;22)(q24;q11)/IGL::MYC. IGH silencing protected HGBCL-DH-BCL2models from killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, HGBCL-DH-BCL2primarily originate from BCR-silenced isotype-switched t(14;18)/IGH::BCL2-positive (pre)FL cells acquiring IGL::MYCtranslocations during IG light chain revision, with clinical implications.

Significance

These findings link BCR silencing in isotype-switched t(14;18)+Follicular Lymphoma cells (or their precursors) to RAG1/2 re-expression, promotingIGL::MYCtranslocations responsible for transformation into high-grade B cell lymphomas (HGBCL). Predominant silencing of the BCR complex in HGBCL withMYCandBCL2rearrangements protects tumor cells from CD79B-directed Polatuzumab-Vedotin killing.
Peripheral CaV2.2 channels in skin regulate prolonged heat hypersensitivity during neuroinflammation
Authors: Salib Anne-Mary N , Crane Meredith J , Jamieson Amanda M , Lipscombe Diane
Published: July 2024

Neuroinflammation can lead to chronic maladaptive pain affecting millions of people worldwide. Neurotransmitters, cytokines, and ion channels are implicated in neuro-immune cell signaling but their roles in specific behavioral responses are not fully elucidated. Voltage-gated CaV2.2 channel activity in skin controls rapid and transient heat hypersensitivity induced by intradermal capsaicin via IL-1α cytokine signaling. CaV2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the same animal model. Here, we show that CaV2.2 channels are also critical for heat hypersensitivity induced by the intradermal (id) Complete Freund’s Adjuvant (CFA) model of chronic neuroinflammation that involves ongoing cytokine signaling for days. Ongoing CFA-induced cytokine signaling cascades in skin lead to pronounced edema, and hypersensitivity to sensory stimuli. Peripheral CaV2.2 channel activity in skin is required for the full development and week-long time course of heat hypersensitivity induced byidCFA. CaV2.2 channels, by contrast, are not involved in paw edema and mechanical hypersensitivity. CFA induced increases in cytokines in hind paws including IL-6 which was dependent on CaV2.2 channel activity. Using IL-6 specific neutralizing antibodies, we show that IL-6 contributes to heat hypersensitivity and, neutralizing both IL-1α and IL-6 was even more effective at reducing the magnitude and duration of CFA-induced heat hypersensitivity. Our findings demonstrate a functional link between CaV2.2 channel activity and the release of IL-6 in skin and show that CaV2.2 channels have a privileged role in the induction and maintenance of heat hypersensitivity during chronic forms of neuroinflammation in skin.

Significance Statement

Neuroinflammation can lead to chronic maladaptive pain. Neurotransmitters, ion channels, cytokines, and cytokine receptors are implicated in neuron-immune signaling, but their importance in mediating specific behavioral responses are not fully elucidated. We show that the activity of peripheral CaV2.2 calcium ion channels in skin play a unique role in the induction and maintenance of heat hypersensitivity in the CFA model of prolonged neuroinflammation, without accompanying effects on edema and mechanical hypersensitivity. Blocking peripheral CaV2.2 channel activity reduces local cytokine levels in hind paws injected with CFA including IL-6 and neutralizing IL-6 reduces CFA- induced heat hypersensitivity. Our studies define key signaling molecules that act locally in skin to trigger and maintain heat hypersensitivity during chronic neuroinflammation.
Lineage-specific genomic imprinting in theZNF791locus
Authors: Ahn Jinsoo , Hwang In-Sul , Park Mi-Ryung , Rosa-Velazquez Milca , Cho In-Cheol , Relling Alejandro E , Hwang Seongsoo , Lee Kichoon
Published: July 2024

Background: Genomic imprinting is the primary epigenetic phenomenon that results in parent-of-origin effects on mammalian development and growth. Research on genomic imprinting in domesticated animals has lagged due to a primary focus on orthologous imprinted genes. This emphasis has limited the discovery of imprinted genes specific to livestock. To identify genomic imprinting in pigs, we generated parthenogenetic porcine embryos alongside biparental normal embryos, and then performed whole-genome bisulfite sequencing and RNA sequencing on these samples. Results: In our analyses, we discovered a maternally methylated differentially methylated region within the orthologousZNF791locus in pigs. Additionally, we identified both a major imprinted isoform of theZNF791-likegene and an unannotated antisense transcript that has not been previously annotated. Importantly, our comparative analyses of the orthologousZNF791gene in various eutherian mammals, including humans, non-human primates, rodents, artiodactyls, and dogs, revealed that this gene is subjected to genomic imprinting exclusively in domesticated animals, thereby highlighting lineage-specific imprinting. Furthermore, we explored the potential mechanisms behind the establishment of maternal DNA methylation imprints in porcine and bovine oocytes, supporting the notion that integration of transposable elements, active transcription, and histone modification may collectively contribute to the methylation of embedded intragenic CpG island promoters. Conclusions: Our findings convey fundamental insights into molecular and evolutionary aspects of livestock species-specific genomic imprinting and provide critical agricultural implications.
Appropriate data segmentation improves speech encoding models
Authors: Bialas Ole , Lalor Edmund C.
Published: July 2024

In recent decades, research on the neural processing of speech and language increasingly investigated ongoing responses to continuously presented naturalistic speech, allowing researchers to ask interesting questions about different representations of speech and their relationships. This requires statistical models that can dissect different sources of variance occurring in the processing of naturalistic speech. One commonly used family of models are temporal response functions (TRFs) which can predict neural responses to speech as a weighted combination of different features and points in time. TRFs model the brain as a linear time-invariant (LTI) system whose responses can be characterized by constant transfer functions. This implicitly assumes that the underlying signals are stationary, varying to a fixed degree around a constant mean. However, continuous neural recordings commonly violate this assumption. Here, we use simulations and EEG recordings to investigate how non-stationarities affect TRF models for continuous speech processing. Our results suggest that non-stationarities may impair the performance of TRF models, but that this can be partially remedied by dividing the data into shorter segments that approximate stationarity.
Oncogene inactivation-induced senescence facilitates tumor relapse
Authors: Schmitt Philipp , Hönig Katrin , Milojkovic Ana , Anders Kathleen , Schröck Evelin , Sauer Sascha , Uyar Bora , Akalin Altuna , Martínez-Reyes Inmaculada , Blankenstein Thomas
Published: July 2024

Oncogene-targeted therapy has emerged as a promising avenue for delaying tumor progression. However, patients often develop drug resistance and early tumor recurrence. We analyzed the effects of oncogene inactivationin vitro, and identified the induction of senescence and metabolic reprogramming as two major adaptive mechanisms.In vivo, we observed that senescent cells exhibited an increased propensity for tumor relapse, accompanied by notable chromosomal abnormalities and the acquisition of alternative oncogenic pathways. Oncogene inactivation- induced senescence rendered cells reliant on autophagy, making them more susceptible to autophagy inhibitionin vitro. However, combining oncogene inactivation with autophagy-targeted senolysisin vivoin immunocompetent mice, unexpectedly facilitated tumor growth compared to oncogene inactivation alone. Similarly, oncogene inactivation in established tumors followed by autophagy inhibition led to increased tumor relapse in immunodeficient mice compared to the placebo group. Our results underscore senescence as a main mechanism allowing cancer cells to survive oncogene deprivation. Oncogene inactivation-induced senescence induces genetic abnormalities and is a main driver of tumor relapse. Our results suggest different metabolic dependencies of senescent cellsin vitroandin vivoand underscore the importance of evaluating potential drug candidates in relevant preclinical mouse models, as therapeutic effects observedin vitromay not necessarily translate to meaningful clinical outcomesin vivo.
Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies
Authors: Bavencoffe Alexis , Zhu Michael Y. , Neerukonda Sanjay V. , Johnson Kayla N. , Dessauer Carmen W. , Walters Edgar T.
Published: July 2024

Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured (“naïve”) rats. Six-hour treatment with the specific Gαs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator, forskolin, induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12-24 hours later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to -45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from -69 to -66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and indications of reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, and protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. An interesting possibility is that these mechanisms can also be reactivated by re-exposure to inflammatory mediators such as serotonin during subsequent challenges to bodily integrity, “reconsolidating” the cellular memory and thereby extending the duration of persistent nociceptor hyperexcitability.

Highlights

Nociceptor long-term hyperexcitability (LTH) can be induced by a 5-HT4R agonist.

5-HT4R-induced LTH manifests as ongoing activity during modest depolarization.

Enhanced ongoing activity is associated with long-term potentiation of DSFs.

Induction of LTH depends upon PKA, CREB, transcription, and protein synthesis.

Nociceptor LTH may be triggered by conserved memory-related plasticity mechanisms.
Many erroneous noncoding transcripts in cancer cells can highly specifically regulate cancer-related genes and pathways
Authors: He Sha , Xiong Wei , Huo Jianping , Lin Jie , Li Jianmin , Zhu Hao
Published: July 2024

Transcription and splicing errors in cancer cells generate erroneous transcripts. Since erroneous transcripts are degraded by the nonsense-mediated mRNA decay (NMD) pathway, whether they are junk or could be functional has been overlooked and understudied. We addressed this question by first performing a pan-cancer analysis and identified substantial erroneous noncoding transcripts (ENT) in cancers. Given that RNA/DNA binding domains (DBD) were predicted in ENTs, we deleted predicted DBDs in multiple ENTs in multiple cell lines, with RNA-sequencing and cell experiments before and after DBD deletion. DBD deletion caused significantly changed expression of ENTs’ target genes (whose promoter regions contain ENTs’ DNA binding sites, DBS) and changed cell migration and proliferation ability, indicating that many ENTs can transcriptionally regulate genes. Tightly coupled data analysis and experiments reveal that ENTs’ functions are highly cancer- and cellular-context specific, making ENTs a new class of safe and specific targets for noncoding RNA-based cancer therapeutics.
Rubisco from two ecotypes ofPlantago lanceolataL. that are native to sites differing in atmospheric CO2levels
Authors: Shi Xiaoxiao , Hannon Nathan M. , Bloom Arnold J.
Published: July 2024

Rubisco, the most prevalent protein on the planet, initiates the conversion of CO2into carbohydrates during photosynthesis. Responses of this process to atmospheric CO2fluctuations daily, seasonally, and over millennia is still poorly understood. We have hypothesized that higher plants maintain carbon-to-nitrogen homeostasis by adjusting the balance of magnesium and manganese in chloroplasts to alter their relative carbon fixation and nitrogen assimilation rates. The following study examined the influence of magnesium and manganese on rubisco carboxylation and oxygenation in protein purified from two ecotypes ofPlantago lanceolata: one adapted to the high atmospheric CO2that occurs near a natural CO2spring and the other adapted to more typical CO2atmospheres that occur nearby. The plastid DNA coding for the large unit of rubisco were similar in both ecotypes. The kinetics of rubiscos from the two ecotypes differed more when they were associated with manganese than magnesium. Specificity for CO2over O2(Sc/o) for rubiscos from both ecotypes were higher when the enzymes were bound to magnesium than manganese. This disparity may account for the adaptation of this species to different CO2environments.
WITHDRAWN: Geometrical determinant of nonlinear synaptic integration in human cortical pyramidal neurons
Authors: Yoon Jaeyoung
Published: July 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to data ownership concerns. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Targeting fatty acid synthase suppresses tumor development inNF2/CDKN2A-deficient malignant pleural mesothelioma
Authors: Karnan Sivasundaram , Ota Akinobu , Hasan Muhammad Nazmul , Murakami Hideki , Rahman Md. Lutfur , Wahiduzzaman Md , Shihan Md Towhid Ahmed , Jahan Nushrat , Vu Lam Quang , Hanamura Ichiro , Inoko Akihito , Riku Miho , Ito Hideaki , Kaneko Yoshifumi , Lin Yinzhi , Hyodo Toshinori , Konishi Hiroyuki , Tsuzuki Shinobu , Hosokawa Yoshitaka
Published: July 2024

Malignant pleural mesothelioma (MPM) is an uncommon yet deadly cancer linked to asbestos exposure. The lack of effective early diagnosis and treatment leads to reduced life expectancy among patients with MPM. This study is aimed to identify a novel molecular target inhibitor to develop more effective therapeutics for MPM. Our drug screening assay showed that the fatty acid synthase (FASN) inhibitor cerulenin demonstrates strong and selective anti-proliferative properties againstNF2/CDKN2A(p16)-deficient MPM cells, surpassing the effects of cisplatin or pemetrexed. FASN protein is frequently detected inNF2/p16-deficient MPM tumor-derived tissues (15/15, 100%), but rarely inNF2/p16-intact MPM tumors (8/25, 32%). Notably, cerulenin administration successfully reduced the growth ofNF2/p16-deficient MPM tumors in xenografted mice. Cerulenin inhibits mitochondrial fission by targeting dynamin-related protein 1 (DRP1) inNF2/p16-deficient cells. Moreover, the disruption of the FASN gene leads to increased ubiquitination of DRP1. These findings suggest that FASN might play a role in the tumorigenesis of MPM cells through the regulation of mitochondrial dynamics. This research offers a novel perspective on the potential development of precision medicine for MPM.
Peptide-enabled ribonucleoprotein delivery for CRISPR engineering (PERC) in primary human immune cells and hematopoietic stem cells
Authors: Sahu Srishti , Castro Madalena , Muldoon Joseph J , Asija Kunica , Wyman Stacia K , Krishnappa Netravathi , de Onate Lorena , Eyquem Justin , Nguyen David N , Wilson Ross C
Published: July 2024

Peptide-enabled ribonucleoprotein delivery for CRISPR engineering (PERC) is a new approach for ex vivo genome editing of primary human cells. PERC uses a single amphiphilic peptide reagent to mediate intracellular delivery of the same pre-formed CRISPR ribonucleoprotein enzymes that are broadly used in research and therapeutics, resulting in high-efficiency editing of stimulated immune cells and cultured hematopoietic stem and progenitor cells (HSPCs). PERC facilitates nuclease-mediated gene knockout, precise transgene knock-in, and base editing. PERC involves mixing the CRISPR ribonucleoprotein enzyme with peptide and then incubating the formulation with cultured cells. For efficient transgene knock-in, adeno-associated virus (AAV) bearing homology-directed repair template DNA may be included. In contrast to electroporation, PERC is appealing as it requires no dedicated hardware and has less impact on cell phenotype and viability. Due to the gentle nature of PERC, delivery can be performed multiple times without substantial impact to cell health or phenotype. Here we report methods for improved PERC-mediated editing of T cells as well as novel methods for PERC-mediated editing of HSPCs, including knockout and precise knock-in. Editing efficiencies can surpass 90% using either Cas9 or Cas12a in primary T cells or HSPCs. Because PERC calls for only three readily available reagents - protein, RNA, and peptide - and does not require dedicated hardware for any step, PERC demands no special expertise and is exceptionally straightforward to adopt. The inherent compatibility of PERC with established cell engineering pipelines makes this approach appealing for rapid deployment in research and clinical settings.
The evolutionary cost of homophily: social stratification facilitates stable variant coexistence and increased rates of evolution in host-associated pathogens
Authors: Li Shuanger , Gulisija Davorka , Carja Oana
Published: July 2024

Coexistence of multiple strains of a pathogen in a host population can present significant challenges to vaccine development or treatment efficacy. Here we discuss a novel mechanism that can increase rates of long-lived strain polymorphism, rooted in the presence of social structure in a host population. We show that social preference of interaction, in conjunction with differences in immunity between host subgroups, can exert varying selection pressure on pathogen strains, creating a balancing mechanism that supports stable viral coexistence, independent of other known mechanisms. We use population genetic models to study rates of pathogen heterozygosity as a function of population size, host population composition, mutant strain fitness differences and host social preferences of interaction. We also show that even small periodic epochs of host population stratification can lead to elevated strain coexistence. These results are robust to varying social preferences of interaction, overall differences in strain fitnesses, and spatial heterogeneity in host population composition. Our results highlight the role of host population social stratification in increasing rates of pathogen strain diversity, with effects that should be considered when designing policies or treatments with a long-term view of curbing pathogen evolution.
Taming the chaos gently: a Predictive Alignment learning rule in recurrent neural networks
Authors: Asabuki Toshitake , Clopath Claudia
Published: July 2024

Recurrent neural circuits often face inherent complexities in learning and generating their desired outputs, especially when they initially exhibit chaotic spontaneous activity. While the celebrated FORCE learning rule can train chaotic recurrent networks to produce coherent patterns by suppressing chaos, it requires non-local plasticity rules and extremely quick plasticity, raising the question of how synapses adapt on local, biologically plausible timescales to handle potential chaotic dynamics. We propose a novel framework called “Predictive Alignment”, which tames the chaotic recurrent dynamics to generate a variety of patterned activities via a biologically plausible plasticity rule. Unlike most recurrent learning rules, predictive alignment does not aim to directly minimize output error to train recurrent connections, but rather it tries to efficiently suppress chaos by aligning recurrent prediction with chaotic activity. We show that the proposed learning rule can perform supervised learning of multiple target signals, including complex low-dimensional attractors, delay matching tasks that require short-term temporal memory, and finally even dynamic movie clips with high-dimensional pixels. Our findings shed light on how predictions in recurrent circuits can support learning.
Using nature-based citizen science initiatives to enhance nature connection and mental health
Authors: Oh Rachel R. Y. , Suarez-Castro Andres F. , Fuller Richard A. , Tervo Michael , Rozario Kevin , Peters Birte , Chowdhury Shawan , von Gönner Julia , Friedrichs-Manthey Martin , Berger Ambros , Schultz Tracy , Dean Angela J. , Tulloch Ayesha , Bonn Aletta
Published: July 2024

The global rise in mental health issues underscores the critical importance of assessing the mental health benefits of engaging with nature. Beyond their primary aim of involving citizens in scientific data collection, nature-based citizen science initiatives offer significant potential for enhancing conservation (e.g. connection to nature) and human health and wellbeing (e.g. emotions, depression, stress, anxiety) outcomes. However, the effectiveness of various types of initiatives in achieving specific health outcomes remain unclear. This study evaluates changes in eight nature connection and health and wellbeing outcomes before and after participation in five such initiatives, specifically three dimensions of connection to nature (Self, Experience and Perspective) measured by the Nature Relatedness scale), and mental health outcomes—depression, stress and anxiety—measured by the DASS-21 scale; along with positive and negative emotions assessed using the Scale of Positive and Negative Experience (SPANE). We found that participants generally reported improvements across all outcomes, but only positive emotions and reduced anxiety and stress symptoms were significantly enhanced. This suggests that short-term nature-based interventions are effective in boosting emotions and alleviating anxiety and stress, though significant changes in nature connection and depression may require prolonged or more intensive engagement. We also found that the Queensland Trust for Nature initiative, characterized by its extended duration and social interactions, emerged as a particularly effective model in achieving synergies between biodiversity and human health goals. Consequently, we advocate for the reimagining of these nature-based initiatives as integral components of broader health-promoting strategies. By aligning citizen science efforts with health promotion frameworks, we can amplify the utility and impact of nature-based citizen science initiatives, enhancing their contributions to scientific knowledge, nature conservation and human health.
Simulating the growth of TAF15 inclusions in neuron soma
Authors: Kuznetsov Andrey V.
Published: July 2024

To the best of the author’s knowledge, this paper presents the first attempt to develop a mathematical model of the formation and growth of inclusions containing misfolded TATA-box binding protein associated factor 15 (TAF15). It has recently been shown that TAF15 inclusions are involved in approximately 10% of cases of frontotemporal lobar degeneration (FTLD). FTLD is the second most common neurodegenerative disease after Alzheimer’s disease (AD). It is characterized by a progressive loss of personality, behavioral changes, and a decline in language skills due to the degeneration of the frontal and anterior temporal lobes. The model simulates TAF15 monomer production, nucleation and autocatalytic growth of free TAF15 aggregates, and their deposition into TAF15 inclusions. The accuracy of the numerical solution of the model equations is validated by comparing it with analytical solutions available for limiting cases. Physiologically relevant parameter values were used to predict TAF15 inclusion growth. It is shown that the growth of TAF15 inclusions is influenced by two opposing mechanisms: the rate at which free TAF15 aggregates are deposited into inclusions and the rate of autocatalytic production of free TAF15 aggregates from monomers. A low deposition rate slows inclusion growth, while a high deposition rate hinders the autocatalytic production of new aggregates, thus also slowing inclusion growth. Consequently, the rate of inclusion growth is maximized at an intermediate deposition rate of free TAF15 aggregates into TAF15 inclusions.
’Disease-smart’ assisted migration can enhance population fitness and increase resistance to pathogens via immune priming
Authors: Ghosh Enakshi , Wallace Matthew , Hufbauer Ruth A.
Published: July 2024

We studied the potential of combining insect immune priming to synergize with introduction of diverse migrant to safeguard small populations from disease outbreaks that might otherwise lead to extinction.

Immune priming in insects refers to the stronger immune response insects have against pathogens after prior exposure. This enhanced immunity can be passed on to offspring and holds promise for insect conservation efforts against diseases.

We compared the fitness benefits to a small, inbred population of adding migrants that had not been primed to adding immune primed migrants. While both types of migrants enhanced reproduction, as in cases of genetic rescue, only primed migrants improved survival on exposure to a pathogen.

Better immunity led to a trade-off with reproduction in the migrants, but not upon outcrossing with the target population, revealing synergies between hybrid vigor and immune priming.

Given the demographic constraints and stochasticity that can exacerbate the effects of disease outbreaks in small populations, combining immune priming with assisted migration offers a proactive strategy to mitigate disease impacts.
Temporal profiling of the phosphate starvation response in Arabidopsis root hair cells reveals that induction of polycomb target genes does not depend on removal of H3K27me3 or H2A.Z
Authors: Holder Dylan H. , Deal Roger B.
Published: July 2024

Altered nutrient conditions can trigger massive transcriptional reprogramming in plants, leading to the activation and silencing of thousands of genes. To gain a deeper understanding of the phosphate starvation response and the relationships between transcriptional and epigenomic changes that occur during this reprogramming, we conducted a time-resolved analysis of transcriptome and chromatin alterations in root hair cells of Arabidopsis thaliana during phosphate (P) starvation and subsequent resupply. We found that 96 hours of P starvation causes induction or repression of thousands of transcripts, and most of these recover to pre-starvation levels within 4 hours of P resupply. Among the phosphate starvation-induced genes are many polycomb targets with high levels of H3K27me3 and histone variant H2A.Z. When induced, these genes often show increased H3K4me3 consistent with active transcription, but surprisingly minimal loss of H3K27me3 or H2A.Z. These results indicate that the removal of silencing marks is not a prerequisite for activation of these genes. Our data provide a cell type- and time-resolved resource for studying the dynamics of a systemic nutrient stress and recovery and suggest that our current understanding of the mechanisms for switching between silent and active transcriptional states is incomplete.
SWR1 is recruited to activated ABA response genes to maintain gene body H2A.Z inArabidopsis thaliana
Authors: Krall Ellen G. , Deal Roger B.
Published: July 2024

The histone variant H2A.Z is important for transcriptional regulation across eukaryotes, where it can alternately promote or repress transcription. In plants, actively transcribed genes show H2A.Z enrichment in nucleosomes immediately downstream of the transcription start site (TSS), while silent genes show H2A.Z enrichment across the gene body. Previous work showed that silent genes responsive to temperature and far-red light lose gene body H2A.Z upon activation, but whether H2A.Z loss is generally required for transcription is not clear. We profiled H2A.Z and components of its deposition complex, SWR1, before and after treatingArabidopsis thalianawith the hormone abscisic acid (ABA). Our results show that transcribed genes with TSS-enriched H2A.Z have high SWR1 binding at steady-state, indicating continuous replacement of H2A.Z, while silent genes with gene body H2A.Z show lower SWR1 binding. Surprisingly, upon ABA treatment, thousands of previously silent genes activate, coincident with recruitment of SWR1 and retention of gene body H2A.Z enrichment. We also found that the SWR1-interacting protein MBD9 is not required for SWR1 recruitment to activated genes. These results provide new insights into the relationship between H2A.Z and transcription and the mechanics of H2A.Z targeting to chromatin.
Uneven Walking Momentum Regulation Exhibit Different Strategies based on Age and State of Lookahead
Authors: Hosseini-Yazdi Seyed-Saleh
Published: July 2024

Uneven terrains enforce challenges to continuously regulate the step parameters. Since forward momentum contributes materially to the walking balance, its step-to-step regulation plays an important role to traverse terrain complexities. Here, we exhibited that young and older adults’ modulation were affected by the state of lookahead. With a normal lookahead, they demonstrated anticipatory control. The young adults encountered terrain irregularities similar to step-up mounting and dismounting in which the total mechanical work was minimum. On the other hand, the older adults might have put more emphasis on foot placement instead, as they slowed down before the encounters. Additionally, their control was extended beyond of young adults. On the other hand, with the restricted lookahead, the control was based on feedback. Since young and older adults’ momentum regulations were very similar, it also supported suggestions that older adults might inherently rely on feedback to control their gait.
Experience improves navigational knowledge of dumpers in desert ants (Melophorus bagoti)
Authors: Cheng Ken , Deeti Sudhakar
Published: July 2024

The Australian red honey ant,Melophorus bagoti, is an excellent desert navigator, performing all the activities outside the nest during the hottest periods of summer days. This species relies heavily on path integration and landmark cues for outbound and inbound navigation. Although the species navigational behaviours have been much studied, the spatial knowledge of workers that dump waste has not been investigated. In our study, we investigated the navigational knowledge of both naive and experienced dumpers by displacing them 2 metres away from the nest. Naive dumpers were not oriented towards the nest in their initial trajectory at any of the test locations, whereas experienced dumpers were significantly oriented towards the nest at all test locations. Naive dumpers were nest-oriented as a group, however, at the test location nearest to where they dumped their waste. Compared with experienced dumpers, the paths of naive dumpers were more sinuous, and naive dumpers scanned more on tests. Overall, our findings suggest that dumpers gain greater spatial knowledge through repeated dumping runs outside the nest, contributing to successful homing behaviour.
Deep Learning Algorithms Reveal Increased Social Activity of Rats at the Start of Evening Twilight
Authors: Popik Piotr , Cyrano Ewelina , Golebiowska Joanna , Malikowska-Racia Natalia , Potasiewicz Agnieszka , Nikiforuk Agnieszka
Published: July 2024

1.

The rapid decrease of light intensity is a potent and natural stimulus of rats’ activity. The nature of this activity, in that, the character of the social behavior and the composition of concomitant ultrasonic vocalizations (USVs) is unknown.

This study, using deep learning algorithms, sought to assess the social life of rats’ pairs kept in the semi-natural conditions at the two twilight periods. Over six days, animals were video and audio recorded during the morning and the evening sessions lasting for 20-minutes each. The videos were used to train and use the DeepLabCut neural network examining animals’ movement in space and time. Numerical data generated by DeepLabCut were subjected to the Simple Behavioral Analysis (SimBA) toolkit, to build models of 11 distinct social and non-social behaviors. DeepSqueak toolkit was used to examine USVs.

Deep learning algorithms revealed lights-off induced increases of fighting, mounting, crawling, and rearing behaviors, as well as of 22-kHz alarm calls and 50-kHz flat and short, but not frequency modulated calls. In contrast, lights-on stimulus increased the general activity, as well as adjacent lying (huddling), anogenital sniffing and rearing behaviors. The animals adapted to the housing conditions showing decreased ultrasonic calls, as well as of grooming and rearing behaviors, but not fighting.

Present study shows lights-off induced increase of aggressive behavior but fail to demonstrate an increase in the positive affect defined by the hedonic USVs. We further confirm and extend the utility of deep learning algorithms in analyzing rat social behavior and ultrasonic vocalizations.

Highlights

- Rats display a natural increase in activity induced by lights-off stimulus

- Deep learning algorithms allow for rapid characterization of social behavior and ultrasonic calls

- The darkness increased aggressive behavior, 22-kHz alarm calls and 50-kHz flat and short, but not frequency modulated calls
Complementary Organization of Driver and Modulator Cortico-Thalamo-Cortical Circuits
Authors: Cassidy Rachel M. , Macias Angel V. , Lagos Willian N. , Ugorji Chiamaka , Callaway Edward M.
Published: July 2024

Corticocortical (CC) projections in the visual system facilitate the hierarchical processing of sensory information. In addition to direct CC connections, indirect cortico-thalamo-cortical (CTC) pathways through the pulvinar nucleus of the thalamus can relay sensory signals and mediate interactions between areas according to behavioral demands. While the pulvinar is extensively connected to the entire visual cortex, it is unknown whether transthalamic pathways link all cortical areas or whether they follow systematic organizational rules. Because pulvinar neurons projecting to different cortical areas are spatially intermingled, their input/output relationships have been difficult to characterize using traditional anatomical methods. To determine the organization of CTC circuits, we mapped the higher visual areas (HVAs) of mice with intrinsic signal imaging and targeted five pulvinar→HVA pathways for projection-specific rabies tracing. We aligned post- mortem cortical tissue toin vivomaps for precise quantification of the areas and cell types projecting to each pulvinar→HVA population. Layer 5 corticothalamic (L5CT) “driver” inputs to the pulvinar originate predominantly from primary visual cortex (V1), consistent with the CC hierarchy. L5CT inputs from lateral HVAs specifically avoid driving reciprocal connections, consistent with the “no-strong-loops” hypothesis. Conversely, layer 6 corticothalamic (L6CT) “modulator” inputs are distributed across areas and are biased toward reciprocal connections. Unlike previous studies in primates, we find that every HVA receives disynaptic input from the superior colliculus. CTC circuits in the pulvinar thus depend on both target HVA and input cell type, such that driving and modulating higher-order pathways follow complementary connection rules similar to those governing first-order CT circuits.

Significance Statement

Understanding the functional role of the visual pulvinar will require knowledge of its anatomical connections. Using state-of-the-art rabies tracing, we establish a comprehensive map of brain-wide and CTC pulvinar connections. While the tectopulvinar pathway in primates selectively targets dorsal visual areas, we find SC input to every projection population in the mouse. This extrageniculate projection can support unconscious visually-guided behavior, suggesting that in mice all visual cortical areas contribute to such functions. Our results also unify several longstanding theories of thalamocortical anatomy. Namely, “driver” CTC inputs are feedforward relays that mirror the CC hierarchy and adhere to the “no-strong-loops” hypothesis. “Modulator” L6CT inputs to pulvinar→HVA projections are overrepresented in the target HVA, reflecting the reciprocal connectivity described in previous bulk tracing studies. Together, these findings constitute a definitive and comprehensive map which can inform future physiological experiments and theoretical models of pulvinar function.
Structure of human PIEZO1 and its slow inactivating channelopathy mutants
Authors: Shan Yuanyue , Guo Xinyi , Zhang Mengmeng , Chen Meiyu , Li Ying , Zhang Mingfeng , Pei Duanqing
Published: July 2024

PIEZO channels transmit mechanical force signals to cells, allowing them to make critical decisions during development and in pathophysiological conditions. Their fast/slow inactivation modes have been implicated in mechanopathologies, but remain poorly understood. Here, we report several near-atomic resolution cryo-EM structures of fast-inactivating wild-type human PIEZO1 (hPIEZO1) and its slow-inactivating channelopathy mutants with or without its auxiliary subunit MDFIC. Our results suggest that hPIEZO1 has a more flattened and extended architecture than curved mouse PIEZO1 (mPIEZO1). The multi-lipidated MDFIC subunits insert laterally into the hPIEZO1 pore module like mPIEZO1, resulting in a more curved and extended state. Interestingly, the high-resolution structures suggest that the pore lipids, which directly seal the central hydrophobic pore, may be involved in the rapid inactivation of hPIEZO1. While the severe hereditary erythrocytosis mutant R2456H significantly slows down the inactivation of hPIEZO1, the hPIEZO1-R2456H-MDFIC complex shows a more curved and contracted structure with an inner helix twist due to the broken link between the pore lipid and R2456H. These results suggest that the pore lipids may be involved in the mechanopathological rapid inactivation mechanism of PIEZO channels.
Conditioned immunological memory: implication for cognition of immune cells
Authors: Zhu Zhu , Qin Wei , Li Qianlin , Zhang Hantao , Lin Zixuan , Chen Lin , Zhao Yunan
Published: July 2024

Associative learning refers to the process by which animals or human beings build the new relationship between two stimuli or events, which has been found throughout the animal kingdom. However, no studies have reported the associative learning in cells in the body to date. In the study, we focused on immune cells, as immunological memory is considered as one of the cardinal features of the immune system. As for a classical conditioning procedure, we designed the analogues of ginsenoside Rh1 (e.g., protopanaxadiol and panaxadiol) as the conditioned stimulus (CS) and the mcKLH-Rh1 conjugate as the unconditioned stimulus (US) and determined the CS-US association by detecting the dynamics of anti-Rh1 antibody production in serum. To test the hypothesis that immune cells also have the same associative learning ability as animals or human beings, mice were divided into control and CS group. Based on above CS and US, two groups of mice were subjected to conditioned learning, conditional memory recall, and deconditioning. When we used protopanaxadiol as the CS, the antibody response to Rh1 in the mice of CS group was slower and weaker than the control mice during conditional memory recall. Interestingly, the difference between two groups in antibody response to the immunogen disappeared during deconditioning. When we used panaxadiol as the CS, the antibody response to Rh1 in the mice of two groups was similar with that in studies regarding protopanaxadiol as the CS throughout three experimental phases. These results suggested that immune cells could acquire new association between a hapten analogue and a hapten-protein conjugate after undergoing a classical conditioning. Moreover, the conditioned immunological memory enables immune cells to make a conditioned response of humoral immunosuppression to prevent US induced immune damage. Our findings open a new frontier to explore cognitive functions of cells in the body and contribute to a novel understanding of cellular bioactivities.