bluuebunny/crossref_metadata_2025_split 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

AbstractPathogen 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

AbstractGlobal 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

AbstractOncolytic 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

AbstractThe 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.SignificanceThese 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

AbstractNeuroinflammation 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 StatementNeuroinflammation 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.
Appropriate data segmentation improves speech encoding models
Authors: Bialas Ole , Lalor Edmund C. 
Published: July 2024

AbstractIn 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

SUMMARYOncogene-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

ABSTRACTPersistent 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.HighlightsNociceptor 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

AbstractTranscription 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

AbstractRubisco, 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.
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

AbstractMalignant 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.
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

AbstractCoexistence 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

AbstractRecurrent 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.