Prime Model Research Articles

Persistent changes in the dorsal root ganglion nociceptor translatome governs hyperalgesic priming in mice: roles of GPR88 and Meteorin.

Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs because of reorganization of translation of mRNA in nociceptors. To test this hypothesis, we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. Translating ribosome affinity purification sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. Among these genes, we identified Gpr88 as upregulated and Metrn as downregulated. To provide functional evidence for these changes in hyperalgesic priming in a related priming model, we used the interleukin-6 priming model. A GPR88 agonist injection into the paw had no effect in naive mice but caused mechanical hypersensitivity and grimacing responses in female primed mice. Systemic Meteorin treatment in primed mice completely reversed established hyperalgesic priming mechanical hypersensitivity and grimacing responses to prostaglandin E2 in female mice. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming in multiple models in female mice.

Elementary embeddability with respect to Weihrauch reducibility

We study the Weihrauch complexity for problems of finding an elementary embedding (within the framework of the classical model theory). We prove that the problem of finding an elementary embedding from a prime model M into an arbitrary model N (which is elementarily equivalent to M) is strongly Weihrauch equivalent to the familiar problem lim (i.e., the problem of finding the limit of a sequence in Baire space). We show that the problem of finding an elementary embedding from an arbitrary model M into a countable saturated model N is also strongly Weihrauch equivalent to lim.

A quality of life promoting model for the elders Apllying social laboratory concept in health region 5, ministry of public health

This research and development project aimed to promote and evaluate the effectiveness of a quality of life of the elders applying social laboratory concept. The study was conducted in three phases, Phase 1: Situational analysis to identify quality of life issues among 270 elders’ participants. Phase 2: Development of the model and piloting with a sample of 30 participants. Phase 3: A pilot implementation and evaluation of the model with 30 experimental and 30 control participants. The study was conducted from June to September 2024. The tools used included, A WHOQOL–BREF–THAI questionnaire for assessing the quality of life of elders, A questionnaire on lifestyle behaviors, and A quality-of-life enhancement model for elders applying social laboratory concept. Data were analyzed using t-tests. Findings, Phase 1: The quality of life of elders in Health Region 5 of the Ministry of Public Health was found to be at a moderate level. Phase 2: A prototype model was developed, emphasizing participatory planning based on social action concepts. The PRIME Model was introduced, comprising, P: Purpose, Plan, and Partnerships, R: Research, Response, and Reflection, I: Insight, Interest, and Influence, M: Materials, Monitoring, and Maintenance, E: Experience, Empowerment, and Environment. This model was aligned with six key lifestyle behaviors for elders. Phase 3: The prototype model was applied to the experimental and control groups, each consisting of 30 participants, over a six-week period. The results revealed, A significant improvement in the quality of life among the experimental group compared to pre-intervention levels (p-value < .001). A significant enhancement in lifestyle behaviors in the experimental group compared to pre-intervention levels (p-value < .001). A significant improvement in overall health status among the experimental group compared to pre-intervention levels (p-value < .001). To sustain and improve the quality of life and health behaviors of elders, continuous application of the quality-of-life enhancement model based on the social laboratory concept is essential.

"You First Have to Check Out the Doctors": Transition Expectations and Experiences of Survivors After Pediatric Cancer.

The shift from child-centered to adult-focused healthcare presents social and psychological challenges for adolescents and young adults with chronic conditions, which can affect their participation in follow-up care. This study aims to investigate the factors that influence patient-driven motivations for adhering to follow-up recommendations, while also exploring the barriers and supports that impact the transition process for pediatric cancer survivors. We developed interview guidelines grounded in the Theory of Planned Behavior (TPB) and the stereotype priming model (SPM). We conducted 10 episodic narrative interviews with pediatric cancer survivors during their transition phase. The interview transcripts were analyzed through qualitative thematic content analysis, followed by quantitative analysis using multiple regression models. This research is a part of the broader VersKiK study, which aims to propose enhancements to the organization of (long-term) follow-up care after cancer in childhood and adolescence in Germany. In this study, pediatric cancer survivors transitioning to adult healthcare showed varied motivations for follow-up care. Positive attitudes, driven by understanding the benefits, improved engagement, while anxiety and fear of losing familiar care created barriers. Family and peer support played a key role in encouraging adherence. Perceived control over healthcare management, supported by organizational help, was crucial, but logistical and financial challenges often undermined this control. Several motives underlying pediatric cancer survivors' behavior significantly influence their transition experiences. Enhancing positive attitudes, strengthening social support, and improving perceived control through targeted interventions may support smoother transitions to adult healthcare facilities. Registered at German Clinical Trial Register (IDs: DRKS00025960 and DRKS00026092).

The Molecular Substrates of Insect Eusociality.

The evolution of eusociality in Hymenoptera-encompassing bees, ants, and wasps-is characterized by multiple gains and losses of social living, making this group a prime model to understand the mechanisms that underlie social behavior and social complexity. Our review synthesizes insights into the evolutionary history and molecular basis of eusociality. We examine new evidence for key evolutionary hypotheses and molecular pathways that regulate social behaviors, highlighting convergent evolution on a shared molecular toolkit that includes the insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) pathways, juvenile hormone and ecdysteroid signaling, and epigenetic regulation. We emphasize how the crosstalk among these nutrient-sensing and endocrine signaling pathways enables social insects to integrate external environmental stimuli, including social cues, with internal physiology and behavior. We argue that examining these pathways as an integrated regulatory circuit and exploring how the regulatory architecture of this circuit evolves alongside eusociality can open the door to understanding the origin of the complex life histories and behaviors of this group.

The roles of Magnaporthe oryzae avirulence effectors involved in blast resistance/susceptibility.

Phytopathogens represent an ongoing threat to crop production and a significant impediment to global food security. During the infection process, these pathogens spatiotemporally deploy a large array of effectors to sabotage host defense machinery and/or manipulate cellular pathways, thereby facilitating colonization and infection. However, besides their pivotal roles in pathogenesis, certain effectors, known as avirulence (AVR) effectors, can be directly or indirectly perceived by plant resistance (R) proteins, leading to race-specific resistance. An in-depth understanding of the intricate AVR-R interactions is instrumental for genetic improvement of crops and safeguarding them from diseases. Magnaporthe oryzae (M. oryzae), the causative agent of rice blast disease, is an exceptionally virulent and devastating fungal pathogen that induces blast disease on over 50 monocot plant species, including economically important crops. Rice-M. oryzae pathosystem serves as a prime model for functional dissection of AVR effectors and their interactions with R proteins and other target proteins in rice due to its scientific advantages and economic importance. Significant progress has been made in elucidating the potential roles of AVR effectors in the interaction between rice and M. oryzae over the past two decades. This review comprehensively discusses recent advancements in the field of M. oryzae AVR effectors, with a specific focus on their multifaceted roles through interactions with corresponding R/target proteins in rice during infection. Furthermore, we deliberated on the emerging strategies for engineering R proteins by leveraging the structural insights gained from M. oryzae AVR effectors.

Glutamine Oxidation in Mouse Dorsal Root Ganglia Regulates Pain Resolution and Chronification.

Chronic pain remains a significant health challenge with limited effective treatments. This study investigates the metabolic changes underlying pain progression and resolution, uncovering a novel compensatory mechanism in sensory neurons. Using the hyperalgesic priming model in male mice, we demonstrate that nerve growth factor (NGF) initially disrupted mitochondrial pyruvate oxidation, leading to acute allodynia. Surprisingly, this metabolic disruption persisted even after the apparent resolution of allodynia. We discovered that during the resolution phase, sensory neurons exhibit increased glutamine oxidation and upregulation of the major glutamine transporter ASCT2 in dorsal root ganglia. This compensatory response plays a crucial role in pain resolution, as demonstrated by our experiments. Knockdown of ASCT2 prevents the resolution of NGF-induced allodynia and precipitates the transition to a chronic state. Furthermore, we show that the glutamine catabolite α-ketoglutarate attenuated glycolytic flux and alleviated allodynia in both acute and chronic phases of the hyperalgesic priming model. The importance of ASCT2 is further confirmed in a translational model, where its knockdown prevented the resolution of allodynia following plantar incision. These findings highlight the pivotal role of metabolic changes in pain resolution and identify ASCT2-mediated glutamine metabolism as a potential therapeutic target for chronic pain. Understanding these endogenous mechanisms that promote pain resolution can guide the development of novel interventions to prevent the transition pain from acute to chronic.

The international cases of vaccinology education and its enlightenment to the discipline development in China

Vaccination is an effective public health measure to prevent and control vaccine-preventable diseases for individual and society. However, China currently confronts significant challenges, including a dearth of skilled professionals in the field of vaccination and disparities in the capacity for immunization services. This review introduced the experiences of four prime international vaccinology education models, including London School of Hygiene & Tropical Medicine, Johns Hopkins University, Leading International Vaccinology Education, and the Bill & Melinda Gates Foundation, in the aspect of personnel development, academic research and communication platforms establishment. It is supposed to give some insights and feasible suggestions on the establishment and advancement of vaccinology as a sub-discipline within high-level public health school in China, with the aim of development of a robust vaccinology education framework in China, which is essential for nurturing the next generation of public health leaders and practitioners for our country.

A Simple Computational Model of Semantic Priming in 18-Month-Olds.

We propose a simple computational model that describes potential mechanisms underlying the organization and development of the lexical-semantic system in 18-month-old infants. We focus on two independent aspects: (i) on potential mechanisms underlying the development of taxonomic and associative priming, and (ii) on potential mechanisms underlying the effect of Inter Stimulus Interval on these priming effects. Our model explains taxonomic priming between words by semantic feature overlap, whereas associative priming between words is explained by Hebbian links between semantic representations derived from co-occurrence relations between words (or their referents). From a developmental perspective, any delay in the emergence of taxonomic priming compared to associative priming during infancy seems paradoxical since feature overlap per se need not be learned. We address this paradox in the model by showing that feature overlap itself is an emergent process. The model successfully replicates infant data related to Inter Stimulus Interval effects in priming experiments and makes testablepredictions.

Comparative genomics of two protozoans Dictyostelium discoideum and Plasmodium falciparum reveals conserved as well as distinct regulatory pathways crucial for exploring novel therapeutic targets for Malaria

Plasmodium falciparum, which causes life-threatening cerebral malaria has rapidly gained resistance against most frontline anti-malarial drugs, thereby generating an urgent need to develop novel therapeutic approaches. Conducting in-depth investigations on Plasmodium in its native form is challenging, thereby necessitating the requirement of an efficient model system. In line, mounting evidence suggests that Dictyostelium discoideum retains both conformational and functional properties of Plasmodium proteins, however, the true potential of Dictyostelium as a host system is not fully explored. In the present study, we have exploited comparative genomics as a tool to extract, compare, and curate the extensive data available on the organism-specific databases to evaluate if D. discoideum can be established as a prime model system for functional characterization of P. falciparum genes. Through comprehensive in silico analysis, we report that despite the presence of adaptation-specific genes, the two display noteworthy conservation in the housekeeping genes, signaling pathway components, transcription regulators, and post-translational modulators. Furthermore, through orthologue analysis, the known, potential, and novel drug target genes of P. falciparum were found to be significantly conserved in D. discoideum. Our findings advocate that D. discoideum can be employed to express and functionally characterize difficult-to-express P. falciparum genes.

Neurogenesis in Caenorhabditis elegans.

Animals rely on their nervous systems to process sensory inputs, integrate these with internal signals, and produce behavioral outputs. This is enabled by the highly specialized morphologies and functions of neurons. Neuronal cells share multiple structural and physiological features, but they also come in a large diversity of types or classes that give the nervous system its broad range of functions and plasticity. This diversity, first recognized over a century ago, spurred classification efforts based on morphology, function, and molecular criteria. Caenorhabditis elegans, with its precisely mapped nervous system at the anatomical level, an extensive molecular description of most of its neurons, and its genetic amenability, has been a prime model for understanding how neurons develop and diversify at a mechanistic level. Here, we review the gene regulatory mechanisms driving neurogenesis and the diversification of neuron classes and subclasses in C. elegans. We discuss our current understanding of the specification of neuronal progenitors and their differentiation in terms of the transcription factors involved and ensuing changes in gene expression and chromatin landscape. The central theme that has emerged is that the identity of a neuron is defined by modules of gene batteries that are under control of parallel yet interconnected regulatory mechanisms. We focus on how, to achieve these terminal identities, cells integrate information along their developmental lineages. Moreover, we discuss how neurons are diversified postembryonically in a time-, genetic sex-, and activity-dependent manner. Finally, we discuss how the understanding of neuronal development can provide insights into the evolution of neuronal diversity.

Examining potential health gains arising from reduced risk consumption in South Africa via the PRIME model

ObjectivesNon-communicable diseases (NCDs) account for over 30% of disability-adjusted life years in South Africa. In this research, we offer an estimate of the potential reduction in NCD incidence that would arise from an improvement in diet, combined with a reduction in both tobacco and alcohol consumption.MethodsWe apply the PRIME model, which simulates the effect of risk reduction on NCD incidence. The model inputs baseline data related to the population, risky consumption behaviour and NCD incidence. The model allows for counterfactual scenarios altering the risky consumption behaviour to yield revised NCD incidence.ResultsWe find that reducing salt, tobacco and alcohol, along with improved fruit, vegetable and fiber consumption would yield a 10% reduction in NCDs from the 2018 baseline. NCD incidence reductions arise primarily from ischemic heart disease (49%), cerebrovascular diseases (33%) and bronchus and lung disease (11%).ConclusionSouth Africa’s NCD incidence is high because of relatively poor behavioural choices, despite plans and policies aimed at changing this. South Africa should increase their efforts to reach NCD goals. If the government is able to reduce harmful behaviour, with respect to a number of the underlying consumption choices, NCD incidence is expected to fall precipitously.

Where Top-Down Meets Bottom-Up: Cell-Type Specific Connectivity Map of the Whisker System

Sensorimotor computation integrates bottom-up world state information with top-down knowledge and task goals to form action plans. In the rodent whisker system, a prime model of active sensing, evidence shows neuromodulatory neurotransmitters shape whisker control, affecting whisking frequency and amplitude. Since neuromodulatory neurotransmitters are mostly released from subcortical nuclei and have long-range projections that reach the rest of the central nervous system, mapping the circuits of top-down neuromodulatory control of sensorimotor nuclei will help to systematically address the mechanisms of active sensing. Therefore, we developed a neuroinformatic target discovery pipeline to mine the Allen Institute’s Mouse Brain Connectivity Atlas. Using network connectivity analysis, we identified new putative connections along the whisker system and anatomically confirmed the existence of 42 previously unknown monosynaptic connections. Using this data, we updated the sensorimotor connectivity map of the mouse whisker system and developed the first cell-type-specific map of the network. The map includes 157 projections across 18 principal nuclei of the whisker system and neuromodulatory neurotransmitter-releasing. Performing a graph network analysis of this connectome, we identified cell-type specific hubs, sources, and sinks, provided anatomical evidence for monosynaptic inhibitory projections into all stages of the ascending pathway, and showed that neuromodulatory projections improve network-wide connectivity. These results argue that beyond the modulatory chemical contributions to information processing and transfer in the whisker system, the circuit connectivity features of the neuromodulatory networks position them as nodes of sensory and motor integration.

Priming of Possessive Constructions in German: A Matter of Preference Effects?

We investigated structural priming in adult native speakers, focusing on possessive constructions in German, where the two alternative structures involved differ in frequency. According to error-based learning approaches to priming, the less frequent structure should lead to a larger prediction error and larger priming effects than the more frequent structure. In a comparison of preferences during a pretest and preferences during priming, we did not find evidence of such an inverse preference effect. Moreover, during priming, we observed increasing production rates of the preferred structure, hence, a cumulative priming effect. In line with hybrid models of priming, we propose that two mechanisms, namely, a mechanism learning from input as well as a mechanism accumulating activation during comprehension and production, are involved in the temporal development of priming effects. Moreover, we suggest that the interaction of the two mechanisms may depend on prior experience with the alternative structures.

Lipid phase separation impairs membrane thickness sensing by the Bacillus subtilis sensor kinase DesK.

The B. subtilis des system is a prime model for direct molecular membrane thickness sensor and, as such, has been well studied in vitro. Our study shows that our understanding of its function in vivo and its importance under temperature and antibiotic stress is still very limited. Specifically, our results suggest that (i) the des system senses very subtle membrane fluidity changes that escape detection by established fluidity reporters like laurdan; (ii) membrane thickness sensing by DesK is impaired by phase separation due to partitioning of the protein into the fluid phase; and (iii) fluidity adaptations by Des are too subtle to elicit growth defects under rigidifying conditions, raising the question of how much the des system contributes to adaptation of overall membrane fluidity.

Bio-Inspired Pressure-Dependent Programmable Mechanical Metamaterial with Self-Sealing Ability.

Self-sealing is one of the fascinating functions in nature that enables living material systems to respond immediately to damage. A prime plant model is Delosperma cooperi, which can rapidly self-seal damaged succulent leaves by systematically deforming until the wound closes. Inspired by this self-sealing principle, a novel programmable mechanical metamaterial has been developed to mimic the underlying damage management concept. This material is able to react autonomously to changes in its physical condition caused by an induced damage. To design this ability into the programmable metamaterial, a permeable unit cell design has been developed that can change size depending on the internal pressure. The parameter space and associated mechanical functionality of the unit cell design is simulated and analyzed under periodic boundary conditions and various pressures. The principles of self-sealing behavior in designed metamaterials are investigated, crack closure efficiency is identified for different crack lengths, the limitations of the proposed approach are discussed, and successful crack closure is experimentally demonstrated in the fabricated metamaterial. Although this study facilitates the first step on the way of integrating new bio-inspired principles in the metamaterials, the results show how programmable mechanical metamaterials might extend materials design space from pure properties to life-likeabilities.

Different states of synaptic vesicle priming explain target cell type–dependent differences in neurotransmitter release

Pronounced differences in neurotransmitter release from a given presynaptic neuron, depending on the synaptic target, are among the most intriguing features of cortical networks. Hippocampal pyramidal cells (PCs) release glutamate with low probability to somatostatin expressing oriens-lacunosum-moleculare (O-LM) interneurons (INs), and the postsynaptic responses show robust short-term facilitation, whereas the release from the same presynaptic axons onto fast-spiking INs (FSINs) is ~10-fold higher and the excitatory postsynaptic currents (EPSCs) display depression. The mechanisms underlying these vastly different synaptic behaviors have not been conclusively identified. Here, we applied a combined functional, pharmacological, and modeling approach to address whether the main difference lies in the action potential-evoked fusion or else in upstream priming processes of synaptic vesicles (SVs). A sequential two-step SV priming model was fitted to the peak amplitudes of unitary EPSCs recorded in response to complex trains of presynaptic stimuli in acute hippocampal slices of adult mice. At PC-FSIN connections, the fusion probability (Pfusion) of well-primed SVs is 0.6, and 44% of docked SVs are in a fusion-competent state. At PC-O-LM synapses, Pfusion is only 40% lower (0.36), whereas the fraction of well-primed SVs is 6.5-fold smaller. Pharmacological enhancement of fusion by 4-AP and priming by PDBU was recaptured by the model with a selective increase of Pfusion and the fraction of well-primed SVs, respectively. Our results demonstrate that the low fidelity of transmission at PC-O-LM synapses can be explained by a low occupancy of the release sites by well-primed SVs.

Towers and the First-order Theories of Hyperbolic Groups

This paper is devoted to the first-order theories of torsion-free hyperbolic groups. One of its purposes is to review some results and to provide precise and correct statements and definitions, as well as some proofs and new results. A key concept is that of a tower (Sela) or NTQ system (Kharlampovich-Myasnikov). We discuss them thoroughly. We state and prove a new general theorem which unifies several results in the literature: elementarily equivalent torsion-free hyperbolic groups have isomorphic cores (Sela); if H H is elementarily embedded in a torsion-free hyperbolic group G G , then G G is a tower over H H relative to H H (Perin); free groups (Perin-Sklinos, Ould-Houcine), and more generally free products of prototypes and free groups, are homogeneous. The converse to Sela and Perin’s results just mentioned is true. This follows from the solution to Tarski’s problem on elementary equivalence of free groups, due independently to Sela and Kharlampovich-Myasnikov, which we treat as a black box throughout the paper. We present many examples and counterexamples, and we prove some new model-theoretic results. We characterize prime models among torsion-free hyperbolic groups, and minimal models among elementarily free groups. Using Fraïssé’s method, we associate to every torsion-free hyperbolic group H H a unique homogeneous countable group M {\mathcal {M}} in which any hyperbolic group H ′ H’ elementarily equivalent to H H has an elementary embedding. In an appendix we give a complete proof of the fact, due to Sela, that towers over a torsion-free hyperbolic group H H are H H -limit groups.

Transposon and Transgene Tribulations in Mosquitoes: A Perspective of piRNA Proportions.

Mosquitoes, like Drosophila, are dipterans, the order of "true flies" characterized by a single set of two wings. Drosophila are prime model organisms for biomedical research, while mosquito researchers struggle to establish robust molecular biology in these that are arguably the most dangerous vectors of human pathogens. Both insects utilize the RNA interference (RNAi) pathway to generate small RNAs to silence transposons and viruses, yet details are emerging that several RNAi features are unique to each insect family, such as how culicine mosquitoes have evolved extreme genomic feature differences connected to their unique RNAi features. A major technical difference in the molecular genetic studies of these insects is that generating stable transgenic animals are routine in Drosophila but still variable in stability in mosquitoes, despite genomic DNA-editing advances. By comparing and contrasting the differences in the RNAi pathways of Drosophila and mosquitoes, in this review we propose a hypothesis that transgene DNAs are possibly more intensely targeted by mosquito RNAi pathways and chromatin regulatory pathways than in Drosophila. We review the latest findings on mosquito RNAi pathways, which are still much less well understood than in Drosophila, and we speculate that deeper study into how mosquitoes modulate transposons and viruses with Piwi-interacting RNAs (piRNAs) will yield clues to improving transgene DNA expression stability in transgenic mosquitoes.

Advanced direct torque control based on neural tree controllers for induction motor drives

This paper introduces a novel direct torque control approach based on the decision tree (T-DTC), employing artificial neural networks that are effectively trained to enhance accuracy and robustness. The main objective of T-DTC is the substantial reduction of flux and torque ripples inherent in the conventional DTC, ensuring effective control of the induction motor. The conventional hysteresis controllers for stator flux and electromagnetic torque are replaced by two advanced controllers named M5 Prime model trees. Additionally, the traditional switching table is substituted with a novel decision tree table utilizing the classifier algorithm 4.5. The effectiveness of the proposed T-DTC strategy is demonstrated through simulation in MATLAB/Simulink and validated in real-time using an HIL platform based on OPAL-RT OP 5600 and Virtex 6 FPGA ML605. The results obtained demonstrate a notable improvement compared to existing techniques in the literature.