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Neural activity can increase the length of nodes of Ranvier (NOR) and slow impulse transmission; however, little is known about the biologically and clinically important recovery process. Sensory deprivation promotes neural plasticity in many phenomena, raising the question of whether recovery of NOR morphology is influenced by sensory deprivation. The results show that NOR gap length recovery in mouse optic nerve was not affected significantly by binocular visual deprivation imposed by maintaining mice in 24 hr dark for 30 days compared to mice recovering under normal visual experience. The findings provide insight into the cellular mechanism of NOR plasticity. • Recovery of node of Ranvier morphology in adult mouse optic nerve is not altered by binocular visual deprivation. • Node of Ranvier morphology is reversibly altered by exocytosis from astrocytes. • This form of node of Ranvier plasticity can take place in adult mice. [ABSTRACT FROM AUTHOR]

Chronic constriction injury (CCI) of the infraorbital nerve induces neuropathic pain, such as allodynia and hyperalgesia, in the orofacial area. However, the changes in the local circuits of the central nervous system following CCI remain unclear. This study aimed to identify the changes following CCI in Thy1-GCaMP6s transgenic mice. Neural activity in the primary somatosensory cortex (S1) and motor cortex (M1) following whisker stimulation was assessed using in vivo Ca2+ imaging. CCI-induced changes in responses were analyzed. Before CCI, whisker stimulation induced a greater Ca2+ response in the contralateral S1 than in the ipsilateral S1 and contralateral M1. The peak Ca2+ response amplitude in the bilateral S1 and contralateral M1 decreased two days after CCI compared to before CCI. Decreased Ca2+ response amplitude in these regions was observed until four days after CCI. Seven days after CCI, the Ca2+ response amplitude in the contralateral S1 decreased, whereas that in the ipsilateral S1 and contralateral M1 recovered to control levels. These results suggest that neural activity in regions receiving excitatory inputs via corticocortical pathways recovers earlier than in regions receiving thalamocortical inputs. (185/250 words) [ABSTRACT FROM AUTHOR]

The tensile properties of sintered C f -ZrB 2 /SiC UHTCMCs were investigated for different lamination sequences, revealing ultimate strengths of 570 MPa (0°/0°), 120 MPa (0°/90°), and 40 MPa (90°/90°). The results facilitated modeling the material's non-linear tensile response, characterized by a remarkably prolonged plateau with pseudo-plastic behavior, followed by stiffness recovery before ultimate failure. A simplified analytical model was developed to predict this behavior originated by residual thermal stresses and inelastic phenomena. A complete constitutive law was then developed and implemented in a FE model, utilizing a bi-phasic approach including Drucker-Prager plasticity and orthotropic ductile damage. Two-step analyses were performed, starting with a thermal step to represent the buildup of a self-equilibrating RTS state in the material phases, followed by a mechanical simulation. This demonstrated the model's efficacy in capturing the non-linear response in both homogeneous and cross-ply lay-ups, contributing to advancements in materials engineering and the design of UHTCMCs-based hot structures. [Display omitted] [ABSTRACT FROM AUTHOR]

• Practical fracture limit surfaces (FLSs) considering data flexibility. • A profile function for nonlinear fracture data variations in strain-based FLS. • Stress-based FLS considering evolution of stress anisotropy in the Lagrangian frame. • Both models were validated by experimental data set. • The model effectively represents the flexibility of fracture data. Ductile fracture limits have been extensively studied from the perspectives of material science and mechanics. While these studies have provided scientifically significant insights into ductile fracture limits, the influence of the evolution of anisotropy observed in actual experimental data suggests a need to account for diversity in the experimental data. To address this, it may be possible to further develop the model by investigating more influences from the field of materials science. However, from an engineering perspective, it can be effective to represent the diversity of acquired experimental data as practical functions for use, rather than solely focusing on the material science aspect. This paper presents mathematical formulations representing the strain- and stress-based fracture limit surfaces of ductile materials, to consider diverse data set for the evolution of anisotropy, under plane-stress conditions within the framework of the Lagrangian formulation. The model introduces a strain-based fracture limit surface (FLS), which has an additional anisotropic profile function based on the commonly used two-dimensional strain-based fracture limit curve (FLC). The anisotropic profile function is capable of capturing the evolving anisotropic profile based on the deformation mode and principal loading direction to represent more flexible shapes. With this function, a three-dimensional strain-based FLS, which can present the variation in fracture strains in the space of the deformation mode and principal loading direction, can be constructed. Then, the proposed model transformed this strain-based FLS into a stress-based FLS by converting the presented state vector in the former into the corresponding vector in the latter in the Lagrangian formulation. To achieve this, this study developed a formulation that considers the nonlinear evolution of stress anisotropy independent of the strain anisotropy during stress evolution. The two proposed models were validated by experimental results on a dual-phase steel. These models provide flexible fracture limit functions for ductile materials under varying stress and strain conditions in engineering applications. [ABSTRACT FROM AUTHOR]

Acute cerebral ischemia triggers a number of cellular mechanisms not only leading to excitotoxic cell death but also to enhanced neuroplasticity, facilitating neuronal reorganization and functional recovery. Transferring these cellular mechanisms to neurophysiological correlates adaptable to patients is crucial to promote recovery post-stroke. The combination of TMS and EEG constitutes a promising readout of neuronal network activity in stroke patients. We used the combination of TMS and EEG to investigate the development of local signal processing and global network alterations in 40 stroke patients with motor deficits alongside neural reorganization from the acute to the chronic phase. We show that the TMS-EEG response reflects information about reorganization and signal alterations associated with persistent motor deficits throughout the entire post-stroke period. In the early post-stroke phase and in a subgroup of patients with severe motor deficits, TMS applied to the lesioned motor cortex evoked a sleep-like slow wave response associated with a cortical off-period, a manifestation of cortical bistability, as well as a rapid disruption of the TMS-induced formation of causal network effects. Mechanistically, these phenomena were linked to lesions affecting ascending activating brainstem fibers. Of note, slow waves invariably vanished in the chronic phase, but were highly indicative of a poor functional outcome. In summary, we found evidence that transient effects of sleep-like slow waves and cortical bistability within ipsilesional M1 resulting in excessive inhibition may interfere with functional reorganization, leading to a less favorable functional outcome post-stroke, pointing to a new therapeutic target to improve recovery of function. • TMS-EEG responses portray both reorganization and persistent signal alterations. • Impaired signal processing is linked to function from the acute to chronic phase. • Motor recovery is accompanied with recovery of global brain complexity. • Mechanisms of cortical bistability early after stroke contribute to motor recovery. • Lesion data link sleep-like waves to ascending activating brainstem fibers. [ABSTRACT FROM AUTHOR]

Cancer cells change phenotype through cancer evolution; some phenotype changes are caused by underlying genetic mutations, but many are due to non-genetic mechanisms. We suggest separating non-genetic phenotype changes into two distinct mechanisms: changes induced by microenvironmental stimuli (that we term 'phenotypic plasticity') and changes induced by stochastic cell-intrinsic effects (that we term 'phenotypic noise'). We discuss how lineage tracing methods – either experimental or those that make use of sporadic mutations to mark lineages – can be used to distinguish between phenotypic plasticity and noise. Distinguishing between phenotypic plasticity and noise guides mechanistic work to determine the molecular causes of phenotype change, and will ultimately accelerate efforts to control or prevent phenotype changes that enable cancer cells to resist therapies. Non-genetic alterations can produce changes in a cell's phenotype. In cancer, these phenomena can influence a cell's fitness by conferring access to heritable, beneficial phenotypes. Herein, we argue that current discussions of 'phenotypic plasticity' in cancer evolution ignore a salient feature of the original definition: namely, that it occurs in response to an environmental change. We suggest 'phenotypic noise' be used to distinguish non-genetic changes in phenotype that occur independently from the environment. We discuss the conceptual and methodological techniques used to identify these phenomena during cancer evolution. We propose that the distinction will guide efforts to define mechanisms of phenotype change, accelerate translational work to manipulate phenotypes through treatment, and, ultimately, improve patient outcomes. [ABSTRACT FROM AUTHOR]

A thorough understanding of the evolution of strain and damage accumulation is a prerequisite for effective control of the surrounding rock to ensure good stability and better maintenance of underground structures. In this work, we have proposed a new way of adjusting the fractional order to obtain a new variable fractional order rheological model to describe the evolution of mechanical properties and to model the stress-strain response of the rock during plastic flow. It is proved that the function law of our variable order fractional model is defined by five parameters a , b , m , n , α 0. An analysis of the different parameters of the fractional model confirms that the mechanical behavior of the rock hardens and softens faster when the confining pressure is high. Moreover, the definition of our fractional model by a continuous function of the plastic strain allows us to explore in more detail the hardening/softening duality of the mechanical behavior of the rock. This fractional model not only allows us to model the stress-strain relationship of the rock more accurately and with a relatively short calculation time, it also allows us to model the stress-strain relationship of the rock more accurately and with a relatively short calculation time, but also to accurately capture the contraction-dilation volume transition of quasi-fragile rocks. We believe that the results of this work will help in the decision making process for the construction of underground structures. • A new fractional model is established by a continuous function of plastic strain. • Its continuous form is necessary to evaluate the influence of confining pressure. • The new model more accurately describes the stress-strain relationship of the rock. • This model also reflects the rock's compression-dilation volume transition. [ABSTRACT FROM AUTHOR]

Zirconia (ZrO 2) ceramics uniquely exhibit transformation-induced plasticity, allowing plastic deformation prior to failure, setting them apart from most other ceramics. However, our understanding of ZrO 2 plasticity is hindered by the challenge of simulating stress-induced atomic-scale phase transformations, owing to lack of an efficient interatomic potential accurately representing polymorphism and phase changes in ZrO 2. In this work, we introduce a novel deep neural network interatomic potential, DP-ZrO 2 , constructed using a concurrent-learning approach. DP-ZrO 2 reproduces properties of various ZrO 2 phases, matching their phase diagrams as well as transformation pathways with accuracy comparable to ab initio density functional theory. Leveraging DP-ZrO 2 , we conducted molecular dynamics simulations of temperature-induced interphase boundary migration and nanocompression. These simulations demonstrate the potential's efficiency and applicability in studying deformation microstructures involving phase transformations in ZrO 2. Our approach opens the door to large-scale simulations under complex loading conditions, which will shed light on the conditions favouring ZrO 2 transformation-induced plasticity. [ABSTRACT FROM AUTHOR]

The first 2 years of life is a period of rapid learning and growth when humans acquire notable motor, perceptual, linguistic, and social capabilities. Because of challenges in measuring brain activity in human infants, many of the neural mechanisms underlying these capabilities have not been identified. Advances in neuroimaging technologies, task designs, and data analyses from studies of older children and adults are starting to be translated into studies of infants. These new methods include frequency tagging designs in electroencephalography (EEG), task-based functional magnetic resonance imaging (fMRI) studies in awake and behaving infants, multivariate analyses of EEG and functional near-infrared spectroscopy (fNIRS), and the emergence of infant-friendly optically pumped magnetometry (OPM). The resulting neural data provide rich new measures of infant cognition, supplementing the limited behavioral data that can be obtained from preverbal infants. The functional properties of the infant brain are poorly understood. Recent advances in cognitive neuroscience are opening new avenues for measuring brain activity in human infants. These include novel uses of existing technologies such as electroencephalography (EEG) and magnetoencephalography (MEG), the availability of newer technologies including functional near-infrared spectroscopy (fNIRS) and optically pumped magnetometry (OPM), and innovative applications of functional magnetic resonance imaging (fMRI) in awake infants during cognitive tasks. In this review article we catalog these available non-invasive methods, discuss the challenges and opportunities encountered when applying them to human infants, and highlight the potential they may ultimately hold for advancing our understanding of the youngest minds. [ABSTRACT FROM AUTHOR]

The effects of the selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressant treatment, have been proposed to be affected, at least in part, by the living environment. Since the quality of the environment depends not only on its objective features, but also on the subjective experience, we hypothesized that the latter plays a key role in determining SSRI treatment outcome. We chronically administered the SSRI fluoxetine to two groups of adult CD-1 male mice that reportedly show distinct subjective experiences of the environment measured as consistent and significantly different responses to the same emotional and social stimuli. These distinct socioemotional profiles were generated by rearing mice either in standard laboratory conditions (SN) or in a communal nest (CN) where three dams breed together their offspring, sharing caregiving behavior. At adulthood, CN mice displayed higher levels of agonistic and anxiety-like behaviors than SN mice, indicating that they experience the environment as more socially challenging and potentially dangerous. We then administered fluoxetine, which increased offensive and anxious response in SN, while producing opposite effects in CN mice. BDNF regulation was modified by the treatment accordingly. Subjective experience in mice was assessed as behavioral response to the environment. These results show that the subjective experience of the environment determines fluoxetine outcome. In a translational perspective, our findings suggest considering not only the objective quality, but also the subjective appraisal, of the patient's living environment for developing effective personalized therapeutic approaches in psychiatry. • SSRI action is affected by the quality of the environment. • The quality of the environment is defined by its subjective appraisal. • Fluoxetine effects differed according to the subjective appraisal of the environment. • SSRI outcome depends on both objective and subjective quality of the environment. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) has emerged as a pivotal noninvasive technique for investigating cortical excitability and plasticity across the lifespan, offering valuable insights into neurodevelopmental and neurodegenerative processes. In this review, we explore the impact of TMS applications on our understanding of normal development, healthy aging, neurodevelopmental disorders, and adult-onset neurodegenerative diseases. By presenting key developmental milestones and age-related changes in TMS measures, we provide a foundation for understanding the maturation of neurotransmitter systems and the trajectory of cognitive functions throughout the lifespan. Building on this foundation, the paper delves into the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, and adolescent depression. Highlighting recent findings on altered neurotransmitter circuits and dysfunctional cortical plasticity, we underscore the potential of TMS as a valuable tool for unraveling underlying mechanisms and informing future therapeutic interventions. We also review the emerging role of TMS in investigating and treating the most common adult-onset neurodegenerative disorders and late-onset depression. By outlining the therapeutic applications of noninvasive brain stimulation techniques in these disorders, we discuss the growing body of evidence supporting their use as therapeutic tools for symptom management and potentially slowing disease progression. The insights gained from TMS studies have advanced our understanding of the underlying mechanisms in both healthy and disease states, ultimately informing the development of more targeted diagnostic and therapeutic strategies for a wide range of neuropsychiatric conditions. [ABSTRACT FROM AUTHOR]

Calcium fluoride (CaF 2) ionic crystals have been observed to be sensitive to humid environments during ultra-precision machining, but further discussion about detailed mechanisms of the corresponding water-induced mechanical behaviors is still lacking. This work aims to perform a systematic investigation to understand the effect of water on the deformation and correlated plastic enhancement of CaF 2 under indentation. Micro-indentation experiments were employed to observe different mechanical responses including the pop-in behavior and surface pile-up to identify the water-enhanced plasticity of CaF 2 preliminarily. Then, atomic simulations were performed to reproduce the indentation process and confirm the close relationship between the indentation behaviors and water. The dislocation activities and crystal slip of both simulations with and without water were captured to analyze the plastic flow induced by hydration. Furthermore, Raman spectroscopy measurement was also adopted in this study to explain the corresponding enhancing mechanisms of plastic behaviors from the perspective of surface effect. • Micro-indentation tests confirm the water-enhanced plasticity of CaF 2. • MD simulations explain the enhanced plasticity from the view of plastic flow. • The deformation mechanisms are uncovered by theoretical analysis. • Water enhances plasticity by pre-stressing and reducing surface effects. • Results of Raman tests further demonstrate the water-induced prestressing. [ABSTRACT FROM AUTHOR]

Ketamine induces a complex cascade of effects on diverse groups of brain cells through several receptors. In the cortex and hippocampus, the concomitant inhibition of interneurons and activation of excitatory neurons is triggered by rapid pharmacological effects and the subsequent engagement of signaling pathways that activate protein synthesis. The lasting effects of ketamine are sustained by the activation of neuronal plasticity mechanisms, including control of excitability and synaptogenesis in the cortex and hippocampus. Correlative evidence suggests the contribution of oligodendrocytes, astroglia, and microglia to the antidepressant effects of ketamine, but the casual involvement of these cell types has not been definitively tested. Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl- d -aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine. Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl-d-aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine. [ABSTRACT FROM AUTHOR]

The high ductility of Mg-Li alloy has been mainly ascribed to a high activity of pyramidal slip to accommodate plastic strain. In the present study, however, a quantitative analysis reveals that Li-addition can only slightly stimulate the activation of pyramidal slip under compression along the normal direction of a hot-rolled Mg-4.5 wt.% Li plate, with a relative activity of approximately 18%. Although the limited activity of pyramidal slip alone cannot accommodate a large plastic strain, it effectively reduces the number of { 10 1 ¯ 1 } − { 10 1 ¯ 2 } double twins, which are believed to be favorable sites for crack initiation. The evidently reduced activity of double twins leads to a lower cracking tendency, and therefore improves ductility. [ABSTRACT FROM AUTHOR]

Dendritic spines are unique postsynaptic structures that emerge from the dendrites of neurons. They undergo activity-dependent morphological changes known as structural plasticity. The changes involve actin cytoskeletal remodeling, which is regulated by actin-binding proteins. CaMKII is a crucial molecule in synaptic plasticity. Notably, CaMKIIβ subtype is known to bind to filamentous-actin and is closely involved in structural plasticity. We have shown that CaMKIIβ binds to drebrin, and is localized in spines as both drebrin-dependent and drebrin-independent pools. However, the nanoscale relationship between drebrin and CaMKIIβ within dendritic spines has not been clarified. In this study, we used stochastic optical reconstruction microscopy (STORM) to examine the detailed localization of these proteins. STORM imaging showed that CaMKIIβ co-localized with drebrin in the core region of spines, and localized in the submembrane region of spines without drebrin. Interestingly, the dissociation of CaMKIIβ and drebrin in the core region was induced by NMDA receptor activation. In drebrin knockdown neurons, CaMKIIβ was decreased in the core region but not in the submembrane region. Together it indicates that the clustering of CaMKIIβ in the spine core region is dependent on drebrin. These findings suggest that drebrin-dependent CaMKIIβ is in a standby state before its activation. • CaMKIIβ localized in the core of dendritic spines in a drebrin-dependent manner. • CaMKIIβ was not colocalized with drebrin in submembrane region. • The interaction between CaMKIIβ and drebrin was abolished by NMDA receptor activation. [ABSTRACT FROM AUTHOR]

The external light environment has been reported to have a pronounced influence on the dislocation-based plasticity in various inorganic semiconductors. Herein, with a specific focus on the pyramidal slip in wurtzite structures, photoindentation tests were performed on the (0001) plane of ZnO crystal to activate the pyramidal slip and evaluate the effects of light on dislocation behaviors. Statistical analyses of the first pop-in events suggested that the corresponding maximum shear stresses in darkness were slightly smaller than those in 405 nm light, indicating a minor effect of light on dislocation nucleation event. Regarding nanoindentation creep tests, light illumination was found to suppress the indentation depth. Further transmission electron microscopy observations demonstrated that indentation-induced pyramidal dislocations were present deeper in darkness than in 405 nm light, revealing a suppressive effect of light illumination on the pyramidal slip in ZnO for the first time. [ABSTRACT FROM AUTHOR]

• Glaucoma patients displayed brain dynamics differences vs. controls. • Glaucoma alters early visual processing in the central nervous system. • Potential compensatory mechanisms were observable in the late cerebral response. To investigate neurophysiological dynamics during a visuocognitive task in glaucoma patients vs. healthy controls. Fifteen patients with early-stage primary open-angle glaucoma (POAG) and fifteen age-matched healthy participants underwent a "go/no-go" task, monitored with EEG. Participants had to semantically categorize visual objects in central vision, with animal or furniture as targets according to the experimental block. Early visual processing was delayed by 50 ms in patients with POAG compared to controls. The patients displayed a smaller difference between animal and furniture categorization during higher-level cognitive processing (at 400–600 ms). Regarding behavioral data, the groups differed in accuracy performance and decision criterion. As opposed to the control group, patients did not display facilitation and a higher accuracy rate for animal stimuli. However, patients maintained a consistent decision criterion throughout the experiment, whereas controls displayed a shift towards worse decision criteria in furniture trials, with higher error rate. The comparative analysis of behavioral and neurophysiological data revealed in POAG patients a delay in early visual processing, and potential high-level cognitive compensation during late, task-dependent activations. To our knowledge, our findings provide the first evidence of modification in cognitive brain dynamics associated with POAG. [ABSTRACT FROM AUTHOR]

• We aim at unpacking the monolithic construct of motor variability • We propose noise, differentiation and adaptability as key domains of variability • (Co)adaptability might be a core regulator to promote effective interactions In the last decade, the source and the functional meaning of motor variability have attracted considerable attention in behavioral and brain sciences. This construct classically combined different levels of description, variable internal robustness or coherence, and multifaceted operational meanings. We provide here a comprehensive review of the literature with the primary aim of building a precise lexicon that goes beyond the generic and monolithic use of motor variability. In the pars destruens of the work, we model three domains of motor variability related to peculiar computational elements that influence fluctuations in motor outputs. Each domain is in turn characterized by multiple sub-domains. We begin with the domains of noise and differentiation. However, the main contribution of our model concerns the domain of adaptability, which refers to variation within the same exact motor representation. In particular, we use the terms learning and (social)fitting to specify the portions of motor variability that depend on our propensity to learn and on our largely constitutive propensity to be influenced by external factors. A particular focus is on motor variability in the context of the sub-domain named co-adaptability. Further groundbreaking challenges arise in the modeling of motor variability. Therefore, in a separate pars construens, we attempt to characterize these challenges, addressing both theoretical and experimental aspects as well as potential clinical implications for neurorehabilitation. All in all, our work suggests that motor variability is neither simply detrimental nor beneficial, and that studying its fluctuations can provide meaningful insights for future research. [ABSTRACT FROM AUTHOR]

• Prolonged experimental pain for hours disrupts the cortical homeostatic response. • Pain relief does not reinstate pre-pain cortical homeostatic plasticity regulation. • Exploring approaches to restore homeostatic regulation during pain is warranted. Homeostatic plasticity (HP) regulates cortical excitability (CE) stability but is disrupted in persistent pain conditions. This study investigated how prolonged experimental pain affects HP and if pain relief modulates disrupted HP. Twenty-four healthy participants were randomised into a PainRelief or NoPainRelief group and attended four sessions; two sessions on consecutive days, separated by two weeks. Transcranial magnetic stimulation motor-evoked potentials reflecting CE and quantitative sensory testing (QST) measures were recorded. A capsaicin (pain condition) or placebo (control condition) patch was applied to the hand. HP was induced by cathodal-cathodal transcranial direct current stimulation (HP1) with CE assessment before and after. The PainRelief group had ice applied to the patch, while the NoPainRelief group waited for five minutes; subsequently another HP induction (HP2) and CE assessment were performed. After 24 h with the patch on, HP induction (HP3), QST, and CE recordings were repeated. Capsaicin reduced CE and the pain condition showed disrupted homeostatic responses at all time points (HP1: showed CE inhibition instead of facilitation; HP2 & HP3: lack of CE facilitation). Conversely, homeostatic responses were induced at all time points for the placebo condition. Capsaicin pain disrupts HP which is not restored by ice-induced pain relief. Future research may explore the prevention of HP disruption by targeting capsaicin-induced nociception but not pain perception. [ABSTRACT FROM AUTHOR]

Flash sintering involves very rapid densification of ceramic powder compacts during a thermal runaway induced by an applied voltage and current. The mechanisms of fast densification are still not well-understood. The present study investigates the impact of high heating rates during flash sintering on densification, dislocation density and plasticity of SrTiO 3. After flash sintering, a high dislocation density of almost 1014 m−2 was observed by TEM. Uniaxial compression at 1150 °C revealed very high deformation rates. It is argued that for SrTiO 3 , dislocations are generated and migrate during flash sintering. This becomes possible by the very high heating rates, which conserve high driving forces for sintering up to high temperatures. High driving forces of several 10 MPa are preserved up to high temperatures. Thus, the sintering stress can be above the flow stress of SrTiO 3 (5 MPa), and the nucleation of dislocations occurs, paving the path for plastic flow. [ABSTRACT FROM AUTHOR]

A commercial composite powder was used to develop a new paste for stereolithography processing (SLA) of dense 11Ce-TZP-based composites containing 8 vol.% of alumina and 8 vol.% of strontium aluminate. The same powder was used to prepare reference ceramics by conventional Cold Isostatic Pressing (CIP) and sintering. The use of SLA gave rise to a microstructure containing larger strontium aluminate clustering surrounded by zirconia grains devoid of alumina particles, which appeared embedded in a matrix of zirconia-alumina grains. This slightly more heterogeneous microstructure favoured the formation of a greater number of thinner transformation bands, causing a larger plastic deformation in SLA samples (failure strain of 0.65 % instead of 0.35 % for CIP samples), without compromising characteristic strength ( σ 0 = 560 and 586 MPa respectively). Thus, SLA does not affect the ductile behaviour that characterizes this type of ceramics and appears as a very promising method for the development of custom-made ceramic prostheses. [ABSTRACT FROM AUTHOR]

Grooming dysfunction is a hallmark of the obsessive-compulsive spectrum disorder trichotillomania. Numerous preclinical studies have utilized SAPAP3-deficient mice for understanding the neurobiology of repetitive grooming, suggesting that excessive grooming is caused by increased metabotropic glutamate receptor 5 (mGluR5) activity in striatal direct- and indirect-pathway medium spiny neurons (MSNs). However, the MSN subtype–specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Here, we investigated the MSN subtype–specific roles of the striatal signaling hub protein spinophilin in mediating repetitive motor dysfunction associated with mGluR5 function. Quantitative proteomics and immunoblotting were utilized to identify how spinophilin impacts mGluR5 phosphorylation and protein interaction changes. Plasticity and repetitive motor dysfunction associated with mGluR5 action were measured using our novel conditional spinophilin mouse model in which spinophilin was knocked out from striatal direct-pathway MSNs and/or indirect-pathway MSNs. Loss of spinophilin only in indirect-pathway MSNs decreased performance of a novel motor repertoire, but loss of spinophilin in either MSN subtype abrogated striatal plasticity associated with mGluR5 function and prevented excessive grooming caused by SAPAP3 knockout mice or treatment with the mGluR5-specific positive allosteric modulator VU0360172 without impacting locomotion-relevant behavior. Biochemically, we determined that the spinophilin-mGluR5 interaction correlates with grooming behavior and that loss of spinophilin shifts mGluR5 interactions from lipid raft–associated proteins toward postsynaptic density proteins implicated in psychiatric disorders. These results identify spinophilin as a novel striatal signaling hub molecule in MSNs that cell subtype specifically mediates behavioral, functional, and molecular adaptations associated with repetitive motor dysfunction in psychiatric disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] Collagen fibrils, which are the lowest level fibrillar unit of organization of collagen, are thus of primary interest towards understanding the mechanical behavior of load-bearing soft tissues. The deformation of collagen fibrils shows unique mechanical features; namely, their high energy dissipation is even superior compared to most engineering materials. Additionally, there are indications that cyclic loading can further improve the toughness of collagen fibrils. Recent experiments from Liu at al. (2018) focused on the response of type I collagen fibrils to uniaxial cyclic loading, revealing some interesting results regarding their rate-dependent and inelastic response. In this work, we aim to develop a model that allows interpreting the complex nonlinear and inelastic response of collagen fibrils under cyclic loading. We propose a constitutive model that accounts for viscoelastic deformations through a decoupled strain-energy density function (into an elastic and a viscous parts), and for plastic deformations through plastic evolution laws. The stress-stretch response results obtained using this constitutive law showed good agreement with experimental data over complex loading paths. Ultimately we use the model to gain more insights on how cyclic loading and rate effects control the interplay between viscoelastic and plastic deformation in collagen fibrils, and to extrapolate the results from experimental data, analyzing how complex cyclic load influences energy dissipation and deformation mechanisms. In this work, we develop a viscoelastic-plastic constitutive model for collagen fibrils with the aim of analyzing the effects of inelasticity and energy dissipation in this material, and more specifically the competition between viscoelasticity and plasticity in the context of cyclic loading and overload. Experimental and theoretical approaches so far have not fully clarified the interplay between viscous and plastic deformations during cyclic loading of collagen fibrils. Here, we aim to interpret the complex nonlinear response of collagen fibrils and, ultimately, suggest predictive capabilities that can inform tissue-level response and injury. To validate our model, we compare our results against the stress-stretch data obtained from experiments of cyclic loaded single fibrils performed by Liu et al. (2018). [ABSTRACT FROM AUTHOR]

Following activation, CD4 T cells undergo metabolic and transcriptional changes as they respond to external cues and differentiate into T helper (Th) cells. T cells exhibit plasticity between Th phenotypes in highly inflammatory environments, such as colitis, in which high levels of IL-6 promote plasticity between regulatory T (Treg) cells and Th17 cells. Protein Kinase C theta (PKCθ) is a T cell-specific serine/threonine kinase that promotes Th17 differentiation while negatively regulating Treg differentiation. Liver kinase B1 (LKB1), also a serine/threonine kinase and encoded by Stk11 , is necessary for Treg survival and function. Stk11 can be alternatively spliced to produce a short variant (Stk11 S) by transcribing a cryptic exon. However, the contribution of Stk11 splice variants to Th cell differentiation has not been previously explored. Here we show that in Th17 cells, the heterogeneous ribonucleoprotein, hnRNPLL, mediates Stk11 splicing into its short splice variant, and that Stk11 S expression is diminished when Hnrnpll is depleted using siRNA knock-down approaches. We further show that PKCθ regulates hnRNPLL and, thus, Stk11 S expression in Th17 cells. We provide additional evidence that exposing induced (i)Tregs to IL-6 culminates in Stk11 splicing downstream of PKCθAltogether our data reveal a yet undescribed outside-in signaling pathway initiated by IL-6, that acts through PKCθ and hnRNPLL to regulate Stk11 splice variants and facilitate Th17 cell differentiation. Furthermore, we show for the first time, that this pathway can also be initiated in developing iTregs exposed to IL-6, providing mechanistic insight into iTreg phenotypic stability and iTreg to Th17 cell plasticity. • Heterologous ribonucleoprotein, hnRNPLL, regulates alternative splicing of Stk11 to modulate LKB1 isoform expression. • hnRNPLL, and its effects on Stk11 splicing, act downstream of PKCθ. • iTregs exposed to pro-inflammatory IL-6 display Stat3-mediated upregulation of Prkcq and Hnrnpll and altered Stk11 splicing. • Overexpressing specific Stk11 splice variants can redirect iTreg and Th17 cell polarization. [ABSTRACT FROM AUTHOR]

Despite an inherent resistance to be changed, remote fear memories can be attenuated by reconsolidation-updating approaches. Reconsolidation-updating capitalizes on an etiologically relevant period of memory malleability induced by recall, which is characterized by elevated levels of neuronal plasticity. Such neuronal plasticity helps fearful memories to be updated toward safety, which has been evidenced at the level of fear circuits, engrams, and molecular changes. Therefore, treatments aimed at fostering this plasticity constitute a promising approach to support reconsolidation-updating for permanently changing remote fear memories. Traumatic events generate some of the most enduring memories, yet little is known about how long-lasting fear memories can be attenuated. In this review, we collect the surprisingly sparse evidence on remote fear memory attenuation from both animal and human research. What is becoming apparent is twofold: although remote fear memories are more resistant to change compared with recent ones, they can nevertheless be attenuated when interventions are targeted toward the period of memory malleability instigated by memory recall, the reconsolidation window. We describe the physiological mechanisms underlying remote reconsolidation-updating approaches and highlight how they can be enhanced through interventions promoting synaptic plasticity. By capitalizing on an intrinsically relevant phase of memory, reconsolidation-updating harbors the potential to permanently alter remote fear memories. [ABSTRACT FROM AUTHOR]

The H-cathodic charging applied to a superaustenitic stainless steel produces a metastable H-expanded phase by interstitial solid solution, which discloses parallels with the austenite N-expanded (S-phase). The ∼1 μm modified layer comprises a high expansion region γ H followed by a low expansion γ e domain, the former presenting a lattice parameter 3% higher than the austenite γ. The complete decay γ H → γ e → γ occurs around 1-day time. The mechanical properties change accordingly: hardness increases twofold and elastic modulus 17% with H-inlet, returning progressively to the pristine values after hydrogen diffuses out from the modified layer, mainly towards the outer surface. This is consistent with a competitive effect, where the solid solution strengthening overcomes the H-enhanced plasticity in the initial period of decomposition. Moreover, the prevalence of one of these phenomena in plastic deformations is strain-rate dependent: high strain rates result in hindered dislocation mobility, whereas the material discloses embrittlement under low strains. • Cathodic hydrogenation produces H-expanded phase in superaustenitic stainless steel. • The H-expanded phase comprises low (first order) and high (second order) expansions. • Hardness and elastic modulus, higher than austenite, decay with the metastable phase. • Solid solution strengthening dominates over enhanced plasticity in indentation tests. • The mechanical response of the H-expanded austenite is strain rate-dependent. [ABSTRACT FROM AUTHOR]

Increased glucose metabolism and uptake are characteristic of many tumors and used clinically to diagnose and monitor cancer progression. In addition to cancer cells, the tumor microenvironment (TME) encompasses a wide range of stromal, innate, and adaptive immune cells. Cooperation and competition between these cell populations supports tumor proliferation, progression, metastasis, and immune evasion. Cellular heterogeneity leads to metabolic heterogeneity because metabolic programs within the tumor are dependent not only on the TME cellular composition but also on cell states, location, and nutrient availability. In addition to driving metabolic plasticity of cancer cells, altered nutrients and signals in the TME can lead to metabolic immune suppression of effector cells and promote regulatory immune cells. Here we discuss how metabolic programming of cells within the TME promotes tumor proliferation, progression, and metastasis. We also discuss how targeting metabolic heterogeneity may offer therapeutic opportunities to overcome immune suppression and augment immunotherapies. Arner and Rathmell discuss how metabolic programs within tumors depend not only on the tumor microenvironment (TME) cellular composition but also on cell states, location, and nutrient availability. Altered nutrient availability and signals in the TME lead to metabolic immune suppression, which drives immune evasion, tumor progression, and metastasis. Understanding and targeting metabolic heterogeneity within the TME may offer therapeutic opportunities to overcome immune suppression and augment immunotherapies. [ABSTRACT FROM AUTHOR]

• Soil thrust allows remotely operated vehicles to move forward. • Three failure modes are geometrically possible at the soil-track interface. • Upper-bound solutions for soil thrust are mathematically derived. • Resultant soil thrust is determined as the least upper-bound solution. • Proposed solution efficiently and accurately predicts the soil thrust. This study proposes a quick and reliable method for estimating the soil thrust in clay ground for a tracked vehicle based on limit analysis in three-dimensional conditions. With respect to the shape and location of failure surfaces in clayey ground, block, triangular wedge, and trapezoidal wedge failure modes were considered. Between the upper-bound solutions from the different failure modes, the least upper-bound solution was proposed as the soil thrust. To verify the proposed solution, it was compared to the model test and numerical simulations for a track system over model clay ground. The proposed upper-bound solution is expected to produce a reliable soil thrust quickly in real time, especially for submerged heavy-weight remotely operated vehicles (ROVs). [ABSTRACT FROM AUTHOR]

• Expression of cofilin 1 in the mouse visual cortex. • Monocular deprivation modulates active and inactive forms of cofilin 1 in the visual cortex. • Potential role of cofilin 1 in experience-dependent plasticity in the visual cortex. Cofilin 1 is an actin depolymerizing protein playing a fundamental role in the turnover of actin filaments specifically in dendritic spines, where it has been associated with structural and functional plasticity processes. Using a differential proteomic approach, we recently identified cofilin 1 as a potential candidate for controlling plasticity levels in the mouse visual cortex. Here, we focus on analyzing the expression of cofilin 1 and of its serine-3 phosphorylated inactive form in the mouse visual cortex during postnatal development and its modulation by visual input. Western blot experiments showed that cofilin 1 decreases from the critical period to the adult stage, in correlation with the decreasing level of cortical plasticity, and that monocular deprivation increases its expression in the cortex contralateral to the deprived eye during the critical period but not in the adult stage. By immunohistochemistry, we identified that the phospho-cofilin 1 immunopositive signal is homogeneously expressed along the different layers of the mouse visual cortex and that it increases during postnatal development. Furthermore, monocular deprivation increases the phospho-cofilin 1 signal in the contralateral cortex to the deprived eye during the critical period but not in the adult stage. Altogether, these results suggest that cofilin 1 and its modification by phosphorylation are relevant players in the processes controlling experience-dependent plasticity in the mouse visual cortex. [ABSTRACT FROM AUTHOR]

Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored. Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC. Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment. Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC. Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology. [Display omitted] • CLDN1 is upregulated in HCC and is associated with stemness and an immune-low tumor microenvironment. • A mAb targeting non-junctional CLDN1 suppresses tumor growth and invasion in patient-derived cell-based and in vivo models. • This mAb perturbs interactions of CLDN1 with signaling proteins, including Notch ligand JAG1. • We provide robust pre-clinical proof-of-concept for a first-in-class CLDN1 mAb for the treatment of advanced HCC. [ABSTRACT FROM AUTHOR]

The load partitioning between the magnesium and titanium phases in an extruded Mg-15%Ti (vol.%) composite from room temperature up to 300 °C using synchrotron radiation diffraction during in-situ compression tests. During compression, the magnesium matrix composite deforms mainly by the activation of the extension twinning system up to 200 °C. The volume fraction of twins increases with the plastic strain but decrease with the compression temperature. Hard titanium particles bear an additional load transferred by the soft magnesium matrix from room temperature up to 300 °C. This effect is amplified after yield stress during plastic deformation. Additionally, twins within magnesium grains behaves as an additional reinforcement at low temperature (below 200 °C) inducing an increase in the work hardening of the composite. [ABSTRACT FROM AUTHOR]

• Clinically meaningful and statistically significant improvements in motor function and behavior observed following a novel robotic rehabilitation two-week program in 18 patients with prior hemispherectomy. • Training camps enhance patient and parent confidence in task performance. • Rehabilitation related improvement in motor function and behavior years after hemispherectomy procedure suggest continued long-term neuroplasticity. Partial preservation of sensory and motor functions in the contralateral extremities after hemispherectomy is likely secondary to cortical reorganization of the remaining hemisphere and can be improved by rehabilitation. This study aims to investigate behavioral changes that may occur after a 2-week novel robotic rehabilitation program in 18 children with prior anatomic hemispherectomy. Other conventional rehabilitation methods were also reviewed and compared. This study examined the impact of a novel robotic rehabilitation 2-week program on 18 hemispherectomy patients (average age 14.3 ± 3.9 years; age at hemispherectomy 5.6 ± 4.5 years). Statistically significant improvements were seen in the six-minute walk test (29 m, p < 0.001), Canadian Occupational Performance Measure performance (1.64 points, p = 0.002) and satisfaction (2.49 points, p = 0.001), and individual perceived performance on survey (1.72 points, p = 0.042). Fifteen patients showed improvement in the upper extremity Fugl-Meyer scores with an average increase of 3 points (p = 0.006). This study demonstrates clinically meaningful and statistically significant improvements in motor function and behavior following a novel robotic rehabilitation two-week program. [ABSTRACT FROM AUTHOR]

The physiological dependence of animals on dietary intake of vitamins, amino acids, and fatty acids is ubiquitous. Sharp differences in the availability of these vital dietary biomolecules among different resources mean that consumers must adopt a range of strategies to meet their physiological needs. We review the emerging work on omega-3 long-chain polyunsaturated fatty acids, focusing predominantly on predator–prey interactions, to illustrate that trade-off between capacities to consume resources rich in vital biomolecules and internal synthesis capacity drives differences in phenotype and fitness of consumers. This can then feedback to impact ecosystem functioning. We outline how focus on vital dietary biomolecules in eco-eco-devo dynamics can improve our understanding of anthropogenic changes across multiple levels of biological organization. Availability of vital dietary biomolecules, such as vitamins, amino acids, and fatty acids, is critical for the evolution and development of animals. Extensive evidence indicates that anthropogenic changes influence the distribution of vital dietary biomolecules in food webs. Shifts in the availability of these vital biomolecules can trigger far-reaching changes in phenotypes of consumers with potential cascading impacts on the functioning of the ecosystems. There is no unified integrative framework to study the role of vital dietary biomolecules in feedbacks between phenotypes of wild consumers and ecosystem functioning. We review evidence on omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) in prey–predator interactions to illustrate how vital dietary biomolecules moderate the feedbacks between behavioral, physiological, and life-history traits of wild consumers and the higher levels of biological organization. [ABSTRACT FROM AUTHOR]

To forecast extinction risks of natural populations under climate change and direct human impacts, an integrative understanding of both phenotypic plasticity and adaptive evolution is essential. To date, the evidence for whether, when, and how much plasticity facilitates adaptive responses in changing environments is contradictory. We argue that explicitly considering three key environmental change components – rate of change, variance, and temporal autocorrelation – affords a unifying framework of the impact of plasticity on adaptive evolution. These environmental components each distinctively effect evolutionary and ecological processes underpinning population viability. Using this framework, we develop expectations regarding the interplay between plasticity and adaptive evolution in natural populations. This framework has the potential to improve predictions of population viability in a changing world. Global biodiversity is jeopardised by unprecedented environmental change, the hallmark of the Anthropocene. To estimate the extinction risks of species, understanding how individuals and populations respond to changing environments is crucial. Adaptive evolution and phenotypic plasticity are two key mechanisms by which natural populations avoid extinction in the face of environmental change. However, the relative roles and interplay between the two are still unresolved. Whether plasticity hinders (H1) or facilitates (H2) adaptive evolution has been ardently researched, but without cross-study standardization of how changing environments impact whether (H1) or (H2) is more likely over time. We propose an integrative framework based on how key environmental components influence the 'building blocks' of ecoevolutionary responses to examine when plasticity aids or hinders adaptive evolution. We synthesise key microevolutionary and ecological processes regarding how natural populations respond to environmental change. Studies may benefit from this framework to deepen our understanding of how plasticity influences adaptive evolution by reframing H1 and H2 in the context of environmental change, and will thus increase our ability to forecast extinction risks in the Anthropocene. [ABSTRACT FROM AUTHOR]

In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner—a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a significant component of the brain, constituting up to 20 % of the brain volume and perform multifarious functions during development, maturation and regeneration of the central nervous system (CNS). ECM molecules assemble systematically to form a relatively rigid and unique lattice-like structure, known as perineuronal nets (PNNs). The PNNs usually envelop the cell body and initial axon segment and are characterized by a mesh-like structure extending along dendrites of neurons. PNNs play prominent role in the early neural development, from migration and differentiation to axonal path finding. They regulate plasticity and regeneration in adulthood by surrounding and stabilizing synaptic contacts. In this review, we have focused on the basic structure, distribution and visualization of PNNs and their role during critical periods of development, synaptogenesis and regulation of synaptic plasticity. Furthermore, we have also tried to evaluate the participation of PNNs in the pathophysiology of several brain disorders and their potential in lowering local oxidative stress. Taken together, the concepts outlined in this review emphasize the heterogeneity of PNNs in response to normal physiological and pathological conditions, highlighting the need for future studies on PNNs to target their role in etiology and potential therapeutic interventions in neurological disorders. • Perineuronal nets (PNNs) are differentially distributed in different brain regions. • PNNs actively support the stabilization of synaptic contacts. • PNNs act as molecular brakes for synaptic plasticity. • PNNs protect the neurons from the influence of oxidative stress and harmful agents. • Removal or degradation of PNNs leads to neurological and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Antibodies are crucial in host defenses as well as in allergic diseases. T follicular helper (T FH) cells play essential roles in germinal center reactions by facilitating B-cell differentiation and immunoglobulin affinity maturation and isotype switching. Although T FH cells have a unique gene transcription program and regulatory network, recently there has been increasing evidence of T FH cell plasticity, with some T FH cells expressing genes typically related to other types of effector T cells associated with different types of Ig subclasses and in the context of different pathogen infections and health conditions. Here, we review the plasticity of T FH cells in various types of immune responses. We also point out the important implications of T FH plasticity in understanding and treating human diseases, including allergy. [ABSTRACT FROM AUTHOR]

Antibody responses are critical for protection against pathogens. However, diseases such as allergic rhinitis or food allergy result from aberrant production of IgE antibodies against otherwise innocuous environmental antigens. The production of allergen-specific IgE requires interaction between B cells and CD4+ T cells, and a granular understanding of these interactions is required to develop novel therapies for allergic disease. CD4+ T cells are exceptionally heterogeneous in their transcriptional, epigenetic, and proteomic profiles, which poses significant challenges when attempting to define subsets relevant to the study of allergy among a continuum of cells. Defining subsets such as the T follicular helper (T FH) cell cluster provides a shorthand to understand the functions of CD4+ T cells in antibody production and supports mechanistic experimentation for hypothesis-driven discovery. With a focus on allergic disease, this Rostrum article broadly discusses heterogeneity among CD4+ T cells and provides a rationale for subdividing T FH cells into both functional and cytokine-skewed subsets. Further, it highlights the plasticity demonstrated by T FH cells during the primary response and after recall, and it explores the possibility of harnessing this plasticity to reprogram immunity for therapeutic benefit in allergic disease. [ABSTRACT FROM AUTHOR]

Most solid cancer-related deaths result from metastasis, a multistep process in which cancer cells exit the primary site, intravasate into the bloodstream, extravasate, and colonize distant organs. Colonization is facilitated by clonal selection and the high phenotypic plasticity of cancer cells that creates reversible switching of cellular states. Cancer cell plasticity leads to intratumor heterogeneity and fitness, yielding cells with molecular and cellular programs that facilitate survival and colonization. While cancer cell plasticity is sometimes limited to the process of epithelial-to-mesenchymal transition (EMT), recent studies have broadened its definition. Plasticity arises from both cell-intrinsic and cell-extrinsic factors and is a major obstacle to efficacious anti-cancer therapies. Here, we discuss the multifaceted notion of cancer cell plasticity associated with metastatic colonization. Cancer cell plasticity results in tumor cells with phenotypic versatility that allows shuttling between cellular states and promotes disease progression. During epithelial-to-mesenchymal transition, hybrid cells have the highest metastatic potential. Dormancy of disseminated tumor cells (DTCs) and their reawakening years after arriving at distant sites is an example of cancer cell plasticity. Metastatic cancer cells can rewire their metabolism depending on the metabolic state of the distant organ, and can adopt stem-like traits, as well as features of normal host tissue, thus favoring the colonization of the new niches. Plasticity may generate site-specific vulnerabilities that could be exploited for novel therapeutic options. [ABSTRACT FROM AUTHOR]

Insect vectors are responsible for spreading many infectious diseases, yet interactions between pathogens/parasites and insect vectors remain poorly understood. Filling this knowledge gap matters because vectors are evolving in response to the deployment of vector control tools (VCTs). Yet, whilst the evolutionary responses of vectors to VCTs are being carefully monitored, the knock-on consequences for parasite evolution have been overlooked. By examining how mosquito responses to VCTs impact upon malaria parasite ecology, we derive a framework for predicting parasite responses. Understanding how VCTs affect the selection pressures imposed on parasites could help to mitigate against parasite evolution that leads to unfavourable epidemiological outcomes. Furthermore, anticipating parasite evolution will inform monitoring strategies for VCT programmes as well as uncovering novel VCT strategies. Vector control tools (VCTs) affect diverse aspects of mosquito biology and are a driver of vector evolution. VCTs change parasite ecology by exposing parasites to insecticides and to vectors with altered genotypes and phenotypes (e.g., lifespan, behaviour, immunity, metabolism, microbiome). Parasite activities are affected by the ways that VCTs alter parasite–vector interactions, and this can drive parasite evolution. Parasite responses to VCTs are likely to include plastic and evolutionary changes to transmission traits expressed during infections in hosts/vectors. Parasite responses could undermine gains made towards malaria elimination and may have knock-on consequences for parasite–host interactions. Knowledge of parasite responses to the selection pressures imposed by VCTs could offer new approaches to reduce disease transmission that are robust to parasite evolution. [ABSTRACT FROM AUTHOR]

A recent Chinese genome-wide association study found evidence for 58 out of the 128 schizophrenia-associated variants previously discovered in Western samples by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). However, the functional impact of these trans-ancestry genome-wide single-nucleotide polymorphisms (SNPs) is not clear. In the current study, we examined the roles of trans-ancestry SNPs in cognitive and neural plasticity. We first performed a behavioral study of 547 healthy volunteers, who received month-long working memory training, and working memory capability assessment both before and after the training. A separate sample of 101 subjects received the same training and received fMRI scans during a working memory task, both before and after the training. The behavioral study found a significant association between the polygenic risk score (PRS) and behavioral plasticity, with higher schizophrenia risk scores being linked to less plasticity. At the SNP level, rs36068923 showed a significant signal, with the risk allele being associated with less plasticity. The fMRI study further found that the PRS and rs36068923 polymorphism were associated with training-induced changes in striatal activation, with higher PRS and the risk allele of rs36068923 being linked to less brain plasticity. In sum, this study found that a high genetic risk for schizophrenia was associated with less plasticity at both behavioral and neural levels. These results provide new insights into the neural and cognitive mechanisms linking genes to schizophrenia. [ABSTRACT FROM AUTHOR]