Progressive long-term synaptic depression at cortical inputs into the amygdala.

The convergence of conditioned and unconditioned stimuli (CS and US) into the lateral amygdala (LA) serves as a substrate for an adequate fear response in vivo. This well-known Pavlovian paradigm modulates the synaptic plasticity of neurons, as can be proved by the long-term potentiation (LTP) phenomenon in vitro. Although there is an increasing body of evidence for the existence of LTP in the amygdala, only a few studies were able to show a reliable long-term depression (LTD) of excitation in this structure. We have used coronal brain slices and conducted patch-clamp recordings in pyramidal neurons of the lateral amygdala (LA). After obtaining a stable baseline excitatory postsynaptic current (EPSC) response at a holding potential of -70 mV, we employed a paired-pulse paradigm at 1 Hz at the same membrane potential and could observe a reliable LTD. The different durations of stimulation (ranging between 1.5-24 min) were tested first in the same neuron, but the intensity was kept constant. The latter paradigm resulted in a step-wise LTD with a gradually increasing magnitude under these conditions.

Short-term dietary changes are reflected in the cerebral content of adult ring-billed gulls.

Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) are produced primarily in aquatic ecosystems and are considered essential nutrients for predators given their structural role in vertebrates' cerebral tissues. Alarmingly, with urbanization, many aquatic animals now rely on anthropogenic foods lacking n3-LCPUFAs. In this study undertaken in Newfoundland (Canada), we tested whether recent or longer term diet explains the cerebral fatty acid composition of ring-billed gulls (Larus delawarensis), a seabird that now thrives in cities. During the breeding season, cerebral levels of n3-LCPUFAs were significantly higher for gulls nesting in a natural habitat and foraging on marine food (mean ± s.d.: 32 ± 1% of total identified fatty acids) than for urban nesters exploiting rubbish (27 ± 1%). Stable isotope analysis of blood and feathers showed that urban and natural nesters shared similar diets in autumn and winter, suggesting that the difference in cerebral n3-LCPUFAs during the breeding season was owing to concomitant and transient differences in diet. We also experimentally manipulated gulls' diets throughout incubation by supplementing them with fish oil rich in n3-LCPUFAs, a caloric control lacking n3-LCPUFAs, or nothing, and found evidence that fish oil increased urban nesters' cerebral n3-LCPUFAs. These complementary analyses provide evidence that the brain of this seabird remains plastic during adulthood and responds to short-term dietary changes.

Dynamic phenotypic shifts and M2 receptor downregulation in bladder smooth muscle cells induced by mirabegron.

Introduction: Mirabegron is available for treatment of overactive bladder (OAB). However, mechanisms underlying symptom improvements and long-term effects on bladder smooth muscle cells are uncertain. Contractility and growth of bladder smooth muscle contribute to OAB, and depend on smooth muscle phenotypes, and on muscarinic receptor expression. Here, we examined prolonged exposure to mirabegron (20-48 h) on phenotype markers, muscarinic receptor expression, and phenotype-dependent functions in human bladder smooth muscle cells (hBSMC). Methods: Expression of markers for contractile (calponin, MYH11) and proliferative (MYH10, vimentin) phenotypes, proliferation (Ki-67), and of muscarinic receptors were assessed by RT-PCR. Proliferation, viability, actin organization and contractions in cultured hBSMC were examined by EdU, CCK-8, phalloidin staining and matrix contraction assays. Results: Calponin-1 mRNA decreased with 100 nM and 150 nM mirabegron applied for 20 h (0.56-0.6 fold of controls). Decreases were resistant to the ß3-AR antagonist L-748,337 (0.34-0.55 fold, 100-150 nM, 20 h). After 40 h, decreases occured in the presence of L-748,337, but not without L-748,337. MYH11 mRNA increased with 150 nM mirabegron (40 h, 1.9 fold). This was partly preserved with L-748,337, but not observed after 20 h mirabegron exposure. Vimentin mRNA reduced with 150 nM mirabegron after 20 h, but not after 40 h, with and without L-748,337 (0.71-0.63 fold). MYH10 mRNA expression remained unaffected by mirabegron. Exposure to 150 nM mirabegron increased Ki-67 mRNA after 20 h in the presence of, but not without L-748,337, and after 40 h without, but not with L-748,337. Proliferation rates and actin organization were stable with 50-150 nM mirabegron (24 h, 48 h). Viability increased significantly after mirabegron exposure for 20 h, and by trend after 40 h, which was fully sensitive to L-748,337. M2 mRNA was reduced by 20 h mirabegron, which was resistant to L-748,337. Carbachol (3 µM) enhanced time-dependent contractions of hBSMC, which was inhibited by mirabegron (150 nM) in late phases (24 h), but not in early phases of contractions. Conclusion: Mirabegron induces dynamic phenotype alterations and M2 downregulation in hBSMC, which is paralleled by time-shifted anticontractile effects. Phenotype transitions may be involved in improvements of storage symptoms in OAB by mirabegron.

A description of COVID-19 related delusional content in admissions to an acute psychiatric unit.

Background: The COVID-19 pandemic had a profound global impact, affecting individuals, including those with mental illness, through early and widespread information dissemination. Although the neurobiological basis of delusions remains unclear, external stimuli and historical events are known to influence them. The pandemic provided a unique opportunity to explore this phenomenon. Aim: To determine the prevalence of COVID-19-related delusional content, among individuals presenting for treatment of psychosis during the peak of the COVID-19 pandemic and investigate associated clinical and demographic factors. Setting: Chris Hani Baragwanath Academic Hospital in-patient psychiatry department. Methods: Data were extracted retrospectively from adult psychiatric admissions spanning April to September 2020 on patients whose presenting complaints included delusions. Demographic factors, symptoms, psychiatric, medical and substance use history, and a documented Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis by the attending psychiatrist were collected. Results: The prevalence of COVID-19-related delusional content was 25.5%. Significant demographic association was observed with education level of Grade 12 and above (p = 0.000338). The odds of a diagnosis of schizophrenia and related disorders were 2.72 times greater than mood and psychotic disorder due to another medical condition in those with COVID- 19-related delusional content (OR 2.19, 95% CI: [1.4-3.4]). Conclusion: The presence of COVID-19-related delusional content in patients admitted to hospital with psychosis provides further evidence of the role of external stimuli in the formation of delusions. Contribution: This study underscores the influence of socio-cultural factors on delusions and advocates for interventions and expanded research to address mental health outcomes.

Rewinding the Tape to Identify Intrinsic Determinants of Reprogramming Potential.

Via retrospective isolation of clones using Rewind, Jain et al. identified primed states of cells that reprogram to induced pluripotent stem cells. Examining clones, they find that cells retain memory of over several rounds of cell division. Moreover, they show that extrinsic factors change the number of primed cells, suggesting that there exist diverse paths of reprogramming and states of priming.

Synaptotagmins 3 and 7 mediate the majority of asynchronous release from synapses in the cerebellum and hippocampus.

Neurotransmitter release consists of rapid synchronous release followed by longer-lasting asynchronous release (AR). Although the presynaptic proteins that trigger synchronous release are well understood, the mechanisms for AR remain unclear. AR is sustained by low concentrations of intracellular Ca2+ and Sr2+, suggesting the involvement of sensors with high affinities for both ions. Synaptotagmin 7 (SYT7) partly mediates AR, but substantial AR persists in the absence of SYT7. The closely related SYT3 binds Ca2+ and Sr2+ with high affinity, making it a promising candidate to mediate AR. Here, we use knockout mice to study the contribution of SYT3 and SYT7 to AR at cerebellar and hippocampal synapses. AR is dramatically reduced when both isoforms are absent, which alters the number and timing of postsynaptic action potentials. Our results confirm the long-standing prediction that SYT3 mediates AR and show that SYT3 and SYT7 act as dominant mechanisms for AR at three central synapses.

Self-Adhesive, Stretchable, and Thermosensitive Iontronic Hydrogels for Highly Sensitive Neuromorphic Sensing-Synaptic Systems.

Artificial sensory afferent nerves that emulate receptor nanochannel perception and synaptic ionic information processing in chemical environments are highly desirable for bioelectronics. However, challenges persist in achieving life-like nanoscale conformal contact, agile multimodal sensing response, and synaptic feedback with ions. Here, a precisely tuned phase transition poly(N-isopropylacrylamide) (PNIPAM) hydrogel is introduced through the water molecule reservoir strategy. The resulting hydrogel with strongly cross-linked networks exhibits excellent mechanical performance (∼2000% elongation) and robust adhesive strength. Importantly, the hydrogel's enhanced ionic conductance and heterogeneous structure of the temperature-sensitive component enable highly sensitive strain information perception (GFmax = 7.94, response time ∼ 87 ms), temperature information perception (TCRmax = -1.974%/°C, response time ∼ 270 ms), and low energy consumption synaptic plasticity (42.2 fJ/spike). As a demonstration, a neuromorphic sensing-synaptic system is constructed integrating iontronic strain/temperature sensors with fiber synapses for real-time information sensing, discrimination, and feedback. This work holds enormous potential in bioinspired robotics and bioelectronics.

Hippocampus-specific knockdown of Shati/Nat8l impairs cognitive function and electrophysiological response in mice.

Shati/Nat8l was identified as an upregulated molecule in the nucleus accumbens (NAc) of mice following repeated methamphetamine administration. Region-specific roles of this molecule are associated with psychiatric disorders. In the present study, we examined the importance of Shati/Nat8l in the hippocampus because of its high expression in this region. Mice with a hippocampus-specific knockdown of Shati/Nat8l (hippocampal Shati-cKD) were prepared by the microinjection of adeno-associated virus (AAV) vectors carrying Cre into the hippocampus of Shati/Nat8lflox/flox mice, and their phenotypes were investigated. Drastic reduction in the expression and function of Shati/Nat8l in the hippocampus was observed in Shati-cKD mice. These mice exhibited cognitive dysfunction in behavioral experiments and impaired the electrophysiological response to the stimuli, which elicits long-term potentiation. Shati/Nat8l in the hippocampus is suggested to possibly play an important role in synaptic plasticity to maintain cognitive function. This molecule could be a therapeutic target for hippocampus-related disorders such as dementia.

Biomarkers of auditory cortical plasticity and development of binaural pathways in children with unilateral hearing loss using a hearing aid.

Congenital or early-onset unilateral hearing loss (UHL) can disrupt the normal development of the auditory system. In extreme cases of UHL (i.e., single sided deafness), consistent cochlear implant use during sensitive periods resulted in cortical reorganization that partially reversed the detrimental effects of unilateral sensory deprivation. There is a gap in knowledge, however, regarding cortical plasticity i.e. the brain's capacity to adapt, reorganize, and develop binaural pathways in milder degrees of UHL rehabilitated by a hearing aid (HA). The current study was set to investigate early-stage cortical processing and electrophysiological manifestations of binaural processing by means of cortical auditory evoked potentials (CAEPs) to speech sounds, in children with moderate to severe-to-profound UHL using a HA. Fourteen children with UHL (CHwUHL), 6-14 years old consistently using a HA for 3.5 (±2.3) years participated in the study. CAEPs were elicited to the speech sounds /m/, /g/, and /t/ in three listening conditions: monaural [Normal hearing (NH), HA], and bilateral [BI (NH + HA)]. Results indicated age-appropriate CAEP morphology in the NH and BI listening conditions in all children. In the HA listening condition: (1) CAEPs showed similar morphology to that found in the NH listening condition, however, the mature morphology observed in older children in the NH listening condition was not evident; (2) P1 was elicited in all but two children with severe-to-profound hearing loss, to at least one speech stimuli, indicating effective audibility; (3) A significant mismatch in timing and synchrony between the NH and HA ear was found; (4) P1 was sensitive to the acoustic features of the eliciting stimulus and to the amplification characteristics of the HA. Finally, a cortical binaural interaction component (BIC) was derived in most children. In conclusion, the current study provides first-time evidence for cortical plasticity and partial reversal of the detrimental effects of moderate to severe-to-profound UHL rehabilitated by a HA. The derivation of a cortical biomarker of binaural processing implies that functional binaural pathways can develop when sufficient auditory input is provided to the affected ear. CAEPs may thus serve as a clinical tool for assessing, monitoring, and managing CHwUHL using a HA.

Motion's privilege in recognizing facial expressions following treatment for blindness.

In his 1872 monograph, Charles Darwin posited that "… the habit of expressing our feelings by certain movements, though now rendered innate, had been in some manner gradually acquired."1 Nearly 150 years later, researchers are still teasing apart innate versus experience-dependent contributions to expression recognition. Indeed, studies have shown that face detection is surprisingly resilient to early visual deprivation,2,3,4,5 pointing to plasticity that extends beyond dogmatic critical periods.6,7,8 However, it remains unclear whether such resilience extends to downstream processing, such as the ability to recognize facial expressions. The extent to which innate versus experience-dependent mechanisms contribute to this ability has yet to be fully explored.9,10,11,12,13 To investigate the impact of early visual experience on facial-expression recognition, we studied children with congenital cataracts who have undergone sight-correcting treatment14,15 and tracked their longitudinal skill acquisition as they gain sight late in life. We introduce and explore two potential facilitators of late-life plasticity: the availability of newborn-like coarse visual acuity prior to treatment16 and the privileged role of motion following treatment.4,17,18 We find that early visual deprivation does not preclude partial acquisition of facial-expression recognition. While rudimentary pretreatment vision is sufficient to allow a low level of expression recognition, it does not facilitate post-treatment improvements. Additionally, only children commencing vision with high visual acuity privilege the use of dynamic cues. We conclude that skipping typical visual experience early in development and introducing high-resolution imagery late in development restricts, but does not preclude, facial-expression skill acquisition and that the representational mechanisms driving this learning differ from those that emerge during typical visual development.

Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies.

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.

Non-canonical function of ADAM10 in presynaptic plasticity.

A Disintegrin And Metalloproteinase 10 (ADAM10) plays a pivotal role in shaping neuronal networks by orchestrating the activity of numerous membrane proteins through the shedding of their extracellular domains. Despite its significance in the brain, the specific cellular localization of ADAM10 remains not well understood due to a lack of appropriate tools. Here, using a specific ADAM10 antibody suitable for immunostainings, we observed that ADAM10 is localized to presynapses and especially enriched at presynaptic vesicles of mossy fiber (MF)-CA3 synapses in the hippocampus. These synapses undergo pronounced frequency facilitation of neurotransmitter release, a process that play critical roles in information transfer and neural computation. We demonstrate, that in conditional ADAM10 knockout mice the ability of MF synapses to undergo this type of synaptic plasticity is greatly reduced. The loss of facilitation depends on the cytosolic domain of ADAM10 and association with the calcium sensor synaptotagmin 7 rather than ADAM10's proteolytic activity. Our findings unveil a new role of ADAM10 in the regulation of synaptic vesicle exocytosis.

Can niche plasticity mediate species persistence under ocean acidification?

Global change stressors can modify ecological niches of species, thereby altering ecological interactions within communities and food webs. Yet, some species might take advantage of a fast-changing environment, allowing species with high niche plasticity to thrive under climate change. We used natural CO2 vents to test the effects of ocean acidification on niche modifications of a temperate rocky reef fish assemblage. We quantified three ecological niche traits (overlap, shift and breadth) across three key niche dimensions (trophic, habitat and behavioural). Only one species increased its niche width along multiple niche dimensions (trophic and behavioural), shifted its niche in the remaining (habitat) was the only species to experience a highly increased density (i.e. doubling) at vents. The other three species that showed slightly increased or declining densities at vents only displayed a niche width increase in one (habitat niche) out of seven niche metrics considered. This niche modification was likely in response to habitat simplification (transition to a system dominated by turf algae) under ocean acidification. We further showed that, at the vents, the less abundant fishes had a negligible competitive impact on the most abundant and common species. This species appeared to expand its niche space, overlapping with other species, which likely led to lower abundances of the latter under elevated CO2. We conclude that niche plasticity across multiple dimensions could be a potential adaptation in fishes to benefit from a changing environment in a high-CO2 world.

Suprachiasmatic nucleus VIPergic fibers show a circadian rhythm of expansion and retraction.

In animals, overt circadian rhythms of physiology and behavior are centrally regulated by a circadian clock located in specific brain regions. In the fruit fly Drosophila and in mammals, these clocks rely on single-cell oscillators, but critical for their function as central circadian pacemakers are network properties that change dynamically throughout the circadian cycle as well as in response to environmental stimuli.1,2,3 In the fly, this plasticity involves circadian rhythms of expansion and retraction of clock neuron fibers.4,5,6,7,8,9,10,11,12,13,14 Whether these drastic structural changes are a universal property of central neuronal pacemakers is unknown. To address this question, we studied neurons of the mouse suprachiasmatic nucleus (SCN) that express vasoactive intestinal polypeptide (VIP), which are critical for the SCN to function as a central circadian pacemaker. By targeting the expression of the fluorescent protein tdTomato to these neurons and using tissue clearing techniques to visualize all SCN VIPergic neurons and their fibers, we show that, similar to clock neurons in the fly, VIPergic fibers undergo a daily rhythm of expansion and retraction, with maximal branching during the day. This rhythm is circadian, as it persists under constant environmental conditions and is present in both males and females. We propose that circadian structural remodeling of clock neurons represents a key feature of central circadian pacemakers that is likely critical to regulate network properties, the response to environmental stimuli, and the regulation of circadian outputs.

Molecular changes and physiological responses involved in migratory bird fuel management and stopover decisions.

Migratory birds undertake long journeys across continents to reach breeding habitats with abundant resources. These migrations are essential for their survival and are shaped by a complex interplay of physiological adaptations, behavioral cues, and gene expression patterns. Central to migration are stopovers, critical resting points where birds replenish energy stores before continuing their journey. In this study, we integrate physiological measurements, behavioral observations, and molecular data from temporarily caged migrating Garden Warblers (Sylvia borin) to gain insights into their stopover strategies and physiological adaptations after crossing the extended ecological barrier formed by the Sahara Desert and the Mediterranean Sea. Depleted individuals, marked by low body mass and flight muscle mass, showcased remarkable plasticity in recovering and rapidly rebuilding energy stores within a short 5-day stopover. Flight muscle mass increased during this period, highlighting a dynamic trade-off between muscle rebuilding and refuelling. Notably, birds prioritizing muscle rebuilding exhibited a trade-off with the downregulation of genes related to lipid transport and metabolism and at the same time showing evidence of skeletal muscle angiogenesis. Early arrivals were more motivated to depart and exhibited higher levels of physiological stress. Our study highlights the importance of understanding the adaptive responses of birds to changing environmental conditions along their migration routes.

Signatures of Bayesian inference emerge from energy-efficient synapses.

Biological synaptic transmission is unreliable, and this unreliability likely degrades neural circuit performance. While there are biophysical mechanisms that can increase reliability, for instance by increasing vesicle release probability, these mechanisms cost energy. We examined four such mechanisms along with the associated scaling of the energetic costs. We then embedded these energetic costs for reliability in artificial neural networks (ANNs) with trainable stochastic synapses, and trained these networks on standard image classification tasks. The resulting networks revealed a tradeoff between circuit performance and the energetic cost of synaptic reliability. Additionally, the optimised networks exhibited two testable predictions consistent with pre-existing experimental data. Specifically, synapses with lower variability tended to have (1) higher input firing rates and (2) lower learning rates. Surprisingly, these predictions also arise when synapse statistics are inferred through Bayesian inference. Indeed, we were able to find a formal, theoretical link between the performance-reliability cost tradeoff and Bayesian inference. This connection suggests two incompatible possibilities: evolution may have chanced upon a scheme for implementing Bayesian inference by optimising energy efficiency, or alternatively, energy-efficient synapses may display signatures of Bayesian inference without actually using Bayes to reason about uncertainty.

How does climate change impact social bees and bee sociality?

Climatic factors are known to shape the expression of social behaviours. Likewise, variation in social behaviour can dictate climate responses. Understanding interactions between climate and sociality is crucial for forecasting vulnerability and resilience to climate change across animal taxa. These interactions are particularly relevant for taxa like bees that exhibit a broad diversity of social states. An emerging body of literature aims to quantify bee responses to environmental change with respect to variation in key functional traits, including sociality. Additionally, decades of research on environmental drivers of social evolution may prove fruitful for predicting shifts in the costs and benefits of social strategies under climate change. In this review, we explore these findings to ask two interconnected questions: (a) how does sociality mediate vulnerability to climate change, and (b) how might climate change impact social organisation in bees? We highlight traits that intersect with bee sociality that may confer resilience to climate change (e.g. extended activity periods, diet breadth, behavioural thermoregulation) and we generate predictions about the impacts of climate change on the expression and distribution of social phenotypes in bees. The social evolutionary consequences of climate change will be complex and heterogeneous, depending on such factors as local climate and plasticity of social traits. Many contexts will see an increase in the frequency of eusocial nesting as warming temperatures accelerate development and expand the temporal window for rearing a worker brood. More broadly, climate-mediated shifts in the abiotic and biotic selective environments will alter the costs and benefits of social living in different contexts, with cascading impacts at the population, community and ecosystem levels.

Phosphodiesterase 7 inhibitor reduces stress-induced behavioral and cytoarchitectural changes in C57BL/6J mice by activating the BDNF/TrkB pathway.

Background: Phosphodiesterase 7 (PDE7) plays a role in neurological function. Increased expression and activity of PDE7 has been detected in several central nervous system diseases. However, the role of PDE7 in regulating stress levels remains unclear. Thus, this study aimed to determine whether and how PDE7 involved in the stress-induced behavioral and neuron morphological changes. Methods: The single prolonged stress (SPS) was used to build a stress exposure model in C57BL/6 J mice and detected PDE7 activity in hippocampus, amygdala, prefrontal cortex and striatum. Next, three doses (0.2, 1, and 5 mg/kg) of the PDE7 inhibitor BRL-50481 were intraperitoneally administered for 10 days, then behavioral, biochemical, and morphological tests were conducted. Results: PDE7 activity in hippocampus of mice significantly increased at all times after SPS. BRL-50481 significantly attenuated SPS induced anxiety-like behavior and fear response in both context and cue. In addition, BRL-50481 increased the levels of key molecules in the cAMP signaling pathway which were impaired by SPS. Immunofluorescent staining and Sholl analysis demonstrated that BRL-50481 also restored the nucleus/cytoplasm ratio of hippocampal neurons and improved neuronal plasticity. These effects of BRL-50481 were partially blocked by the TrkB inhibitor ANA-12. Conclusion: PDE7 inhibitors attenuate stress-induced behavioral changes by protecting the neuron cytoarchitecture and the neuronal plasticity in hippocampus, which is mediated at least partly through the activation of BDNF/TrkB signaling pathway. These results proved that PDE7 is a potential target for treating stress-induced behavioral and physiological abnormalities.

Epithelial-mesenchymal plasticity in cancer: signaling pathways and therapeutic targets.

Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial-mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial-mesenchymal transition (EMT), partial EMT, and mesenchymal-epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor-ß, Wnt/ß-catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune-related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP-driven tumor deterioration. Additionally, we explore the potential technique for EMP-based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP.

Macrophage plasticity: signaling pathways, tissue repair, and regeneration.

Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.