Research on the shared function of central neurons and breast cancer based on gene expression profile data mining: The role of EMID1 protein antibody expression.

In recent years, the incidence of breast cancer has gradually increased, and the research on it has become a hot spot in the scientific community. Central neurons play an important role in breast cancer. This study aims to explore the application of gene expression profile data mining in the study of shared function between central neurons and breast cancer, and focuses on the expression of EMID1 protein antibody. The study collected biomedical images and gene expression profile data of breast cancer patients. Then, we use image processing and analysis technology to extract and analyze features of biomedical images to obtain quantitative features of breast cancer. Gene expression profile data were preprocessed and analyzed to obtain information about breast cancer related genes. Integrating and fusing biomedical images and gene expression profile data, and exploring the sharing function between central neurons and breast cancer through data mining algorithms and statistical analysis methods. The results showed that the expression of EMID1 protein was high in breast cancer tissues, and the expression pattern was similar to that of central neurons. Further functional studies have shown that EMID1 protein is involved in the regulation of proliferation and invasion of breast cancer cells. By regulating the expression level of EMID1 protein, we observed that the proliferation and invasion ability of breast cancer cells were significantly affected. The research results show that through the comprehensive analysis of biomedical images and gene expression profile data, we found the sharing function between central neurons and breast cancer. The central neuronal cell marker genes EMID1 and GREB1L may be used as key biomarkers to regulate the pathogenesis of breast cancer and affect the occurrence and development of breast cancer.

[Microglia-neuron interactions in the caudate nucleus in different course of schizophrenia]. / Vzaimodeistviya mikroglii i neironov v khvostatom yadre pri raznykh tipakh techeniya shizofrenii.

OBJECTIVE: To study the ultrastructure of microglia and neurons in contact with each other in the head of the caudate nucleus in continuous schizophrenia (CS) and paroxysmal-progressive schizophrenia (PPS) as compared to controls and to analyze correlations between the parameters of microglia and neurons in the control and schizophrenia groups. MATERIAL AND METHODS: Post-mortem electron microscopic morphometric study of microglia and neurons in contact with each other was performed in the head of the caudate nucleus in 9 cases of CS, 10 cases of PPS and 20 controls without mental pathology. Group comparisons were made using analysis of covariance and Pearson correlation analysis. RESULTS: The PPS group showed increased numerical density of microglia in young (≤50 years old) patients compared to elderly (>50 years old) controls and increased area of endoplasmic reticulum vacuoles in microglia in young patients compared to young controls. Decreased numerical density of microglia was found in the CS group compared to the PPS group (p<0.05), and increased volume fraction (Vv) and the number of lipofuscin granules in microglia were found in the CS group in elderly patients compared with young and elderly controls. In this group, negative correlations were revealed between the numerical density of microglia, microglia nuclear area and the duration of disease (r= -0.72, p=0.03; r= -0.8; p=0.01). Decreased Vv and the number of mitochondria in microglia and increased area and perimeter of neurons were revealed in both groups compared to the control group. In neurons, increased vacuole area was found in the PPS group and mitochondrial area in the NTS group compared to the control group. Correlation violations were found between the parameters of mitochondria in microglia and neurons in both PPS and CS groups and between the area of mitochondria in neurons and the area of vacuoles in microglia in the CS group compared to the control group. CONCLUSION: Disturbed interactions between microglia and neurons in the caudate nucleus are associated with the types of course of schizophrenia and with microglial reactivity. They might be caused by the damage of energy metabolism in microglia in both types of schizophrenia course and by stress of endoplasmic reticulum in microglia in CS.

[Amyotrophic lateral sclerosis associated with a new pathogenic variant of the ERBB4 gene]. / Sluchai bokovogo amiotroficheskogo skleroza, svyazannogo s novoi mutatsiei v gene ERBB4.

Amyotrophic lateral sclerosis (ALS) is a sporadic disease in most of the cases; in 10-15% of cases genetic forms are recorded. A genetic form of ALS associated with the mutation in the ERBB4 gene (ALS19) has been reported in 2013. A protein encoded by the ERBB4 is probably involved in ubiquitous component of the pathogenesis of ALS. We present a case of ALS associated with a new pathogenic variant of the ERBB4 gene, with early bulbar onset and slow progression of the disease within 10 years.

Navigating the Fractional Calcium Dynamics of Orai Mechanism in Polar Dimensions.

Calcium plays a crucial role as a second messenger in neuronal signal transduction pathways. The influx of calcium ions through various physicochemical gating channels activates neuronal calcium signaling. The Endoplasmic Reticulum (ER) is a significant intracellular structure that sequesters calcium and controls signaling through SERCA, IPR, and leak channel mechanisms. Disruption of calcium dynamics can trigger intrinsic dyshomeostasis, cell damage, and apoptosis. The present study articulates a Caputo fractional time derivative in the polar coordinate dimensions to investigate the role of nonlocal calcium-free ions in the neuron through the Orai channel, and ER fluxes, incorporating various physiological parameters. The solution was obtained through the hybrid integral transform technique for analytical form. The closed form was generated using Green's function in terms of Mainardi and Wright's functions. Our simulation uncovered the calcium concentration bandwidth of interaction with different neuronal parameters. Parameters and calcium ion synergy show normal and Alzheimer's disease-impacted interaction through different illustrations. Our simulation reveals that S100B and BAPTA have significant calcium-controlling behavior.

Utility of melatonin on brain injury, synaptic transmission, and energy metabolism in rats with sepsis.

Melatonin is a powerful endogenous antioxidant hormone. Its healing effects on energy balance and neuronal damage associated with oxidative metabolism disorders have been reported in pathologic conditions. We aimed to determinate the utility of melatonin on neuronal damage, synaptic transmission, and energy balance in the brain tissue of rats with sepsis induced with LPS. Rats was divided into four groups such as control, LPS (20 mg/kg i.p.), melatonin (10 mg/kg i.p. × 3), and LPS + Melatonin (LPS + Mel). After 6 h from the first injection, rats were decapitated, and also tissue and serum samples were taken. Lipid peroxidation and neuron-specific enolase (NSE) levels were determined from the serum in all group. High energy compounds, creatine, and creatine phosphate are measured by HPLC methods from the homogenized tissue. Counts of living neurons are marked with NeuN (neuronal nuclei), degenerated neurons are marked with S100-ß and synaptic vesicles transmission is analyzed with synaptophysin antibodies immunoreactivities. One-way ANOVA and post hoc Tukey tests were used to statistical analysis. In LPS group, AMP, ATP, creatine, and creatine phosphate levels were significantly decreased (p < 0.05), and also ADP levels were significantly increased compared with the other groups (p < 0.01). Living neurons counts were significantly decreased in LPS (p < 0.01), melatonin, and LPS + Melatonin (p < 0.05) groups compared with control. Degenerated neurons counts were increased in LPS group compared with control (p < 0.01) and also decreased in both of melatonin and LPS + Melatonin groups (p < 0.01). Synaptophysin immunoreactivity was decreased in LPS group compared with the other groups (p < 0.05). We observed that melatonin administration prevents neuronal damage, regulates energy metabolism, and protects synaptic vesicle proteins from sepsis-induced reduction.

Generalised Neuronal Calcium Dynamics of Membrane and ER in the Polar Dimension.

Calcium ions are the second messenger playing as regulators for various cellular activities. Its spatiotemporal control is critical for various brain functions, including neuroplasticity, apoptosis, and cell death. The Endoplasmic Reticulum (ER) plays an important role in determining these spatiotemporal calcium dynamics. Stromal interaction molecule (STIM) - Orai channel on the membrane generates additional calcium flow, whereas other membrane fluxes contribute to cytosolic flux. Due to their anomalous character, we used the Caputo fractional differential operator to mimic these interactions in polar coordinates. Solutions were generated using hybrid integral transform methods to control the analytical approach. Using Green's function yielded a closed-form solution for Mittag-Leffler-type functions. This work emphasizes the significant relationship between calcium and various buffer levels in neurons. The differential transition simulation of a time derivative with space across different parameters indicated a decrease in calcium concentration. Anomalously low buffer levels exhibited the impact of Alzheimer's disease on calcium higher concentration, leading to the death of neurons. Additionally, the research introduces a method involving S100B, BAPTA, and calmodulin buffers to uphold optimal calcium levels within the neuronal cytosol. The applicability of this model with different buffer properties and parameters and memory impacts the calcium concentration with the neurological disorder.

Cholinergic stimulation stabilizes TRPM4 in the plasma membrane of cortical pyramidal neurons.

TRPM4 is a calcium activated non-selective cation channel, impermeable to Ca2+, in neurons it has been implicated in the regulation of the excitability and in the persistent firing. Cholinergic stimulation is also implicated in changes in excitability that leads neurons to an increased firing frequency, however it is not clear whether TRPM4 is involved in the cholinergic-induced increase in firing frequency. Here using a combination of patch clamp electrophysiology, Ca2+ imaging, immunofluorescence, fluorescence recovery after photobleaching (FRAP) and pharmacological approach, we demonstrate that carbachol (Cch) increases firing frequency, intracellular Ca2+ and that TRPM4 inhibition using 9-Ph and CBA reduces firing frequency and decreases the peak in intracellular Ca2+ induced by Cch in cortical pyramidal neurons in culture. Moreover, we determined that cholinergic stimulation reduces TRPM4 recycling and stabilizes TRPM4 in the plasma membrane. Together our results indicate that cholinergic stimulation increases firing in a TRPM4 dependent manner, and also increases the TRPM4 stability in the membrane, suggesting that TRPM4 is locked in microdomains in the membrane, possibly signaling or cytoskeleton proteins complexes.

Spectral resonance in Fitzhugh-Nagumo neuron system: relation with stochastic resonance and its role in EMG signal characterization.

This paper examines the existence of spectral resonance in the Fitzhugh-Nagumo (FHN) system driven by periodical signal and unbounded noise having Gaussian distribution. It is newly revealed that if the inter-spike-interval (ISI) distribution is accumulated on a single cluster, there exists a dual relationship between stochastic resonance and spectral resonance determined by commonly used metric normalized standard deviation of ISI. Furthermore, the ISI distribution is also concentrated on more than one cluster depending on different driving signal frequency. Consequently, the apparent regular spiking behavior is observed to occur at specified driving signal frequencies which result in a local minimum in entropy function indicating spectral resonance. Therefore it is proposed that occurrence of spectral resonance strongly depends on the shape of ISI distribution tuned by the stochastic and deterministic driving signal parameters and conventional metrics may not indicate entire resonance behavior. Correspondingly, the entropy function is utilized in this paper as an alternative metric to enable the detection of the spectral resonance occurrence. The ISI distribution obtained from the FHN system is investigated to relate the real electromyography (EMG) measurements under different conditions such as myokymia and neuromyotonia. It is seen that ISI distribution observed from myokymic EMG exhibits notably close behavior as in the case of spectral resonance generated by FHN whereas a wider distribution is monitored in the case of neuromyotonia. It is contributed that the modeling and parameterization based on ISI distribution can be potentially used to identify different neural activities.

Energy and synchronization between two neurons with nonlinear coupling.

Consensus and synchronous firing in neural activities are relative to the physical properties of synaptic connections. For coupled neural circuits, the physical properties of coupling channels control the synchronization stability, and transient period for keeping energy diversity. Linear variable coupling results from voltage coupling via linear resistor by consuming certain Joule heat, and electric synapse coupling between neurons derives from gap junction connection under special electrophysiological condition. In this work, a voltage-controlled electric component with quadratic relation in the i-v (current-voltage) is used to connect two neural circuits composed of two variables. The energy function obtained by using Helmholtz theorem is consistent with the Hamilton energy function converted from the field energy in the neural circuit. Chaotic signals are encoded to approach a mixed signal within certain frequency band, and then its amplitude is adjusted to excite the neuron for detecting possible occurrence of nonlinear resonance. External stimuli are changed to trigger different firing modes, and nonlinear coupling activates changeable coupling intensity. It is confirmed that nonlinear coupling behaves functional regulation as hybrid synapse, and the synchronization transition between neurons can be controlled for reaching possible energy balance. The nonlinear coupling is helpful to keep energy diversity and prevent synchronous bursting because positive and negative feedback is switched with time. As a result, complete synchronization is suppressed and phase lock is controlled between neurons with energy diversity.

Coincidence detection and integration behavior in spiking neural networks.

Recently, the interest in spiking neural networks (SNNs) remarkably increased, as up to now some key advances of biological neural networks are still out of reach. Thus, the energy efficiency and the ability to dynamically react and adapt to input stimuli as observed in biological neurons is still difficult to achieve. One neuron model commonly used in SNNs is the leaky-integrate-and-fire (LIF) neuron. LIF neurons already show interesting dynamics and can be run in two operation modes: coincidence detectors for low and integrators for high membrane decay times, respectively. However, the emergence of these modes in SNNs and the consequence on network performance and information processing ability is still elusive. In this study, we examine the effect of different decay times in SNNs trained with a surrogate-gradient-based approach. We propose two measures that allow to determine the operation mode of LIF neurons: the number of contributing input spikes and the effective integration interval. We show that coincidence detection is characterized by a low number of input spikes as well as short integration intervals, whereas integration behavior is related to many input spikes over long integration intervals. We find the two measures to linearly correlate via a correlation factor that depends on the decay time. Thus, the correlation factor as function of the decay time shows a powerlaw behavior, which could be an intrinsic property of LIF networks. We argue that our work could be a starting point to further explore the operation modes in SNNs to boost efficiency and biological plausibility. Supplementary Information: The online version of this article (10.1007/s11571-023-10038-0) contains supplementary material, which is available to authorized users.

A Temperature Sensory Leaky Integrate-and-Fire Artificial Neuron Based on Chitosan/PNIPAM Bilayer Volatile Complementary Resistive Switching Memristor.

The presence of neurons is crucial in neuromorphic computing systems as they play a vital role in modulating the strength of synapses through the release of either excitatory or inhibitory stimuli. Hence, the development of sensory neurons plays a pivotal role in broadening the scope of brain-inspired neural computing. The present study introduces an artificial sensory neuron, which is constructed using a temperature-sensitive volatile complementary resistance switch memristor based on the functional layer of the chitosan/PNIPAM bilayer. The resistive switching behavior arises from the formation and ionization of oxygen vacancy filaments, whereby the threshold voltage and low resistive resistance of the device exhibit a temperature-dependent increase within the range of 290-410 K. A functional replication of a neuron with leaky integration and firing has been successfully developed, effectively simulating essential biological functions such as firing triggered by threshold, refractory period implementation, and modulation of spiking frequency. The artificial sensory neuron exhibits characteristics similar to those of leaky integrated firing neurons that receive temperature inputs. It has the potential to control the output frequency and amplitude under varying temperature conditions, making it suitable for temperature-sensing applications. This study presents a potential hardware implementation for developing efficient artificial intelligence systems that can support temperature detections.

Early detection of dopaminergic dysfunction and glymphatic system impairment in Parkinson's disease.

PURPOSE: This study aimed to assess the glymphatic function and its correlation with clinical characteristics and the loss of dopaminergic neurons in Parkinson's disease (PD) using hybrid positron emission tomography (PET)-magnetic resonance imaging (MRI) combined with diffusion tensor image analysis along the perivascular space (DTI-ALPS), choroid plexus volume (CPV), and enlarged perivascular space (EPVS) volume. METHODS: Twenty-five PD patients and thirty matched healthy controls (HC) participated in the study. All participants underwent 18F-fluorodopa (18F-DOPA) PET-MRI scanning. The striatal standardized uptake value ratio (SUVR), DTI-ALPS index, CPV, and EPVS volume were calculated. Furthermore, we also analysed the relationship between the DTI-ALPS index, CPV, EPVS volume and striatal SUVR as well as clinical characteristics of PD patients. RESULTS: PD patients demonstrated significantly lower values in DTI-ALPS (t = 3.053, p = 0.004) and larger CPV (t = 2.743, p = 0.008) and EPVS volume (t = 2.807, p = 0.008) compared to HC. In PD group, the ALPS-index was negatively correlated with the Unified Parkinson's Disease Rating Scale III (UPDRS-III) scores (r = -0.730, p < 0.001), and positively correlated with the mean putaminal SUVR (r = 0.560, p = 0.007) and mean caudal SUVR (r = 0.459, p = 0.032). Moreover, the mean putaminal SUVR was negatively associated with the UPDRS-III scores (r = -0.544, p = 0.009). CONCLUSION: DTI-ALPS has the potential to uncover glymphatic dysfunction in patients with PD, with this dysfunction correlating strongly with the severity of disease, together with the mean putaminal and caudal SUVR. PET- MRI can serve as a potential multimodal imaging biomarker for early-stage PD.

Decreasing the physical gap in the neural-electrode interface and related concepts to improve cochlear implant performance.

Cochlear implants (CI) represent incredible devices that restore hearing perception for those with moderate to profound sensorineural hearing loss. However, the ability of a CI to restore complex auditory function is limited by the number of perceptually independent spectral channels provided. A major contributor to this limitation is the physical gap between the CI electrodes and the target spiral ganglion neurons (SGNs). In order for CI electrodes to stimulate SGNs more precisely, and thus better approximate natural hearing, new methodologies need to be developed to decrease this gap, (i.e., transitioning CIs from a far-field to near-field device). In this review, strategies aimed at improving the neural-electrode interface are discussed in terms of the magnitude of impact they could have and the work needed to implement them. Ongoing research suggests current clinical efforts to limit the CI-related immune response holds great potential for improving device performance. This could eradicate the dense, fibrous capsule surrounding the electrode and enhance preservation of natural cochlear architecture, including SGNs. In the long term, however, optimized future devices will likely need to induce and guide the outgrowth of the peripheral process of SGNs to be in closer proximity to the CI electrode in order to better approximate natural hearing. This research is in its infancy; it remains to be seen which strategies (surface patterning, small molecule release, hydrogel coating, etc.) will be enable this approach. Additionally, these efforts aimed at optimizing CI function will likely translate to other neural prostheses, which face similar issues.

[Electrodiagnostic support in an atypical form of amyotrophic lateral sclerosis (Vulpian-Bernhardt syndrome)]. / Apoyo del electrodiagnóstico en una forma atípica de esclerosis lateral amiotrófica (síndrome de Vulpian-Bernhardt).

Background: Vulpian-Bernhardt syndrome is an atypical form of the motor neuron disease described since the 19th century. The importance of a timely diagnosis lies in the increased survival present in this variant. Due to the clinical rarity and complex diagnosis we report a clinical case of this disease, which is why we describe the typical clinical presentation, the diagnostic approach, and we make a bibliographic review of this neurodegenerative disorder as well. Clinical case: Latin American man whose clinical case onset was characterized by thoracic asymmetric and increasing limb weakness, showing affection from distal to proximal upper limbs area. Subsequently, symptoms worsened to the point of limiting day-to-day activities and conditioning patient's physical independence. Physical examination was consistent with motor neuron disease. Nerve conduction studies were performed and confirmed findings compatible with motor neuron involvement limited to thoracic limbs. Conclusion: Vulpian-Bernhardt syndrome is an uncommon form of motor neuron disease. Due to the rarity of its presentation, it is frequent to confuse clinical profile even for trained physicians. The importance of electrodiagnosis relies in identifying the neurogenic origin of the disease, as well as the active denervation and reinnervation data. Considering that with this syndrome patients have a longer survival than with the classic form of amyotrophic lateral sclerosis, it is important to have a clear diagnosis approach in order to provide a better quality of life and supportive treatment.

Introducción: el síndrome de Vulpian-Bernhardt es una forma atípica de la enfermedad de la motoneurona descrita desde el siglo XIX. La importancia de un diagnóstico oportuno radica en la mayor supervivencia que presenta esta variante. Debido a la rareza clínica y al diagnóstico complejo presentamos un caso clínico de esta enfermedad, por lo que describimos el cuadro clínico típico, el abordaje diagnóstico y hacemos una revisión bibliográfica de este trastorno neurodegenerativo. Caso clínico: hombre de origen latinoamericano que comenzó su padecimiento con debilidad de miembros torácicos, asimétrica y progresiva de distal a proximal. Los síntomas progresaron hasta limitar sus actividades de la vida diaria y su independencia física. La exploración física fue compatible con enfermedad de motoneurona. Se hicieron estudios de extensión y neuroconducción que confirmaron hallazgos compatibles con afectación en motoneurona limitada a miembros torácicos. Conclusión: el síndrome Vulpian-Bernhardt es una forma clínica poco común. Debido a su rareza, es fácil confundir el cuadro clínico, incluso por parte de experimentados. La importancia del electrodiagnóstico radica en identificar el origen neurogénico de la enfermedad, los datos de denervación activa y reinervación. Al ser una forma en la que se presenta una supervivencia mayor que en la forma clásica, es importante el diagnóstico claro para dar una mejor calidad de vida y tratamiento de soporte.

Endoplasmic reticulum associated degradation preserves neurons viability by maintaining endoplasmic reticulum homeostasis.

Endoplasmic reticulum-associated degradation (ERAD) is a principal quality-control mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. Evidence suggests that impairment of ERAD contributes to neuron dysfunction and death in neurodegenerative diseases, many of which are characterized by accumulation and aggregation of misfolded proteins. However, the physiological role of ERAD in neurons remains unclear. The Sel1L-Hrd1 complex consisting of the E3 ubiquitin ligase Hrd1 and its adaptor protein Sel1L is the best-characterized ERAD machinery. Herein, we showed that Sel1L deficiency specifically in neurons of adult mice impaired the ERAD activity of the Sel1L-Hrd1 complex and led to disruption of ER homeostasis, ER stress and activation of the unfold protein response (UPR). Adult mice with Sel1L deficiency in neurons exhibited weight loss and severe motor dysfunction, and rapidly succumbed to death. Interestingly, Sel1L deficiency in neurons caused global brain atrophy, particularly cerebellar and hippocampal atrophy, in adult mice. Moreover, we found that cerebellar and hippocampal atrophy in these mice resulted from degeneration of Purkinje neurons and hippocampal neurons, respectively. These findings indicate that ERAD is required for maintaining ER homeostasis and the viability and function of neurons in adults under physiological conditions.

Cortical inexcitability in ALS: correlating a clinical phenotype.

BACKGROUND: Cortical inexcitability, a less studied feature of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis (ALS), was identified in a large cross-sectional cohort of ALS patients and their demographic and clinical characteristics were contrasted with normal or hyperexcitable ALS cohorts to assess the impact of cortical inexcitability on ALS phenotype and survival. METHODS: Threshold-tracking transcranial magnetic stimulation (TMS) technique with measurement of mean short interval intracortical inhibition (SICI) differentiated ALS patients into three groups (1) inexcitable (no TMS response at maximal stimulator output in the setting of preserved lower motor neuron (LMN) function), (2) hyperexcitable (SICI≤5.5%) and (3) normal cortical excitability (SICI>5.5%). Clinical phenotyping and neurophysiological assessment of LMN function were undertaken, and survival was recorded in the entire cohort. RESULTS: 417 ALS patients were recruited, of whom 26.4% exhibited cortical inexcitability. Cortical inexcitability was associated with a younger age of disease onset (p<0.05), advanced Awaji criteria (p<0.01) and Kings stage (p<0.01) scores. Additionally, patients with cortical inexcitability had higher UMN score (p<0.01), lower revised ALS Functional Rating Scale score (p<0.01) and reduced upper limb strength score (MRC UL, p<0.01). Patient survival (p=0.398) was comparable across the groups, despite lower riluzole use in the cortical inexcitability patient group (p<0.05). CONCLUSION: The present study established that cortical inexcitability was associated with a phenotype characterised by prominent UMN signs, greater motor and functional decline, and a younger age of onset. The present findings inform patient management and could improve patient stratification in clinical trials.

Genome-wide and cell-type-selective profiling of in vivo small noncoding RNA:target RNA interactions by chimeric RNA sequencing.

Small noncoding RNAs (sncRNAs) regulate biological processes by impacting post-transcriptional gene expression through repressing the translation and levels of targeted transcripts. Despite the clear biological importance of sncRNAs, approaches to unambiguously define genome-wide sncRNA:target RNA interactions remain challenging and not widely adopted. We present CIMERA-seq, a robust strategy incorporating covalent ligation of sncRNAs to their target RNAs within the RNA-induced silencing complex (RISC) and direct detection of in vivo interactions by sequencing of the resulting chimeric RNAs. Modifications are incorporated to increase the capacity for processing low-abundance samples and permit cell-type-selective profiling of sncRNA:target RNA interactions, as demonstrated in mouse brain cortex. CIMERA-seq represents a cohesive and optimized method for unambiguously characterizing the in vivo network of sncRNA:target RNA interactions in numerous biological contexts and even subcellular fractions. Genome-wide and cell-type-selective CIMERA-seq enhances researchers' ability to study gene regulation by sncRNAs in diverse model systems and tissue types.

Exploring the PDZ, DUF, and LIM Domains of Pdlim5 in Dendrite Branching.

The branched architecture of neuronal dendrites is a key factor in how neurons form ordered networks and discoveries continue to be made identifying proteins and protein-protein interactions that direct or execute the branching and extension of dendrites. Our prior work showed that the molecular scaffold Pdlim5 and delta-catenin, in conjunction, are two proteins that help regulate the branching and elongation of dendrites in cultured hippocampal neurons and do so through a phosphorylation-dependent mechanism triggered by upstream glutamate signaling. In this report we have focused on Pdlim5's multiple scaffolding domains and how each contributes to dendrite branching. The three identified regions within Pdlim5 are the PDZ, DUF, and a trio of LIM domains; however, unresolved is the intra-molecular conformation of Pdlim5 as well as which domains are essential to regulate dendritic branching. We address Pdlim5's structure and function by examining the role of each of the domains individually and using deletion mutants in the context of the full-length protein. Results using primary hippocampal neurons reveal that the Pdlim5 DUF domain plays a dominant role in increasing dendritic branching. Neither the PDZ domain nor the LIM domains alone support increased branching. The central role of the DUF domain was confirmed using deletion mutants in the context of full-length Pdlim5. Guided by molecular modeling, additional domain mapping studies showed that the C-terminal LIM domain forms a stable interaction with the N-terminal PDZ domain, and we identified key amino acid residues at the interface of each domain that are needed for this interaction. We posit that the central DUF domain of Pdlim5 may be subject to modulation in the context of the full-length protein by the intra-molecular interaction between the N-terminal PDZ and C-terminal LIM domains. Overall, our studies reveal a novel mechanism for the regulation of Pdlim5's function in the regulation of neuronal branching and highlight the critical role of the DUF domain in mediating these effects.

Olfactory Ecto-Mesenchymal Stem Cells in Modeling and Treating Alzheimer's Disease.

Alzheimer's disease (AD) is a condition in the brain that is marked by a gradual and ongoing reduction in memory, thought, and the ability to perform simple tasks. AD has a poor prognosis but no cure yet. Therefore, the need for novel models to study its pathogenesis and therapeutic strategies is evident, as the brain poorly recovers after injury and neurodegenerative diseases and can neither replace dead neurons nor reinnervate target structures. Recently, mesenchymal stem cells (MSCs), particularly those from the human olfactory mucous membrane referred to as the olfactory ecto-MSCs (OE-MSCs), have emerged as a potential avenue to explore in modeling AD and developing therapeutics for the disease due to their lifelong regeneration potency and facile accessibility. This review provides a comprehensive summary of the current literature on isolating OE-MSCs and delves into whether they could be reliable models for studying AD pathogenesis. It also explores whether healthy individual-derived OE-MSCs could be therapeutic agents for the disease. Despite being a promising tool in modeling and developing therapies for AD, some significant issues remain, which are also discussed in the review.

Epigenetic Regulation and Molecular Mechanisms of Burn Injury-Induced Nociception in the Spinal Cord of Mice.

Epigenetic mechanisms, including histone post-translational modifications (PTMs), play a critical role in regulating pain perception and the pathophysiology of burn injury. However, the epigenetic regulation and molecular mechanisms underlying burn injury-induced pain remain insufficiently explored. Spinal dynorphinergic (Pdyn) neurons contribute to heat hyperalgesia induced by severe scalding-type burn injury through p-S10H3-dependent signaling. Beyond p-S10H3, burn injury may impact various other histone H3 PTMs. Double immunofluorescent staining and histone H3 protein analyses demonstrated significant hypermethylation at H3K4me1 and H3K4me3 sites and hyperphosphorylation at S10H3 within the spinal cord. By analyzing Pdyn neurons in the spinal dorsal horn, we found evidence of chromatin activation with a significant elevation in p-S10H3 immunoreactivity. We used RNA-seq analysis to compare the effects of burn injury and formalin-induced inflammatory pain on spinal cord transcriptomic profiles. We identified 98 DEGs for burn injury and 86 DEGs for formalin-induced inflammatory pain. A limited number of shared differentially expressed genes (DEGs) suggest distinct central pain processing mechanisms between burn injury and formalin models. KEGG pathway analysis supported this divergence, with burn injury activating Wnt signaling. This study enhances our understanding of burn injury mechanisms and uncovers converging and diverging pathways in pain models with different origins.