Search Results (343)

Developmental exposure to polybrominated diphenyl ethers (PBDEs), which are commonly used as flame retardants, results in irreversible cognitive impairments. Postnatal hippocampal neurogenesis, which occurs in the subgranular zone (SGZ) of the dentate gyrus, is critical for neuronal circuits and plasticity. Wnt7a-Frizzled5 (FZD5) is essential for both neurogenesis and synapse formation; moreover, Wnt signaling participates in PBDE neurotoxicity and also contributes to the neuroprotective effects of melatonin. Therefore, we investigated the impacts of perinatal decabromodiphenyl ether (BDE-209) exposure on hippocampal neurogenesis and synaptogenesis in juvenile rats through BrdU injection and Golgi staining, as well as the alleviation of melatonin pretreatment. Additionally, we identified the structural basis of Wnt7a and two compounds via molecular docking. The hippocampal neural progenitor pool (Sox2+BrdU+ and Sox2+GFAP+cells), immature neurons (DCX+) differentiated from neuroblasts, and the survival of mature neurons (NeuN+) in the dentate gyrus were inhibited. Moreover, in BDE-209-exposed offspring rats, it was observed that dendritic branching and spine density were reduced, alongside the long-lasting suppression of the Wnt7a-FZD5/β-catenin pathway and targeted genes (Prox1, Neurod1, Neurogin2, Dlg4, and Netrin1) expression. Melatonin alleviated BDE-209-disrupted memory, along with hippocampal neurogenesis and dendritogenesis, for which the restoration of Wnt7a-FZD5 signaling may be beneficial. This study suggested that melatonin could represent a potential intervention for the cognitive deficits induced by PBDEs. Full article

Microglia, as the immune guardians of the central nervous system (CNS), have the ability to maintain neural homeostasis, respond to environmental changes, and remodel the synaptic landscape. However, persistent microglial activation can lead to chronic neuroinflammation, which can alter neuronal signaling pathways, resulting in accelerated cognitive decline. Phosphoinositol 3-kinase (PI3K) has emerged as a critical driver, connecting inflammation to neurodegeneration, serving as the nexus of numerous intracellular processes that govern microglial activation. This review focuses on the relationship between PI3K signaling and microglial activation, which might lead to cognitive impairment, inflammation, or even neurodegeneration. The review delves into the components of the PI3K signaling cascade, isoforms, and receptors of PI3K, as well as the downstream effects of PI3K signaling, including its effectors such as protein kinase B (Akt) and mammalian target of rapamycin (mTOR) and the negative regulator phosphatase and tensin homolog (PTEN). Experiments have shown that the overproduction of certain cytokines, coupled with abnormal oxidative stress, is a consequence of poor PI3K regulation, resulting in excessive synapse pruning and, consequently, impacting learning and memory functions. The review also highlights the implications of autonomously activated microglia exhibiting M1/M2 polarization driven by PI3K on hippocampal, cortical, and subcortical circuits. Conclusions from behavioral studies, electrophysiology, and neuroimaging linking cognitive performance and PI3K activity were evaluated, along with new approaches to therapy using selective inhibitors or gene editing. The review concludes by highlighting important knowledge gaps, including the specific effects of different isoforms, the risks associated with long-term pathway modulation, and the limitations of translational potential, underscoring the crucial role of PI3K in mitigating cognitive impairment driven by neuroinflammation. Full article

Electroporation-mediated gene delivery is a cornerstone of synthetic biology, offering several advantages over other methods: higher efficiencies, broader applicability, and simpler sample preparation. Yet, electroporation protocols are often challenging to integrate into highly multiplexed workflows, owing to limitations in their scalability and tunability. These challenges ultimately increase the time and cost per transformation. As a result, rapidly screening genetic libraries, exploring combinatorial designs, or optimizing electroporation parameters requires extensive iterations, consuming large quantities of expensive custom-made DNA and cell lines or primary cells. To address these limitations, we have developed a High-Throughput Microfluidic Electroporation (HTME) platform that includes a 384-well electroporation plate (E-Plate) and control electronics capable of rapidly electroporating all wells in under a minute with individual control of each well. Fabricated using scalable and cost-effective printed-circuit-board (PCB) technology, the E-Plate significantly reduces consumable costs and reagent consumption by operating on nano to microliter volumes. Furthermore, individually addressable wells facilitate rapid exploration of large sets of experimental conditions to optimize electroporation for different cell types and plasmid concentrations/types. Use of the standard 384-well footprint makes the platform easily integrable into automated workflows, thereby enabling end-to-end automation. We demonstrate transformation of E. coli with pUC19 to validate the HTME’s core functionality, achieving at least a single colony forming unit in more than 99% of wells and confirming the platform’s ability to rapidly perform hundreds of electroporations with customizable conditions. This work highlights the HTME’s potential to significantly accelerate synthetic biology Design-Build-Test-Learn (DBTL) cycles by mitigating the transformation/transfection bottleneck. Full article

The dynamic phosphorylation of the human RNA Pol II CTD establishes a code applicable to all eukaryotic transcription processes. However, the ability of these specific post-translational modifications to convey molecular signals through structural changes remains unclear. We previously explained that each gene can be modeled as a combination of n circuits connected in parallel. RNA Pol II accesses these circuits and, through a series of pulses, matches the resonance frequency of the DNA qubits, enabling it to extract genetic information and quantum teleport it. Negatively charged phosphates react under RNA Pol II catalysis, which increases the electron density on the deoxyribose acceptor carbon (2’C in the DNA sugar backbone). The phosphorylation effect on the stability of a carbon radical connects tyrosine to the nitrogenous base, while the subsequent pulses link the protein to molecular water through hydrogen bonds. The selective activation of inert C(sp³)–H bonds begins by reading the quantum information stored in the nitrogenous bases. The coupling of hydrogen proton transfer with electron transfer in water generates a supercurrent, which is explained by the correlation of pairs of the same type of fermions exchanging a boson. All these changes lead to the formation of a molecular protein–DNA–water transcriptional condensate. Full article

Introduction: Huntington’s disease (HD) disrupts cortico-striato-thalamocortical circuits decades before clinical onset. Electroencephalography (EEG) offers millisecond temporal resolution, low cost, and broad accessibility, yet its mechanistic and biomarker potential in HD remains underexplored. We conducted a mechanistic review to synthesize half a century of EEG findings, identify reproducible electrophysiological signatures, and outline translational next steps. Methods: Two independent reviewers searched PubMed, Scopus, Google Scholar, ResearchGate, and the Cochrane Library (January 1970–April 2025) using the terms “EEG” OR “electroencephalography” AND “Huntington’s disease”. Clinical trials published in English that reported raw EEG (not ERP-only) in human HD gene carriers were eligible. Abstract/title screening, full-text appraisal, and cross-reference mining yielded 22 studies (~700 HD recordings, ~600 controls). We extracted sample characteristics, acquisition protocols, spectral/connectivity metrics, and neuroclinical correlations. Results: Across diverse platforms, a consistent spectral trajectory emerged: (i) presymptomatic carriers show a focal 7–9 Hz (low-alpha) power loss that scales with CAG repeat length; (ii) early-manifest patients exhibit widespread alpha attenuation, delta–theta excess, and a flattened anterior-posterior gradient; (iii) advanced disease is characterized by global slow-wave dominance and low-voltage tracings. Source-resolved studies reveal early alpha hypocoherence and progressive delta/high-beta hypersynchrony, microstate shifts (A/B ↑, C/D ↓), and rising omega complexity. These electrophysiological changes correlate with motor burden, cognitive slowing, sleep fragmentation, and neurovascular uncoupling, and achieve 80–90% diagnostic accuracy in shallow machine-learning pipelines. Conclusions: EEG offers a coherent, stage-sensitive window on HD pathophysiology—from early thalamocortical disinhibition to late network fragmentation—and fulfills key biomarker criteria. Translation now depends on large, longitudinal, multi-center cohorts with harmonized high-density protocols, rigorous artifact control, and linkage to clinical milestones. Such infrastructure will enable the qualification of alpha-band restoration, delta-band hypersynchrony, and neurovascular coupling as pharmacodynamic readouts, fostering precision monitoring and network-targeted therapy in Huntington’s disease. Full article

Background: Diabetic foot ulcers (DFUs) are a severe complication of diabetes and are characterized by impaired wound healing and a high amputation risk. Exosomes—which are nanovesicles carrying proteins, RNAs, and lipids—mediate intercellular communication in wound microenvironments, yet their biomarker potential in DFUs remains underexplored. Methods: We analyzed transcriptomic data from GSE134431 (13 DFU vs. 8 controls) as a training set and validated findings in GSE80178 (6 DFU vs. 3 controls). A sum of 7901 differentially expressed genes (DEGs) of DFUs were detected and intersected with 125 literature-curated exosome-related genes (ERGs) to yield 51 candidates. This was followed by GO/KEGG analyses and a PPI network construction. Support vector machine–recursive feature elimination (SVM-RFE) and the Boruta random forest algorithm distilled five biomarkers (DIS3L, EXOSC7, SDC1, STX11, SYT17). Expression trends were confirmed in both datasets. Analyses included nomogram construction, functional and correlation analyses, immune infiltration, GSEA, gene co-expression and regulatory network construction, drug prediction, molecular docking, and RT-qPCR validation in clinical samples. Results: A nomogram combining these markers achieved an acceptable calibration (Hosmer–Lemeshow p = 0.0718, MAE = 0.044). Immune cell infiltration (CIBERSORT) revealed associations between biomarker levels and NK cell and neutrophil subsets. Gene set enrichment analysis (GSEA) implicated IL-17 signaling, proteasome function, and microbial infection pathways. A GeneMANIA network highlighted RNA processing and vesicle trafficking. Transcription factor and miRNA predictions uncovered regulatory circuits, and DGIdb-driven drug repurposing followed by molecular docking identified Indatuximab ravtansine and heparin as high-affinity SDC1 binders. Finally, RT-qPCR validation in clinical DFU tissues (n = 5) recapitulated the bioinformatic expression patterns. Conclusions: We present five exosome-associated genes as novel DFU biomarkers with diagnostic potential and mechanistic links to immune modulation and vesicular transport. These findings lay the groundwork for exosome-based diagnostics and therapeutic targeting in DFU management. Full article

Spinal cord injury (SCI) is a severe neurological condition that typically results in irreversible loss of motor and sensory function. Emerging evidence indicates that neuroplasticity, the ability of the nervous system to reorganize by forming new neural connections, plays a pivotal role in structural and functional recovery post-injury. This insight lays the groundwork for the development of rehabilitation and therapeutic strategies designed to leverage neuroplasticity. In this review, we offer an exhaustive overview of the neuroplastic alterations and mechanisms that occur following an SCI. We examine the role of neuroplasticity in functional recovery and outline therapeutic approaches designed to augment neuroplasticity post-SCI. The process of neuroplasticity post-SCI involves several physiological processes, such as neurogenesis, synaptic remodeling, dendritic spine formation, and axonal sprouting. Together, these processes contribute to the reestablishment of neural circuits and functional restoration. Enhancing neuroplasticity is a promising strategy for improving functional outcomes post-SCI; however, its effectiveness is influenced by numerous factors, including age, injury severity, time since the injury, and the specific therapeutic interventions employed. A variety of strategies have been suggested to promote neuroplasticity and expedite recovery, including pharmacological treatments, biomaterial-based therapies, gene editing, stem cell transplantation, and rehabilitative training. The combination of personalized rehabilitation programs with innovative therapeutic techniques holds considerable potential for maximizing the benefits of neuroplasticity and enhancing clinical outcomes in SCI management. Full article

Quantum neural networks (QNNs) represent an emerging technology that uses a quantum computer for neural network computations. The QNNs have demonstrated potential advantages over classical neural networks in certain tasks. As a core component of a QNN, the parameterized quantum circuit (PQC) plays a crucial role in determining the QNN’s overall performance. However, quantum circuit architectures designed manually based on experience or using specific hardware structures can suffer from inefficiency due to the introduction of redundant quantum gates, which amplifies the impact of noise on system performance. Recent studies have suggested that the advantages of quantum evolutionary algorithms (QEAs) in terms of precision and convergence speed can provide an effective solution to quantum circuit architecture-related problems. Currently, most QEAs adopt a fixed rotation mode in the evolution process, and a lack of an adaptive updating mode can cause the QEAs to fall into a local optimum and make it difficult for them to converge. To address these problems, this study proposes an adaptive quantum evolution algorithm (AQEA). First, an adaptive mechanism is introduced to the evolution process, and the strategy of combining two dynamic rotation angles is adopted. Second, to prevent the fluctuations of the population’s offspring, the elite retention of the parents is used to ensure the inheritance of good genes. Finally, when the population falls into a local optimum, a quantum catastrophe mechanism is employed to break the current population state. The experimental results show that compared with the QNN structure based on manual design and QEA search, the proposed AQEA can reduce the number of network parameters by up to 20% and increase the accuracy by 7.21%. Moreover, in noisy environments, the AQEA-optimized circuit outperforms traditional circuits in maintaining high fidelity, and its excellent noise resistance provides strong support for the reliability of quantum computing. Full article

Floral ontogeny in soybean (Glycine max) is governed by multilayered regulatory hierarchies that integrate phytohormonal cues with precisely choreographed gene-expression programs. Yet, the transcriptomic architecture underpinning this continuum remains only partially resolved. Here, we generated a strand-specific, high-depth temporal transcriptome atlas of soybean inflorescences spanning four morphologically defined stadiums (Stadium 0–Stadium 3). We detected transcriptional activity for 60,889 loci; pairwise stadium contrasts revealed 4000–7000 differentially expressed genes, with the most extensive reprogramming coinciding with the onset of anthesis (Stadium 2). Unsupervised clustering delineated ~600 genes peaking at the pre-anthesis phase (Stadium 1), a cohort enriched for transcriptional regulators and floral organ-identity determinants. Stadium-resolved gene-set enrichment and KEGG mapping uncovered dynamic modulation of canonical hormone-signaling pathways—including auxin, cytokinin, gibberellin, abscisic acid, ethylene, jasmonate, and salicylate circuits—reflecting shifting developmental priorities. Forty-five MADS-box transcription factor genes were expressed; notably, JOINTLESS was strongly induced at anthesis, while the root-predominant factor GmNMH7 exhibited unexpected floral expression, implicating a hitherto unappreciated role in reproductive development. Quantitative RT-PCR of representative loci corroborated RNA-seq measurements. This high-resolution atlas refines our understanding of the hormonal and genetic circuitry of soybean floral morphogenesis, furnishing molecular targets for engineering flowering time and inflorescence architecture under fluctuating environmental conditions. Full article

Chronic pain is a multifactorial and complex condition that significantly affects individuals’ quality of life. The underlying mechanisms of chronic pain involve complex alterations in neural circuits, gene expression, and cellular signaling pathways. Recently, ncRNAs, such as miRNAs, lncRNAs, circRNAs, and siRNAs, have been identified as crucial regulators in the pathophysiology of chronic pain. These ncRNAs modulate gene expression at both the transcriptional and post-transcriptional levels, affecting pain-related pathways like inflammation, neuronal plasticity, and sensory processing. miRNAs have been shown to control genes involved in pain perception and nociceptive signaling, while lncRNAs interact with chromatin remodeling factors and transcription factors to modify pain-related gene expression. CircRNAs act as sponges for miRNAs, thereby influencing pain mechanisms. siRNAs, recognized for their gene-silencing capabilities, also participate in regulating the expression of pain-related genes. This review examines the diverse roles of ncRNAs in chronic pain, emphasizing their potential as biomarkers for pain assessment and as targets for novel therapeutic strategies. A profound understanding of the ncRNA-mediated regulatory networks involved in chronic pain could result in more effective and personalized pain management solutions. Full article

Low-cost mini-bioreactor platforms are becoming increasingly important in synthetic biology and biotechnology for the characterization of genetic constructs and their initial scaling-up to large-scale cultures. Key process variables are the specific growth rate of cells and the synthesis rate of reporter proteins associated with transcriptional units of interest. These variables are of paramount importance for the characterization of gene synthetic circuits. In addition, their on-line estimation can be used for real-time monitoring of cells’ metabolic state and gene circuit dynamic performance, thus allowing for on-line decision taking. In this work, we first describe a procedure for the calibration of absorbance and fluorescence measurements, ensuring standardized and comparable units across different experimental setups and measurement devices. Then, we implement an observer-based software sensor that uses the calibrated on-line measurements to simultaneously estimate the specific growth and protein synthesis rates. We implemented the calibration procedure and software sensor in a Chi.Bio mini-bioreactor platform. The experimental results show very good performance and pave the way for the use of mini-bioreactor platforms in the real-time characterization of gene synthetic circuits under dynamically regulated time-varying complex scenarios. Full article

Erythropoiesis, the process driving the differentiation of hematopoietic stem and progenitor cells to mature erythrocytes, unfolds through tightly orchestrated developmental stages, each defined by profound epigenetic remodeling. From the initial commitment of hematopoietic progenitors to the terminal enucleation of erythrocytes, dynamic changes in chromatin accessibility, transcription factor occupancy, and three-dimensional genome architecture govern lineage specification and stage-specific gene expression. Advances in our understanding of the regulatory genome have uncovered how non-coding elements, including enhancers, silencers, and insulators, shape the transcriptional landscape of erythroid cells. These elements work in concert with lineage-determining transcription factors to establish and maintain erythroid identity. Disruption of these epigenetic programs—whether by inherited mutations, somatic alterations, or environmental stress—can lead to a wide range of hematologic disorders. Importantly, this growing knowledge base has opened new therapeutic avenues, enabling the development of precision tools that target regulatory circuits to correct gene expression. These include epigenetic drugs, enhancer-targeted genome editing, and lineage-restricted gene therapies that leverage endogenous regulatory logic. As our understanding of erythroid epigenomics deepens, so too does our ability to design rational, cell-type-specific interventions for red blood cell disorders. Full article

Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the formation of neural circuits. Neurexins are alternatively spliced at different splice sites, yielding thousands of isoforms with different properties of interaction with post-synaptic molecules for a quick adaptation to internal and external inputs. The endocannabinoid system also plays a central role in synaptic plasticity, regulating key retrograde signaling at both excitatory and inhibitory synapses. This study aims at elucidating the crosstalk between alternative splicing of neurexin and the endocannabinoid system in the hippocampus. By employing an ex vivo hippocampal system, we found that pharmacological activation of cannabinoid receptor 1 (CB1) with the specific agonist ACEA led to reduced neurotransmission, associated with increased expression of the Nrxn1–3 spliced isoforms excluding the exon at splice site 4 (SS4−). In contrast, treatment with the CB1 antagonist AM251 increased glutamatergic activity and promoted the expression of the Nrxn variants including the exon (SS4+) Knockout of the involved splicing factor SLM2 determined the suppression of the exon splicing at SS4 and the expression only of the SS4+ variants of Nrxns1–3 transcripts. Interestingly, in SLM2 ko hippocampus, modulation of neurotransmission by AM251 or ACEA was abolished. These findings suggest a direct crosstalk between CB1-dependent signaling, neurotransmission and expression of specific Nrxns splice variants in the hippocampus. We propose that the fine-tuned regulation of Nrxn1–3 genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system. Full article

Background: Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, with a rare juvenile-onset form (JoHD) marked by early, rigid motor symptoms. This study examined cortical and subcortical resting-state connectivity in JoHD, hypothesizing preserved cortical networks but altered striatal connectivity, in line with early subcortical atrophy despite relatively spared cortical volume. Methods: Participants included children and young adults with clinician-confirmed Juvenile-Onset Huntington’s Disease (JoHD; n = 19) and gene-non-expanded (GNE) controls (n = 64), both drawn from longitudinal studies at the University of Iowa. Resting-state functional MRI scans were analyzed to assess canonical cortical network and striatal connectivity, and linear mixed-effects models tested group differences and associations with motor, cognitive, and clinical outcomes. Results: JoHD participants showed reduced connectivity within the left somatomotor network and striatal circuits, despite largely typical cortical network connectivity. Striatal connectivity was associated with disease burden and cognitive ability, while left somatomotor connectivity was unrelated to clinical outcomes. Conclusions: These findings support the hypothesis of antagonistic pleiotropy in JoHD, where early neural advantages—such as relatively preserved or possibly enhanced cortical function—may contribute to later striatal vulnerability and degeneration. The observed left-lateralized somatomotor hypoconnectivity aligns with prior volumetric and gene expression research, highlighting the role of excitotoxic glutamatergic input and the selective vulnerability of high-functioning circuits in disease progression. Full article

Investigating transcriptomic changes during healthy development and aging provides insights into the molecular mechanisms that regulate the maturation of brain functions and drive age-related decline. Although it has been speculated that aging may represent a reversal of late-stage brain development, direct molecular comparisons between these two processes have remained limited. This study employs spatial transcriptomics to analyze the mouse brain at three key timepoints: postnatal day 21 (P21), 3 months (adult), and 28 months (aged), to identify region-specific differential gene expression dynamics. We identify widespread transcriptional changes across both brain development and aging, with all brain regions exhibiting distinct, region-specific gene expression dynamics that reflect divergent regulatory trajectories across the lifespan. During development, gene expression patterns were strongly enriched for neurogenesis, synaptic plasticity, and myelination, reflecting active circuit formation and white matter maturation. In contrast, aging was characterized by a decline in myelination-related gene expression and a pronounced increase in inflammatory and glial activation pathways, particularly within the hippocampus. While both development and aging involved changes in myelination-associated genes, the underlying mechanisms appear distinct: developmental upregulation supports circuit establishment and refinement, whereas aging-related downregulation may reflect secondary consequences of neuroinflammation and reactive gliosis. These findings underscore that, despite some overlap in affected pathways, neural maturation and age-related decline are driven by fundamentally different regulatory programs. These findings establish a novel spatial transcriptomic reference for brain development and aging, offering a valuable data resource for investigating neurodevelopmental and neurodegenerative mechanisms. Full article