Myeloid cell leukemia 1 (MCL-1) is a canonical anti-apoptotic protein crucial for early neurodevelopment. Loss of MCL-1 results in embryonic-lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the B cell lymphoma 2 (BCL-2) family. Here, we pharmacologically inhibit MCL-1 in human neural progenitor cells and find non-apoptotic roles for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation and neural progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, leading to a swollen network with disorganized cristae and destabilized OPA1-MICOS machinery that fails to maintain inner mitochondrial membrane architecture. These structural defects are accompanied by displacement of ACSL1 from the outer mitochondrial membrane, impaired fatty acid oxidation, lipid droplet accumulation and reduced mitochondrial oxygen consumption, revealing a tight link between cristae architecture and metabolic competence. Mechanistically, MCL-1 acts through two coordinated functions: maintaining cristae integrity at the inner mitochondrial membrane and retaining ACSL1 at the outer mitochondrial membrane, both independently of caspase activation. Functionally, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings position MCL-1 upstream of OPA1, MICOS and ACSL1, and identify it as a critical coordinator of cristae organization, lipid metabolism and neural progenitor fate. This establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights non-canonical MCL-1 functions as critical regulators of human brain development.

Glioblastoma is the most aggressive and lethal malignancy of the central nervous system and exhibits a complex interplay with endoplasmic reticulum (ER) stress (ERS). The multifunctional ER is the primary site of the unfolded protein response (UPR), which is activated under conditions of ERS to enhance protein-folding capacity and promote cell survival. However, persistent ERS can trigger apoptosis. Despite extensive research over the past decades, the mechanistic insights into the impact of ERS and the UPR on glioblastoma pathogenesis and progression remain unclear. The UPR operates through three canonical signaling pathways: inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK, also known as EIF2AK3) and activating transcription factor 6 (ATF6). These pathways regulate glioblastoma development through both independent and synergistic mechanisms. In this Review, we discuss the current state of research on the role of the UPR in glioblastoma and delineate the distinct mechanisms of each signaling pathway. Furthermore, we evaluate the challenges associated with UPR-targeting therapeutic agents and propose possible treatment strategies to leverage the regulatory mechanisms of the different UPR pathways to overcome these limitations.

Ergothioneine (EGT), a micromolecular derivative of histidine containing sulfur, is found in various organisms, including humans. It demonstrates antioxidant properties, reduces inflammation, and potentially possesses antiaging effects for neurodegenerative conditions, positioning EGT as a potential candidate for health enhancement and healthy aging. EGT appears to offer strong protective properties at the cellular level and shows decreased concentration levels in blood plasma in different neurological conditions such as cognitive impairment, Parkinson's disease, macular degeneration, and other neurodegenerative diseases. Further, emerging evidence from both preclinical and currently limited clinical studies indicates EGT's therapeutic potential for neurological disorders. For instance, EGT treatment slowed the progression of age-related hearing loss and alleviated the cisplatin-induced hearing loss in mouse models, especially in male mice. Similarly, EGT intervention in older adults (aged 60 years or older) has shown some effectiveness in improving cognitive ability, memory, and sleep quality. In this review, we present a thorough examination of its function in neuroprotection, particularly within the nervous system and explore its potential intracellular targeting pathways and their underlying mechanisms.

Spinal neurocysticercosis (NCC) is an uncommon manifestation of NCC involving the spinal cord, meninges, nerve roots, and subarachnoid spaces. Although less common than intracranial disease, spinal involvement can cause substantial neurological morbidity because even small lesions within the confined spinal canal may produce progressive myelopathy. Disease may result from hematogenous dissemination or cerebrospinal fluid (CSF) spread of Taenia solium larvae and may present as intramedullary, intradural extramedullary, subarachnoid, or, rarely, extradural lesions. Clinical manifestations are diverse and include paraparesis, quadriparesis, cauda equina syndrome, and chronic meningitis. Magnetic resonance imaging is the diagnostic modality of choice, providing detailed assessment of lesion location, evolutionary stage, inflammatory activity, and associated complications. CSF analysis and immunological or molecular tests provide supportive evidence, while histopathological examination confirms the diagnosis when tissue is available. Treatment is individualized and may include antiparasitic agents, corticosteroids, and surgery when indicated. Although outcomes are generally favorable with early diagnosis and appropriate treatment, delayed treatment, extensive arachnoiditis, diffuse leptomeningeal disease, and established spinal cord damage may result in permanent neurological deficits. Further prospective studies are needed to refine diagnostic strategies and optimize management. PubMed database was searched from inception to 13 July 2026, for spinal neurocysticercosis and spinal cysticercosis.

Due to the ongoing opioid epidemic, there has been a rise in the use of medications for opioid use disorder (MOUD) during pregnancy. This paper examines how buprenorphine (BUP), the new golden standard for MOUD, may disrupt maternal care through dysregulation of the oxytocin (OXT) system. OXT is central to parturition, lactation, caregiving, and coordinating activity across the maternal brain network (MBN), including the paraventricular (PVN) and supraoptic nucleus, medial preoptic area, and nucleus accumbens. The endogenous opioid system normally regulates OXT release, with μ-opioid receptor (μOR) and κ-opioid receptor (κOR) signaling influencing OXT neurons. BUP has a unique mechanism of action as it is a partial μOR agonist and a κOR antagonist, which may lead to complex interactions with endogenous opioids and subsequently the OXT system during pregnancy. In line with this, recent preclinical research suggests that BUP exposure during gestation results in reduced maternal motivation and inconsistent pup-directed care in rodent models. Therefore, this paper will explore the possible underlying mechanisms of how BUP exposure may dysregulate the OXT system and thus play a role in the observed maternal care deficits. In particular, we propose that chronic BUP exposure dampens PVN OXT output, disrupts synchrony across the MBN, and constrains OXT-driven neuroplasticity. Further, we will discuss the potential of postpartum OXT administration to restore maternal behaviors by re-engaging OXT signaling and network activity in both clinical and preclinical models. By integrating receptor, network, and behavioral evidence, this review provides a framework for understanding BUP's impact on maternal care through oxytocinergic disruptions and for potential translational interventions.

A brain tumor is characterized by the uncontrolled growth of cells that causes a severe impact on the quality of life. Nowadays, various methods based on multimodal medical images are used to identify brain tumors. Meanwhile, these methods require extensive amounts of labeled information to identify disease tissues and often encounter various challenges based on privacy and accuracy. This paper establishes a Taylor-based Focal Log-cosh Entropy Network (TFLE-Net) to classify brain tumors from demographic data and Magnetic Resonance Imaging (MRI) images by utilizing clustered federated learning in an edge-based Internet of Things (IoT) network. The detection process is executed in clustered federated learning concerning two entities: server and nodes. In a local training model, an input MRI scan is pre-processed, further brain tumor areas are segmented, and then, the mining of various features is performed. Simultaneously, the normalization of input demographic data is done, and the suitable features are selected using information gain. Further, the extracted features and chosen features are subjected to TFLE-Net to classify brain tumors. Additionally, the TFLE-Net yielded Mean Absolute Error (MAE) of 0.057, Root Mean Square Error (RMSE) of 0.047, True Positive Rate (TPR) of 97.789%, and accuracy of 96.987%.

Objective.Synchrocyclotrons deliver radiation in distinct macro pulses with high instantaneous dose rate that distinguish them from isochronous cyclotrons and synchrotrons. The relatively high instantaneous dose rates associated with synchrocyclotrons require special consideration in measurement of the neutron dose. The objective of this work is to measure the out-of-field neutron ambient dose equivalent (H*(10)) as a conservative operational surrogate to assess the fetal dose due to secondary neutrons for a gantry-mounted synchrocyclotron proton therapy system when an intensity modulated proton therapy (IMPT) brain treatment is delivered with the dynamic aperture (DA), static aperture (SA), and no aperture (NA).Approach.A pencil beam scanning (PBS) gantry-mounted synchrocyclotron was used for beam delivery. IMPT plans employing the DA, SA, and NA, each with 3 fields (vertex, lateral, and posterior-anterior (PA)) were optimized using the treatment planning system to treat a left-sided spherical brain target with 6 cm diameter to a total dose of 66 Gy (weighted by radiobiological effectiveness [RBE] 1.1) in 33 fractions. The plans were delivered to an anthropomorphic phantom and the neutron H*(10) was measured using two commercial rem-meters, a WENDI-II and a LUPIN-BF3-NP counter at 43, 53, 61, and 71 cm distance from the isocenter intended to mimic distances to a fetus at various gestational periods. To investigate the influence of the couch angle for the PA field, the neutron dose from the PA field was measured at several couch angles including 0°, 180°, and 270°.Main results.WENDI-II suffers from dead-time associated issues and underestimated the dose by a factor of ∼1.7-2.7 compared to LUPIN-BF3-NP. H*(10) showed dependence on the measurement location and the use of field shaping system. The total H*(10) for 66 Gy-equivalent proton dose was estimated to be 10.7 mSv (9.7 mSv) and 4.9 mSv (4.5 mSv) at 43 and 71 cm distance from the isocenter, respectively, when the SA (DA) was used. Without an aperture the corresponding values were 11.8 mSv and 5.3 mSv. The 270°-couch-angle resulted in the highest neutron dose from the PA field by ∼15% relative to the 0°-couch-angle, resulting in an increase in the neutron dose by ∼5% for the whole treatment.Significance.WENDI-II is not a reliable device for in-room neutron dose measurement for synchrocyclotrons with high instantaneous dose rates. Employing appropriate use of the aperture system as well as avoiding the 270° couch angle for the PA field can minimize the neutron dose in the gantry-mounted system studied in this work.

Sonic Hedgehog-activated medulloblastomas (SHH-MBs) are aggressive, heterogeneous embryonal neuroepithelial tumors predominantly occurring in the pediatric posterior fossa. Postoperative recurrence and metastasis closely associate with aberrant mitochondrial subcellular localization and dysfunctional mitochondrial quality control. Mitophagy, the selective autophagic degradation of damaged or superfluous mitochondria, is intricately regulated by the PINK1-Parkin signaling pathway in metazoan cells. Nevertheless, the biological significance and the regulatory mechanisms underlying Sonic Hedgehog-mediated medulloblastoma (SHH-MB) proliferation, invasion, metastasis, and recurrence are not yet fully elucidated. In this study, integrated molecular and microscopy-based analyses revealed that PINK1 mRNA and protein levels were significantly downregulated in primary human SHH-MB specimens versus adjacent non-tumor brain tissues, as well as in a panel of SHH-MB cell lines. Transmission electron microscopy (TEM) directly visualized impaired mitophagic flux, fragmented mitochondrial morphology, and accumulated damaged mitochondria in PINK1-deficient SHH-MB cells. In vitro functional assays showed that PINK1 overexpression minimally affected apoptosis but markedly suppressed cell proliferation, migration, and invasion, and potently restored mitophagic activity as validated by mitochondrial autophagy imaging. Combined RNA-sequencing, KEGG pathway enrichment, and Western blot verification further demonstrated that PINK1 depletion was associated with hyperactivation of the PI3K/AKT signaling cascade. Collectively, our microscopy-supported mechanistic data demonstrate that PINK1 downregulation inhibits mitophagy in SHH-MB, an effect associated with sustained PI3K/AKT pathway activation. These findings highlight PINK1 as a promising diagnostic biomarker and potential therapeutic target for SHH-driven medulloblastoma, although the precise mechanistic relationship between PINK1 and PI3K/AKT signaling requires further investigation.

Multiple sclerosis (MS) is thought to be mediated by human leukocyte antigen (HLA) class II-restricted autoreactive CD4 T cells producing interleukin (IL)-17A and/or interferon γ (IFNγ), but the necessity of these cytokines for disease pathogenesis is unclear. Utilizing HLA-DR3 (DRβ1*0301) transgenic mice lacking IFNγ or IL-17A in experimental autoimmune encephalomyelitis (EAE), a model of MS, we found that neither cytokine is essential for disease induction, although both have distinct roles. The absence of IFNγ caused atypical, brain-predominant EAE characterized by high levels of IL-17A, while the absence of IL-17A resulted in classical EAE, targeting the spinal cord. To assess whether IL-17A drives atypical EAE in the absence of IFNγ, we generated HLA-DR3.IFNγ-/-.IL-17A-/- double knockout (DKO) mice. DKO mice developed atypical EAE with brain infiltration and inflammation of the brainstem and cerebellum, indicating that IL-17A is dispensable for brain-predominant disease in the absence of IFNγ. DKO mice exhibited significant CD4 T cell infiltration and increased expression of CD4 T cell-associated genes at peak disease. Prior to central nervous system infiltration, CD4 T cell accumulated in the spleen and inguinal lymph nodes of DKO mice, where they exhibited an altered cytokine milieu and upregulated genes involved in recruitment, activation, and migration to the brain. DKO mice exhibited elevated expression of tumor necrosis factor α (TNFα), granulocyte-macrophage colony-stimulating factor, and IL-17F; however, only TNFα inhibition ameliorated atypical disease. Together, our findings indicate TNFα promotes brain-predominant inflammatory pathology in the absence of IFNγ and IL-17A.

Successful recanalization after ischemic stroke does not always restore adequate microvascular perfusion within previously ischemic tissue, partly because persistent microcirculatory dysfunction, impaired neurovascular coupling, and perfusion-metabolism mismatch continue to disrupt cerebral blood flow regulation. Conventional continuous oxygen therapy primarily increases systemic oxygen availability, but may be insufficient to restore impaired cerebrovascular responsiveness, while excessive or prolonged oxygen exposure may increase oxidative stress and attenuate adaptive oxygen-sensitive pathways. In this Review, we propose programmed oscillatory oxygen therapy (POOT) as a treatment-design framework for dynamic oxygen modulation after ischemic stroke. Rather than treating oxygen solely as a metabolic substrate, POOT reframes oxygen as a dynamic biological signal that may engage hypoxia-inducible factor, reactive oxygen species, nitric oxide, and related oxygen-sensitive pathways to support cerebral blood flow regulation and neurovascular coupling. Unlike fixed intermittent hypoxia, intermittent hyperoxia, or hypoxia-hyperoxia training protocols, POOT is proposed as a parameter-explicit and potentially feedback-informed framework targeting post-recanalization microvascular dysfunction. This framework integrates response window, oxygen intensity, cycle structure, treatment frequency and duration, and physiological feedback, providing a conceptual basis for advancing oxygen therapy toward more individualized and precision-oriented modulation after ischemic stroke.