Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.

Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.

Rescaling protein-protein interactions improves Martini 3 for flexible proteins in solution.

Multidomain proteins with flexible linkers and disordered regions play important roles in many cellular processes, but characterizing their conformational ensembles is difficult. We have previously shown that the coarse-grained model, Martini 3, produces too compact ensembles in solution, that may in part be remedied by strengthening protein-water interactions. Here, we show that decreasing the strength of protein-protein interactions leads to improved agreement with experimental data on a wide set of systems. We show that the 'symmetry' between rescaling protein-water and protein-protein interactions breaks down when studying interactions with or within membranes; rescaling protein-protein interactions better preserves the binding specificity of proteins with lipid membranes, whereas rescaling protein-water interactions preserves oligomerization of transmembrane helices. We conclude that decreasing the strength of protein-protein interactions improves the accuracy of Martini 3 for IDPs and multidomain proteins, both in solution and in the presence of a lipid membrane.

DNA tetrahedral nanocages as a promising nanocarrier for dopamine delivery in neurological disorders.

Dopamine is a neurotransmitter in the central nervous system that is essential for many bodily and mental processes, and a lack of it can cause Parkinson's disease. DNA tetrahedral (TD) nanocages are promising in bio-nanotechnology, especially as a nanocarrier. TD is highly programmable, biocompatible, and capable of cell differentiation and proliferation. It also has tissue and blood-brain barrier permeability, making it a powerful tool that could overcome potential barriers in treating neurological disorders. In this study, we used DNA TD as a carrier for dopamine to cells and zebrafish embryos. We investigated the mechanism of complexation between TD and dopamine hydrochloride using gel electrophoresis, fluorescence and circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), and molecular dynamic (MD) simulation tools. Further, we demonstrate that these dopamine-loaded DNA TD nanostructures enhanced cellular uptake and differentiation ability in SH-SY5Y neuroblastoma cells. Furthermore, we extended the study to zebrafish embryos as a model organism to examine survival and uptake. The research provides valuable insights into the complexation mechanism and cellular uptake of dopamine-loaded DNA tetrahedral nanostructures, paving the way for further advancements in nanomedicine for Parkinson's disease and other neurological disorders.

Multi-level authentication for security in cloud using improved quantum key distribution.

Cloud computing is an on-demand virtual-based technology to develop, configure, and modify applications online through the internet. It enables the users to handle various operations such as storage, back-up, and recovery of data, data analysis, delivery of software applications, implementation of new services and applications, hosting websites and blogs, and streaming of audio and video files. Thereby, it provides us many benefits although it is backlashed due to problems related to cloud security like data leakage, data loss, cyber attacks, etc. To address the security concerns, researchers have developed a variety of authentication mechanisms. This means that the authentication procedure used in the suggested method is multi-levelled. As a result, a better QKD method is offered to strengthen cloud security against different types of security risks. Key generation for enhanced QKD is based on the ABE public key cryptography approach. Here, an approach named CPABE is used in improved QKD. The Improved QKD scored the reduced KCA attack ratings of 0.3193, this is superior to CMMLA (0.7915), CPABE (0.8916), AES (0.5277), Blowfish (0.6144), and ECC (0.4287), accordingly. Finally, this multi-level authentication using an improved QKD approach is analysed under various measures and validates the enhancement over the state-of-the-art models.

Anterior Communicating Artery Aneurysms: Surgical Strategy and Outcome based on Proposed Newer Classification.

BACKGROUND: The ruptured anterior communicating artery aneurysm is the most frequent intra-cranial aneurysm treated at any neurosurgical department. These aneurysms arise from either the A1-A2-Acom artery junction or Acom artery. The surgical outcome depends on the age of the patient, time duration between ictus and surgery, and Hunt and Hess grade at admission. In this article, we intend to analyze the surgical outcome based on our proposed classification with our overall experience of Acom aneurysm. METHODS: A retrospective review of our surgical database with 250 patients of ruptured Acom was done, and the location, morphology, and direction of aneurysm, along with other clinical parameters including the demographic profile, radiological findings, and intra-operative details, were studied. We classified the Acom based on both site of origin and morphology (Type I, junctional on the dominant side; Type II, fusiform with an ill-defined neck and branching pattern; Type III, saccular true Acom A) and secondarily as described in the literature on the basis of the direction of fundus (Type A-E). The clinical parameters were compared among the above groups using Fischer-exact and one-way analysis of variance test. RESULTS: A total of 250 patients (M: F =113:137) were included (mean age 52.1 ± 11.5 standard deviation years). 55.2% patients had left A1 dominance. Type I Acom A was commonly found on the left dominant circulation (P = 0.00). The difference in aspect ratio of Type I (2.0 ± 0.8) and Type II (1.8 ± 0.52) aneurysms was insignificant (P = 0.28). However, a significant difference in post-operative vasospasm among different types of aneurysms was found (P < 0.05). The Type I Acom A were anteriorly directed, while Type II and III were posteriorly directed (P = 0.001). The mean follow-up of the study was 44.4 ± 25.7 months, with age (P = 0.007) and Hunt and Hess grade (P = 0.001) at admission correlating with surgical outcome. CONCLUSION: Classifying the Acom A pre-operatively based on site and morphology, location, and direction of fundus helps in surgical planning and prognosis. The junctional 'Type IA aneurysms' are most common and possess a high intra-operative rupture rate. The anteriorly directed aneurysms have a better prognosis, and visual complaints are usually associated with anterior-inferiorly directed aneurysms.

Optimum Surgical Strategies for Medial Sphenoid Wing Meningiomas: A Comprehensive Evaluation of Resection Extent, Visual Outcomes, and Vascular Injury.

BACKGROUND/OBJECTIVE: Visual impairment affects 55%-80% of medial sphenoid wing meningiomas (mSWMs) patients, making optic nerve decompression a critical surgical goal. Complete resection often leads to better visual outcomes. However, involvement of critical neurovascular structures increases postoperative morbidity and mortality, with vascular injury reported in 18%-20% of cases. This study aims to evaluate the relationship between the extent of resection (EOR), visual outcomes, and the incidence of vascular injury, seeking to identify the optimal surgical approach for mSWMs. METHODS: We retrospectively analyzed data from patients undergoing surgery for mSWM at our tertiary care center from January 2001 to December 2021. Inclusion criteria included histopathologically confirmed globoid mSWMs (N = 89). Patients with recurrent tumors (n = 14) or lost to follow-up (n = 9) were excluded. We classified patients into 2 groups based on EOR using Simpson's grade: Group 1 (good-resection,Simpson Grade-I/II,n = 51) and Group 2 (poor-resection,Simpson Grade III/IV, n = 15). RESULTS: Among 66 (=N) patients, visual impairment was the most common symptom (81.8%), followed by headaches (77.3%) and seizures (27%). T2-hyperintensity on magnetic resonance imaging [(OR:5.4, 95%CI:1.5-18.6) (P-value<0.01)] and cavernous sinus-extension [(OR:3.9, 95%CI:1.1-13.1) (p-value-0.02)] were independent significant predictors of poor resection. Visual status was preserved in 90.3% of Group-1 and 86.6% of Group-2, with no significant difference based on EOR. Vascular involvement was noted in 87.9%, higher than the vessel encasement (>1800) (57.6%, P = 0.04). Vessel injury occurred in 7.8% of Group-1 and 6.6% of Group-2, with no significant impact on EOR. CONCLUSIONS: Cavernous sinus-extension and T2-hyperintensity predict poor resection rates in mSWMs. While visual outcomes are not directly affected by EOR, long-term visual status may decline due to tumor recurrence and radiotherapy. Vascular injury incidence is not associated with EOR. Thus, the "maximal safe resection" of mSWMs involves a surgical strategy balancing targeted aggressive and conservative resection for maximal cytoreduction and functional preservation.

Diphenylbutadiene Fluorescent Analogues in Sub-cellular Imaging and Monitoring Mitophagy.

A series of donor-acceptor (D-π-A) substituted diphenylbutadienes exhibiting solvatochromic emission and a large Stokes shift (100-200 nm) were designed and synthesized for distinctive organelle labelling, enabling real-time monitoring of organelle behaviour such as lysosomal dynamics, mitophagy monitoring, and stress responses. The morpholine-substituted D-A-D diphenylbutadiene (M2) was employed to investigate selective imaging of lysosomes, the uptake of damaged mitochondria through mitophagy, and monitoring lysosomal viscosity or pH changes. Other diphenylbutadiene derivatives (M1, M3, M4) selectively accumulated in lipid droplets. All the synthesized derivatives demonstrated significant uptake in 5-day post-fertilization zebrafish larvae, with M2 showing maximum uptake in the enterocyte-containing heart and intestinal regions, which include the lysosomes.

Advancements in rheumatoid arthritis therapy: a journey from conventional therapy to precision medicine via nanoparticles targeting immune cells.

Rheumatoid arthritis (RA) is a progressive autoimmune disease that mainly affects the inner lining of the synovial joints and leads to chronic inflammation. While RA is not known as lethal, recent research indicates that it may be a silent killer because of its strong association with an increased risk of chronic lung and heart diseases. Patients develop these systemic consequences due to the regular uptake of heavy drugs such as disease-modifying antirheumatic medications (DMARDs), glucocorticoids (GCs), nonsteroidal anti-inflammatory medicines (NSAIDs), etc. Nevertheless, a number of these medications have off-target effects, which might cause adverse toxicity, and have started to become resistant in patients as well. Therefore, alternative and promising therapeutic techniques must be explored and adopted, such as post-translational modification inhibitors (like protein arginine deiminase inhibitors), RNA interference by siRNA, epigenetic drugs, peptide therapy, etc., specifically in macrophages, neutrophils, Treg cells and dendritic cells (DCs). As the target cells are specific, ensuring targeted delivery is also equally important, which can be achieved with the advent of nanotechnology. Furthermore, these nanocarriers have fewer off-site side effects, enable drug combinations, and allow for lower drug dosages. Among the nanoparticles that can be used for targeting, there are both inorganic and organic nanomaterials such as solid-lipid nanoparticles, liposomes, hydrogels, dendrimers, and biomimetics that have been discussed. This review highlights contemporary therapy options targeting macrophages, neutrophils, Treg cells, and DCs and explores the application of diverse nanotechnological techniques to enhance precision RA therapies.

Trans-temporal trans-choroidal resection of thalamic and thalamopeduncular tumors: how I do it.

BACKGROUND:  Surgical resection is the cornerstone of treatment for low-grade tumors, albeit total excision is beneficial. As the thalamus is surrounded by vital neurovascular system, lesions here present a surgical challenge. METHOD: This article aims to demonstrate the trans-temporal, trans-choroidal fissure approach's effective surgical therapy on patients with thalamic lesions. With this approach, we were able to remove the tumor completely in three patients and almost completely in six more. Here we discuss a few technical details and potential hazards of the procedure with an operative video. CONCLUSION: This approach  provides excellent access to the deep areas of brain.

Health Care Expenditures and Use Associated with Hypertension Among U.S. Adults.

INTRODUCTION: This study seeks to estimate health care expenditures and use associated with hypertension, focusing on differences among racial and ethnic groups. METHODS: Data were from the 2019 Medical Expenditure Panel Survey, analyzed in 2023. The study sample included noninstitutionalized U.S. adults aged ≥18 years. Outcome variables were health care expenditures and events. Hypertension was determined by a self-reported diagnosis or diagnosis codes. Race and ethnicity were self-reported. A 2-part model was used to estimate expenditures associated with hypertension. A zero-inflated negative binomial model was used to estimate events associated with hypertension. Sampling designs were applied to generate nationally representative estimates. RESULTS: Hypertension was associated with $2,759 (95% confidence interval [CI]: $2,039, $3,479) in health care expenditures and 10.3 (95% CI: 9.3, 11.3) health care events, including prescriptions filled, in 2019 per person. Compared with non-Hispanic White adults, hypertension-associated health care expenditures were significantly lower among Hispanic adults (difference: -$1,877; 95% CI: -$3,389, -$364) and Asian adults (difference: -$2,452; 95% CI: -$4,093, -$811), and hypertension-associated health care events were significantly lower among Hispanic adults (difference: -3.8; 95% CI: -6.1, -1.6) and non-Hispanic Asian adults (difference: -4.1; 95% CI: -6.9, -1.2). Differences between non-Hispanic White adults and non-Hispanic Black adults were not statistically significant in health care expenditures (difference: -$954; 95% CI: -$2,849, $941) and events (difference: 0.3; 95% CI: -2.1, 2.8). CONCLUSIONS: This study reveals differences in health care expenditures and use associated with hypertension among racial and ethnic groups. Future studies are needed to examine potential drivers of these differences.

Anatomical correlates for the newly discovered meningeal layer in the existing literature: A systematic review.

The existence of a previously unrecognized subarachnoid lymphatic-like membrane (SLYM) was reported in a recent study. SLYM is described as an intermediate leptomeningeal layer between the arachnoid and pia mater in mouse and human brains, which divides the subarachnoid space (SAS) into two functional compartments. Being a macroscopic structure, having missed detection in previous studies is surprising. We systematically reviewed the published reports in animals and humans to explore whether prior descriptions of this meningeal layer were reported in some way. A comprehensive search was conducted in PubMed/Medline, EMBASE, Google Scholar, Science Direct, and Web of Science databases using combinations of MeSH terms and keywords with Boolean operators from inception until 31 December 2023. We found at least eight studies that provided structural evidence of an intermediate leptomeningeal layer in the brain or spinal cord. However, unequivocal descriptions for this layer all along the central nervous system were scarce. Obscure names like the epipial, intermediate meningeal, outer pial layers, or intermediate lamella were used to describe it. Its microscopic/ultrastructural details closely resemble the recently reported SLYM. We further examined the counterarguments in current literature that are skeptical of the existence of this layer. The potential physiological and clinical implications of this new meningeal layer are significant, underscoring the urgent need for further exploration of its structural and functional details.

Importance of Genetic Testing in Children With Generalized Epilepsy.

INTRODUCTION: Epilepsy is a neurological disorder characterized by the predisposition for recurrent unprovoked seizures. It can broadly be classified as focal, generalized, unclassified, and unknown in its onset. Focal epilepsy originates in and involves networks localized to one region of the brain. Generalized epilepsy engages broader, more diffuse networks. The etiology of epilepsy can be structural, genetic, infectious, metabolic, immune, or unknown. Many generalized epilepsies have presumed genetic etiologies. The aim of this study is to compare the role of genetic testing to brain MRI as diagnostic tools for identifying the underlying causes of idiopathic (genetic) generalized epilepsy (IGE). METHODS:  We evaluated the diagnostic yield of these two categories in children diagnosed with IGE. Data collection was completed using ICD10 codes filtered by TriNetX to select 982 individual electronic medical records (EMRs) of children in the Penn State Children's Hospital who received a diagnosis of IGE. The diagnosis was confirmed after reviewing the clinical history and electroencephalogram (EEG) data for each patient. RESULTS: From this dataset, neuroimaging and genetic testing results were gathered. A retrospective chart review was done on 982 children with epilepsy, of which 143 (14.5%) met the criteria for IGE. Only 18 patients underwent genetic testing. Abnormalities that could be a potential cause for epilepsy were seen in 72.2% (13/18) of patients with IGE and abnormal genetic testing, compared to 30% (37/123) for patients who had a brain MRI with genetic testing. CONCLUSION: This study suggests that genetic testing may be more useful than neuroimaging for identifying an etiological diagnosis of pediatric patients with IGE.

Dopamine-Functionalized, Red Carbon Quantum Dots for In Vivo Bioimaging, Cancer Therapeutics, and Neuronal Differentiation.

One of the crucial requirements of quantum dots for biological applications is their surface modification for very specific and enhanced biological recognition and uptake. Toward this end, we present the green synthesis of bright, red-emitting carbon quantum dots derived from mango leaf extract (mQDs). These mQDs are conjugated electrostatically with dopamine to form mQDs-dopamine (mQDs:DOPA) bioconjugates. Bright-red fluorescence of mQDs was used for bioimaging and uptake in cancerous and noncancerous cell lines, tissues, and in vivo models like zebrafish. mQDs exhibited the highest uptake in brain tissue compared to the heart, kidney, and liver. mQD:DOPA conjugates killed breast cancer cells and increased uptake in epithelial RPE-1 cells and zebrafish. Additionally, mQDs:DOPA promoted neuronal differentiation of SH-SY5Y cells to differentiated neurons. Both mQDs and mQDs:DOPA exhibited the potential for higher collective cell migrations, implicating their future potential as next-generation tools for advanced biological and biomedical applications.

Occipital encephalocele: a retrospective analysis and assessment of post-surgical neurodevelopmental outcome.

BACKGROUND: Encephalocele represent a group of disorders which is characterised by extracranial herniation of the leptomeninges, brain, and CSF through a structural defect in the cranium. They are usually associated with other intracranial anomalies which may impact the neurological development. AIM: This study aimed to assess the predictors of neurological development of patients undergone surgical excision of occipital encephalocele. METHODS: All patients with occipital encephaloceles operated over the last decade (2012-2022). The sac size, presence of hydrocephalous, and associated anomalies were noted. The biopsy of these patients were reviewed and categorised as those which contains mature neural tissue and those without. The neurological outcomes were assessed by social, language, cognitive, and motor milestone and has been stratified into no delay, mild (1 of 4), moderate (2 or 3 of 4), and severe development delay (4 of 4). RESULTS: Total of 35 patients were included with median age of 10 months (IQR = 5-20 months). Fifteen (42.9%) patients had sac size of ≥ 5 cm, and 23 (65.7%) patients had mature neural tissues on biopsy. The median follow-up period was 6.4 years (IQR = 4.38-10.65) years. Seventeen (49.6%) patients had moderate to severe developmental delay. The sac size of ≥ 5 cm (AOR = 33.5; 95%CI = 3.35-334.8) (p = 0.003) and presence of mature neural content in the sac (AOR = 13.32; 95%CI = 1.1-160.36) (p = 0.041) were associated with significant neurodevelopmental delay. CONCLUSION: The presence of a large sac of ≥ 5 cm and the presence of mature neural tissues on histopathological specimen of patients with encephalocele point towards the possibility of poor neurological development.

Missense Mutations in Myc Box I Influence Nucleocytoplasmic Transport to Promote Leukemogenesis.

PURPOSE: Somatic missense mutations in the phosphodegron domain of the MYC gene (MYC Box I or MBI) are detected in the dominant clones of a subset of patients with acute myeloid leukemia (AML), but the mechanisms by which they contribute to AML are unknown. EXPERIMENTAL DESIGN: To investigate the effects of MBI MYC mutations on hematopoietic cells, we employed a multi-omic approach to systematically compare the cellular and molecular consequences of expressing oncogenic doses of wild type, threonine-58 and proline-59 mutant MYC proteins in hematopoietic cells, and we developed a knockin mouse harboring the germline MBI mutation p.T58N in the Myc gene. RESULTS: Both wild-type and MBI mutant MYC proteins promote self-renewal programs and expand highly selected subpopulations of progenitor cells in the bone marrow. Compared with their wild-type counterparts, mutant cells display decreased cell death and accelerated leukemogenesis in vivo, changes that are recapitulated in the transcriptomes of human AML-bearing MYC mutations. The mutant phenotypes feature decreased stability and translation of mRNAs encoding proapoptotic and immune-regulatory genes, increased translation of RNA binding proteins and nuclear export machinery, and distinct nucleocytoplasmic RNA profiles. MBI MYC mutant proteins also show a higher propensity to aggregate in perinuclear regions and cytoplasm. Like the overexpression model, heterozygous p.T58N knockin mice displayed similar changes in subcellular MYC localization, progenitor expansion, transcriptional signatures, and develop hematopoietic tumors. CONCLUSIONS: This study uncovers that MBI MYC mutations alter RNA nucleocytoplasmic transport mechanisms to contribute to the development of hematopoietic malignancies.

Cutting-edge approaches for targeted drug delivery in breast cancer: beyond conventional therapies.

Breast cancer is a global health challenge with staggering statistics underscoring its pervasive impact. The burden of this disease is measured in terms of its prevalence and the challenges it poses to healthcare systems, necessitating a closer look at its epidemiology and impact. Current breast cancer treatments, including surgery, chemotherapy, radiation therapy, and targeted therapies, have made significant strides in improving patient outcomes. However, they are not without limitations, often leading to adverse effects and the development of drug resistance. This comprehensive review delves into the complex landscape of breast cancer, including its incidence, current treatment modalities, and the inherent limitations of existing therapeutic approaches. It also sheds light on the promising role of nanotechnology, encompassing both inorganic and organic nanoparticles equipped with the ability to selectively deliver therapeutic agents to tumor sites, in the battle against breast cancer. The review also addresses the emerging therapies, their associated challenges, and the future prospects of targeted drug delivery in breast cancer management.

Engineered microbubbles decorated with red emitting carbon nanoparticles for efficient delivery and imaging.

Altering the route of uptake by the cells is an attractive strategy to overcome drug-receptor adaptation problems. Carbon nanoparticles (CNPs) with emission beyond tissue autofluorescence for imaging biological tissues were used to study the phenomenon of uptake by the cells. In this regard, red-emitting carbon nanoparticles (CNPs) were synthesized and incorporated onto lipid microbubbles (MBs). The CNPs showed red emissions in the range of 640 nm upon excitation with 480 nm wavelength of light. Atomic force microscopic and confocal microscopic images showed the successful loading of CNPs onto the MB. Carbon nanoparticle loaded microbubbles (CNP-MBs) were treated with NIH 3 T3 cells at different concentrations. Confocal microscopic imaging studies confirm the presence of CNPs inside the treated cells. Cytotoxicity studies revealed that the CNPs showed minimal toxicity towards cells after loading onto MBs. The CNPs are usually taken up by the cells through the clathrin-mediated (CME) pathway, but when loaded onto MBs, the mechanism of uptake of CNPs is altered, and the uptake by the cells was observed even in the presence of inhibitors for the CME pathway. Loading CNPs onto MBs resulted in the uptake of CNPs by the cell through micropinocytosis and sonophoresis in the presence of ultrasound. The in vivo uptake CNP-MBs were performed in Danio rerio (Zebrafish larvae). This study provides insights into altering the uptake pathway through reformulation by loading nanoparticles onto MBs.