AD-Syn-Net: systematic identification of Alzheimer's disease-associated mutation and co-mutation vulnerabilities via deep learning.

Alzheimer's disease (AD) is one of the most challenging neurodegenerative diseases because of its complicated and progressive mechanisms, and multiple risk factors. Increasing research evidence demonstrates that genetics may be a key factor responsible for the occurrence of the disease. Although previous reports identified quite a few AD-associated genes, they were mostly limited owing to patient sample size and selection bias. There is a lack of comprehensive research aimed to identify AD-associated risk mutations systematically. To address this challenge, we hereby construct a large-scale AD mutation and co-mutation framework ('AD-Syn-Net'), and propose deep learning models named Deep-SMCI and Deep-CMCI configured with fully connected layers that are capable of predicting cognitive impairment of subjects effectively based on genetic mutation and co-mutation profiles. Next, we apply the customized frameworks to data sets to evaluate the importance scores of the mutations and identified mutation effectors and co-mutation combination vulnerabilities contributing to cognitive impairment. Furthermore, we evaluate the influence of mutation pairs on the network architecture to dissect the genetic organization of AD and identify novel co-mutations that could be responsible for dementia, laying a solid foundation for proposing future targeted therapy for AD precision medicine. Our deep learning model codes are available open access here: https://github.com/Pan-Bio/AD-mutation-effectors.

Recent Mechanisms of Neurodegeneration and Photobiomodulation in the Context of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease and the world's primary cause of dementia, a condition characterized by significant progressive declines in memory and intellectual capacities. While dementia is the main symptom of Alzheimer's, the disease presents with many other debilitating symptoms, and currently, there is no known treatment exists to stop its irreversible progression or cure the disease. Photobiomodulation has emerged as a very promising treatment for improving brain function, using light in the range from red to the near-infrared spectrum depending on the application, tissue penetration, and density of the target area. The goal of this comprehensive review is to discuss the most recent achievements in and mechanisms of AD pathogenesis with respect to neurodegeneration. It also provides an overview of the mechanisms of photobiomodulation associated with AD pathology and the benefits of transcranial near-infrared light treatment as a potential therapeutic solution. This review also discusses the older reports and hypotheses associated with the development of AD, as well as some other approved AD drugs.

Salinomycin as a potent anticancer stem cell agent: State of the art and future directions.

Cancer stem cells (CSCs) are a small subpopulation of cells within a tumor that can both self-renew and differentiate into other cell types forming the heterogeneous tumor bulk. Since CSCs are involved in all aspects of cancer development, including tumor initiation, cell proliferation, metastatic dissemination, therapy resistance, and recurrence, they have emerged as attractive targets for cancer treatment and management. Salinomycin, a widely used antibiotic in poultry farming, was identified by the Weinberg group as a potent anti-CSC agent in 2009. As a polyether ionophore, salinomycin exerts broad-spectrum activities, including the important anti-CSC function. Studies on the mechanism of action of salinomycin against cancer have been continuously and rapidly published since then. Thus, it is imperative for us to update its literature of recent research findings in this area. We here summarize the notable work reported on salinomycin's anticancer activities, intracellular binding target(s), effects on tumor microenvironment, safety, derivatives, and tumor-specific drug delivery; after that we also discuss the translational potential of salinomycin toward clinical application based on current multifaceted understandings.

Meningeal immunity: Structure, function and a potential therapeutic target of neurodegenerative diseases.

Meningeal immunity refers to immune surveillance and immune defense in the meningeal immune compartment, which depends on the unique position, structural composition of the meninges and functional characteristics of the meningeal immune cells. Recent research advances in meningeal immunity have demonstrated many new ways in which a sophisticated immune landscape affects central nervous system (CNS) function under physiological or pathological conditions. The proper function of the meningeal compartment might protect the CNS from pathogens or contribute to neurological disorders. Since the concept of meningeal immunity, especially the meningeal lymphatic system and the glymphatic system, is relatively new, we will provide a general review of the meninges' basic structural elements, organization, regulation, and functions with regards to meningeal immunity. At the same time, we will emphasize recent evidence for the role of meningeal immunity in neurodegenerative diseases. More importantly, we will speculate about the feasibility of the meningeal immune region as a drug target to provide some insights for future research of meningeal immunity.

Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets.

Traumatic Brain Injury (TBI) is the most frequent cause of death and disability in young adults and children in the developed world, occurring in over 1.7 million persons and resulting in 50,000 deaths in the United States alone. The Centers for Disease Control and Prevention estimate that between 3.2 and 5.3 million persons in the United States live with a TBI-related disability, including several neurocognitive disorders and functional limitations. Following the primary mechanical injury in TBI, literature suggests the presence of a delayed secondary injury involving a variety of neuroinflammatory changes. In the hours to days following a TBI, several signaling molecules and metabolic derangements result in disruption of the blood-brain barrier, leading to an extravasation of immune cells and cerebral edema. The primary, sudden injury in TBI occurs as a direct result of impact and therefore cannot be treated, but the timeline and pathophysiology of the delayed, secondary injury allows for a window of possible therapeutic options. The goal of this review is to discuss the pathophysiology of the primary and delayed injury in TBI as well as present several preclinical studies that identify molecular targets in the potential treatment of TBI. Additionally, certain recent clinical trials are briefly discussed to demonstrate the current state of TBI investigation.

The Relationship between Insecure Attachment to Depression: Mediating Role of Sleep and Cognitive Reappraisal.

Previously, we have shown that neuromodulators are important factors in stress-induced emotional disorders, such as depression, for example, serotonin is the major substance for depression. Many psychological studies have proved that depression is due to insecure attachment. In addition, sleep is a major symptom of depression. Furthermore, serotonin is the substrate for both sleep and depression. To explore the role of sleep in the relationships between insecure attachment and depression, we investigated 755 college students with Close Relationship Inventory, Emotion Regulation Questionnaire, Self-rated Depression Scale, and Pittsburgh Sleep Quality Index. The results showed that (1) insecure attachment positively predicted poor sleep quality; (2) sleep quality partially affected depression, possibly due the same stress neuromodulators such as norepinephrine and cortisol; and (3) cognitive reappraisal moderated the mediating path leading from attachment anxiety to poor sleep quality. These findings highlight the moderating role of cognitive reappraisal in the effects of attachment anxiety on sleep quality and finally on depression. In conclusion, sleep quality links attachment anxiety and emotional disorders.

Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells.

The aim of this study is to illuminate a novel therapeutic approach by identifying a functional binding target of salinomycin, an emerging anticancer stem cell (CSC) agent, and to help dissect the underlying action mechanisms. By utilizing integrated strategies, we identify that nucleolin (NCL) is likely a salinomycin-binding target and a critical regulator involved in human neuroblastoma (NB) CSC activity. Salinomycin markedly suppresses NB CD34 expression and reduces CD34+ cell population in an NCL-dependent manner via disruption of the interaction of NCL with CD34 promoter. The elevated levels of NCL expression in NB tumors are associated with poor patient survival. Altogether, these results indicate that NCL is likely a novel functional salinomycin-binding target that exhibits the potential to be a prognostic marker for NB therapy.

An overview of the American trauma system.

The American trauma system is designed to provide an organized response to injury. It draws its foundations from lessons learned from America's involvement in the wars of the 20th century as well as principles developed in urban community hospitals. Although run at the local and state government level, it is guided by national societies and has become a world class example. It also currently faces challenges with declining reimbursement and providing equal access to care for all Americans. Professional societies and legislative bodies are continuing to work together for fair and equitable solutions to these issues.

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition.

Blood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability followed by brain edema are hallmark features of several brain pathologies, including traumatic brain injuries (TBI). Recent studies indicate that pro-inflammatory cytokine interleukin-1ß (IL-1ß) that is up-regulated following traumatic injuries also promotes BBB dysfunction and hyperpermeability, but the underlying mechanisms are not clearly known. The objective of this study was to determine the role of calpains in mediating BBB dysfunction and hyperpermeability and to test the effect of calpain inhibition on the BBB following traumatic insults to the brain. In these studies, rat brain microvascular endothelial cell monolayers exposed to calpain inhibitors (calpain inhibitor III and calpastatin) or transfected with calpain-1 siRNA demonstrated attenuation of IL-1ß-induced monolayer hyperpermeability. Calpain inhibition led to protection against IL-1ß-induced loss of zonula occludens-1 (ZO-1) at the tight junctions and alterations in F-actin cytoskeletal assembly. IL-1ß treatment had no effect on ZO-1 gene (tjp1) or protein expression. Calpain inhibition via calpain inhibitor III and calpastatin decreased IL-1ß-induced calpain activity significantly (p < 0.05). IL-1ß had no detectable effect on intracellular calcium mobilization or endothelial cell viability. Furthermore, calpain inhibition preserved BBB integrity/permeability in a mouse controlled cortical impact model of TBI when studied using Evans blue assay and intravital microscopy. These studies demonstrate that calpain-1 acts as a mediator of IL-1ß-induced loss of BBB integrity and permeability by altering tight junction integrity, promoting the displacement of ZO-1, and disorganization of cytoskeletal assembly. IL-1ß-mediated alterations in permeability are neither due to the changes in ZO-1 expression nor cell viability. Calpain inhibition has beneficial effects against TBI-induced BBB hyperpermeability.

Single fraction spine stereotactic ablative body radiotherapy with volumetric modulated arc therapy.

This study investigated a single institution's experience with volumetric modulated arc therapy (VMAT) directed stereotactic ablative body radiotherapy (SABR) for vertebral metastases. From 2010 to 2014, 95 lesions of spinal metastases in 73 patients were treated with SABR using VMAT. Clinical local control, pain level, and use of steroid medication were employed to evaluate treatment responses. The majority (79%) of patients were treated with a radiation dose of 20 Gy in a single fraction. However, when normal tissue constraints could not be achieved, the dose was reduced to 18 Gy (11%) or 16 Gy (8%) in 1 fraction. At the median follow up of 12.7 months (mean 18.0, range 1-56 months), clinical local control was 97% (92 out of 95). There was a mean 81% (median 100%, range 28-100%) decrease in subjective pain score. Seventy-seven percent of patients had a decrease in narcotic pain medication use. Pain was completely resolved at the treatment site for 69% (66/95) of patients. Prior to the SABR treatment, 33% (31/95) of patients had epidural extension of tumor. Among patients with epidural involvement, 45% (14/31) exhibited neurologic impairment prior to treatment. Twenty-three percent (7/31) experienced spinal cord compression. Prior to treatment, 34 patients experienced some form of neurologic impairment. Of these patients, 24% (8/34) experienced improved motor functioning; the remaining 76% (26/34) of patients' neurological dysfunction were stable. Our results indicate the SABR regimen using VMAT technique is clinically effective in achieving clinical local control and palliation. This is the first publication reporting clinical outcomes of VMAT directed SABR.

Neurological presentations of intravascular lymphoma (IVL): meta-analysis of 654 patients.

BACKGROUND: Patients with intravascular lymphoma (IVL) frequently have neurological signs and symptoms. Prompt diagnosis and treatment is therefore crucial for their survival. However, the spectrum of neurological presentations and their respective frequencies have not been adequately characterized. Our aim is to document the spectrum of clinical symptoms and their respective frequencies and to create a clinical framework for the prompt diagnosis of IVL. METHODS: A comprehensive meta-analysis of 654 cases of IVL published between 1957 and 2012 was performed to provide better insight into the neurological presentations of this disease. Neurologic complications were mainly divided into central nervous system (CNS) and peripheral nervous system (PNS) presentations. RESULTS: There were no differences in occurrences of CNS IVL based on gender or geographic locations (Asian Vs non-Asian). However, most patients with CNS IVL were younger than 70 years of age (p < 0.05). Our limited data do not support the treatment efficacy of methotrexate. CNS symptoms were seen in 42% of all cases. The most common CNS complications identified were cognitive impairment/dementia (60.9%), paralysis (22.2%), and seizures (13.4%). PNS complications were seen in 9.5% of cases. Out of these, muscle weakness (59.7%), neurogenic bladder (37.1%), and paresthesia (16.1%) were the most common presentations. CONCLUSIONS: CNS complications are more common among IVL patients. Out of these, dementia and seizures outnumber stroke-like presentations.

Neuroimaging and traumatic brain injury: State of the field and voids in translational knowledge.

Traumatic brain injury (TBI) is a leading cause of death and disability in every developed country in the world and is believed to be a risk factor in the later development of depression, anxiety disorders and neurodegenerative diseases including chronic traumatic encephalopathy (CTE), Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). One challenge faced by those who conduct research into TBI is the lack of a verified and validated biomarker that can be used to diagnose TBI or for use as a prognostic variable which can identify those at risk for poor recovery following injury or at risk for neurodegeneration later in life. Neuroimaging continues to hold promise as a TBI biomarker but is limited by a lack of clear relationship between the neuropathology of injury/recovery and the quantitative and image based data that is obtained. Specifically lacking is the data on biochemical and biologic changes that lead to alterations in neuroimaging markers. There are multiple routes towards developing the knowledge required to more definitively link pathology to imaging but the most efficient approach is expanded leveraging of in vivo human blood, serum, and imaging biomarkers with both in vivo and ex vivo animal findings. This review describes the current use and limitations of imaging in TBI including a discussion of currently used animal injury models and the available animal imaging data and extracted markers that hold the greatest promise for helping translate alterations in imaging back to injury pathology. Further, it reviews both the human and animal TBI literature supporting current standards, identifies the remaining voids in the literature, and briefly highlights recent advances in molecular imaging. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

Neuromodulator and Emotion Biomarker for Stress Induced Mental Disorders.

Affective disorders are a leading cause of disabilities worldwide, and the etiology of these many affective disorders such as depression and posttraumatic stress disorder is due to hormone changes, which includes hypothalamus-pituitary-adrenal axis in the peripheral nervous system and neuromodulators in the central nervous system. Consistent with pharmacological studies indicating that medical treatment acts by increasing the concentration of catecholamine, the locus coeruleus (LC)/norepinephrine (NE) system is regarded as a critical part of the central "stress circuitry," whose major function is to induce "fight or flight" behavior and fear and anger emotion. Despite the intensive studies, there is still controversy about NE with fear and anger. For example, the rats with LC ablation were more reluctant to leave a familiar place and took longer to consume the food pellets in an unfamiliar place (neophobia, i.e., fear in response to novelty). The reason for this discrepancy might be that NE is not only for flight (fear), but also for fight (anger). Here, we try to review recent literatures about NE with stress induced emotions and their relations with mental disorders. We propose that stress induced NE release can induce both fear and anger. "Adrenaline rush or norepinephrine rush" and fear and anger emotion might act as biomarkers for mental disorders.

Screening for neuropathic characteristics in failed back surgery syndromes: challenges for guiding treatment.

OBJECTIVE: Neuropathic pain screening tools have shown promise in identifying common neuropathic pain characteristics that derive from diverse etiologies (e.g., diabetic peripheral neuropathy, postherpetic neuralgia). However, no prior studies have specifically assessed whether these tools are capable of discerning the underlying pain mechanisms in the vast, heterogeneous group of patients diagnosed with failed back surgery syndrome (FBSS). DESIGN: In this clinical observational study, two tests for neuropathic pain characteristics, the Douleur Neuropathique en 4 (DN4) and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaires, were performed on 43 subjects with FBSS. Subjects underwent physical or neurosensory exam components of the DN4 and LANSS in the region of most severe pain (e.g., axial low back or lower extremities). DN4 and LANSS scores were correlated with clinical history and neurologic exam, pain-related quality of life questionnaires, and compared to an independent assessment of pain distribution. RESULTS: The presence of neuropathic characteristics, determined by the DN4 (62% sensitivity, 44% specificity), LANSS (38% sensitivity, 75% specificity; cut-offs of 4 and 12, respectively), or their combination (20% sensitivity, 58% specificity) was associated with higher pain intensity as measured by the visual analog scale (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.042), modified Brief Pain Inventory-Short Form (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.082), and Neuropathic Pain Symptom Inventory (DN4 > 4, P = 0.001; LANSS ≥ 12, P = 0.001), and greater pain-related functional impairment as measured by the Roland-Morris Disability Questionnaire (DN4 > 4, P = 0.006; LANSS ≥ 12, P = 0.018). The percentage of subjects characterized as neuropathic by the DN4 and LANSS lacked concordance (67.4 vs. 25.6), and the distribution of most severe symptoms (i.e., axial vs radicular) did not correlate with subjects determined to have neuropathic pain. CONCLUSIONS: Unlike other neuropathic syndromes, the neuropathic component of FBSS is less reliably identified by the LANSS and DN4.

Blood-brain barrier dysfunction following traumatic brain injury.

Traumatic brain injury is a serious cause of morbidity and mortality worldwide. After traumatic brain injury, the blood-brain barrier, the protective barrier between the brain and the intravascular compartment, becomes dysfunctional, leading to leakage of proteins, fluid, and transmigration of immune cells. As this leakage has profound clinical implications, including edema formation, elevated intracranial pressure and decreased perfusion pressure, much interest has been paid to better understanding the mechanisms responsible for these events. Various molecular pathways and numerous mediators have been found to be involved in the intricate process of regulating blood-brain barrier permeability following traumatic brain injury. This review provides an update to the existing knowledge about the various pathophysiological pathways and advancements in the field of blood-brain barrier dysfunction and hyperpermeability following traumatic brain injury, including the role of various tight junction proteins involved in blood-brain barrier integrity and regulation. We also address pitfalls of existing systems and propose strategies to improve the various debilitating functional deficits caused by this progressive epidemic.

Photolysis of caged Ca2+ but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release.

Astrocytes in hippocampal slices can dynamically regulate synaptic transmission in a process mediated by increases in intracellular Ca(2+). However, it is debated whether astrocytic Ca(2+) signals result in release of glutamate. We here compared astrocytic Ca(2+) signaling triggered by agonist exposure versus photolysis side by side. Using transgenic mice in which astrocytes selectively express the MrgA1 receptor, we found that receptor-mediated astrocytic Ca(2+) signaling consistently triggered neuronal hyperpolarization and decreased the frequency of miniature excitatory postsynaptic currents (EPSCs). In contrast, photolysis of caged Ca(2+) (o-nitrophenyl-EGTA) in astrocytes led to neuronal depolarization and increased the frequency of mEPSCs through a metabotropic glutamate receptor-mediated pathway. Analysis of transgenic mice in which astrocytic vesicular release is suppressed (dominant-negative SNARE mice) and pharmacological manipulations suggested that glutamate is primarily released by opening of anion channels rather than exocytosis. Combined, these studies show that photolysis but not by agonists induced astrocytic Ca(2+) signaling triggers glutamate release.

Imaging chronic traumatic brain injury as a risk factor for neurodegeneration.

Population-based studies have supported the hypothesis that a positive history of traumatic brain injury (TBI) is associated with an increased incidence of neurological disease and psychiatric comorbidities, including chronic traumatic encephalopathy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These epidemiologic studies, however, do not offer a clear definition of that risk, and leave unanswered the bounding criteria for greater lifetime risk of neurodegeneration. Key factors that likely mediate the degree of risk of neurodegeneration include genetic factors, significant premorbid and comorbid medical history (e.g. depression, multiple head injuries and repetitive subconcussive impact to the brain, occupational risk, age at injury, and severity of brain injury). However, given the often-described concerns in self-report accuracy as it relates to history of multiple TBIs, low frequency of patient presentation to a physician in the case of mild brain injuries, and challenges with creating clear distinctions between injury severities, disentangling the true risk for neurodegeneration based solely on population-based studies will likely remain elusive. Given this reality, multiple modalities and approaches must be combined to characterize who are at risk so that appropriate interventions to alter progression of neurodegeneration can be evaluated. This article presents data from a study that highlights uses of neuroimaging and areas of needed research in the link between TBI and neurodegenerative disease.

Association between toll-like receptor 4 expression and neural stem cell proliferation in the hippocampus following traumatic brain injury in mice.

Whether or how neural stem cells (NSCs) respond to toll-like receptor 4 (TLR4) in an inflammatory environment caused by traumatic brain injury (TBI) has not been understood. In the present study, association between TLR4 expression and NSCs proliferation in the hippocampus was investigated in a mouse model of TBI using controlled cortical impact (CCI). Hippocampal proliferating cells were labeled with the thymidine analog 5-bromo-2-deoxyuridine (BrdU). In order to identify NSCs, the proliferating cells were further co-labeled with BrdU/sex determination region of Y chromosome related high mobility group box gene 2 (SOX2). Morphological observation on the expression of BrdU, SOX2, and TLR4 in the hippocampus was performed by inmmunofluorescence (IF). Relative quantification of TLR4 expression at the protein and mRNA level was performed using Western blotting and real-time polymerase chain reaction (PCR). It was observed that BrdU+/SOX2+cells accounted for 95.80%±7.91% among BrdU+ cells; several BrdU+ cells and SOX2+ cells in the hippocampus were also TLR4-positive post injury, and that BrdU+ cell numbers, together with TLR4 expression at either protein or mRNA level, increased significantly in TBI mice over 1, 3, 7, 14, and 21 days survivals and changed in a similar temporal pattern with a peak at 3 day post-injury. These results indicate that hippocampal proliferating cells (suggestive of NSCs) expressed TLR4, and that there was a potential association between increased expression of TLR4 and the proliferation of NSCs post TBI. It is concluded that hippocampal TLR4 may play a potential role in endogenous neurogenesis after TBI.

Expression of S100A6 in rat hippocampus after traumatic brain injury due to lateral head acceleration.

In a rat model of traumatic brain injury (TBI), we investigated changes in cognitive function and S100A6 expression in the hippocampus. TBI-associated changes in this protein have not previously been reported. Rat S100A6 was studied via immunohistochemical staining, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR) after either lateral head acceleration or sham. Reduced levels of S100A6 protein and mRNA were observed 1 h after TBI, followed by gradual increases over 6, 12, 24, and 72 h, and then a return to sham level at 14 day. Morris water maze (MWM) test was used to evaluate animal spatial cognition. TBI- and sham-rats showed an apparent learning curve, expressed as escape latency. Although TBI-rats displayed a relatively poorer cognitive ability than sham-rats, the disparity was not significant early post-injury. Marked cognitive deficits in TBI-rats were observed at 72 h post-injury compared with sham animals. TBI-rats showed decreased times in platform crossing in the daily MWM test; the performance at 72 h post-injury was the worst. In conclusion, a reduction in S100A6 may be one of the early events that lead to secondary cognitive decline after TBI, and its subsequent elevation is tightly linked with cognitive improvement. S100A6 may play important roles in neuronal degeneration and regeneration in TBI.

Astrocytic calcium waves: unveiling their roles in sleep and arousal modulation.

Neuron-astrocyte interactions are vital for the brain's connectome. Understanding astrocyte activities is crucial for comprehending the complex neural network, particularly the population-level functions of neurons in different cortical states and associated behaviors in mammals. Studies on animal sleep and wakefulness have revealed distinct cortical synchrony patterns between neurons. Astrocytes, outnumbering neurons by nearly fivefold, support and regulate neuronal and synaptic function. Recent research on astrocyte activation during cortical state transitions has emphasized the influence of norepinephrine as a neurotransmitter and calcium waves as key components of ion channel signaling. This summary focuses on a few recent studies investigating astrocyte-neuron interactions in mouse models during sleep, wakefulness, and arousal levels, exploring the involvement of noradrenaline signaling, ion channels, and glutamatergic signaling in different cortical states. These findings highlight the significant impact of astrocytes on large-scale neuronal networks, influencing brain activity and responsiveness. Targeting astrocytic signaling pathways shows promise for treating sleep disorders and arousal dysregulation. More research is needed to understand astrocytic calcium signaling in different brain regions and its implications for dysregulated brain states, requiring future human studies to comprehensively investigate neuron-astrocyte interactions and pave the way for therapeutic interventions in sleep- and arousal-related disorders.