Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by SpaEV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.

Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by SpaEV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.

Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by SpaEV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.

Recent studies have shown an increased abundance of Sphingomonas paucimobilis, an aerobic, Gram-negative bacterium with a distinctive cell envelope rich in glycosphingolipids, within the gut microbiome of individuals with Alzheimer Disease (AD). However, the fact that S. paucimobilis is a well-known pathogen associated with nosocomial infections presents a significant challenge in investigating whether its presence in the gut microbiome is detrimental or beneficial, particularly in the context of AD. This study examines the impact of S. paucimobilis-derived extracellular vesicles (Spa-EV) on Aβ-induced pathology in cellular and animal models of AD. Microarray analysis reveals that Spa-EV treatment modulates Aβ42-induced alterations in gene expression in both HT22 neuronal cells and BV2 microglia cells. Among the genes significantly affected by SpaEV, notable examples include Bdnf, Nt3/4, and Trkb, which are key players of neurotrophic signaling; Pgc1α, an upstream regulator of mitochondrial biogenesis; Mecp2 and Sirt1, epigenetic factors that regulate numerous gene expressions; and Il1β, Tnfα, and Nfκb-p65, which are associated with neuroinflammation. Remarkably, Spa-EV effectively reverses Aβ42-induced alteration in the expression of these genes through the upregulation of Mecp2. Furthermore, administration of Spa-EV in Tg-APP/PS1 mice restores the reduced expression of neurotrophic factors, Pgc1α, MeCP2, and Sirt1, while suppressing the increased expression of proinflammatory genes in the brain. Our results indicate that Spa-EV has the potential to reverse Aβ-induced dysregulation of gene expression in neuronal and microglial cells. These alterations encompass those essential for neurotrophic signaling and neuronal plasticity, mitochondrial function, and the regulation of inflammatory processes.

Various probiotic strains have been reported to affect emotional behavior. However, the underlying mechanisms by which specific probiotic strains change brain function are not clearly understood. Here, we report that extracellular vesicles derived from Lactobacillus paracasei (Lpc-EV) have an ability to produce genome-wide changes against glucocorticoid (GC)-induced transcriptional responses in HT22 hippocampal neuronal cells. Genome-wide analysis using microarray assay followed by Rank-Rank Hypergeometric Overlap (RRHO) method leads to identify the top 20%-ranked 1,754 genes up- or down-regulated following GC treatment and their altered expressions are reversed by Lpc-EV in HT22 cells. Serial k-means clustering combined with Gene Ontology enrichment analyses indicate that the identified genes can be grouped into multiple functional clusters that contain functional modules of “responses to stress or steroid hormones”, “histone modification”, and “regulating MAPK signaling pathways”. While all the selected genes respond to GC and Lpc-EV at certain levels, the present study focuses on the clusters that contain Mkp-1, Fkbp5, and Mecp2, the genes characterized to respond to GC and Lpc-EV in opposite directions in HT22 cells. A translational study indicates that the expression levels of Mkp-1, Fkbp5, and Mecp2 are changed in the hippocampus of mice exposed to chronic stress in the same directions as those following GC treatment in HT22 cells, whereas Lpc-EV treatment restored stress-induced changes of those factors, and alleviated stress-induced depressive-like behavior. These results suggest that Lpc-EV cargo contains bioactive components that directly induce genome-wide transcriptional responses against GC-induced transcriptional and behavioral changes.

Although patellofemoral arthritis is a common and debilitating orthopedic disorder, its treatment varies and remains controversial. This review aims to provide an overview of the current understanding of the pathophysiology of patellofemoral arthritis, as well as its various diagnostic and treatment options.Current Concepts: The pathophysiology of patellofemoral arthritis includes lower limb malalignment, trochlear and/or patellar dysplasia, patellar instability, trauma, and obesity. The disorder is characterized by chronic anterior knee pain aggravated by flexion of the knee joint. A critical imaging study of the Merchant and lateral knee radiographs may show the progression of patellofemoral arthritis and dysplasia of the patellofemoral joints. Non-pharmacologic treatment options for patellofemoral arthritis include patient education, self-management, exercise, weight loss, taping, bracing, and orthotics. Pharmacologic agents (non-steroidal anti-inflammatory drugs, acetaminophen, oral narcotics, and duloxetine) and intra-articular injection therapies (glucocorticoids, hyaluronic acid, platelet-rich plasma, and other regenerative therapies) can be helpful for symptom relief in patients with patellofemoral arthritis. The surgical treatment can begin with lateral retinacular release to realign and decompress the patellofemoral joint. If failure in the improvement of symptoms is noted, a tibial tubercle osteotomy can be considered in young and active patients. While the early design and technique of patellofemoral arthroplasty were less than encouraging, more recent implant design and surgical techniques have demonstrated robust results.Discussion and Conclusion: Patellofemoral arthritis is a unique entity compared with tibiofemoral arthritis marked by distinct epidemiology, biomechanics, and risk factors and treatment options. It is essential to understand its pathophysiology and ensure proper treatment options.

Purpose: This study aimed to investigate whether a deep learning model for automated detection of unruptured intracranial aneurysms on time-of-flight (TOF) magnetic resonance angiography (MRA) can achieve a target diagnostic performance comparable to that of human radiologists for approval from the Korean Ministry of Food and Drug Safety as an artificial intelligence-applied software. Materials and Methods: In this single-center, retrospective, confirmatory clinical trial, the diagnostic performance of the model was evaluated in a predetermined test set. After sample size estimation, the test set consisted of 135 aneurysm-containing examinations with 168 intracranial aneurysms and 197 aneurysm-free examinations. The target sensitivity and specificity were set as 87% and 92%, respectively. The patient-wise sensitivity and specificity of the model were analyzed. Moreover, the lesion-wise sensitivity and false-positive detection rate per case were also investigated. Results: The sensitivity and specificity of the model were 91.11% [95% confidence interval (CI): 84.99, 95.32] and 93.91% (95% CI:89.60, 96.81), respectively, which met the target performance values. The lesion-wise sensitivity was 92.26%. The overall falsepositive detection rate per case was 0.123. Of the 168 aneurysms, 13 aneurysms from 12 examinations were missed by the model. Conclusion The present deep learning model for automated detection of unruptured intracranial aneurysms on TOF MRA achieved the target diagnostic performance comparable to that of human radiologists. With high standalone performance, this model may be useful for accurate and efficient diagnosis of intracranial aneurysm.

Purpose: This study aimed to investigate whether a deep learning model for automated detection of unruptured intracranial aneurysms on time-of-flight (TOF) magnetic resonance angiography (MRA) can achieve a target diagnostic performance comparable to that of human radiologists for approval from the Korean Ministry of Food and Drug Safety as an artificial intelligence-applied software. Materials and Methods: In this single-center, retrospective, confirmatory clinical trial, the diagnostic performance of the model was evaluated in a predetermined test set. After sample size estimation, the test set consisted of 135 aneurysm-containing examinations with 168 intracranial aneurysms and 197 aneurysm-free examinations. The target sensitivity and specificity were set as 87% and 92%, respectively. The patient-wise sensitivity and specificity of the model were analyzed. Moreover, the lesion-wise sensitivity and false-positive detection rate per case were also investigated. Results: The sensitivity and specificity of the model were 91.11% [95% confidence interval (CI): 84.99, 95.32] and 93.91% (95% CI:89.60, 96.81), respectively, which met the target performance values. The lesion-wise sensitivity was 92.26%. The overall falsepositive detection rate per case was 0.123. Of the 168 aneurysms, 13 aneurysms from 12 examinations were missed by the model. Conclusion The present deep learning model for automated detection of unruptured intracranial aneurysms on TOF MRA achieved the target diagnostic performance comparable to that of human radiologists. With high standalone performance, this model may be useful for accurate and efficient diagnosis of intracranial aneurysm.

T-type calcium channels are low voltage-activated calcium channels that evoke small and transient calcium currents. Recently, T-type calcium channels have been implicated in neurodevelopmental disorders such as autism spectrum disorder and neural tube defects. However, their function during embryonic development is largely unknown. Here, we investigated the function and expression of T-type calcium channels in embryonic neural progenitor cells (NPCs). First, we compared the expression of T-type calcium channel subtypes (CaV3.1, 3.2, and 3.3) in NPCs and differentiated neural cells (neurons and astrocytes). We detected all subtypes in neurons but not in astrocytes. In NPCs, CaV3.1 was the dominant subtype, whereas CaV3.2 was weakly expressed, and CaV3.3 was not detected. Next, we determined CaV3.1 expression levels in the cortex during early brain development. Expression levels of CaV3.1 in the embryonic period were transiently decreased during the perinatal period and increased at postnatal day 11. We then pharmacologically blocked T-type calcium channels to determine the effects in neuronal cells. The blockade of T-type calcium channels reduced cell viability, and induced apoptotic cell death in NPCs but not in differentiated astrocytes. Furthermore, blocking T-type calcium channels rapidly reduced AKT-phosphorylation (Ser473) and GSK3β-phosphorylation (Ser9). Our results suggest that T-type calcium channels play essential roles in maintaining NPC viability, and T-type calcium channel blockers are toxic to embryonic neural cells, and may potentially be responsible for neurodevelopmental disorders.
Apoptosis ; Astrocytes ; Autism Spectrum Disorder ; Brain ; Calcium ; Calcium Channels ; Calcium Channels, T-Type* ; Cell Death ; Cell Survival ; Embryonic Development ; Female ; Neural Tube Defects ; Neurodevelopmental Disorders ; Neurons ; Pregnancy ; Stem Cells*

Individuals with autism spectrum disorder (ASD) have altered gut microbiota, which appears to regulate ASD symptoms via gut microbiota-brain interactions. Rapid assessment of gut microbiota profiles in ASD individuals in varying physiological contexts is important to understanding the role of the microbiota in regulating ASD symptoms. Microbiomes secrete extracellular membrane vesicles (EVs) to communicate with host cells and secreted EVs are widely distributed throughout the body including the blood and urine. In the present study, we investigated whether bacteria-derived EVs in urine are useful for the metagenome analysis of microbiota in ASD individuals. To address this, bacterial DNA was isolated from bacteria-derived EVs in the urine of ASD individuals. Subsequent metagenome analysis indicated markedly altered microbiota profiles at the levels of the phylum, class, order, family, and genus in ASD individuals relative to control subjects. Microbiota identified from urine EVs included gut microbiota reported in previous studies and their up- and down-regulation in ASD individuals were partially consistent with microbiota profiles previously assessed from ASD fecal samples. However, overall microbiota profiles identified in the present study represented a distinctive microbiota landscape for ASD. Particularly, the occupancy of g_Pseudomonas, g_Sphingomonas, g_Agrobacterium, g_Achromobacter, and g_Roseateles decreased in ASD, whereas g_Streptococcus, g_Akkermansia, g_Rhodococcus, and g_Halomonas increased. These results demonstrate distinctively altered gut microbiota profiles in ASD, and validate the utilization of urine EVs for the rapid assessment of microbiota in ASD.
Autism Spectrum Disorder* ; Autistic Disorder* ; DNA, Bacterial ; Down-Regulation ; Gastrointestinal Microbiome ; Humans ; Membranes* ; Metagenome ; Microbiota*