Intrinsic network abnormalities in children with autism spectrum disorder: an independent component analysis.

Aberrant intrinsic brain networks are consistently observed in individuals with autism spectrum disorder. However, studies examining the strength of functional connectivity across brain regions have yielded conflicting results. Therefore, this study aimed to investigate the functional connectivity of the resting brain in children with low-functioning autism, including during the early developmental stages. We explored the functional connectivity of 43 children with autism spectrum disorder and 54 children with typical development aged 2 to 12 years using resting-state functional magnetic resonance imaging data. We used independent component analysis to classify the brain regions into six intrinsic networks and analyzed the functional connectivity within each network. Moreover, we analyzed the relationship between functional connectivity and clinical scores. In children with autism, the under-connectivities were observed within several brain networks, including the cognitive control, default mode, visual, and somatomotor networks. In contrast, we found over-connectivities between the subcortical, visual, and somatomotor networks in children with autism compared with children with typical development. Moderate effect sizes were observed in entire networks (Cohen's d = 0.43-0.77). These network alterations were significantly correlated with clinical scores such as the communication sub-score (r = - 0.442, p = 0.045) and the calibrated severity score (r = - 0.435, p = 0.049) of the Autism Diagnostic Observation Schedule. These opposing results observed based on the brain areas suggest that aberrant neurodevelopment proceeds in various ways depending on the functional brain regions in individuals with autism spectrum disorder.

Effect of onion (Allium cepa L.) peel extract on natural killer cell and cytokines in a randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: Onion, particularly onion peel, is a quercetin-rich food with, anti-inflammatory and immunomodulatory effects. However, the effect of onion peel extract (OPE) in humans is unclear. Thus, the present study aimed to investigate whether OPE improves natural killer (NK) cell activity and cytokine concentration in a randomized double-blind placebo-controlled trial. SUBJECTS/METHODS: Eighty participants aged 19-64 yrs old with a white blood cell count of 4,000-10,000 cells/µL, symptoms of upper respiratory infection at least once within the previous 12 mon, and perceived stress scale (PSS) over 14 were included. Participants were randomly assigned to take either 1,000 mg/day OPE or a placebo for 8 weeks. RESULTS: Compliance were 87.4 ± 8.6% and 86.9 ± 79.0% in OPE and placebo groups. Compared to the placebo, OPE supplementation improved "Hoarseness" (P = 0.038) of the Wisconsin Upper Respiratory Symptom Survey (WURSS)-21 symptom, and stress scores (P = 0.001; 0.021) of PSS. Supplementation of OPE had no significant effect on NK cell activity and concentrations of cytokines such as interleukin (IL)-2, IL-6, IL-12, IL-1ß, interferon-γ, and tumor necrosis factor-α. At baseline, the WURSS-21 symptom and PSS score (P = 0.024; 0.026) were higher in the OPE group than the placebo group. Among participants with higher than median WURSS-21 symptom score, OPE supplementation increased NK cell activity (P = 0.038). Supplementation of OPE had no significant effects on safety measurements and adverse events. CONCLUSIONS: The present study suggested that OPE supplementation improves NK cell activity in participants with moderate upper respiratory symptoms without any significant adverse effects. Trial Registration: ClinicalTrials.gov Identifier: NCT05666752.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits ß-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (ß2AR). Co-treatment with CXCL12 and the ß2AR agonist epinephrine synergistically increases ß-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

Impact of a multidomain lifestyle intervention on white matter integrity: the SUPERBRAIN exploratory sub-study.

In the South Korean study to prevent cognitive impairment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN), we evaluated the impact of a 24-week facility-based multidomain intervention (FMI) and home-based MI (HMI) on white matter integrity. Among 152 participants, aged 60-79 years without dementia but with ≥1 modifiable dementia risk factor, 19 FMI, 20 HMI, and 16 controls underwent brain MRI at baseline and 24 weeks. Between the intervention and control groups, we compared changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) at regions-of-interest (ROI) including the cingulum cingulate gyrus (CgC), cingulum hippocampus (CgH), superior longitudinal fasciculus (SLF), as well as the uncinate fasciculus (UF). In addition, correlations between total and standard scores cognitive domains of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) or serum brain-derived neurotrophic factor (BDNF) and changes in brain image measures were evaluated at a statistical significance level of p < 0.05 (uncorrected for multiple corrections). The FA, MD, AD, and RD at each ROI at the baseline were not different among groups after Bonferroni correction. In the statistical analysis using two-way repeated measures ANOVA, any significant difference in longitudinal changes in the FA, MD, AD, and RD was not revealed. The statistical analysis, among the significant regions in paired t-test of the intervention group, compared with the control group, the FMI, HMI, and intervention group yielded significantly more beneficial effects on the AD of the CgC. In addition, longitudinal AD changes of the left CgC correlated with the BDNF changes (r = 0.280, p = 0.048). In this study, enhanced cognitive reserve after the multidomain lifestyle intervention could be revealed by changes in brain imaging for white matter integrity.

The characteristics of online gerontophobia expressions in South Korea.

Recently, South Korea has been transitioning into a super-aged society. The purpose of this paper is to identify the patterns and underlying causes of gerontophobia expressions in South Korea. This paper refines the patterns of gerontophobia expressions into five types: "Fear of Aging," "Resource Burden," "Social Isolation," "Criticism of Social Behavior," and "Stereotypes of Political Orientation." Based on these types, this study develops a deep learning algorithm to detect the type of gerontophobia expressions. To do this, kc-BERT was used and 760,140 news comments (for six years from May 1, 2017, to June 31, 2021) in Naver news was used. The result shows that "Fear of Aging" type exhibited a significant decreasing trend, while the other types showed no meaningful changes. The results of topic modeling on news articles indicated that various aspects of elderly life, unresolved historical events, COVID-19, digital and financial exclusion, economic and social welfare, and other critical societal issues co-occur and contribute to gerontophobia. This study provides a framework to understand the characteristics of online gerontophobia, offering insights into its underlying causes, and providing practical implications for policy makers.

A preliminary trial of botulinum toxin type A in patients with vestibular migraine: A longitudinal fMRI study.

Objective: This study aims to investigate the efficacy of botulinum toxin type A (BTX-A) in the prophylactic management of vestibular migraine (VM) and to determine whether this treatment modulates intrinsic functional brain network. Methods: Vestibular migraine patients (n = 20, mean age 45.4 years) who were resistant to conventional prophylactic therapies had BTX-A injection and rs-fMRI before and 2 months after the injection. We also measured the changes in the frequency of vertigo and migraine attacks, symptomatic functional disability scores, and neuropsychiatric inventories. Results: After BTX-A injection, the mean monthly frequencies of migraine and vertigo episodes decreased significantly compared with the baseline (p < 0.01, paired t-test). The Headache Impact Test-6 score and the Migraine Disability Assessment, and the vertigo parameters, measured by the Dizziness Handicap Inventory and the Vertigo Symptom Scale, showed an improvement, as did the anxiety and depression scores 2 months after BTX-A treatment. The low-frequency fluctuation analysis of the rs-fMRI data found significant changes in the functional connectivity of the right superior temporal gyrus. Adoption of this cluster as the seed region increased the functional connectivity with the left post-central gyrus, right supramarginal gyrus, and right middle temporal gyrus after BTX-A treatment. Conclusion: This prospective study suggests that BTX-A treatment is effective at ameliorating migraine and vertigo symptoms in VM patients who were resistant to conventional therapies. Along with symptomatic improvements, changes in the functional connectivity within the multisensory vestibular and pain networks suggest a dysmodulation of multimodal sensory integration and abnormal cortical processing of the vestibular and pain signals in VM patients.

Impact of Multidomain Lifestyle Intervention on Cerebral Cortical Thickness and Serum Brain-Derived Neurotrophic Factor: the SUPERBRAIN Exploratory Sub-study.

In the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN), we evaluated the impact of a 24-week facility-based multidomain intervention (FMI) and home-based MI (HMI) on cortical thickness, brain volume, and the serum brain-derived neurotrophic factor (BDNF). Totally, 152 participants, aged 60-79 years without dementia but with ≥ 1 modifiable dementia risk factor, were randomly assigned to the FMI, HMI, or control groups. Among them, 55 participants (20 FMI, 19 HMI, and 16 controls) underwent brain MRI at baseline and 24 weeks. We compared changes in global/regional mean cortical thickness at the region-of-interest (ROI) between the intervention and control groups. The changes in the total cortical gray matter volume and global mean cortical thickness were compared using analysis of covariance with age, sex, and education as covariates. ComBat site harmonization was applied for cortical thickness values across the scanners. ROI-based analysis was controlled for multiple comparisons, with a false discovery rate threshold of p < 0.05. Serum BDNF levels were significantly higher in the FMI group than in the control group (p = 0.029). Compared with the control group, the mean global cortical thickness increased in the FMI group (0.033 ± 0.070 vs. - 0.003 ± 0.040, p = 0.013); particularly, cortical thickness of the bilateral frontotemporal lobes, cingulate gyri, and insula increased. The increase in cortical thickness and serum BDNF in the FMI group suggests that group preventive strategies at the facility may be beneficial through structural neuroplastic changes in brain areas, which facilitates learning and neurotrophic factors.

Cilostazol Versus Aspirin on White Matter Changes in Cerebral Small Vessel Disease: A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is characterized by progressive cerebral white matter changes (WMCs). This study aimed to compare the effects of cilostazol and aspirin on changes in WMC volume in patients with cerebral small vessel disease. METHODS: In a multicenter, double-blind, randomized controlled trial, participants with moderate or severe WMCs and at least one lacunar infarction detected on brain magnetic resonance imaging were randomly assigned to the cilostazol and aspirin groups in a 1:1 ratio. Cilostazol slow release (200 mg) or aspirin (100 mg) capsules were administered once daily for 2 years. The primary outcome was the change in WMC volume on magnetic resonance images from baseline to 2 years. Secondary imaging outcomes include changes in the number of lacunes or cerebral microbleeds, fractional anisotropy, and mean diffusivity on diffusion tensor images, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all ischemic vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability. RESULTS: Between July 2013 and August 2016, 256 participants were randomly assigned to the cilostazol (n=127) and aspirin (n=129) groups. Over 2 years, the percentage of WMC volume to total WM volume and the percentage of WMC volume to intracranial volume increased in both groups, but neither analysis showed significant differences between the groups. The peak height of the mean diffusivity histogram in normal-appearing WMs was significantly reduced in the aspirin group compared with the cilostazol group. Cilostazol significantly reduced the risk of ischemic vascular event compared with aspirin (0.5 versus 4.5 cases per 100 person-years; hazard ratio, 0.11 [95% CI, 0.02-0.89]). CONCLUSIONS: There was no significant difference between the effects of cilostazol and aspirin on WMC progression in patients with cerebral small vessel disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01932203.

Lipid Transfer Proteins and Membrane Contact Sites in Human Cancer.

Lipid-transfer proteins (LTPs) were initially discovered as cytosolic factors that facilitate lipid transport between membrane bilayers in vitro. Since then, many LTPs have been isolated from bacteria, plants, yeast, and mammals, and extensively studied in cell-free systems and intact cells. A major advance in the LTP field was associated with the discovery of intracellular membrane contact sites (MCSs), small cytosolic gaps between the endoplasmic reticulum (ER) and other cellular membranes, which accelerate lipid transfer by LTPs. As LTPs modulate the distribution of lipids within cellular membranes, and many lipid species function as second messengers in key signaling pathways that control cell survival, proliferation, and migration, LTPs have been implicated in cancer-associated signal transduction cascades. Increasing evidence suggests that LTPs play an important role in cancer progression and metastasis. This review describes how different LTPs as well as MCSs can contribute to cell transformation and malignant phenotype, and discusses how "aberrant" MCSs are associated with tumorigenesis in human.

General rules for functional microRNA targeting.

The functional rules for microRNA (miRNA) targeting remain controversial despite their biological importance because only a small fraction of distinct interactions, called site types, have been examined among an astronomical number of site types that can occur between miRNAs and their target mRNAs. To systematically discover functional site types and to evaluate the contradicting rules reported previously, we used large-scale transcriptome data and statistically examined whether each of approximately 2 billion site types is enriched in differentially downregulated mRNAs responding to overexpressed miRNAs. Accordingly, we identified seven non-canonical functional site types, most of which are novel, in addition to four canonical site types, while also removing numerous false positives reported by previous studies. Extensive experimental validation and significantly elevated 3' UTR sequence conservation indicate that these non-canonical site types may have biologically relevant roles. Our expanded catalog of functional site types suggests that the gene regulatory network controlled by miRNAs may be far more complex than currently understood.

The lipid-transfer protein Nir2 enhances epithelial-mesenchymal transition and facilitates breast cancer metastasis.

The involvement of epithelial-mesenchymal transition (EMT) in breast cancer metastasis has been demonstrated in many studies. However, the intracellular proteins and signaling pathways that regulate EMT have not been fully identified. Here, we show that the lipid-transfer protein Nir2 (also known as PITPNM1) enhances EMT in mammary epithelial and breast cancer cells. Nir2 overexpression decreases the expression of epithelial markers and concomitantly increases the expression of mesenchymal markers, whereas silencing of Nir2 expression by small hairpin RNA (shRNA) has opposite effects. Additionally, Nir2 expression is increased during EMT and affects cell morphology, whereas Nir2 depletion attenuates growth factor-induced cell migration. These effects of Nir2 on EMT-associated processes are mainly mediated through the PI3K/AKT and the ERK1/2 pathways. Nir2 depletion also inhibits cell invasion in vitro and lung metastasis in animal models. Immunohistochemical analysis of breast cancer tissue samples reveals a correlation between high Nir2 expression and tumor grade, and Kaplan-Meier survival curves correlate Nir2 expression with poor disease outcome. These results suggest that Nir2 not only enhances EMT in vitro and breast cancer metastasis in animal models, but also contributes to breast cancer progression in human patients.

The phosphatidylinositol-transfer protein Nir2 binds phosphatidic acid and positively regulates phosphoinositide signalling.

Phosphatidic acid (PA) and phosphoinositides are metabolically interconverted lipid second messengers that have central roles in many growth factor (GF)-stimulated signalling pathways. Yet, little is known about the mechanisms that coordinate their production and downstream signalling. Here we show that the phosphatidylinositol (PI)-transfer protein Nir2 translocates from the Golgi complex to the plasma membrane in response to GF stimulation. This translocation is triggered by PA formation and is mediated by its C-terminal region that binds PA in vitro. We further show that depletion of Nir2 substantially reduces the PI(4,5)P2 levels at the plasma membrane and concomitantly GF-stimulated PI(3,4,5)P3 production. Finally, we show that Nir2 positively regulates the MAPK and PI3K/AKT pathways. We propose that Nir2 through its PA-binding capability and PI-transfer activity can couple PA to phosphoinositide signalling, and possibly coordinates their local lipid metabolism and downstream signalling.

Structural requirements for VAP-B oligomerization and their implication in amyotrophic lateral sclerosis-associated VAP-B(P56S) neurotoxicity.

The integral endoplasmic reticulum (ER)-membrane protein VAP-B interacts with various lipid-transfer/binding proteins containing an FFAT motif through its N-terminal MSP domain. A genetic mutation within its MSP domain, P56S, was identified in familial forms of motor neuron diseases. This mutation induces the formation of insoluble VAP-B(P56S) protein aggregates by an unknown mechanism. In this study, we defined the structural requirements for VAP-B oligomerization and demonstrated their contribution for VAP-B(P56S) aggregation and neurotoxicity. We show that the oligomerization of VAP-B is mainly mediated by its coiled-coil domain and that the GXXXG dimerization motif within the transmembrane domain mediates transmembrane domains self-association but is insufficient to drive VAP-B oligomerization. We further show that the oligomerization of the wild-type VAP-B is independent of its MSP domain. However, we found that the P56S mutation induces conformational changes within the MSP domain and facilitates its propensity to aggregate by exposing hydrophobic patches to the solvent. These conformational changes have no direct effect on FFAT binding. Rather, they enhance VAP-B(P56S) oligomerization driven by the combined contributions of the coiled-coil and the transmembrane domains, thereby preventing accessibility to FFAT-binding site, facilitating the production of VAP-B(P56S)-insoluble aggregates and consequently its neurotoxicity. These results shed light on the mechanism by which VAP-B(P56S) aggregates are formed and induce familial motor neuron diseases.

Insulin sensitization of MAP kinase signaling by fibroin in insulin-resistant Hirc-B cells.

Fibroin has been shown to enhance insulin-stimulated glucose uptake in 3T3-L1 adipocytes, and the mechanism underlying the fibroin effect focused on phosphatidylinositol 3-kinase (PI 3-K) pathway has been reported. In the present study, for defining the insulin-sensitizing effects of fibroin synthetically, we have used the Hirc-B cells which are rat fibroblasts over-expressing wild-type human insulin receptors to investigate the insulin-stimulation of mitogen-activated protein (MAP) kinase signaling cascades. Cultivation of Hirc-B cells in high-glucose medium for 6 days led to an insulin-resistant state in which insulin-stimulated DNA synthesis was blocked completely. Chronic exposure to fibroin for 16 h markedly recovered DNA synthesis in insulin-resistant cells. Development of insulin resistance caused a reduction of c-Jun N-terminal kinase (JNK) phosphorylation, which was also recovered by fibroin exposure. Fibroin sensitized the insulin-stimulated c-Jun accumulation and phosphorylation in insulin-resistant cells. In the time course for c-Jun accumulation, fibroin had a vanadate-like effect. Further, fibroin was shown to delay the degradation of c-Jun. It is suggested that fibroin may sensitize insulin action by blocking JNK dephosphorylation caused by MAP kinase phosphatase-1 (MKP-1).