Altered thalamocortical tract trajectory growth with undisrupted thalamic parcellation pattern in human lissencephaly brain at mid-gestational stage.

Proper topographically organized neural connections between the thalamus and the cerebral cortex are mandatory for thalamus function. Thalamocortical (TC) fiber growth begins during the embryonic period and completes by the third trimester of gestation, so that human neonates at birth have a thalamus with a near-facsimile of adult functional parcellation. Whether congenital neocortical anomaly (e.g., lissencephaly) affects TC connection in humans is unknown. Here, via diffusion MRI fiber-tractography analysis of long-term formalin-fixed postmortem fetal brain diagnosed as lissencephaly in comparison with an age-matched normal one, we found similar topological patterns of thalamic subregions and of internal capsule parcellated by TC fibers. However, lissencephaly fetal brain showed white matter structural changes, including fewer/less organized TC fibers and optic radiations, and much less cortical plate invasion by TC fibers - particularly around the shallow central sulcus. Diffusion MRI fiber tractography of normal fetal brains at 15, 23, and 26 gestational weeks (GW) revealed dynamic volumetric change of each parcellated thalamic subregion, suggesting coupled developmental progress of the thalamus with the corresponding cortex. Moreover, from GW23 and GW26 normal fetal brains, TC endings in the cortical plate could be delineated to reflect cumulative progressive TC invasion of cortical plate. By contrast, lissencephaly brain showed a dramatic decrease in TC invasion of the cortical plate. Our study thus shows the feasibility of diffusion MRI fiber tractography in postmortem long-term formalin-fixed fetal brains to disclose the developmental progress of TC tracts coordinating with thalamic and neocortical growth both in normal and lissencephaly fetal brains at mid-gestational stage.

Atrophy of the cholinergic regions advances from early to late mild cognitive impairment.

PURPOSE: We investigated the volumetric changes in the components of the cholinergic pathway for patients with early mild cognitive impairment (EMCI) and those with late mild cognitive impairment (LMCI). The effect of patients' apolipoprotein 4 (APOE-ε4) allele status on the structural changes were analyzed. METHODS: Structural magnetic resonance imaging data were collected. Patients' demographic information, plasma data, and validated global cognitive composite scores were included. Relevant features were extracted for constructing machine learning models to differentiate between EMCI (n = 312) and LMCI (n = 541) and predict patients' neurocognitive function. The data were analyzed primarily through one-way analysis of variance and two-way analysis of covariance. RESULTS: Considerable differences were observed in cholinergic structural changes between patients with EMCI and LMCI. Cholinergic atrophy was more prominent in the LMCI cohort than in the EMCI cohort (P < 0.05 family-wise error corrected). APOE-ε4 differentially affected cholinergic atrophy in the LMCI and EMCI cohorts. For LMCI cohort, APOE-ε4 carriers exhibited increased brain atrophy (left amygdala: P = 0.001; right amygdala: P = 0.006, and right Ch123, P = 0.032). EMCI and LCMI patients showed distinctive associations of gray matter volumes in cholinergic regions with executive (R2 = 0.063 and 0.030 for EMCI and LMCI, respectively) and language (R2 = 0.095 and 0.042 for EMCI and LMCI, respectively) function. CONCLUSIONS: Our data confirmed significant cholinergic atrophy differences between early and late stages of mild cognitive impairment. The impact of the APOE-ε4 allele on cholinergic atrophy varied between the LMCI and EMCI groups.

Post-ischemic protection of hepatocyte growth factor requires the type II transmembrane serine protease matriptase-A reciprocal regulation of the two for neuroprotection in stroke brain.

In a rat middle cerebral artery occlusion (MACo) model of ischemic stroke, intracerebroventricular administration of human recombinant hepatocyte growth factor (HGF) mitigated motor impairment and cortical infarction. Recombinant HGF reduced MCAo-induced TNFα and IL1ß expression, and alleviated perilesional reactivation of microglia and astrocyte. All of the aforementioned beneficial effects of HGF were antagonized by an inhibitor to the type II transmembrane serine protease matriptase (MTP). MCAo upregulated MTP mRNA and protein in the lesioned cortex. MTP protein, not the mRNA, was increased further by recombinant HGF but reduced when MTP inhibitor (MTPi) was added to the treatment. Changes of the endogenous active HGF by MCAo, HGF or MTPi paralleled with the changes of MTP protein under the same conditions whilst neither HGF mRNA nor the total endogenous HGF protein were altered. These data showed that the therapeutic effects of HGF in stroke brain is attributed to its proteolytic activation and that MTP is a main protease of the event. MCAo enhanced MTP mRNA and thus protein expression; the initial use of the recombinant active HGF stabilized MCAo-induced MTP protein and subsequent activation of endogenous latent HGF which in turn stabilized further MTP protein. A reciprocal regulation between MTP and HGF appears to be present where MTP promotes HGF activation and the active HGF prevents MTP protein turnover. This study, for the first time, shows that MTP can participate in neural protection in stroke brain through activation of HGF. The cycles of HGF-MTP regulation achieved preservation of the neurological activity.

Personal socio-cultural preferences modulate neural correlates of decisions to socialize with powerful persons.

Social power differences fundamentally shape the behavioral interaction dynamics of groups and societies. While it has long been recognized that individual socio-cultural preferences mitigate social interactions involving persons of power, there is limited empirical data on the underlying neural correlates. To bridge this gap, we asked university student participants to decide whether they were willing to engage in social activities involving their teachers (higher power status), classmates (equal power status), or themselves (control) while functional brain images were acquired. Questionnaires assessed participants' preferences for power distance, uncertainty avoidance, and cultural intelligence. As expected, participants generally accepted more social interactions with classmates than teachers. Also, left inferior frontal activity was higher when accepting than when rejecting social interactions with teachers. Critically, power distance preferences further modulated right lateral frontoparietal activity contrasting approach relative to avoidance decisions towards teachers. In addition, uncertainty avoidance modulated activity in medial frontal, precuneus, and left supramarginal areas distinguishing approach decisions towards teachers relative to classmates. Cultural intelligence modulated neural responses to classmate approach/avoidance decisions in anterior cingulate and left parietal areas. Overall, functional activities in distinct brain networks reflected different personal socio-cultural preferences despite observed social decisions to interact with others of differential power status. Such findings highlight that social approach or avoidance behaviors towards powerful persons involves differential subjective neural processes possibly involved in computing implicit social utility.

White matter pathology in alzheimer's transgenic mice with chronic exposure to low-level ambient fine particulate matter.

BACKGROUND: Air pollution, especially fine particulate matter (PM), can cause brain damage, cognitive decline, and an increased risk of neurodegenerative disease, especially alzheimer's disease (AD). Typical pathological findings of amyloid and tau protein accumulation have been detected in the brain after exposure in animal studies. However, these observations were based on high levels of PM exposure, which were far from the WHO guidelines and those present in our environment. In addition, white matter involvement by air pollution has been less reported. Thus, this experiment was designed to simulate the true human world and to discuss the possible white matter pathology caused by air pollution. RESULTS: 6 month-old female 3xTg-AD mice were divided into exposure and control groups and housed in the Taipei Air Pollutant Exposure System (TAPES) for 5 months. The mice were subjected to the Morris water maze test after exposure and were then sacrificed with brain dissection for further analyses. The mean mass concentration of PM2.5 during the exposure period was 13.85 µg/m3. After exposure, there was no difference in spatial learning function between the two groups, but there was significant decay of memory in the exposure group. Significantly decreased total brain volume and more neuronal death in the cerebral and entorhinal cortex and demyelination of the corpus callosum were noted by histopathological staining after exposure. However, there was no difference in the accumulation of amyloid or tau on immunohistochemistry staining. For the protein analysis, amyloid was detected at significantly higher levels in the cerebral cortex, with lower expression of myelin basic protein in the white matter. A diffuse tensor image study also revealed insults in multiple white matter tracts, including the optic tract. CONCLUSIONS: In conclusion, this pilot study showed that even chronic exposure to low PM2.5 concentrations still caused brain damage, such as gross brain atrophy, cortical neuron damage, and multiple white matter tract damage. Typical amyloid cascade pathology did not appear prominently in the vulnerable brain region after exposure. These findings imply that multiple pathogenic pathways induce brain injury by air pollution, and the optic nerve may be another direct invasion route in addition to olfactory nerve.

Employing CRISPR-Cas9 to Generate CD133 Synthetic Lethal Melanoma Stem Cells.

Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC) implicated in tumorigenesis, invasion, and drug resistance, and is characterized by the elevated expression of stem cell markers, including CD133. The siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. This study investigates the underlying mechanisms of CD133's anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockout or Dox-inducible expression of CD133. MACS-sorted CD133(+) BAKP cells were conditionally reprogrammed to derive BAKR cells with sustained CD133 expression and MIC features. Compared to BAKP, CD133(+) BAKR exhibit increased cell survival and reduced apoptosis in response to trametinib or the chemotherapeutic dacarbazine (DTIC). CRISPR-Cas9-mediated CD133 knockout in BAKR cells (BAKR-KO) re-sensitized cells to trametinib. CD133 knockout in BAKP and POT cells increased trametinib-induced apoptosis by reducing anti-apoptotic BCL-xL, p-AKT, and p-BAD and increasing pro-apoptotic BAX. Conversely, Dox-induced CD133 expression diminished apoptosis in both trametinib-treated cell lines, coincident with elevated p-AKT, p-BAD, BCL-2, and BCL-xL and decreased activation of BAX and caspases-3 and -9. AKT1/2 siRNA knockdown or inhibition of BCL-2 family members with navitoclax (ABT-263) in BAKP-KO cells further enhanced caspase-mediated apoptotic PARP cleavage. CD133 may therefore activate a survival pathway where (1) increased AKT phosphorylation and activation induces (2) BAD phosphorylation and inactivation, (3) decreases BAX activation, and (4) reduces caspases-3 and -9 activity and caspase-mediated PARP cleavage, leading to apoptosis suppression and drug resistance in melanoma. Targeting nodes of the CD133, AKT, or BCL-2 survival pathways with trametinib highlights the potential for combination therapies for NRAS-mutant melanoma stem cells for the development of more effective treatments for patients with high-risk melanoma.

Spatiotemporal characterisation of ischaemic lesions in transient stroke animal models using diffusion free water elimination and mapping MRI with echo time dependence.

BACKGROUND AND PURPOSE: The excess fluid as a result of vasogenic oedema and the subsequent tissue cavitation obscure the microstructural characterisation of ischaemic tissue by conventional diffusion and relaxometry MRI. They lead to a pseudo-normalisation of the water diffusivity and transverse relaxation time maps in the subacute and chronic phases of stroke. Within the context of diffusion MRI, the free water elimination and mapping method (FWE) with echo time dependence has been proposed as a promising approach to measure the amount of free fluid in brain tissue robustly and to eliminate its biasing effect on other biomarkers. In this longitudinal study of transient middle cerebral artery occlusion (MCAo) in the rat brain, we investigated the use of FWE MRI with echo time dependence for the characterisation of the tissue microstructure and explored the potential of the free water fraction as a novel biomarker of ischaemic tissue condition. METHODS: Adult rats received a transient MCAo. Diffusion- and transverse relaxation-weighted MRI experiments were performed longitudinally, pre-occlusion and on days 1, 3, 4, 5, 6, 7 and 10 after MCAo on four rats. Histology was performed for non-stroke and 1, 3 and 10 days after MCAo on three different rats at each time point. RESULTS: The free water fraction was homogeneously increased in the ischaemic cortex one day after stroke. Between three and ten days after stroke, the core of the ischaemic tissue showed a progressive normalisation in the amount of free water, whereas the inner and outer border zones of the ischaemic cortex depicted a large, monotonous increase with time. The specific lesions in brain sections were verified by H&E and immunostaining. The tissue-specific diffusion and relaxometry MRI metrics in the ischaemic cortex were significantly different compared to their conventional counterpart. CONCLUSIONS: Our results demonstrate that the free water fraction in FWE MRI with echo time dependence is a valuable biomarker, sensitive to the progressive degeneration in ischaemic tissue. We showed that part of the heterogeneity previously observed in conventional parameter maps can be accounted for by a heterogeneous distribution of free water in the tissue. Our results suggest that the temporal evolution of the free fluid fraction map at the core and inner border zone can be associated with the pathological changes linked to the evolution of vasogenic oedema. Namely, the homogeneous increase in free water one day after stroke and its tendency to normalise in the core of the ischaemic cortex starting three days after stroke, followed by a progressive increase in free water at the inner border zone from three to ten days after stroke. Finally, the monotonous increase in free fluid in the outer border zone of the cortex reflects the formation of fluid-filled cysts.

Discriminating subcortical ischemic vascular disease and Alzheimer's disease by diffusion kurtosis imaging in segregated thalamic regions.

Differentiating between subcortical ischemic vascular disease (SIVD), Alzheimer's disease (AD), and normal cognition (NC) remains a challenge, and reliable neuroimaging biomarkers are needed. The current study, therefore, investigated the discriminative ability of diffusion kurtosis imaging (DKI) metrics in segregated thalamic regions and compare with diffusion tensor imaging (DTI) metrics. Twenty-three SIVD patients, 30 AD patients, and 24 NC participants underwent brain magnetic resonance imaging. The DKI metrics including mean kurtosis (MK), axial kurtosis (Kaxial ) and radial kurtosis (Kradial ) and the DTI metrics including diffusivity and fractional anisotropy (FA) were measured within the whole thalamus and segregated thalamic subregions. Strategic correlations by group, thalamo-frontal connectivity, and canonical discriminant analysis (CDA) were used to demonstrate the discriminative ability of DKI for SIVD, AD, and NC. Whole and segregated thalamus analysis suggested that DKI metrics are less affected by white matter hyperintensities compared to DTI metrics. Segregated thalamic analysis showed that MK and Kradial were notably different between SIVD and AD/NC. The correlation analysis between Kaxial and MK showed a nonsignificant relationship in SIVD group, a trend of negative relationship in AD group, and a significant positive relationship in NC group. A wider spatial distribution of thalamo-frontal connectivity differences across groups was shown by MK compared to FA. CDA showed a discriminant power of 97.4% correct classification using all DKI metrics. Our findings support that DKI metrics could be more sensitive than DTI metrics to reflect microstructural changes within the gray matter, hence providing complementary information for currently outlined pathogenesis of SIVD and AD.

Dedicated diffusion phantoms for the investigation of free water elimination and mapping: insights into the influence of T2 relaxation properties.

Conventional diffusion-weighted (DW) MRI suffers from free water contamination due to the finite voxel size. The most common case of free water contamination occurs with cerebrospinal fluid (CSF) in voxels located at the CSF-tissue interface, such as at the ventricles in the human brain. Another case refers to intra-tissue free water as in vasogenic oedema. In order to avoid the bias in diffusion metrics, several multi-compartment methods have been introduced, which explicitly model the presence of a free water compartment. However, fitting multi-compartment models in DW MRI represents a well known ill conditioned problem. Although during the last decade great effort has been devoted to mitigating this estimation problem, the research field remains active. The aim of this work is to introduce the design, characterise the NMR properties and demonstrate the use of two dedicated anisotropic diffusion fibre phantoms, useful for the study of free water elimination (FWE) and mapping models. In particular, we investigate the recently proposed FWE diffusion tensor imaging approach, which takes explicit account of differences in the transverse relaxation times between the free water and tissue compartments.

E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness.

Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long-term exposure to estrogen could increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen-mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c-Kit, by epigenetic silencing the tumor suppressor miR-193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c-KIT, but downregulated miR-193a. Luciferase assays further confirmed that microRNA-193a targets both E2F6 and c-Kit. Interestingly, ChIP-PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR-193a, through recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, whereas E2F6 or EZH2 depletion derepressed miR-193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR-193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen-mediated E2F6 ceRNA network epigenetically and competitively inhibits microRNA-193a activity, promoting ovarian cancer stemness and tumorigenesis.

Effects of signal averaging, gradient encoding scheme, and spatial resolution on diffusion kurtosis imaging: An empirical study using 7T MRI.

BACKGROUND: Although diffusion gradient directions and b-values have been optimized for diffusion kurtosis imaging (DKI), little is known about the effect of signal averaging on DKI reliability. PURPOSE: To evaluate how signal averaging influences the reliability of DKI indices using two gradient encoding schemes with three spatial resolutions. STUDY TYPE: Prospective. ANIMAL MODEL: Fifteen naïve Sprague-Dawley rats. FIELD STRENGTH/SEQUENCE: DKI was performed at 7T using two schemes (30 directions with three b-values [30d-3b] and six directions with 15 b-values [6d-15b]), three resolutions, and eight repetitions. ASSESSMENT: DKI reliability was assessed using voxelwise relative error (σ) and test-retest error of fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) within gray matter (GM) and white matter (WM). The number of excitations (NEX) was optimized by considering DKI reliability. The influence of the partial volume effect (PVE) was also assessed. STATISTICAL TEST: One-way analysis of variance. RESULTS: The 30d-3b scheme, compared with the 6d-15b scheme, exhibited apparently smaller σFA and σMK (eg, at NEX 1, in GM, for three resolutions, σFA : 19.9-38.2% vs. 34.2-61.4%, σMK : 6.9-11.4% vs. 14.1-15.4%) and similar σMD (all differences between two schemes <1.6%). The optimal NEX was determined as 2 for enabling a reliable measurement of DKI-derived indices. The PVE at the lowest resolution apparently increased σFA for both schemes (19.9% for 30d-3b and 34.2% for 6d-15b) and σMK for the 6d-15b scheme (14.7%) in GM, and exerted lower effects on MK values for the 30d-3b scheme (P > 0.05). DATA CONCLUSION: A higher number of diffusion directions would benefit FA and MK estimation. A higher spatial resolution helps to reduce PVE. By using the 30d-3b scheme, MK is considered a robust index to reflect microstructural changes in GM and WM. We propose a systematic approach to determine the optimal DKI protocols for appropriate preclinical settings. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1593-1603.

Chronic pulmonary exposure to traffic-related fine particulate matter causes brain impairment in adult rats.

BACKGROUND: Effects of air pollution on neurotoxicity and behavioral alterations have been reported. The objective of this study was to investigate the pathophysiology caused by particulate matter (PM) in the brain. We examined the effects of traffic-related particulate matter with an aerodynamic diameter of < 1 µm (PM1), high-efficiency particulate air (HEPA)-filtered air, and clean air on the brain structure, behavioral changes, brainwaves, and bioreactivity of the brain (cortex, cerebellum, and hippocampus), olfactory bulb, and serum after 3 and 6 months of whole-body exposure in 6-month-old Sprague Dawley rats. RESULTS: The rats were exposed to 16.3 ± 8.2 (4.7~ 68.8) µg/m3 of PM1 during the study period. An MRI analysis showed that whole-brain and hippocampal volumes increased with 3 and 6 months of PM1 exposure. A short-term memory deficiency occurred with 3 months of exposure to PM1 as determined by a novel object recognition (NOR) task, but there were no significant changes in motor functions. There were no changes in frequency bands or multiscale entropy of brainwaves. Exposure to 3 months of PM1 increased 8-isoporstance in the cortex, cerebellum, and hippocampus as well as hippocampal inflammation (interleukin (IL)-6), but not in the olfactory bulb. Systemic CCL11 (at 3 and 6 months) and IL-4 (at 6 months) increased after PM1 exposure. Light chain 3 (LC3) expression increased in the hippocampus after 6 months of exposure. Spongiosis and neuronal shrinkage were observed in the cortex, cerebellum, and hippocampus (neuronal shrinkage) after exposure to air pollution. Additionally, microabscesses were observed in the cortex after 6 months of PM1 exposure. CONCLUSIONS: Our study first observed cerebral edema and brain impairment in adult rats after chronic exposure to traffic-related air pollution.

Investigating hyperoxic effects in the rat brain using quantitative susceptibility mapping based on MRI phase.

PURPOSE: To test whether susceptibility imaging can detect microvenous oxygen saturation changes, induced by hyperoxia, in the rat brain. METHODS: A three-dimensional gradient-echo with a flow compensation sequence was used to acquire T2*-weighted images of rat brains during hyperoxia and normoxia. Quantitative susceptibility mapping (QSM) and QSM-based microvenous oxygenation venography were computed from gradient-echo (GRE) phase images and compared between the two conditions. Pulse oxygen saturation (SpO2 ) in the cortex was examined and compared with venous oxygen saturation (SvO2 ) estimated by QSM. Oxygen saturation change calculated by a conventional Δ R2* map was also compared with the ΔSvO2 estimated by QSM. RESULTS: Susceptibilities of five venous and tissue regions were quantified separately by QSM. Venous susceptibility was reduced by nearly 10%, with an SvO2 shift of 10% during hyperoxia. A hyperoxic effect, confirmed by SpO2 measurement, resulted in an SvO2 increase in the cortex. The ΔSvO2 between hyperoxia and normoxia was consistent with what was estimated by the Δ R2* map in five regions. CONCLUSION: These findings suggest that a quantitative susceptibility map is a promising technique for SvO2 measurement. This method may be useful for quantitatively investigating oxygenation-dependent functional MRI studies. Magn Reson Med 77:592-602, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Resting-State Network Analysis Reveals Altered Functional Brain Connectivity in Essential Tremor.

Introduction: Essential tremor (ET) comprises motor and non-motor-related features, whereas the current neuro-pathogenetic basis is still insufficient to explain the etiologies of ET. Although cerebellum-associated circuits have been discovered, the large-scale cerebral network connectivity in ET remains unclear. This study aimed to characterize the ET in terms of functional connectivity as well as network. We hypothesized that the resting-state network (RSN) within cerebrum could be altered in patients with ET. Methods: Resting-state functional magnetic resonance imaging (fMRI) was used to evaluate the inter- and intra-network connectivity as well as the functional activity in ET and normal control. Correlation analysis was performed to explore the relationship between RSN metrics and tremor features. Results: Comparison of inter-network connectivity indicated a decreased connectivity between default mode network and ventral attention network in the ET group (p < 0.05). Differences in functional activity (assessed by amplitude of low-frequency fluctuation, ALFF) were found in several brain regions participating in various RSNs (p < 0.05). The ET group generally has higher degree centrality over normal control. Correlation analysis has revealed that tremor features are associated with inter-network connectivity (|r| = 0.135-0.506), ALFF (|r| = 0.313-0.766), and degree centrality (|r| = 0.523-0.710). Conclusion: Alterations in the cerebral network of ET were detected by using resting-state fMRI, demonstrating a potentially useful approach to explore the cerebral alterations in ET.

CD133 Stimulates Cell Proliferation via the Upregulation of Amphiregulin in Melanoma.

CD133, a cancer stem cell (CSC) marker in tumors, including melanoma, is associated with tumor recurrence, chemoresistance, and metastasis. Patient-derived melanoma cell lines were transduced with a Tet-on vector expressing CD133, generating doxycycline (Dox)-inducible cell lines. Cells were exposed to Dox for 24 h to induce CD133 expression, followed by RNA-seq and bioinformatic analyses, revealing genes and pathways that are significantly up- or downregulated by CD133. The most significantly upregulated gene after CD133 was amphiregulin (AREG), validated by qRT-PCR and immunoblot analyses. Induced CD133 expression significantly increased cell growth, percentage of cells in S-phase, BrdU incorporation into nascent DNA, and PCNA levels, indicating that CD133 stimulates cell proliferation. CD133 induction also activated EGFR and the MAPK pathway. Potential mechanisms highlighting the role(s) of CD133 and AREG in melanoma CSC were further delineated using AREG/EGFR inhibitors or siRNA knockdown of AREG mRNA. Treatment with the EGFR inhibitor gefitinib blocked CD133-induced cell growth increase and MAPK pathway activation. Importantly, siRNA knockdown of AREG reversed the stimulatory effects of CD133 on cell growth, indicating that AREG mediates the effects of CD133 on cell proliferation, thus serving as an attractive target for novel combinatorial therapeutics in melanoma and cancers with overexpression of both CD133 and AREG.

Joint diffusional kurtosis magnetic resonance imaging analysis of white matter and the thalamus to identify subcortical ischemic vascular disease.

Identifying subcortical ischemic vascular disease (SIVD) in older adults is important but challenging. Growing evidence suggests that diffusional kurtosis imaging (DKI) can detect SIVD-relevant microstructural pathology, and a systematic assessment of the discriminant power of DKI metrics in various brain tissue microstructures is urgently needed. Therefore, the current study aimed to explore the value of DKI and diffusion tensor imaging (DTI) metrics in detecting early-stage SIVD by combining multiple diffusion metrics, analysis strategies, and clinical-radiological constraints. This prospective study compared DKI with diffusivity and macroscopic imaging evaluations across the aging spectrum including SIVD, Alzheimer's disease (AD), and cognitively normal (NC) groups. Using a white matter atlas and segregated thalamus analysis with considerations of the pre-identified macroscopic pathology, the most effective diffusion metrics were selected and then examined using multiple clinical-radiological constraints in a two-group or three-group paradigm. A total of 122 participants (mean age, 74.6 ± 7.38 years, 72 women) including 42 with SIVD, 50 with AD, and 30 NC were evaluated. Fractional anisotropy, mean kurtosis, and radial kurtosis were critical metrics in detecting early-stage SIVD. The optimal selection of diffusion metrics showed 84.4-100% correct classification of the results in a three-group paradigm, with an area under the curve of .909-.987 in a two-group paradigm related to SIVD detection (all P < .001). We therefore concluded that greatly resilient to the effect of pre-identified macroscopic pathology, the combination of DKI/DTI metrics showed preferable performance in identifying early-stage SIVD among adults across the aging spectrum.

Targeting Tryptophan Catabolism in Ovarian Cancer to Attenuate Macrophage Infiltration and PD-L1 Expression.

High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited because of the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6-high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME. SIGNIFICANCE: Developing strategies to improve response to chemotherapy is essential to extending disease-free intervals for patients with HGSC of the fallopian tube, ovary, and peritoneum. In this article, we demonstrate that targeting TRP catabolism, particularly with dual inhibition of TDO2 and IDO1, attenuates the immune-suppressive microenvironment and, when combined with chemotherapy, extends survival compared with chemotherapy alone.

White and gray matter integrity evaluated by MRI-DTI can serve as noninvasive and reliable indicators of structural and functional alterations in chronic neurotrauma.

We aimed to evaluate whether white and gray matter microstructure changes observed with magnetic resonance imaging (MRI)-based diffusion tensor imaging (DTI) can be used to reflect the progression of chronic brain trauma. The MRI-DTI parameters, neuropathologic changes, and behavioral performance of adult male Wistar rats that underwent moderate (2.1 atm on day "0") or repeated mild (1.5 atm on days "0" and "2") traumatic brain injury (TBI or rmTBI) or sham operation were evaluated at 7 days, 14 days, and 1-9 months after surgery. Neurobehavioral tests showed that TBI causes long-term motor, cognitive and neurological deficits, whereas rmTBI results in more significant deficits in these paradigms. Both histology and MRI show that rmTBI causes more significant changes in brain lesion volumes than TBI. In vivo DTI further reveals that TBI and rmTBI cause persistent microstructural changes in white matter tracts (such as the body of the corpus callosum, splenium of corpus callus, internal capsule and/or angular bundle) of both two hemispheres. Luxol fast blue measurements reveal similar myelin loss (as well as reduction in white matter thickness) in ipsilateral and contralateral hemispheres as observed by DTI analysis in injured rats. These data indicate that the disintegration of microstructural changes in white and gray matter parameters analyzed by MRI-DTI can serve as noninvasive and reliable markers of structural and functional level alterations in chronic TBI.

Phase locking route behind complex periodic windows in a forced oscillator.

Chaotic systems have complex reactions against an external driving force; even in cases with low-dimension oscillators, the routes to synchronization are diverse. We proposed a stroboscope-based method for analyzing driven chaotic systems in their phase space. According to two statistic quantities generated from time series, we could realize the system state and the driving behavior simultaneously. We demonstrated our method in a driven bi-stable system, which showed complex period windows under a proper driving force. With increasing periodic driving force, a route from interior periodic oscillation to phase synchronization through the chaos state could be found. Periodic windows could also be identified and the circumstances under which they occurred distinguished. Statistical results were supported by conditional Lyapunov exponent analysis to show the power in analyzing the unknown time series.

Improving the brain image resolution of generalized q-sampling MRI revealed by a three-dimensional CNN-based method.

Background: Understanding neural connections facilitates the neuroscience and cognitive behavioral research. There are many nerve fiber intersections in the brain that need to be observed, and the size is between 30 and 50 nanometers. Improving image resolution has become an important issue for mapping the neural connections non-invasively. Generalized q-sampling imaging (GQI) was used to reveal the fiber geometry of straight and crossing. In this work, we attempted to achieve super-resolution with a deep learning method on diffusion weighted imaging (DWI). Materials and methods: A three-dimensional super-resolution convolutional neural network (3D SRCNN) was utilized to achieve super-resolution on DWI. Then, generalized fractional anisotropy (GFA), normalized quantitative anisotropy (NQA), and the isotropic value of the orientation distribution function (ISO) mapping were reconstructed using GQI with super-resolution DWI. We also reconstructed the orientation distribution function (ODF) of brain fibers using GQI. Results: With the proposed super-resolution method, the reconstructed DWI was closer to the target image than the interpolation method. The peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM) were also significantly improved. The diffusion index mapping reconstructed by GQI also had higher performance. The ventricles and white matter regions were much clearer. Conclusion: This super-resolution method can assist in postprocessing low-resolution images. With SRCNN, high-resolution images can be effectively and accurately generated. The method can clearly reconstruct the intersection structure in the brain connectome and has the potential to accurately describe the fiber geometry on a subvoxel scale.