Progressive Disruption of Sphingosine-1-Phosphate Receptor 1 Correlates with Blood-Brain Barrier Leakage in A Rat Model of Chronic Hypoxic Hypoperfusion.

Endothelial dysfunction and blood-brain barrier (BBB) leakage have been suggested as a fundamental role in the development of cerebral small vessel disease (SVD) pathology. However, the molecular and cellular mechanisms that link cerebral hypoxic hypoperfusion and BBB disruption remain elusive. Sphingosine-1-phosphate (S1P) regulates the BBB integrity by binding to its receptor isoform 1 (S1PR1) on endothelial cells. This study tested the hypothesis that hypoxic hypoperfusion triggers capillary endothelial S1PR1 disruption, which compromises BBB integrity and leads to SVD-related neuropathological changes, using a chronic hypoxic hypoperfusion model with BBB dysfunction. Spontaneously hypertensive rat stroke-prone underwent unilateral carotid artery occlusion (UCAO) followed by a Japanese permissive diet (JPD) for up to 9 weeks. Selective S1PR1 agonist SEW2871 was used to activate S1PR1. Significant progressive reduction of S1PR1 was detected in rat brains from 4 to 9 weeks following UCAO/JPD onset, which was also detected in cerebral vasculature in human SVD. S1PR1 activation by SEW2871 significantly reduced lesions in both white and grey matter and ameliorated cerebral blood flow. SEW2871 reversed the loss of endothelial S1PR1 and tight junction proteins, and significantly attenuated UCAO/JPD induced accumulation of neuronal phosphorylated tau. This protective role of SEW2871 is associated with promotion of Akt phosphorylation and inhibition of S1PR2/Erk1/2 activation. Our data suggest S1PR1 signalling as a potential molecular mechanistic basis that links hypoxic hypoperfusion with BBB damage in the neuropathological cascades in SVD. The reversal of BBB disruption through pharmacological intervention of S1PR1 signalling likely reveals a novel therapeutic target for SVD.

Empirical optimization of energy bin weights for compressing measurements with realistic photon counting x-ray detectors.

BACKGROUND: Photon counting detectors (PCDs) provide higher spatial resolution, improved contrast-to-noise ratio (CNR), and energy discriminating capabilities. However, the greatly increased amount of projection data in photon counting computed tomography (PCCT) systems becomes challenging to transmit through the slip ring, process, and store. PURPOSE: This study proposes and evaluates an empirical optimization algorithm to obtain optimal energy weights for energy bin data compression. This algorithm is universally applicable to spectral imaging tasks including 2 and 3 material decomposition (MD) tasks and virtual monoenergetic images (VMIs). This method is simple to implement while preserving spectral information for the full range of object thicknesses and is applicable to different PCDs, for example, silicon detectors and CdTe detectors. METHODS: We used realistic detector energy response models to simulate the spectral response of different PCDs and an empirical calibration method to fit a semi-empirical forward model for each PCD. We numerically optimized the optimal energy weights by minimizing the average relative Cramér-Rao lower bound (CRLB) due to the energy-weighted bin compression, for MD and VMI tasks over a range of material area density ρ A , m ${\rho }_{A,m}$ (0-40 g/cm2 water, 0-2.16 g/cm2 calcium). We used Monte Carlo simulation of a step wedge phantom and an anthropomorphic head phantom to evaluate the performance of this energy bin compression method in the projection domain and image domain, respectively. RESULTS: The results show that for 2 MD, the energy bin compression method can reduce PCCT data size by 75% and 60%, with an average variance penalty of less than 17% and 3% for silicon and CdTe detectors, respectively. For 3 MD tasks with a K-edge material (iodine), this method can reduce the data size by 62.5% and 40% with an average variance penalty of less than 12% and 13% for silicon and CdTe detectors, respectively. CONCLUSIONS: We proposed an energy bin compression method that is broadly applicable to different PCCT systems and object sizes, with high data compression ratio and little loss of spectral information.

Progressive failure analysis of perforated composite laminates considering nonlinear shear effect.

Composites are widely used in high performance structures such as aerospace structures due to their excellent properties. The analysis of failure evolution of composite perforated structures by finite element simulation is of great significance for practical work as engineering composite structures often contain notches and voids. In this paper, the numerical simulation of failure evolution and failure modes of carbon fiber reinforced resin composite laminates with large openings was carried out. A UMAT subroutine was written based on the 3D Hashin-Ye failure criterion and progressive damage model theory. The characteristic length and viscosity coefficient were introduced into the model to reduce mesh dependency and improve computational convergence. The nonlinear shear constitutive relationship defined by the Ramberg-Osgood equation was introduced into the continuous damage degradation model. The effect of nonlinear shear on the failure evolution of laminates with different stacking sequence was studied.

A high-quality chromosome-level wild rice genome of Oryza coarctata.

Oryza coarctata (2n = 4X = 48, KKLL) is an allotetraploid, undomesticated relative of rice and the only species in the genus Oryza with tolerance to high salinity and submergence. Therefore, it contains important stress and tolerance genes/factors for rice. The initial draft genome published was limited by data and technical restrictions, leading to an incomplete and highly fragmented assembly. This study reports a new, highly contiguous chromosome-level genome assembly and annotation of O. coarctata. PacBio high-quality HiFi reads generated 460 contigs with a total length of 573.4 Mb and an N50 of 23.1 Mb, which were assembled into scaffolds with Hi-C data, anchoring 96.99% of the assembly onto 24 chromosomes. The genome assembly comprises 45,571 genes, and repetitive content contributes 25.5% of the genome. This study provides the novel identification of the KK and LL genome types of the genus Oryza, leading to valuable insights into rice genome evolution. The chromosome-level genome assembly of O. coarctata is a valuable resource for rice research and molecular breeding.

Identification of a two metastasis-related prognostic signature in the process of predicting the survival of laryngeal squamous cell carcinoma.

Metastasis is a major cause of treatment failure and poor outcomes in cancer patients. The data used in the current study was downloaded from TCGA and GEO databases. Differentially expressed metastasis-related genes were identified and the biological functions were implemented. Kaplan-Meier analysis univariate, and, multivariate Cox regression analyses were performed to identify robust prognostic biomarkers, followed by construction of the risk model and nomogram. Gene set enrichment analysis was performed to identify pathways enriched in low- and high-risk groups. POLR2J3 and MYH11 were treated as prognostic biomarkers in LSCC and the risk model was constructed. Receiver operating characteristic curves revealed the good performance of the risk model. A nomogram with high accuracy was constructed, as evidenced by calibration and decision curves. Moreover, we found that the expressions of POLR2J3 and MYH11 was significantly higher in metastasis tissues compared with those in non-metastasis tissues by RT-qPCR and IHC. Our study identified novel metastasis-related prognostic biomarkers in LSCC and constructed a unique nomogram for predicting the prognosis of LSCC patients. Moreover, we explored the related mechanisms of metastasis-related genes in regulating LSCC.

Construction and validation of a nomogram model to predict symptomatic intracranial hemorrhage after intravenous thrombolysis in severe white matter lesions.

Cerebral white matter lesions (WMLs) increase the risk of bleeding after intravenous thrombolysis (IVT) but are also considered to require IVT. Its risk factors and predictive models are still poorly studied. The aim of this study is to develop a clinically applicable model for post-IVT haemorrhage. It offers the possibility to prevent symptomatic intracranial hemorrhage (sICH) in patients with IVT in severe WMLs. A large single-center observational study conducted a retrospective analysis of IVT in patients with severe WMLs from January 2018 to December 2022. Univariate and multi-factor logistic regression results were used to construct nomogram model, and a series of validations were performed on the model. More than 2,000 patients with IVT were screened for inclusion in this study after cranial magnetic resonance imaging evaluation of 180 patients with severe WMLs, 28 of whom developed sICH. In univariate analysis, history of hypertension (OR 3.505 CI 2.257-4.752, p = 0.049), hyperlipidemia (OR 4.622 CI 3.761- 5.483, p < 0.001), the NIHSS score before IVT (OR 41.250 CI 39.212-43.288, p < 0.001), low-density lipoprotein levels (OR 1.995 CI 1.448-2.543, p = 0.013), cholesterol levels (OR 1.668 CI 1.246-2.090, p = 0.017), platelet count (OR 0.992 CI 0.985-0.999, p = 0.028), systolic blood pressure (OR 1.044 CI 1.022-1.066, p < 0.001), diastolic blood pressure (OR 1.047 CI 1.024-1.070, p < 0.001) were significantly associated with sICH. In a multifactorial analysis, the NIHSS score before IVT (OR 94.743 CI 92.311-97.175, p < 0.001), and diastolic blood pressure (OR 1.051 CI 1.005-1.097, p = 0.033) were considered to be significantly associated with sICH after IVT as risk factors for the occurrence of sICH. The four most significant factors from logistic regression are subsequently fitted to create a predictive model. The accuracy was verified using ROC curves, calibration curves, decision curves, and clinical impact curves, and the model was considered to have high accuracy (AUC 0.932, 95% 0.888-0.976). The NHISS score before IVT and diastolic blood pressure are independent risk factors for sICH after IVT in patients with severe WMLs. The models based on hyperlipidemia, the NIHSS score before IVT, low-density lipoprotein and diastolic blood pressure are highly accurate and can be applied clinically to provide a reliable predictive basis for IVT in patients with severe WMLs.

Non-Invasive Vagus Nerve Stimulation Improves Brain Lesion Volume and Neurobehavioral Outcomes in a Rat Model of Traumatic Brain Injury.

Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. This study assessed the effectiveness of non-invasive vagus nerve stimulation (nVNS) in reducing brain lesion volume and improving neurobehavioral performance in a rat model of TBI. Animals were randomized into three experimental groups: (1) TBI with sham stimulation treatment (Control), (2) TBI treated with five lower doses (2-min) nVNS, and (3) TBI treated with five higher doses (2 × 2-min) nVNS. We used the gammaCore nVNS device to deliver stimulations. Magnetic resonance imaging studies were performed 1 and 7 days post-injury to confirm lesion volume. We observed smaller brain lesion volume in the lower dose nVNS group compared with the control group on days 1 and 7. The lesion volume for the higher dose nVNS group was significantly smaller than either the lower dose nVNS or the control groups on days 1 and 7 post-injury. The apparent diffusion coefficient differences between the ipsilateral and contralateral hemispheres on day 1 were significantly smaller for the higher dose (2 × 2 min) nVNS group than for the control group. Voxel-based morphometry analysis revealed an increase in the ipsilateral cortical volume in the control group caused by tissue deformation and swelling. On day 1, these abnormal volume changes were 13% and 55% smaller in the lower dose and higher dose nVNS groups, respectively, compared with the control group. By day 7, nVNS dampened cortical volume loss by 35% and 89% in the lower dose and higher dose nVNS groups, respectively, compared with the control group. Rotarod, beam walking, and anxiety performances were significantly improved in the higher-dose nVNS group on day 1 compared with the control group. The anxiety indices were also improved on day 7 post-injury compared with the control and the lower-dose nVNS groups. In conclusion, the higher dose nVNS (five 2 × 2-min stimulations) reduced brain lesion volume to a level that further refined the role of nVNS therapy for the acute treatment of TBI. Should nVNS prove effective in additional pre-clinical TBI models and later in clinical settings, it would have an enormous impact on the clinical practice of TBI in both civilian and military settings, as it can easily be adopted into routine clinical practice.

Clinical efficacy of styloid incision truncation via percutaneous punching in treating styloid process syndrome.

OBJECTIVE: To clarify the clinical efficacy of styloid incision truncation via percutaneous punching in treating styloid process (styloid) syndrome. METHODS: The clinical data of 40 styloid syndrome patients treated in our hospital from July 2018 to August 2021 were chosen and divided into an observation group and a control group in a random manner, with 20 cases in each. The control group received treatment with styloid truncation via an external cervical approach, and the observation group received treatment with styloid incision truncation via percutaneous punching. The operation time, intraoperative blood loss, length of truncated styloid, clinical efficacy, pain scores, postoperative complications and inflammatory cytokine levels were assessed in the both groups. RESULTS: The intraoperative blood loss, operation time, length of truncated styloid and hospital stay in the observation group were significantly lower than those in the control group (P < 0.05). VAS pain scores were higher in both groups after the operation compared to before the operation. However, the observation group showed a statistically significant reduction in comparison with the control group (P < 0.05). The treatment effectiveness and complication rates of the two groups exhibited significant differences (P < 0.05). After the operation, TNF-α, CRP, and IL-6 levels in both groups were elevated compared to those before the operation. The observation group, however, showed significant depletion compared to the control group (P < 0.05). CONCLUSION: Styloid incision truncation via percutaneous punching was not only effective in treating styloid syndrome, but also caused less trauma and fewer complications. It promotes patient recovery and requires a simple operation, making it worthy of promotion in hospitals.

Strategies for manipulating Rubisco and creating photorespiratory bypass to boost C3 photosynthesis: Prospects on modern crop improvement.

Photosynthesis is a process that uses solar energy to fix CO2 in the air and converts it into sugar, and ultimately powers almost all life activities on the earth. C3 photosynthesis is the most common form of photosynthesis in crops. Current efforts of increasing crop yields in response to growing global food requirement are mostly focused on improving C3 photosynthesis. In this review, we summarized the strategies of C3 photosynthesis improvement in terms of Rubisco properties and photorespiratory limitation. Potential engineered targets include Rubisco subunits and their catalytic sites, Rubisco assembly chaperones, and Rubisco activase. In addition, we reviewed multiple photorespiratory bypasses built by strategies of synthetic biology to reduce the release of CO2 and ammonia and minimize energy consumption by photorespiration. The potential strategies are suggested to enhance C3 photosynthesis and boost crop production.

Monitoring Therapeutic Responses to Silicified Cancer Cell Immunotherapy Using PET/MRI in a Mouse Model of Disseminated Ovarian Cancer.

Current imaging approaches used to monitor tumor progression can lack the ability to distinguish true progression from pseudoprogression. Simultaneous metabolic 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) offers new opportunities to overcome this challenge by refining tumor identification and monitoring therapeutic responses to cancer immunotherapy. In the current work, spatial and quantitative analysis of tumor burden were performed using simultaneous [18F]FDG-PET/MRI to monitor therapeutic responses to a novel silicified cancer cell immunotherapy in a mouse model of disseminated serous epithelial ovarian cancer. Tumor progression was validated by bioluminescence imaging of luciferase expressing tumor cells, flow cytometric analysis of immune cells in the tumor microenvironment, and histopathology. While PET demonstrated the presence of metabolically active cancer cells through [18F]FDG uptake, MRI confirmed cancer-related accumulation of ascites and tissue anatomy. This approach provides complementary information on disease status without a confounding signal from treatment-induced inflammation. This work provides a possible roadmap to facilitate accurate monitoring of therapeutic responses to cancer immunotherapies.

Spatiotemporal characteristics of ground microtremor in advance of rockfalls.

Identifying cliffs that are prone to fall and providing a sufficient lead time for rockfall warning are crucial steps in disaster risk reduction and preventive maintenance work, especially that led by local governments. However, existing rockfall warning systems provide uncertain rockfall location forecasting and short warning times because the deformation and cracking of unstable slopes are not sufficiently detected by sensors before the rock collapses. Here, we introduce ground microtremor signals for early rockfall forecasting and demonstrate that microtremor characteristics can be used to detect unstable rock wedges on slopes, quantitatively describe the stability of slopes and lengthen the lead time for rockfall warning. We show that the change in the energy of ground microtremors can be an early precursor of rockfall and that the signal frequency decreases with slope instability. This finding indicates that ground microtremor signals are remarkably sensitive to slope stability. We conclude that microtremor characteristics can be used as an appropriate slope stability index for early rockfall warning systems and predicting the spatiotemporal characteristics of rockfall hazards. This early warning method has the advantages of providing a long lead time and on-demand monitoring, while increasing slope stability accessibility and prefailure location detectability.

Effects of Different Intervention Methods on Intestinal Cleanliness in Children Undergoing Colonoscopy.

Objective: To explore the effects of different intervention methods on intestinal cleanliness in children undergoing colonoscopy. Methods: 61 children who underwent colonoscopy in our hospital from May 2020 to May 2021 were randomly divided into group A (n = 21), group B (n = 30), and group C (n = 10). The children in the three groups were intervened in different ways before the colonoscopy. Group A received a long-handled Kaiselu +1 cathartic intervention, while group B received a long-handled Kaiselu +2 cathartic intervention, and group C received an enema plus one cathartic intervention. The patients in the three groups were given the same diet before the examination until the examination was completed. The time-related indexes, cleanliness, adverse reactions, tolerance, and adaptability of the three groups under different dietary interventions and cleaning methods were evaluated. Results: The first defecation time in group C was lower than that in group A and group B, the hospital stay was longer than that in group A and group B (p > 0.05), and the colonoscopy time in group C was shorter than that in group A and group B (p < 0.05). The BBPS score of group C was (2.10 ± 0.32), which was significantly higher than that of group A (1.16 ± 0.19) and group B (1.77 ± 0.18) (p < 0.05). The BBPS scores of children with liquid food in the three groups were significantly higher than those of common food, and the BBPS scores of liquid food and common food in group C were significantly higher than those in group A and group B (p < 0.05). The incidence of adverse reactions in group C was 20.00%, which was significantly lower than 33.33% in group A and 23.33% in group B (p < 0.05). The proportion of grade I in group C was 50.00%, which was significantly higher than 38.10% in group A and 43.33% in group B (p < 0.05). Conclusion: Children undergoing colonoscopy take preintestinal preparation under different diets and intervention methods. The cleanliness of liquid food and enema + one-time laxative one day before colonoscopy is the best, which can significantly reduce adverse reactions and increase the acceptability and adaptability of children. It is worthy of clinical application.

Endogenous zinc protoporphyrin formation critically contributes to hemorrhagic stroke-induced brain damage.

Hemorrhagic stroke is a leading cause of death. The causes of intracerebral hemorrhage (ICH)-induced brain damage are thought to include lysis of red blood cells, hemin release and iron overload. These mechanisms, however, have not proven very amenable to therapeutic intervention, and so other mechanistic targets are being sought. Here we report that accumulation of endogenously formed zinc protoporphyrin (ZnPP) also critically contributes to ICH-induced brain damage. ICH caused a significant accumulation of ZnPP in brain tissue surrounding hematoma, as evidenced by fluorescence microscopy of ZnPP, and further confirmed by fluorescence spectroscopy and supercritical fluid chromatography-mass spectrometry. ZnPP formation was dependent upon both ICH-induced hypoxia and an increase in free zinc accumulation. Notably, inhibiting ferrochelatase, which catalyzes insertion of zinc into protoporphyrin, greatly decreased ICH-induced endogenous ZnPP generation. Moreover, a significant decrease in brain damage was observed upon ferrochelatase inhibition, suggesting that endogenous ZnPP contributes to the damage in ICH. Our findings reveal a novel mechanism of ICH-induced brain damage through ferrochelatase-mediated formation of ZnPP in ICH tissue. Since ferrochelatase can be readily inhibited by small molecules, such as protein kinase inhibitors, this may provide a promising new and druggable target for ICH therapy.

Circ_0023028 contributes to the progression of laryngeal squamous cell carcinoma by upregulating LASP1 through miR-486-3p.

Circular RNAs (circRNAs) are implicated in the tumorigenesis of human cancers. However, the effects of circRNAs on laryngeal squamous cell carcinoma (LSCC) are largely unknown. Here, we aimed to explore the roles of circ_0023028 in LSCC development. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure circ_0023028, miR-486-3p, and Lin-Isl-Mec (LIM) and SH3 domain protein 1 (LASP1) mRNA. The characteristics of circ_0023028 were determined by RNase R digestion assay and Actinomycin D assay. Cell Counting Kit-8 (CCK-8) assay and colony formation assay were utilized for cell proliferation. Transwell assay was adopted for cell invasion and migration. Flow cytometry analysis was carried out to analyze cell cycle and apoptosis. RNA pull-down assay and dual-luciferase reporter assay were used to explore the association between miR-486-3p and circ_0023028 or LASP1. Western blot assay was adopted to measure LASP1 protein level. Murine xenograft model was executed to investigate the function of circ_0023028 in vivo. High expression of circ_0023028 was observed in LSCC tissues and cells. Circ_0023028 was stable and possessed a loop structure. Circ_0023028 silencing suppressed LSCC cell proliferation, metastasis and cell cycle process and induced apoptosis in vitro and hampered tumor growth in vivo. Further mechanism analysis demonstrated that circ_0023028 could sponge miR-486-3p to regulate LASP1 expression in LSCC cells. The malignant behaviors of LSCC cells mediated by circ_0023028 knockdown were rescued by the inhibition of miR-486-3p. Moreover, miR-486-3p suppressed LSCC cell progression via binding to LASP1. Circ_0023028 knockdown might impede the progression of LSCC by regulating miR-486-3p/LASP1 axis, which could provide a novel insight on the mechanism of LSCC progression.

Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells. RNA sequencing and confirmatory expression studies demonstrated robust expression of Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical H+-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl-/H+ exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with H+-ATPase on the apical membrane of cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and H+-ATPase expression, completely abrogated the cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to H+-ATPase activation, caused significant reduction in cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their acid/base/electrolyte transport machinery (H+-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation and/or enlargement in TSC.

Treatment with Atorvastatin During Vascular Remodeling Promotes Pericyte-Mediated Blood-Brain Barrier Maturation Following Ischemic Stroke.

We previously showed that newly formed vessels in ischemic rat brain have high blood-brain barrier (BBB) permeability at 3 weeks after stroke due to a lack of major endothelial tight junction proteins (TJPs), which may exacerbate edema in stroke patients. Atorvastatin was suggested a dose-dependent pro-angiogenic effect and ameliorating BBB permeability beyond its cholesterol-lowering effects. This study examined our hypothesis that, during vascular remodeling after stroke, treatment with atorvastatin could facilitate BBB maturation in remodeling vasculature in ischemic brain. Adult spontaneously hypertensive rats underwent middle cerebral artery occlusion with reperfusion (MCAO/RP). Atorvastatin, at dose of 3 mg/kg, was delivered daily starting at 14 days after MCAO/RP onset for 7 days. The rats were studied at multiple time points up to 8 weeks with multimodal-MRI, behavior tests, immunohistochemistry, and biochemistry. The delayed treatment of atorvastatin significantly reduced infarct size and BBB permeability, restored cerebral blood flow, and improved the neurological outcome at 8 weeks after MCAO/RP. Postmortem studies showed that atorvastatin promoted angiogenesis and stabilized the newly formed vessels in peri-infarct areas. Importantly, atorvastatin facilitated maturation of BBB properties in the new vessels by promoting endothelial tight junction (TJ) formation. Further in vivo and in vitro studies demonstrated that proliferating peri-vascular pericytes expressing neural-glial antigen 2 (NG2) mediated the role of atorvastatin on BBB maturation through regulating endothelial TJ strand formations. Our results suggested a therapeutic potential of atorvastatin in facilitating a full BBB integrity and functional stroke recovery, and an essential role for pericyte-mediated endothelial TJ formation in remodeling vasculature.

Manganese-enhanced MRI reveals changes within brain anxiety and aversion circuitry in rats with chronic neuropathic pain- and anxiety-like behaviors.

Chronic pain often predicts the onset of psychological distress. Symptoms including anxiety and depression after pain chronification reportedly are caused by brain remodeling/recruitment of the limbic and reward/aversion circuitries. Pain is the primary precipitating factor that has caused opioid overprescribing and continued overuse of opioids leading to the current opioid epidemic. Yet experimental pain therapies often fail in clinical trials. Better understanding of underlying pathologies contributing to pain chronification is needed to address these chronic pain related issues. In the present study, a chronic neuropathic pain model persisting 10 weeks was studied. The model develops both anxiety- and pain-related behavioral measures to mimic clinical pain. The manganese-enhanced magnetic resonance imaging (MEMRI) utilized improved MRI signal contrast in brain regions with higher neuronal activity in the rodent chronic constriction trigeminal nerve injury (CCI-ION) model. T1-weighted MEMRI signal intensity was increased compared to controls in supraspinal regions of the anxiety and aversion circuitry, including anterior cingulate gyrus (ACC), amygdala, habenula, caudate, ventrolateral and dorsomedial periaqueductal gray (PAG). Despite continuing mechanical hypersensitivity, MEMRI T1 signal intensity as the neuronal activity measure, was not significantly different in thalamus and decreased in somatosensory cortex (S1BF) of CCI-ION rats compared to naïve controls. This is consistent with decreased fMRI BOLD signal intensity in thalamus and cortex of patients with longstanding trigeminal neuropathic pain reportedly associated with gray matter volume decrease in these regions. Significant increase in MEMRI T2 signal intensity in thalamus of CCI-ION animals was indication of tissue water content, cell dysfunction and/or reactive astrogliosis. Decreased T2 signal intensity in S1BF cortex of rats with CCI-ION was similar to findings of reduced T2 signals in clinical patients with chronic orofacial pain indicating prolonged astrocyte activation. These findings support use of MEMRI and chronic rodent models for preclinical studies and therapeutic trials to reveal brain sites activated only after neuropathic pain has persisted in timeframes relevant to clinical pain and to observe treatment effects not possible in short-term models which do not have evidence of anxiety-like behaviors. Potential improvement is predicted in the success rate of preclinical drug trials in future studies with this model.

Longitudinal monitoring of microglial/macrophage activation in ischemic rat brain using Iba-1-specific nanoparticle-enhanced magnetic resonance imaging.

Microglial/macrophage activation plays a dual role in response to brain injury after a stroke, promoting early neuroinflammation and benefit for neurovascular recovery. Therefore, the dynamics of stroke-induced cerebral microglial/macrophage activation are of substantial interest. This study used novel anti-Iba-1-targeted superparamagnetic iron-platinum (FePt) nanoparticles in conjunction with magnetic resonance imaging (MRI) to measure the spatiotemporal changes of the microglial/macrophage activation in living rat brain for four weeks post-stroke. Ischemic lesion areas were identified and measured using T2-weighted MR images. After injection of the FePt-nanoparticles, T2*-weighted MR images showed that the nanoparticles were seen solely in brain regions that coincided with areas of active microglia/macrophages detected by post-mortem immunohistochemistry. Good agreement in morphological and distributive dynamic changes was also observed between the Fe+-cells and the Iba-1+-microglia/macrophages. The spatiotemporal changes of nanoparticle detected by T2*-weighted images paralleled the changes of microglial/macrophage activation and phenotypes measured by post-mortem immunohistochemistry over the four weeks post-stroke. Maximum microglial/macrophage activation occurred seven days post-stroke for both measures, and the diminished activation found after two weeks continued to four weeks. Our results suggest that nanoparticle-enhanced MRI may constitute a novel approach for monitoring the dynamic development of neuroinflammation in living animals during the progression and treatment of stroke.

Metal artifact reduction for practical dental computed tomography by improving interpolation-based reconstruction with deep learning.

PURPOSE: Metal artifact is a quite common problem in diagnostic dental computed tomography (CT) images. Due to the high attenuation of heavy materials such as metal, severe global artifacts can occur in reconstructions. Typical metal artifact reduction (MAR) techniques segment out the metal regions and estimate the corrupted projection data by various interpolation methods. However, interpolations are not accurate and introduce new artifacts or even deform the teeth in the reconstructed image. This work presents a new strategy to take advantage of the power of deep learning for metal artifact reduction. METHOD: The analysis first uses coarse reconstructions from simulated locally interpolated data affected by metal fillings as a starting point. A deep learning network is then trained using the simulated data and applied to practical data. Thus, an easily implemented three-step MAR method is formed: Firstly, use the acquired projection data to create a preliminary image reconstruction with linearly interpolated data for the metal-related projections. Secondly, a deep learning network is used to remove the artifacts from the linear interpolation and recover the nonmetal region information. Thirdly, the method adds the ROI reconstruction of the metal regions. The structures behind the shading artifacts in the direct filtered back-projection (FBP) reconstruction can be partially recovered by interpolation-based MAR (I-MAR) with the network further correcting for interpolation errors. The key to this method is that the linear interpolation reconstruction errors can be easily simulated to train a network and the effectiveness of the network can be easily generalized to I-MAR results in real situations. RESULTS: We trained a network with a simulation dataset and validated the network against a separate simulation dataset. Then, the network was tested using simulation data that did not overlap with the training/validation datasets and real patient datasets. Both tests gave encouraging results with accurate tooth structure recovery and few artifacts. The relative root mean square error and structure similarity index method indexes were significantly improved in the tests. The method was also evaluated by two experienced dentists who gave positive evaluations. CONCLUSIONS: This work presents a strategy to build a transferable learning from simulations to practical systems for metal artifact reduction using a supervised deep learning method. The system transforms the MAR analyses to an interpolation-artifact reduction problem to recover structural details from the coarse interpolation reconstruction. In this way, training data from simulations with ground truth labels can easily model the similar features in real data with I-MAR as the bridge. The network can seamlessly optimize both simulations and real data. The whole method is easily implemented with little computational cost. Test results demonstrated that this is an effective MAR method applicable to practical dental CT systems.

Downregulation of miR­143 modulates KRAS expression in colorectal carcinoma cells.

MicroRNAs (miRs) are a class of non­coding small RNAs that have been demonstrated to be involved in the pathogenesis of human cancer. There is even evidence that microRNAs can act as oncogenes or tumor suppressors. Although microRNA expression profiles have been characterized in colorectal carcinoma, their precise physiological functions are largely unknown. It has become clear that the activated KRAS Proto­Oncogene, GTPase (KRAS) oncogene plays an important role in colorectal carcinogenesis. In the present study, it was found that the level of mature miR­143 was lower in colorectal carcinoma tissues compared with that observed in normal adjacent tissues. A lack of miR­143 was detected in human colorectal carcinoma cell lines, SW480, LoVo and HT­29, compared to the high expression observed in normal colon epithelial cell line NCM460. pcDNA3.1­pri­miR­143 and its mutant were successfully constructed and transfected into colorectal carcinoma cells. Increased accumulation of mature miR­143 was observed in the pcDNA3.1­pri­miR­143­transfected cells. In SW480 cells, transfection of pcDNA3.1­pri­miR­143 resulted in a 35 and 47% reduction in cell growth after incubation for 4 and 5 days, respectively, compared with transfection of the pcDNA3.1­pri­miR­143 mutant; while in LoVo cells, transfection of pcDNA3.1­pri­miR­143 resulted in a 33 and 46% reduction in cell growth respectively. In contrast, transfection of pcDNA3.1­pri­miR­143 had no significantly effects on HT­29 cell growth. We also found that transfection of pcDNA3.1­pri­miR­143 had no effect on levels of KRAS mRNA, but resulted in a 58% decrease in the KRAS protein level in the transfected SW480 cells, while an approximate 54 and 43% KRAS protein reduction in LoVo and HT­29 cells, respectively, compared with the pcDNA3.1­pri­miR­143 mutant. Two fragments containing the putative complementary site were cloned into the pGL3 vector, constructing the luciferase reporter pGL3­KRAS­CS1 and pGL3­KRAS­CS2. Cotransfection of pcDNA3.1­pri­miR­143 with pGL3­KRAS­CS1 and pGL3­KRAS­CS2 respectively resulted in 4.6­ and 3.3­fold inhibition of luciferase activity in the SW480 cells, while a 4.0­ and 3.2­fold inhibition of luciferase activity in the LoVo cells, 3.7­ and 3.1­fold inhibition in the HT­29 cells. Differences in pGL3­KRAS­CS1 and pGL3­KRAS­CS2 activity were not significant. Our results revealed that increased accumulation of miR­143 is likely to modulate levels of KRAS protein expression at the post­transcriptional level by interacting specifically with the complementary site, and consequently inhibiting proliferation of the transfected cells.