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.

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.

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.

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.

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.

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.

Microstructural and microglial changes after repetitive mild traumatic brain injury in mice.

Traumatic brain injury (TBI) is a major public health issue, with recently increased awareness of the potential long-term sequelae of repetitive injury. Although TBI is common, objective diagnostic tools with sound neurobiological predictors of outcome are lacking. Indeed, such tools could help to identify those at risk for more severe outcomes after repetitive injury and improve understanding of biological underpinnings to provide important mechanistic insights. We tested the hypothesis that acute and subacute pathological injury, including the microgliosis that results from repeated mild closed head injury (rmCHI), is reflected in susceptibility-weighted magnetic resonance imaging and diffusion-tensor imaging microstructural abnormalities. Using a combination of high-resolution magnetic resonance imaging, stereology, and quantitative PCR, we studied the pathophysiology of male mice that sustained seven consecutive mild traumatic brain injuries over 9 days in acute (24 hr) and subacute (1 week) time periods. rmCHI induced focal cortical microhemorrhages and impaired axial diffusivity at 1 week postinjury. These microstructural abnormalities were associated with a significant increase in microglia. Notably, microgliosis was accompanied by a change in inflammatory microenvironment defined by robust spatiotemporal alterations in tumor necrosis factor-α receptor mRNA. Together these data contribute novel insight into the fundamental biological processes associated with repeated mild brain injury concomitant with subacute imaging abnormalities in a clinically relevant animal model of repeated mild TBI. These findings suggest new diagnostic techniques that can be used as biomarkers to guide the use of future protective or reparative interventions. © 2016 Wiley Periodicals, Inc.

In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke.

A multifunctional microRNA, miR-155, has been recently recognized as an important modulator of numerous biological processes. In our previous in vitro studies, miR-155 was identified as a potential regulator of the endothelial morphogenesis. The present study demonstrates that in vivo inhibition of miR-155 supports cerebral vasculature after experimental stroke. Intravenous injections of a specific miR-155 inhibitor were initiated at 48 h after mouse distal middle cerebral artery occlusion (dMCAO). Microvasculature in peri-infarct area, infarct size, and animal functional recovery were assessed at 1, 2, and 3 weeks after dMCAO. Using in vivo two-photon microscopy, we detected improved blood flow and microvascular integrity in the peri-infarct area of miR-155 inhibitor-injected mice. Electron microscopy revealed that, in contrast to the control group, these animals demonstrated well preserved capillary tight junctions (TJs). Western blot analysis data indicate that improved TJ integrity in the inhibitor-injected animals could be associated with stabilization of the TJ protein ZO-1 and mediated by the miR-155 target protein Rheb. MRI analysis showed significant (34%) reduction of infarct size in miR-155 inhibitor-injected animals at 21 d after dMCAO. Reduced brain injury was confirmed by electron microscopy demonstrating decreased neuronal damage in the peri-infarct area of stroke. Preservation of brain tissue was reflected in efficient functional recovery of inhibitor-injected animals. Based on our findings, we propose that in vivo miR-155 inhibition after ischemia supports brain microvasculature, reduces brain tissue damage, and improves the animal functional recovery. Significance statement: In the present study, we investigated an effect of the in vivo inhibition of a microRNA, miR-155, on brain recovery after experimental cerebral ischemia. To our knowledge, this is the first report describing the efficiency of intravenous anti-miRNA injections in a mouse model of ischemic stroke. The role of miRNAs in poststroke revascularization has been unexplored and in vivo regulation of miRNAs during the subacute phase of stroke has not yet been proposed. Our investigation introduces a new and unexplored approach to cerebral regeneration: regulation of poststroke angiogenesis and recovery through direct modulation of specific miRNA activity. We expect that our findings will lead to the development of novel strategies for regulating neurorestorative processes in the postischemic brain.

Zinc contributes to acute cerebral ischemia-induced blood-brain barrier disruption.

Zinc ions are stored in synaptic vesicles and cerebral ischemia triggers their release from the terminals of neurons. Zinc accumulation in neurons has been shown to play an important role in neuronal death following ischemia. However, almost nothing is known about whether zinc is involved in ischemia-induced blood-brain barrier (BBB) disruption. Herein, we investigated the contribution of zinc to ischemia-induced acute BBB disruption and the possible molecular mechanisms using both cellular and animal models of cerebral ischemia. Zinc greatly increased BBB permeability and exacerbated the loss of tight junction proteins (Occludin and Claudin-5) in the endothelial monolayer under oxygen glucose deprivation conditions. In cerebral ischemic rats, a dramatically elevated level of zinc accumulation in microvessels themselves was observed in isolated microvessels and in situ, showing the direct interaction of zinc on ischemic microvessels. Treatment with a specific zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), even at 60-min post-ischemia onset, could greatly attenuate BBB permeability in the ischemic rats as measured by Evan's Blue extravasation, edema volume and magnetic resonance imaging. Furthermore, zinc accumulation in microvessels activated the superoxide/matrix metalloproteinase-9/-2 pathway, which leads to the loss of tight junction proteins (Occludin and Claudin-5) and death of endothelial cells in microvessels themselves. Our findings reveal a novel mechanism of cerebral ischemia-induced BBB damage, and implicate zinc as an effective and viable new target for reducing acute BBB damage following ischemic stroke.

High Intracranial Pressure Induced Injury in the Healthy Rat Brain.

OBJECTIVES: We recently showed that increased intracranial pressure to 50 mm Hg in the healthy rat brain results in microvascular shunt flow characterized by tissue hypoxia, edema, and increased blood-brain barrier permeability. We now determined whether increased intracranial pressure results in neuronal injury by Fluoro-Jade stain and whether changes in cerebral blood flow and cerebral metabolic rate for oxygen suggest nonnutritive microvascular shunt flow. DESIGN: Intracranial pressure was elevated by a reservoir of artificial cerebrospinal fluid connected to the cisterna magna. Arterial blood gases, cerebral arterial-venous oxygen content difference, and cerebral blood flow by MRI were measured. Fluoro-Jade stain neurons were counted in histologic sections of the right and left dorsal and lateral cortices and hippocampus. SETTING: University laboratory. SUBJECTS: Male Sprague Dawley rats. INTERVENTIONS: Arterial pressure support if needed by IV dopamine infusion and base deficit corrected by sodium bicarbonate. MEASUREMENTS AND MAIN RESULTS: Fluoro-Jade stain neurons increased 2.5- and 5.5-fold at intracranial pressures of 30 and 50 mm Hg and cerebral perfusion pressures of 57 ± 4 (mean ± SEM) and 47 ± 6 mm Hg, respectively (p < 0.001) (highest in the right and left cortices). Voxel frequency histograms of cerebral blood flow showed a pattern consistent with microvascular shunt flow by dispersion to higher cerebral blood flow at high intracranial pressure and decreased cerebral metabolic rate for oxygen. CONCLUSIONS: High intracranial pressure likely caused neuronal injury because of a transition from normal capillary flow to nonnutritive microvascular shunt flow resulting in tissue hypoxia and edema, and it is manifest by a reduction in the cerebral metabolic rate for oxygen.

Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery.

BACKGROUND: Minocycline reduces reperfusion injury by inhibiting matrix metalloproteinases (MMPs) and microglia activity after cerebral ischemia. Prior studies of minocycline investigated short-term neuroprotective effects during subacute stage of stroke; however, the late effects of minocycline against early reperfusion injury on neurovascular remodeling are less well studied. We have shown that spontaneous angiogenesis vessels in ischemic brain regions have high blood-brain barrier (BBB) permeability due to lack of major tight junction proteins (TJPs) in endothelial cells at three weeks. In the present study, we longitudinally investigated neurological outcome, neurovascular remodeling and microglia/macrophage alternative activation after spontaneous and minocycline-induced stroke recovery. METHODS: Adult spontaneously hypertensive rats had a 90 minute transient middle cerebral artery occlusion. At the onset of reperfusion they received a single dose of minocycline (3 mg/kg intravenously) or a vehicle. They were studied at multiple time points up to four weeks with magnetic resonance imaging (MRI), immunohistochemistry and biochemistry. RESULTS: Minocycline significantly reduced the infarct size and prevented tissue loss in the ischemic hemispheres compared to vehicle-treated rats from two to four weeks as measured with MRI. Cerebral blood flow measured with arterial spin labeling (ASL) showed that minocycline improved perfusion. Dynamic contrast-enhanced MRI indicated that minocycline reduced BBB permeability accompanied with higher levels of TJPs measured with Western blot. Increased MMP-2 and -3 were detected at four weeks. Active microglia/macrophage, surrounding and within the peri-infarct areas, expressed YM1, a marker of M2 microglia/macrophage activation, at four weeks. These microglia/macrophage expressed both pro-inflammatory factors tumor necrosis factors-α (TNF-α) and interleukin-1ß (IL-1ß) and anti-inflammatory factors transforming growth factor-ß (TGF-ß) and interleukin-10 (IL-10). Treatment with minocycline significantly reduced levels of TNF-α and IL-1ß, and increased levels of TGF-ß, IL-10 and YM1. CONCLUSIONS: Early minocycline treatment against reperfusion injury significantly promotes neurovascular remodeling during stroke recovery by reducing brain tissue loss, enhancing TJP expression in ischemic brains and facilitating neuroprotective phenotype alternative activation of microglia/macrophages.

In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry.

Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O2 may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O2 is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO2 in vivo remains largely uncharacterized. This study investigated striatal tissue pO2 changes in male C57BL/6 mice (16-20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO2 in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO2 was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO2 to 64%. More importantly, pO2 did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO2 indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO2, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults.

Emulating Low-Dose PCCT Image Pairs with Independent Noise for Self-Supervised Spectral Image Denoising.

Photon counting CT (PCCT) acquires spectral measurements and enables generation of material decomposition (MD) images that provide distinct advantages in various clinical situations. However, noise amplification is observed in MD images, and denoising is typically applied. Clean or high-quality references are rare in clinical scans, often making supervised learning (Noise2Clean) impractical. Noise2Noise is a self-supervised counterpart, using noisy images and corresponding noisy references with zero-mean, independent noise. PCCT counts transmitted photons separately, and raw measurements are assumed to follow a Poisson distribution in each energy bin, providing the possibility to create noise-independent pairs. The approach is to use binomial selection to split the counts into two low-dose scans with independent noise. We prove that the reconstructed spectral images inherit the noise independence from counts domain through noise propagation analysis and also validated it in numerical simulation and experimental phantom scans. The method offers the flexibility to split measurements into desired dose levels while ensuring the reconstructed images share identical underlying features, thereby strengthening the model's robustness for input dose levels and capability of preserving fine details. In both numerical simulation and experimental phantom scans, we demonstrated that Noise2Noise with binomial selection outperforms other common self-supervised learning methods based on different presumptive conditions.

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.

Spectral optimization using fast kV switching and filtration for photon counting CT with realistic detector responses: a simulation study.

Purpose: Photon counting CT (PCCT) provides spectral measurements for material decomposition. However, the image noise (at a fixed dose) depends on the source spectrum. Our study investigates the potential benefits from spectral optimization using fast kV switching and filtration to reduce noise in material decomposition. Approach: The effect of the input spectra on noise performance in both two-basis material decomposition and three-basis material decomposition was compared using Cramer-Rao lower bound analysis in the projection domain and in a digital phantom study in the image domain. The fluences of different spectra were normalized using the CT dose index to maintain constant dose levels. Four detector response models based on Si or CdTe were included in the analysis. Results: For single kV scans, kV selection can be optimized based on the imaging task and object size. Furthermore, our results suggest that noise in material decomposition can be substantially reduced with fast kV switching. For two-material decomposition, fast kV switching reduces the standard deviation (SD) by ∼ 10 % . For three-material decomposition, greater noise reduction in material images was found with fast kV switching (26.2% for calcium and 25.8% for iodine, in terms of SD), which suggests that challenging tasks benefit more from the richer spectral information provided by fast kV switching. Conclusions: The performance of PCCT in material decomposition can be improved by optimizing source spectrum settings. Task-specific tube voltages can be selected for single kV scans. Also, our results demonstrate that utilizing fast kV switching can substantially reduce the noise in material decomposition for both two- and three-material decompositions, and a fixed Gd filter can further enhance such improvements for two-material decomposition.

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.

Ultrasensitive detection of aggregated α-synuclein using quiescent seed amplification assay for the diagnosis of Parkinson's disease.

BACKGROUND: Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson's disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation. METHODS: We introduced a modified form of SAA, known as Quiescent SAA (QSAA), and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies (control group). Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies. Additionally, skin samples were collected from 214 PD patients and 208 control subjects. Data were analyzed from April 2019 to May 2023. RESULTS: QSAA successfully amplified αSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils. In the skin samples from 214 PD cases and 208 non-PD cases, QSAA demonstrated high sensitivity (90.2%) and specificity (91.4%) in differentiating between PD and non-PD cases. Notably, more αSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples. CONCLUSION: We introduced the new QSAA method tailored for in situ amplification of αSyn aggregates in brain and skin samples while maintaining tissue integrity, providing a streamlined approach to diagnosing PD with individual variability. The integration of seeding activities with the location of deposition of αSyn seeds advances our understanding of the mechanism underlying αSyn misfolding in PD.

[Study on KIR gene polymorphisms in 416 renal transplantation recipients from southern Zhejiang].

OBJECTIVE: To investigate polymorphisms of killer cell immunoglobulin-like receptor gene (KIR) in renal transplant recipients from southern Zhejiang. METHODS: KIR genotypes were analyzed by PCR-SSP in 416 renal transplant recipients, and the genotype frequencies were compared with populations from Eastern China and worldwide. RESULTS: All 16 known KIR genes were detected in the renal transplant recipients, and KIR2DL4, 3DL2-3, 3PD1 were found in all. As a pseudogene, 2DP1 has a high genotype frequency (99%). The frequencies of KIR2DL1, 2DL3, 3DL1, 2DS4 have ranged from 92.1% to 98.8%. Compared with 11 groups in Eastern China and other countries, the KIR2DL2 phenotype frequency was higher (34.6%) than those of Shanghai, Zhejiang and Jiangsu populations (P<0.05). Among 41 genotypes, three have not been reported previously. The most common genotype was AA1, with a frequency of 43.51%, which was significantly lower than those of Jiangsu and Northern Zhejiang. CONCLUSION: Renal transplant recipients from southern Zhejiang share similar features with Eastern China Han population with regard to KIR polymorphisms, but also have unique frequencies for KIR genotypes.

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.

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.