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Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase-dependent reactive oxygen species (ROS) overproduction and decreased nitric oxide (NO) bioavailability lead to vascular dysfunction and development of hypertension. The goal of our study was to analyze an effect of salt diet and NO synthase (NOS) inhibition with NG-nitro-Larginine methyl ester (L-NAME) on blood pressure (BP), arterial reactivity, NO production, as well as ROS level in adult rats pretreated with low dose of L-NAME (2 mg/kg/day) for three weeks. Higher dose of L-NAME (40 mg/kg/day), or salt diet (8% NaCl), or combination of both were applied for the following four weeks. The administration of L-NAME in low dose had no effect on BP but enhanced the expression of eNOS. Both higher dose of L-NAME and salt diet elevated BP, decreased NOS activity, and impaired the endothelium-dependent arterial relaxation. However, salt diet did not increase ROS production and sympathoadrenergic arterial contractions in low dose L-NAME-pretreated rats. Combination of salt diet with higher dose of L-NAME did not evoke additive decrease of NOS activity, but it caused elevation of conjugated dienes (CD) concentration and NADPH oxidase 2 (Nox-2) protein expression. In conclusion, these findings indicate that chronic low dose of L-NAME treatment has a potential to trigger adapting mechanisms to attenuate some cardiovascular disorders. [ABSTRACT FROM AUTHOR]

Introduction: The interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. The aim of this study was to compare mathematical reaction-diffusion models encoding distinct cross-species couplings to identify which interactions were key to model success., Methods: We tested competing mathematical models of network spread, aggregation, and amyloid-tau interactions on publicly available data from ADNI., Results: Although network spread models captured the spatiotemporal evolution of tau and amyloid in human subjects, the model including a one-way amyloid-to-tau aggregation interaction performed best., Discussion: This mathematical exposition of the "pas de deux" of co-evolving proteins provides quantitative, whole-brain support to the concept of amyloid-facilitated-tauopathy rather than the classic amyloid-cascade or pure-tau hypotheses, and helps explain certain known but poorly understood aspects of AD.

Mounting evidence implicates trans-synaptic connectome-based spread as a shared mechanism behind different tauopathic conditions, yet also suggests there is divergent spatiotemporal progression between them. A potential parsimonious explanation for this apparent contradiction could be that different conditions incur differential rates and directional biases in tau transmission along fiber tracts. In this meta-analysis we closely examined this hypothesis and quantitatively tested it using spatiotemporal tau pathology patterns from 11 distinct models across 4 experimental studies. For this purpose, we extended a network-based spread model by incorporating net directionality along the connectome. Our data unambiguously supports the directional transmission hypothesis. First, retrograde bias is an unambiguously better predictor of tau progression than anterograde bias. Second, while spread exhibits retrograde character, our best-fitting biophysical models incorporate the mixed effects of both retrograde- and anterograde-directed spread, with notable tau-strain-specific differences. We also found a nontrivial association between directionality bias and tau strain aggressiveness, with more virulent strains exhibiting less retrograde character. Taken together, our study implicates directional transmission bias in tau transmission along fiber tracts as a general feature of tauopathy spread and a strong candidate explanation for the diversity of spatiotemporal tau progression between conditions. This simple and parsimonious mechanism may potentially fill a critical gap in our knowledge of the spatiotemporal ramification of divergent tauopathies., Competing Interests: Conflict of interest: The authors declare no competing financial interests.

A fundamental neuroscience topic is the link between the brain's molecular, cellular, and cytoarchitectonic properties and structural connectivity. Recent studies relate inter-regional connectivity to gene expression, but the relationship to regional cell-type distributions remains understudied. Here, we utilize whole-brain mapping of neuronal and non-neuronal subtypes via the matrix inversion and subset selection algorithm to model inter-regional connectivity as a function of regional cell-type composition with machine learning. We deployed random forest algorithms for predicting connectivity from cell-type densities, demonstrating surprisingly strong prediction accuracy of cell types in general, and particular non-neuronal cells such as oligodendrocytes. We found evidence of a strong distance dependency in the cell connectivity relationship, with layer-specific excitatory neurons contributing the most for long-range connectivity, while vascular and astroglia were salient for short-range connections. Our results demonstrate a link between cell types and connectivity, providing a roadmap for examining this relationship in other species, including humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

With the increasing prevalence of Alzheimer's disease (AD) among aging populations and the limited therapeutic options available to slow or reverse its progression, the need has never been greater for improved diagnostic tools for identifying patients in the preclinical and prodomal phases of AD. Biophysics models of the connectome-based spread of amyloid-beta (Aβ) and microtubule-associated protein tau (τ) have enjoyed recent success as tools for predicting the time course of AD-related pathological changes. However, given the complex etiology of AD, which involves not only connectome-based spread of protein pathology but also the interactions of many molecular and cellular players over multiple spatiotemporal scales, more robust, complete biophysics models are needed to better understand AD pathophysiology and ultimately provide accurate patient-specific diagnoses and prognoses. Here we discuss several areas of active research in AD whose insights can be used to enhance the mathematical modeling of AD pathology as well as recent attempts at developing improved connectome-based biophysics models. These efforts toward a comprehensive yet parsimonious mathematical description of AD hold great promise for improving both the diagnosis of patients at risk for AD and our mechanistic understanding of how AD progresses., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The prion-like transsynaptic propagation of misfolded tau along the brain's connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological "milieu" in the neurodegenerative brain and proteinopathic species can also contribute to pathology propagation. Such a molecular nexopathy framework posits that the distinct characteristics of neurodegenerative disorders stem from interactions between the network and surrounding molecular players. However, the effects of these modulators remain unquantified. Here, we present Nexopathy in silico ("Nexis"), a quantitative model of tau progression augmenting earlier models by including parameters of pathology propagation defined by the molecular modulators of connectome-based spread. Our Nexis:microglia model provides the first quantitative characterization of this effect on the whole brain by expanding previous models of neuropathology progression by incorporating microglial influence. We show that Trem2, but not microglial homeostasis genes, significantly improved the model's predictive power. Trem2 appears to reduce tau accumulation rate while increasing its interregional spread from the hippocampal seed area, causing higher tau burden in the striatum, pallidum, and contralateral hippocampus. Nexis provides an improved understanding and quantification of microglial contribution to tau propagation and can be flexibly modified to include other modulators of progressive neurodegeneration., (© 2022. The Author(s).)

The advent of increasingly sophisticated imaging platforms has allowed for the visualization of the murine nervous system at single-cell resolution. However, current experimental approaches have not yet produced whole-brain maps of a comprehensive set of neuronal and nonneuronal types that approaches the cellular diversity of the mammalian cortex. Here, we aim to fill in this gap in knowledge with an open-source computational pipeline, Matrix Inversion and Subset Selection (MISS), that can infer quantitatively validated distributions of diverse collections of neural cell types at 200-μm resolution using a combination of single-cell RNA sequencing (RNAseq) and in situ hybridization datasets. We rigorously demonstrate the accuracy of MISS against literature expectations. Importantly, we show that gene subset selection, a procedure by which we filter out low-information genes prior to performing deconvolution, is a critical preprocessing step that distinguishes MISS from its predecessors and facilitates the production of cell-type maps with significantly higher accuracy. We also show that MISS is generalizable by generating high-quality cell-type maps from a second independently curated single-cell RNAseq dataset. Together, our results illustrate the viability of computational approaches for determining the spatial distributions of a wide variety of cell types from genetic data alone.

Study Design: Retrospective cohort study., Objective: The purpose of this study was to compare outcomes between different treatment modalities for metastatic disease with indeterminate instability (Spinal Instability Neoplastic Score [SINS] 7-12)., Methods: We retrospectively reviewed neurologically intact patients treated for spinal metastatic disease with a SINS of 7 to 12. The cohort was stratified by treatment approach: external beam radiation therapy alone (EBRT), surgery + EBRT (S+E), and cement augmentation + EBRT (K+E). Kaplan-Meier analysis was used to assess differences in length of survival (LOS) and ability to ambulate at time of death. Multivariate analysis was performed to assess adjusted LOS and ability to ambulate at time of death., Results: The cohort included 211 patients, S+E (n = 57), EBRT (n = 128), and K+E (n = 27). In the S+E group, the median LOS was 430 days, which was statistically longer than the median LOS for the EBRT group (121 days) and the K+E group (169 days). In the S+E group, 52 patients (91.2%) and in the K+E group 24 patients (92.3%) retained the ability to ambulate at their time of death compared to 99 patients (77.3%) of the EBRT patients ( P = .01). The overall rate of revision treatment at the spinal level initially treated was 17.5%, S+E (15.8%), EBRT (20.3%), and K+E (7.7%)., Conclusions: The length of survival, ability to maintain ambulatory ability, and revision treatment rates were all improved following surgical management and radiation therapy compared to radiation therapy alone. The authors' conclusion from these results are that patients with indeterminate spinal instability should be discussed in a multidisciplinary setting for the need of spinal stabilization in addition to radiation therapy.

The aim of the current study was to evaluate the influence of a high-fat diet and its combination with high-fructose intake on young normotensive rats, with focus on the modulatory effect of perivascular adipose tissue (PVAT) on the reactivity of isolated arteries. Six-week-old Wistar-Kyoto rats were treated for 8 weeks with a control diet (10% fat), a high-fat diet (HFD; 45% fat), or a combination of the HFD with a 10% solution of fructose. Contractile and relaxant responses of isolated rat arteries, with preserved and removed PVAT for selected vasoactive stimuli, were recorded isometrically by a force displacement transducer. The results demonstrated that, in young rats, eight weeks of the HFD might lead to body fat accumulation and early excitation of the cardiovascular sympathetic nervous system, as shown by increased heart rate and enhanced arterial contractile responses induced by endogenous noradrenaline released from perivascular sympathetic nerves. The addition of high-fructose intake deteriorated this state by impairment of arterial relaxation and resulted in mild elevation of systolic blood pressure; however, the increase in arterial neurogenic contractions was not detected. The diet-induced alterations in isolated arteries were observed only in the presence of PVAT, indicating that this structure is important in initiation of early vascular changes during the development of metabolic syndrome.

Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the impact of 4D-CBCT image quality on radiomic analysis and the efficacy of using deep learning based image enhancement to improve the accuracy of radiomic features of 4D-CBCT., Material and Methods: In this study, 4D-CT data from 16 lung cancer patients were obtained. Digitally reconstructed radiographs (DRRs) were simulated from the 4D-CT, and then used to reconstruct 4D CBCT using the conventional FDK (Feldkamp et al 1984 J. Opt. Soc. Am. A 1 612-9) algorithm. Different projection numbers (i.e. 72, 120, 144, 180) and projection angle distributions (i.e. evenly distributed and unevenly distributed using angles from real 4D-CBCT scans) were simulated to generate the corresponding 4D-CBCT. A deep learning model (TecoGAN) was trained on 10 patients and validated on 3 patients to enhance the 4D-CBCT image quality to match with the corresponding ground-truth 4D-CT. The remaining 3 patients with different tumor sizes were used for testing. The radiomic features in 6 different categories, including histogram, GLCM, GLRLM, GLSZM, NGTDM, and wavelet, were extracted from the gross tumor volumes of each phase of original 4D-CBCT, enhanced 4D-CBCT, and 4D-CT. The radiomic features in 4D-CT were used as the ground-truth to evaluate the errors of the radiomic features in the original 4D-CBCT and enhanced 4D-CBCT. Errors in the original 4D-CBCT demonstrated the impact of image quality on radiomic features. Comparison between errors in the original 4D-CBCT and enhanced 4D-CBCT demonstrated the efficacy of using deep learning to improve the radiomic feature accuracy., Results: 4D-CBCT image quality can substantially affect the accuracy of the radiomic features, and the degree of impact is feature-dependent. The deep learning model was able to enhance the anatomical details and edge information in the 4D-CBCT as well as removing other image artifacts. This enhancement of image quality resulted in reduced errors for most radiomic features. The average reduction of radiomics errors for 3 patients are 20.0%, 31.4%, 36.7%, 50.0%, 33.6% and 11.3% for histogram, GLCM, GLRLM, GLSZM, NGTDM and Wavelet features. And the error reduction was more significant for patients with larger tumors. The findings were consistent across different respiratory phases, projection numbers, and angle distributions., Conclusions: The study demonstrated that 4D-CBCT image quality has a significant impact on the radiomic analysis. The deep learning-based augmentation technique proved to be an effective approach to enhance 4D-CBCT image quality to improve the accuracy of radiomic analysis.

Objective: Stereotactic body radiation therapy (SBRT) offers efficient, noninvasive treatment of spinal neoplasms. Single-fraction (SF) high-dose SBRT has a relatively narrow therapeutic window, while hypofractionated delivery of SBRT may have an improved safety profile with similar efficacy. Because the optimal approach of delivery is unknown, the authors examined whether hypofractionated SBRT improves pain and/or functional outcomes and results in better tumor control compared with SF-SBRT., Methods: This is a single-institution retrospective study of adult patients with spinal metastases treated with SF- or three-fraction (3F) SBRT from 2008 to 2019. Demographics and baseline characteristics, radiographic data, and posttreatment outcomes at a minimum follow-up of 3 months are reported., Results: Of the 156 patients included in the study, 70 (44.9%) underwent SF-SBRT (median total dose 1700 cGy) and 86 (55.1%) underwent 3F-SBRT (median total dose 2100 cGy). At baseline, a higher proportion of patients in the 3F-SBRT group had a worse baseline profile, including severity of pain (p < 0.05), average use of pain medication (p < 0.001), and functional scores (p < 0.05) compared with the SF-SBRT cohort. At the 3-month follow-up, the 3F-SBRT cohort experienced a greater frequency of improvement in pain compared with the SF-SBRT group (p < 0.05). Furthermore, patients treated with 3F-SBRT demonstrated a higher frequency of improved Karnofsky Performance Scale (KPS) scores (p < 0.05) compared with those treated with SF-SBRT, with no significant difference in the frequency of improvement in modified Rankin Scale scores. Local tumor control did not differ significantly between the two cohorts., Conclusions: Patients who received spinal 3F-SBRT more frequently achieved significant pain relief and an increased frequency of improvement in KPS compared with those treated with SF-SBRT. Local tumor control was similar in the two groups. Future work is needed to establish the relationship between fractionation schedule and clinical outcomes.

Obesity is associated with increased sympathetic nervous system activation, possibly contributing to higher cardiovascular risk. The aim of this study was to assess the relationship between body adiposity and sympathoadrenergic contractions in rat isolated mesenteric arteries, and the modulatory effect of mesenteric perivascular adipose tissue (PVAT). Experiments were performed on male 38-week-old Wistar, Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Paired rings of isolated rat superior mesenteric arteries with or without PVAT were prepared and connected to a force-displacement transducer for the recording of isometric tension. Contractile responses were elicited by increasing doses of exogenous noradrenaline and by endogenous noradrenaline released during electrical stimulation of perivascular adrenergic nerves. In ZDF rats, mesenteric PVAT had marked anticontractile effect leading to significant reduction in adrenergic contractions of their superior mesenteric arteries; however, in arterial preparations without PVAT, obese rats showed significantly increased sensitivity in their contractile responses to adrenergic stimulation when compared to other rat groups. In Wistar rats, ranging in the level of body adiposity between ZL and ZDF rats, neurogenic contractions in arterial preparations with preserved PVAT were higher compared to those without PVAT. No vasomodulatory effect of PVAT was detected in mesenteric arteries from ZL rats. The results of this study indicate that the modulatory effect of mesenteric PVAT on arterial adrenergic contractions did not change in proportion with increasing adiposity; however, it could be influenced by the rat strain-specific distribution of sympathetic nerves between PVAT and the proper mesenteric arterial wall. In ZDF rats, characterized by higher vascular sympathetic tone, the mesenteric arteries might be specifically regulated by the anticontractile effect of PVAT, leading to higher mesenteric blood flow. This could be associated with hyperphagia and increased nutrient-induced mesenteric vasodilatation in this rat strain.

There is enormous clinical value in inferring the brain regions initially atrophied in Parkinson disease for individual patients and understanding its relationship with clinical and genetic risk factors. The aim of this study is to leverage a new seed-inference algorithm demonstrated for Alzheimer's disease to the Parkinsonian context and to cluster patients in meaningful subgroups based on these incipient atrophy patterns. Instead of testing brain regions separately as the likely initiation site for each patient, we solve an L1-penalized optimization problem that can return a more predictive heterogeneous, multi-locus seed patterns. A cluster analysis of the individual seed patterns reveals two distinct subgroups (S1 versus S2). The S1 subgroup is characterized by the involvement of the brainstem and ventral nuclei, and S2 by cortex and striatum. Post hoc analysis in features not included in the clustering shows significant differences between subgroups regarding age of onset and local transcriptional patterns of Parkinson-related genes. Top genes associated with regional microglial abundance are strongly associated with subgroup S1 but not with S2. Our results suggest two distinct aetiological mechanisms operative in Parkinson disease. The interplay between immune-related genes, lysosomal genes, microglial abundance and atrophy initiation sites may explain why the age of onset for patients in S1 is on average 4.5 years later than for those in S2. We highlight and compare the most prominently affected brain regions for both subgroups. Altogether, our findings may improve current screening strategies for early Parkinson onsetters., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background : Quercetin (QCT) was shown to exert beneficial cardiovascular effects in young healthy animals. The aim of the present study was to determine cardiovascular benefits of QCT in older, 6-month and 1-year-old Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). Methods : Lean (fa/+) and obese (fa/fa) ZDF rats of both ages were treated with QCT for 6 weeks (20 mg/kg/day). Isolated hearts were exposed to ischemia-reperfusion (I/R) injury (30 min/2 h). Endothelium-dependent vascular relaxation was measured in isolated aortas. Expression of selected proteins in heart tissue was detected by Western blotting. Results : QCT reduced systolic blood pressure in both lean and obese 6-month-old rats but had no effect in 1-year-old rats. Diabetes worsened vascular relaxation in both ages. QCT improved vascular relaxation in 6-month-old but worsened in 1-year-old obese rats and had no impact in lean controls of both ages. QCT did not exert cardioprotective effects against I/R injury and even worsened post-ischemic recovery in 1-year-old hearts. QCT up-regulated expression of eNOS in younger and PKCε expression in older rats but did not activate whole PI3K/Akt pathway. Conclusions : QCT might be beneficial for vascular function in diabetes type 2; however, increasing age and/or progression of diabetes may confound its vasculoprotective effects. QCT seems to be inefficient in preventing myocardial I/R injury in type 2 diabetes and/or higher age. Impaired activation of PI3K/Akt kinase pathway might be, at least in part, responsible for failing cardioprotection in these subjects.

The purpose of this work was to investigate the potential relationship between radiomic features extracted from pre-treatment x-ray CT images and clinical outcomes following stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC). Seventy patients who received SBRT for stage-1 NSCLC were retrospectively identified. The tumor was contoured on pre-treatment free-breathing CT images, from which 43 quantitative radiomic features were extracted to collectively capture tumor morphology, intensity, fine-texture, and coarse-texture. Treatment failure was defined based on cancer recurrence, local cancer recurrence, and non-local cancer recurrence following SBRT. The univariate association between each radiomic feature and each clinical endpoint was analyzed using Welch's t-test, and p-values were corrected for multiple hypothesis testing. Multivariate associations were based on regularized logistic regression with a singular value decomposition to reduce the dimensionality of the radiomics data. Two features demonstrated a statistically significant association with local failure: Homogeneity2 (p  =  0.022) and Long-Run-High-Gray-Level-Emphasis (p  =  0.048). These results indicate that relatively dense tumors with a homogenous coarse texture might be linked to higher rates of local recurrence. Multivariable logistic regression models produced maximum [Formula: see text] values of [Formula: see text], and [Formula: see text], for the recurrence, local recurrence, and non-local recurrence endpoints, respectively. The CT-based radiomic features used in this study may be more associated with local failure than non-local failure following SBRT for stage I NSCLC. This finding is supported by both univariate and multivariate analyses.

Alzheimer's disease, the most common form of dementia, is characterized by the emergence and spread of senile plaques and neurofibrillary tangles, causing widespread neurodegeneration. Though the progression of Alzheimer's disease is considered to be stereotyped, the significant variability within clinical populations obscures this interpretation on the individual level. Of particular clinical importance is understanding where exactly pathology, e.g. tau, emerges in each patient and how the incipient atrophy pattern relates to future spread of disease. Here we demonstrate a newly developed graph theoretical method of inferring prior disease states in patients with Alzheimer's disease and mild cognitive impairment using an established network diffusion model and an L1-penalized optimization algorithm. Although the 'seeds' of origin using our inference method successfully reproduce known trends in Alzheimer's disease staging on a population level, we observed that the high degree of heterogeneity between patients at baseline is also reflected in their seeds. Additionally, the individualized seeds are significantly more predictive of future atrophy than a single seed placed at the hippocampus. Our findings illustrate that understanding where disease originates in individuals is critical to determining how it progresses and that our method allows us to infer early stages of disease from atrophy patterns observed at diagnosis.

Introduction: The purpose of this study was to evaluate the role of consolidation radiation therapy (RT) in advanced Hodgkin lymphoma (HL) in the setting of a complete metabolic response (CR) to chemotherapy (ChT)., Patients and Methods: Patients with stage III/IV HL treated with ChT alone or combined modality therapy (CMT) between 1992 and 2012 were reviewed. Only patients in a CR according to positron emission tomography-computed tomography (PET-CT) or gallium imaging were included. Clinical end points were estimated using the Kaplan-Meier method and a multivariate analysis using the Cox proportional hazards model was performed., Results: Ninety patients were identified (46 CMT; 44 ChT alone). Median follow-up was 50 months. ChT (median 6 cycles) consisted primarily of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine; 74%) or an ABVD hybrid (10%). Post-ChT imaging consisted of PET-CT (71%) or gallium (29%). RT plans primarily included all initially involved sites of disease with a median dose of 21 Gy (range, 13-31 Gy). CMT was associated with improved 5-year progression-free survival (PFS; 88% vs. 65%, respectively; P < .001) and overall survival (97% vs. 78%, respectively; P = .002) compared with ChT alone. In multivariate analysis, age younger than 45 years (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.07-0.74; P = .013) and CMT (HR, 0.32; 95% CI, 0.11-0.96; P = .04) were independently associated with improved PFS. Secondary malignancies were comparable in both cohorts (5 with CMT, 4 with ChT), whereas cardiac events were slightly more frequent with CMT (5 vs. 2)., Conclusion: Low-dose RT, administered to all sites of original involvement, was associated with improved PFS, even in the setting of a metabolic CR after ABVD., (Copyright © 2017 Elsevier Inc. All rights reserved.)