Background: Chordomas are rare malignant skull-base/spine cancers with devastating neurological morbidities and mortality. Unfortunately, no reliable prognostic factors exist to guide treatment decisions. This work identifies DNA methylation-based prognostic chordoma subtypes that are detectable non-invasively in plasma. Methods: Sixty-eight tissue samples underwent DNA methylation profiling and plasma methylomes were obtained for available paired samples. Immunohistochemical staining and publicly available methylation and gene expression data were utilized for validation. Results: Unsupervised clustering identified two prognostic tissue clusters (log-rank p=0.0062) predicting disease-specific survival independent of clinical factors (Multivariable Cox: HR=16.5, 95%CI: 2.8-96, p=0.0018). The poorer-performing cluster showed immune-related pathway promoter hypermethylation and higher immune cell abundance within tumours, which was validated with external RNA-seq data and immunohistochemical staining. The better-performing cluster showed higher tumour cellularity. Similar clusters were seen in external DNA methylation data. Plasma methylome-based models distinguished chordomas from differential diagnoses in independent testing sets (AUROC=0.84, 95%CI: 0.52-1.00). Plasma methylomes were highly correlated with tissue-based signals for both clusters (r=0.69 & 0.67) and leave-one-out models identified the correct cluster in all plasma cases. Conclusions: Prognostic molecular chordoma subgroups are for the first time identified, characterized, and validated. Plasma methylomes can detect and subtype chordomas which may transform chordoma treatment with personalized approaches tailored to prognosis.

This paper presents Parallel World Framework as a solution for simulations of complex systems within a time-varying knowledge graph and its application to the electric grid of Jurong Island in Singapore. The underlying modeling system is based on the Semantic Web Stack. Its linked data layer is described by means of ontologies, which span multiple domains. The framework is designed to allow what-if scenarios to be simulated generically, even for complex, inter-linked, cross-domain applications, as well as conducting multi-scale optimizations of complex superstructures within the system. Parallel world containers, introduced by the framework, ensure data separation and versioning of structures crossing various domain boundaries. Separation of operations, belonging to a particular version of the world, is taken care of by a scenario agent. It encapsulates functionality of operations on data and acts as a parallel world proxy to all of the other agents operating on the knowledge graph. Electric network optimization for carbon tax is demonstrated as a use case. The framework allows to model and evaluate electrical networks corresponding to set carbon tax values by retrofitting different types of power generators and optimizing the grid accordingly. The use case shows the possibility of using this solution as a tool for CO2 reduction modeling and planning at scale due to its distributed architecture.

Background: Molecular signatures are being increasing used to classify central nervous system (CNS) tumors with incorporation into World Health Organization (WHO) classifications. A recently published genome-wide DNA methylation-based CNS tumor classifier assisted in diagnostically challenging cases. However its impact on patient care has not been reported, limiting translation to other centres. Methods: All 55 challenging CNS tumour diagnoses over three years underwent DNA methylation profiling. Tumor classification along with copy number variant (CNV) plot results were integrated with histopathological findings to determine final diagnoses and corresponding clinical impact was assessed. Results: After methylation profiling 46/55 (84%) received clinically relevant diagnostic changes, 30 (55%) with a new diagnosis or resolved differential diagnosis and 16 (29%) with clinically important molecular diagnostic or subtyping changes. WHO grade changed in 15 (27%), with two-thirds upgraded. Nine new IDH mutations in gliomas, four new molecular subtypes in medulloblastomas/ependymomas, and three false positive 1p/19q codeletions were identified. Patient care was directly changed by methylation profiling in 7/47 (15%) followed-up cases to avoid unnecessary treatment in three, insufficient treatment in three, and medically assisted death in one. Conclusions: This real-world use of methylation-based CNS tumor classification substantially impacts patient care for diagnostically challenging tumors and also avoids misdiagnosis-related uncessary resource use.

Background: Challenges in predicting risk of recurrence for individual patients with meningioma limits appropriate selection of patients who may benefit from adjuvant radiation therapy to delay recurrence. Here, we aimed to develop and validate a combined clinicomolecular predictor of early recurrence for individual patients with meningiomas. Methods: A methylation-based predictor of 5-year recurrence-free-survival (RFS) was developed using DNA-methylation profiles from a training cohort of 228 patients. Model performance was compared to a standard-of-care histological-based model using three independent cohorts (N=54 ;N=140; N=64 patients). Subsequently, a nomogram that integrated the methylome-based predictor with prognostic clinical factors was developed and validated. Results: The methylome-based predictor of 5-year RFS performed favorably compared to a grade-based predictor when tested using the three validation cohorts (ΔAUC=0.10, 95%CI 0.03 – 0.018) and was independently associated with RFS on multivariable Cox regression analysis (HR=3.6, 95%CI 1.8–7.2, P<0.001). A nomogram combining the methylome-predictor with clinical factors demonstrated greater discrimination for recurrence than a nomogram using clinical factors alone (ΔAUC=0.25, 95%CI 0.22–0.27) and resulted in two risk groups with distinct recurrence patterns (HR=7.7, 95%CI 5.3–11.1, P<0.001) and clinical implications. Conclusions: Our validated models provide important novel prognostic information that could be used to individualize decisions regarding post-operative therapeutic interventions in meningioma.

Carbohydrate-rich diets may increase urinary excretion of chromium (Cr) and increase its requirements. This study was conducted to investigate the effect of grain type (barley v. corn) and Cr supplementation on feed intake, feeding behavior and weight gain in dairy calves. Forty-eight neonatal Holstein female calves were assigned randomly to four experimental diets in a 2×2 factorial arrangement. Experimental diets were either barley-based diet (BBD) or corn-based diet (CBD) supplemented with (+Cr) or without (−Cr) Cr as Cr-methionine (0.05 mg/kg of BW0.75). Chromium was provided in milk (from days 3 to 73 of life) during the pre-weaning period and then in pre-warmed water (from day 74 until day 94 of life) after weaning. Meal length tended to increase in calves fed the BBD v. CBD during the pre-weaning period. During the post-weaning period, meal size, inter-meal interval, and eating rate increased concurrently but meal frequency and eating time decreased in the BBD v. CBD. During the pre-weaning period, feed efficiency, BW at weaning, and heart girth increased and non-nutritive oral behaviors tended to decrease with Cr supplementation. Due to increased meal frequency, the starter feed intake but not eating time increased by Cr supplementation during the post-weaning period. Supplementing Cr increased starter feed intake, final BW, average daily gain and heart girth during the overall period. Rumination time increased in BBD+Cr calves due to increases in the frequency and duration of rumination, or decreased rumination bout interval. Overall, the type of grain had no effect on feed intake and growth performance; however, Cr supplementation decreased non-nutritive oral behaviors and increased starter feed intake via increasing the meal frequency and thereby improved growth performance.

Stressful situations may result in serum chromium (Cr) depletion with increased urinary excretion of the mineral and increased Cr requirements. The objective of this study was to investigate the effects of Cr supplementation on growth performance, feeding behavior, blood metabolites and hormones, indicators of oxidative stress and glucose-insulin kinetics of summer-exposed weaned dairy calves. In total, 48 Holstein female calves (63 days of age; 77.0±1.45 kg of BW) were assigned randomly to one of two treatments: (1) a control group with no supplemental Cr (Cr−), and (2) a supplemental Cr group (Cr+) to supply 0.05 mg Cr as Cr-methionine/kg of BW0.75. Chromium was provided in the starter feed and adjusted weekly based on BW over the experimental period. All calves were on experiment for 4 weeks after weaning. The average maximum temperature–humidity index was 76.1 units during the study period, indicating a mild degree of environmental heat load. Results indicated that in summer-exposed dairy calves, increased dietary Cr provision tended to decrease fecal score, tended to change rumination pattern, increased antioxidant capacity by increasing serum concentration of catalase, but had no effects on growth performance, metabolic status or peripheral glucose and insulin metabolism.

The date palm hopper, Ommatissus lybicus, is a key pest of the date palm, which is expected to be comprised of many allopatric populations. The current study was carried out to determine bacterial endosymbiont diversity in the different populations of this pest. Ten date palm hopper populations were collected from the main date palm growing regions in Iran and an additional four samples from Pakistan, Oman, Egypt and Tunisia for detection of primary and secondary endosymbionts using polymerase chain reaction (PCR) assay with their specific primers. The PCR products were directly sequenced and edited using SeqMan software. The consensus sequences were subjected to a BLAST similarity search. The results revealed the presence of ‘Candidatus Sulcia muelleri’ (primary endosymbiont) and Wolbachia, Arsenophonus and Enterobacter (secondary endosymbionts) in all populations. This assay failed to detect ‘Candidatus Nasuia deltocephalinicola’ and Serratia in these populations. ‘Ca. S. muelleri’ exhibited a 100% infection frequency in populations and Wolbachia, Arsenophonus and Enterobacter demonstrated 100, 93.04 and 97.39% infection frequencies, respectively. The infection rate of Arsenophonus and Enterobacter ranged from 75 to 100% and 62.5 to 100%, respectively, in different populations of the insect. The results demonstrated multiple infections by ‘Ca. Sulcia muelleri’, Wolbachia, Arsenophonus and Enterobacter in the populations and may suggest significant roles for these endosymbionts on date palm hopper population fitness. This study provides an insight to endosymbiont variation in the date palm hopper populations; however, further investigation is needed to examine how these endosymbionts may affect host fitness.

Small perturbation evolution in compressible Poiseuille flow is contrasted against the incompressible case using direct simulations and non-modal linear analysis. The onset of compressibility effects leads to a profound change in the behaviour of pressure and its interaction with the velocity field. Linear analysis shows that the most significant compressibility outcome is the harmonic coupling between pressure and wall-normal velocity perturbations. Oscillations in normal perturbations can lead to periods of negative production causing suppression of perturbation growth. The extent of the influence of compressibility can be characterized in terms of an effective gradient Mach number ($M_{g}^{e}$). Analysis shows that $M_{g}^{e}$ diminishes as the angle of the perturbation increases with respect to the shear plane. Direct numerical simulations show that streamwise perturbations, which would lead to Tollmien–Schlichting instability in the incompressible case, are completely suppressed in the compressible case and experience the highest $M_{g}^{e}$. At the other extreme, computations reveal that spanwise perturbations, which experience negligible $M_{g}^{e}$, are entirely unaltered from the incompressible case. Perturbation behaviour at intermediate obliqueness angles is established. Moreover, the underlying pressure–velocity interactions are explicated.

Factors which might influence outcome in patients with meningioma are not well-understood. Previous studies have examined associations of laboratory blood values including hemoglobin levels with patient outcomes in cancer. We hypothesized those changes in CBC before tumor resection can be used as one of the prognostic factors for tumor recurrence/progression in meningioma. To address this, we gathered the clinical and pre-operative CBC results for final analysis from 226 patients (64 males and 162 females) who underwent craniotomy for primary meningioma (grades: 157 WHO GI, 59 GII, 10 GIII) at our institution between 2001 and 2015.Individual parameters were analyzed for correlation with progression-free survival. The median recurrence free survival (RFS) was not reached and follow-up ranged 0.3-14 years. Fifty-six patients (25%) had anemia and 30% of the patients showed leukocytosis using standard cut-offs. On univariate analyses, low hemoglobin (Hb) level, as well as high leukocytes (Lkc), neutrophil (Neutro) and monocyte counts correlated with worse RFS. As expected, tumor grade was correlated with RFS. Low Hb level, high Lkc and Neutro counts were all significantly associated with RFS after adjusting for grade. Strikingly, 32% of patients with pre-operative anemia experienced a recurrence at 5 years, compared with only 11% of non-anemic patients. Conclusion: In this exploratory study, we find that pre-operative CBC data, which is readily available, may contain prognostic information relevant to subsequent risk of recurrence or progression in meningioma. While the biological mechanism for these associations is not clear, they represent hypotheses for further investigation.

The Lattice Boltzmann Method (LBM) has established itself as a popular numerical method in computational fluid dynamics. Several advancements have been recently made in LBM, which include multiple-relaxation-time LBM to simulate anisotropic advection-diffusion processes. Because of the importance of LBM simulations for transport problems in subsurface and reactive flows, one needs to study the accuracy and structure preserving properties of numerical solutions under the LBM. The solutions to advective-diffusive systems are known to satisfy maximum principles, comparison principles, the non-negative constraint, and the decay property. In this paper, using several numerical experiments, it will be shown that current single- and multiple-relaxation-time lattice Boltzmann methods fail to preserve these mathematical properties for transient diffusion-type equations. We will also show that these violations may not be removed by simply refining the discretization parameters. More importantly, it will be shown that meeting stability conditions alone does not guarantee the preservation of the aforementioned mathematical principles and physical constraints in the discrete setting. A discussion on the source of these violations and possible approaches to avoid them is included. A condition to guarantee the non-negativity of concentration under LBM in the case of isotropic diffusion is also derived. The impact of this research is twofold. First, the study poses several outstanding research problems, which should guide researchers to develop LBM-based formulations for transport problems that respect important mathematical properties and physical constraints in the discrete setting. This paper can also serve as a good source of benchmark problems for such future research endeavors. Second, this study cautions the practitioners of the LBM for transport problems with the associated numerical deficiencies of the LBM, and provides guidelines for performing predictive simulations of advective-diffusive processes using the LBM.

Atherosclerosis is the underlying cause of cardiovascular disease and stroke. Endothelial cell dysfunctions are early events in atherosclerosis, resulting in the recruitment of circulating monocytes. The immune system can elicit an inflammatory response toward the atherosclerotic lesion, thereby accelerating lesion growth. Risk factors for atherosclerosis include hypertension, smoking, stress perception or low birth weight. As prenatal stress challenge decreases the birth weight and affects the offspring's postnatal immune response, we aimed to investigate whether prenatal stress contributes to the development of atherosclerosis in mice. Syngenic pregnant apolipoprotein E-deficient (apoE−/−) dams were exposed to sound stress on gestation days 12.5 and 14.5. The presence and size of atherosclerotic plaques in the offspring at the age of 15 weeks was evaluated by histomorphology, accompanied by flow cytometric analysis of the frequency and phenotype of monocytes/macrophages and regulatory T (Treg) cells in the blood. Further, cytokine secretion of peripheral blood lymphocytes was analyzed. In response to prenatal stress challenge, an increased frequency of large atherosclerotic plaques was detectable in apoE−/− offspring, which was particularly profound in females. Prenatal stress also resulted in alterations of the offspring's immune response, such as a decreased frequency of Treg cells in blood, alterations of macrophage populations in blood and an increased secretion of inflammatory cytokines. We provide novel evidence that prenatally stressed adult offspring show an increased severity of atherosclerosis. As Treg cells are key players in dampening inflammation, the observed increase in atherosclerosis may be due to the lack of Treg cell frequency. Future interdisciplinary research is urgently required to understand the developmental origin of prenatal stress-induced atherosclerosis. The availability of our model may facilitate and foster such research endeavors.

Calculations are presented of the effective dosesper unit neutron fluence according to the ICRP publications 60 and 103.Monte Carlo N-Particle (MCNPX) code was used for six geometricalconditions of irradiation (Anterior-Posterior, Posterior-Anterior,Left-Lateral, Right-Lateral, Rotation and Isotropic) on Oak RidgeNational Laboratory (ORNL) modified mathematical adult phantomsfor monoenergetic neutrons from 10-9 MeV to 20 MeV. The conversioncoefficients were compared with the results of an analytical phantom(Medical Internal Radiation Dose (MIRD-5)) and some voxel model(ICRP/ICRU Reference Voxel Phantom (ICRP/ICRU RVP), HANAKO, TAROand Visible Human Project (VIPMAN)). From these comparisons, one canconclude that large discrepancies between data sets appear whenwR and different sizes of the phantoms have been used for calculations.Furthermore, the differences in applied Monte Carlo codes or simulatedbody models could make some discrepancies less than 15%.