Simulation of soil-to-tool interaction using Discrete Element Method (DEM) and Multibody Dynamics (MBD) coupling

Multi-physics simulation of soil-to-tool interaction using a coupled Discrete Element Method (DEM) and Multibody dynamics (MBD) techniques can support the design of off-road equipment. Quantitative prediction of the soil reaction forces on the equipment is essential to provide a reliable simulation-based design. DEM is a computational method for simulating the dynamic behavior of granular materials. In the coupling interface, DEM gives a high fidelity prediction of the forces for soil-to-soil and soil-to-tool interaction, which can be used in the MBD simulation workflow. Two laboratory tests were used to capture the bulk material behavior: the angle of repose test for calibration of coefficients of static friction and rolling friction, and the cone penetrometer test to calibrate the soil shear modulus and normal and shear stiffnesses (related to the Hertz-Mindlin with bonding contact model). A simple pendulum test was developed to validate the DEM soil model in a soil-to-tool interaction application. The test was conducted in a soil bin filled loosely with loam soil at soil moisture content of 10% and initial soil bulk density of 1330 kg/m3. A cutting plate connected to the pendulum cut the soil at two levels of cutting depths (25 mm and 50 mm). The same application was simulated using the DEM simulation and DEM-MBD co-simulation. The horizontal and vertical soil cutting forces were compared between simulations and test. The magnitude of the maximum horizontal cutting forces for the experiment, DEM simulation, and DEM-MBD co-simulation were 73 N, 365 N, and 187 N, respectively for the 25 mm cutting depth and 108 N, 766 N, and 278 N, respectively for the 50 mm cutting depth. The DEM-MBD coupling improved the force prediction both for 25 mm and 50 mm cutting depths. It also closely predicted the trend in the increase in horizontal forces by cutting depth. The maximum horizontal soil cutting forces from experiment and DEM-MBD co-simulation increase by 48% and 49% by increasing the depth, respectively

Discrete element modeling of cultivator sweep-to-soil interaction: Worn and hardened edges effects on soil-tool forces and soil flow

Simulation of tool-to-soil interaction provides opportunities to accelerate new equipment design and evaluate performance of tillage tools. Simulation based evaluation of worn tillage tools performance on soil flow has not been done. Discrete Element Modelling (DEM) has a potential to simulate worn tool to soil interaction problems, where worn tools CAD can be generated using 3D scanning. The DEM parameters of Hertz-Mindlin with Parallel Bond model were calibrated to match draft force and soil failure zone measured from a tool bar moving at 0.22 m/s and 38 mm cutting depth. The draft force and soil forward failure zone were predicted at 7% and 24% relative errors compared to measured values, respectively. Using the optimized DEM soil model, the interaction of three 3D reconstructed sweeps (new sweep, carbide treated-worn, untreated-worn) with soil were simulated to compare their geometric wear dimensional loss, performance on soil forces and soil flow. Results showed that the carbide treated-worn sweep had similar soil draft force and soil forward failure distance as the new sweep. The untreated-worn sweep showed lower vertical force (less suction) and its wing induced soil failure zone (front and lateral) showed poor soil tilth quality compared with the carbide treated-worn sweep and the new sweep

Regulation of tyrosine hydroxylase is preserved across different homo- and heterodimeric 14-3-3 proteins

Tyrosine hydroxylase (TH) is regulated by members of the 14-3-3 protein family. However, knowledge about the variation between 14-3-3 proteins in their regulation of TH is still limited. We examined the binding, effects on activation and dephosphorylation kinetics of tyrosine hydroxylase (TH) by abundant midbrain 14-3-3 proteins (β, η, ζ, γ and ε) of different dimer composition. All 14-3-3 homodimers and their respective 14-3-3ε-heterodimers bound with similar high affinity (Kd values of 1.4–3.8 nM) to serine19 phosphorylated human TH (TH-pS19). We similarly observed a consistent activation of bovine (3.3- to 4.4-fold) and human TH-pS19 (1.3–1.6 fold) across all the different 14-3-3 dimer species, with homodimeric 14-3-3γ being the strongest activator. Both hetero- and homodimers of 14-3-3 strongly inhibited dephosphorylation of TH-pS19, and we speculate if this is an important homeostatic mechanism of 14-3-3 target-protein regulation in vivo. We conclude that TH is a robust interaction partner of different 14-3-3 dimer types with moderate variability between the 14-3-3 dimers on their regulation of TH.publishedVersio

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

Hereditary tyrosinemia Type 1 (HT‐1) is a rare metabolic disease where the enzyme catalyzing the final step of tyrosine breakdown is defect, leading to accumulation of toxic metabolites. Nitisinone inhibits the degradation of tyrosine and thereby the production of harmful metabolites, however, the concentration of tyrosine also increases. We investigated the relationship between plasma tyrosine concentrations and cognitive functions and how tyrosine levels affected enzyme activities of human tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2). Eight Norwegian children between 6 and 18 years with HT‐1 were assessed using questionnaires measuring Attention Deficit Hyperactivity Disorder (ADHD)‐symptoms and executive functioning. Recent and past levels of tyrosine were measured and the enzyme activities of TH and TPH2 were studied at conditions replicating normal and pathological tyrosine concentrations. We observed a significant positive correlation between mean tyrosine levels and inattention symptoms. While TH exhibited prominent substrate inhibition kinetics, TPH2 activity also decreased at elevated tyrosine levels. Inhibition of both enzymes may impair syntheses of dopamine, noradrenaline, and serotonin in brain tissue. Inattention in treated HT‐1 patients may be related to decreased production of these monoamines. Our results support recommendations of strict guidelines on plasma tyrosine levels in HT‐1. ADHD‐related deficits, particularly inattention, should be monitored in HT‐1 patients to determine whether intervention is necessary.publishedVersio

Мотивационная политика предприятия как основа новой философии управления

В современной концепции управления ключевое место отводится человеку. Именно люди, характеризующиеся не только специальным образованием и профессиональными навыками, но и яркой индивидуальностью, способны генерировать новые идеи и решать непростые задачи в высококонкурентной и динамичной бизнес-среде. Такова закономерность в развитии экономических отношений и совершенствовании менеджмента организаций. Акценты в управлении компанией смещаются к идеологическим (культурным, духовным) ценностям предприятия, носителем которых является его персонал, конкретные сотрудники, способные в этих условиях обеспечивать эффективную работу в высококонкурентной среде

Involvement of the 14-3-3 gene family in autism spectrum disorder and schizophrenia: Genetics, transcriptomics and functional analyses

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10-7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Simulation of soil-to-tool interaction using Discrete Element Method (DEM) and Multibody Dynamics (MBD) coupling

Multi-physics simulation of soil-to-tool interaction using a coupled Discrete Element Method (DEM) and Multibody dynamics (MBD) techniques can support the design of off-road equipment. Quantitative prediction of the soil reaction forces on the equipment is essential to provide a reliable simulation-based design. DEM is a computational method for simulating the dynamic behavior of granular materials. In the coupling interface, DEM gives a high fidelity prediction of the forces for soil-to-soil and soil-to-tool interaction, which can be used in the MBD simulation workflow. Two laboratory tests were used to capture the bulk material behavior: the angle of repose test for calibration of coefficients of static friction and rolling friction, and the cone penetrometer test to calibrate the soil shear modulus and normal and shear stiffnesses (related to the Hertz-Mindlin with bonding contact model). A simple pendulum test was developed to validate the DEM soil model in a soil-to-tool interaction application. The test was conducted in a soil bin filled loosely with loam soil at soil moisture content of 10% and initial soil bulk density of 1330 kg/m3. A cutting plate connected to the pendulum cut the soil at two levels of cutting depths (25 mm and 50 mm). The same application was simulated using the DEM simulation and DEM-MBD co-simulation. The horizontal and vertical soil cutting forces were compared between simulations and test. The magnitude of the maximum horizontal cutting forces for the experiment, DEM simulation, and DEM-MBD co-simulation were 73 N, 365 N, and 187 N, respectively for the 25 mm cutting depth and 108 N, 766 N, and 278 N, respectively for the 50 mm cutting depth. The DEM-MBD coupling improved the force prediction both for 25 mm and 50 mm cutting depths. It also closely predicted the trend in the increase in horizontal forces by cutting depth. The maximum horizontal soil cutting forces from experiment and DEM-MBD co-simulation increase by 48% and 49% by increasing the depth, respectively.</p

Modelling cellular signal communication mediated by phosphorylation dependent interaction with 14-3-3 proteins

The 14-3-3 proteins are important effectors of Ser/Thr phosphorylation in eukaryotic cells. Using mathematical modelling we investigated the roles of these proteins as effectors in signalling pathways that involve multi-phosphorylation events. We defined optimal conditions for positive and negative cross-talk. Particularly, synergistic signal interaction was evident at very different sets of binding affinities and phosphorylation kinetics. We identified three classes of 14-3-3 targets that all have two binding sites, but displayed synergistic interaction between converging signalling pathways for different ranges of parameter values. Consequently, these protein targets will respond differently to interventions that affect 14-3-3 binding affinities or phosphorylation kinetics