Transcription factor networks play a key role in human brain evolution and disorders

Although the human brain has been studied over past decades at morphological and histological levels, much remains unknown about its molecular and genetic mechanisms. Furthermore, when compared with our closest relative the chimpanzee, the human brain strikingly shows great morphological changes that have been often associated with our cognitive specializations and skills. Nevertheless, such drastic changes in the human brain may have arisen not only through morphological changes but also through changes in the expression levels of genes and transcripts. Gene regulatory networks are complex and large-scale sets of protein interactions that play a fundamental role at the core of cellular and tissue functions. Among the most important players of such regulatory networks are transcription factors (TFs) and the transcriptional circuitries in which TFs are the central nodes. Over past decades, several studies have focused on the functional characterization of brain-specific TFs, highlighting their pathways, interactions, and target genes implicated in brain development and often disorders. However, one of the main limitations of such studies is the data collection which is generally based on an individual experiment using a single TF. To understand how TFs might contribute to such human-specific cognitive abilities, it is necessary to integrate the TFs into a system level network to emphasize their potential pathways and circuitry. This thesis proceeds with a novel systems biology approach to infer the evolution of these networks. Using human, chimpanzee, and rhesus macaque, we spanned circa 35 million years of evolution to infer ancestral TF networks and the TF-TF interactions that are conserved or shared in important brain regions. Additionally, we developed a novel method to integrate multiple TF networks derived from human frontal lobe next-generation sequencing data into a high confidence consensus network. In this study, we also integrated a manually curated list of TFs important for brain function and disorders. Interestingly, such “Brain-TFs” are important hubs of the consensus network, emphasizing their biological role in TF circuitry in the human frontal lobe. This thesis describes two major studies in which DNA microarray and RNA-sequencing (RNA-seq) datasets have been mined, directing the TFs and their potential target genes into co-expression networks in human and non-human primate brain genome-wide expression datasets. In a third study we functionally characterized ZEB2, a TF implicated in brain development and linked with Mowat-Wilson syndrome, using human, chimpanzee, and orangutan cell lines. This work introduces not only an accurate analysis of ZEB2 targets, but also an analysis of the evolution of ZEB2 binding sites and the regulatory network controlled by ZEB2 in great apes, spanning circa 16 million years of evolution. In summary, those studies demonstrated the critical role of TFs on the gene regulatory networks of human frontal lobe evolution and functions, emphasizing the potential relationships between TF circuitries and such cognitive skills that make humans unique

Species-Specific Changes in a Primate Transcription Factor Network Provide Insights into the Molecular Evolution of the Primate Prefrontal Cortex

The human prefrontal cortex (PFC) differs from that of other primates with respect to size, histology, and functional abilities. Here, we analyzed genome-wide expression data of humans, chimpanzees, and rhesus macaques to discover evolutionary changes in transcription factor (TF) networks that may underlie these phenotypic differences. We determined the co-expression networks of all TFs with species-specific expression including their potential target genes and interaction partners in the PFC of all three species. Integrating these networks allowed us inferring an ancestral network for all three species. This ancestral network as well as the networks for each species is enriched for genes involved in forebrain development, axonogenesis, and synaptic transmission. Our analysis allows us to directly compare the networks of each species to determine which links have been gained or lost during evolution. Interestingly, we detected that most links were gained on the human lineage, indicating increase TF cooperativity in humans. By comparing network changes between different tissues, we discovered that in brain tissues, but not in the other tissues, the human networks always had the highest connectivity. To pinpoint molecular changes underlying species-specific phenotypes, we analyzed the sub-networks of TFs derived only from genes with species-specific expression changes in the PFC. These sub-networks differed significantly in structure and function between the human and chimpanzee. For example, the human-specific sub-network is enriched for TFs implicated in cognitive disorders and for genes involved in synaptic plasticity and cognitive functions. Our results suggest evolutionary changes in TF networks that might have shaped morphological and functional differences between primate brains, in particular in the human PFC

Selenium Biofortification in Radish Enhances Nutritional Quality via Accumulation of Methyl-Selenocysteine and Promotion of Transcripts and Metabolites Related to Glucosinolates, Phenolics, and Amino Acids

Two selenium (Se) fertilization methods were tested for their effects on levels of anticarcinogenic selenocompounds in radish (Raphanus sativus), as well as other nutraceuticals. First, radish was grown on soil and foliar selenate applied 7d before harvest at 0, 5, 10 and 20 mg Se per plant. Selenium levels were up to 1,200 mg Se/kg DW in leaves and 120 mg Se/kg DW in roots. The thiols cysteine and glutathione were present at 2-3 fold higher levels in roots of Se treated plants, and total glucosinolate levels were 35% higher, due to increases in glucoraphanin. The only seleno-aminoacid detected in Se treated plants was Se-methyl-SeCys (100 mg/kg FW in leaves, 33 mg/kg FW in roots). The levels of phenolic aminoacids increased with selenate treatment, as did root total nitrogen and protein content, while the level of several polyphenols decreased. Second, radish was grown in hydroponics and supplied with 0, 5, 10, 20, or 40 \uf06dM selenate for one week. Selenate treatment led to a 20-30% increase in biomass. Selenium concentration was 242 mg Se/kg DW in leaves and 85 mg Se/kg DW in roots. Cysteine levels decreased with Se in leaves but increased in roots; glutatione levels decreased in both. Total glucosinolate levels in leaves decreased with Se treatment due to repression of genes involved in glucosinolates metabolism. Se-methyl-SeCys concentration ranged from 7-15 mg/kg FW. Aminoacid concentration increased with Se treatment in leaves but decreased in roots. Roots of Se treated plants contained elevated transcript levels of sulfate transporters (Sultr) and ATP sulfurylase, a key enzyme of S/Se assimilation. No effects on polyphenols were observed. In conclusion, Se biofortification of radish roots may be achieved via foliar spray or hydroponic supply. One to ten radishes could fulfill the daily human requirement (70 \uf06dg) after a single foliar spray of 5 mg selenate per plant or one week of 5-10 \uf06dM selenate supply in hydroponics. The radishes metabolized selenate to the anticarcinogenic compound Se-methyl-selenocysteine. Selenate treatment enhanced levels of other nutraceuticals in radish roots, including glucoraphanin. Therefore, Se biofortification can produce plants with superior health benefit

Two-Phase Heat Transfer of Low GWP Ternary Mixtures

Refrigerant blends obtained mixing hydrofluorocarbons (HFC) and hydrofluoroolefins (HFO) have recently been proposed as substitutes for high GWP (Global Warming Potential) fluids employed in refrigeration and air-conditioning systems. As a general trend, the dimension of pipes used in heat exchangers is decreasing: diameters around 5 mm are often employed in finned-tube coil heat exchangers and minichannels heat exchangers (with internal diameter around 1-2 mm) are also a common solution for the automotive sector and for air-cooled chillers. Condensation and flow boiling heat transfer coefficients of zeotropic ternary mixtures R455A (R32, R1234yf and R744 at 21.5/75.5/3.0% by mass composition) and R452B (R32, R1234yf and R125 at 67.0/26.0/7.0% by mass composition) have been measured inside a minichannel (0.96 mm diameter) and inside a conventional tube (8.0 mm diameter). R455A exhibits a temperature glide around 10 K at 35 °C bubble temperature whereas R452B presents a temperature glide around 1 K at 40 °C bubble temperature. The experimental results are compared with selected correlations for condensation and flow boiling heat transfer which account for the additional mass transfer resistance occurring during two-phase heat transfer of zeotropic mixtures. It emerges the importance of including the mass transfer resistance for the prediction of heat transfer coefficient when considering high temperature-glide mixtures

Learning Efficient Surrogate Dynamic Models with Graph Spline Networks

While complex simulations of physical systems have been widely used in engineering and scientific computing, lowering their often prohibitive computational requirements has only recently been tackled by deep learning approaches. In this paper, we present GraphSplineNets, a novel deep-learning method to speed up the forecasting of physical systems by reducing the grid size and number of iteration steps of deep surrogate models. Our method uses two differentiable orthogonal spline collocation methods to efficiently predict response at any location in time and space. Additionally, we introduce an adaptive collocation strategy in space to prioritize sampling from the most important regions. GraphSplineNets improve the accuracy-speedup tradeoff in forecasting various dynamical systems with increasing complexity, including the heat equation, damped wave propagation, Navier-Stokes equations, and real-world ocean currents in both regular and irregular domains.Comment: Published as a conference paper in NeurIPS 202

fatigue properties of austempered ductile iron to steel dissimilar arc welded joints

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Condensation Heat Transfer Coefficient Measurements and Flow Pattern Visualizations of R515B and R450A Inside a 3.4 mm Diameter Channel

An alternative low Global Warming Potential (GWP) refrigerant that could be used to replace R134a in heat pumps, refrigeration and air-conditioning systems is the hydrofluoroolefin R1234ze(E). As a drawback, R1234ze(E) is classified as a mildly flammable fluid (A2L ANSI/ASHRAE classification) and it presents a lower volumetric cooling capacity compared to R134a. In the search for non-flammable R134a substitutes, hydrofluorocarbon/hydrofluoroolefin binary mixtures can be considered. R515B (R1234ze(E)/R227ea at 91.1/8.9% by mass) and R450A (R1234ze(E)/R134a at 58.0/42.0% by mass) are two alternatives classified as A1 (not flammable). R515B is an azeotropic mixture with GWP100-years = 299, whereas R450A is a near-azeotropic blend (temperature glide 0.6 K at 40 °C) with GWP100-years = 547. In this work, condensation tests are performed with R515B and R450A inside a circular cross-section channel with an inner diameter equal to 3.4 mm. The test section is composed of two copper heat exchangers designed for the measurement of the quasi-local heat transfer coefficient. A glass tube, located between the two diabatic parts of the test section allows the visualization of the two-phase flow patterns by a high-speed camera. Heat transfer coefficients are measured at 40 °C mean saturation temperature and mass flux between 50 and 300 kg m-2 s-1. The prediction accuracy of condensation heat transfer models is then assessed against the experimental results. Measured heat transfer coefficients are also compared with those of R1234ze(E) at the same operative conditions. Regarding the diameter of the present test tube, it is worthy to point out that small diameter tubes are often employed in finned coil heat exchangers and minichannel heat exchangers are a common solution for air-cooled condensers

Fatigue assessment of welded joints by means of the Strain Energy Density method: Numerical predictions and comparison with Eurocode 3: Numerical predictions and comparison with Eurocode 3

The main aim of the present work is to investigate the effects of different parameters on the fatigue strength of four different welded details through an energetic approach based on the Strain Energy Density failurecriteria.The results of the finite element analyses have been compared with the fatigue strength predicted by the design guidance EN 1993-1-9:2005, also known as Eurocode 3, which establishes the rules for the fatigue design of steel welded joints.The results obtained in this work highlight an overestimation of the fatigue strength by the Eurocode 3 with regard to the details considered

Introgression of mitochondrial DNA among Myodes voles: consequences for energetics?

Background Introgression of mitochondrial DNA (mtDNA) is among the most frequently described cases of reticulate evolution. The tendency of mtDNA to cross interspecific barriers is somewhat counter-intuitive considering the key function of enzymes that it encodes in the oxidative-phosphorylation process, which could give rise to hybrid dysfunction. How mtDNA reticulation affects the evolution of metabolic functions is, however, uncertain. Here we investigated how morpho-physiological traits vary in natural populations of a common rodent (the bank vole, Myodes glareolus) and whether this variation could be associated with mtDNA introgression. First, we confirmed that M. glareolus harbour mtDNA introgressed from M. rutilus by analyzing mtDNA (cytochrome b, 954 bp) and nuclear DNA (four markers; 2333 bp in total) sequence variation and reconstructing loci phylogenies among six natural populations in Finland. We then studied geographic variation in body size and basal metabolic rate (BMR) among the populations of M. glareolus and tested its relationship with mtDNA type. Results Myodes glareolus and its arctic neighbour, M. rutilus, are reciprocally monophyletic at the analyzed nuclear DNA loci. In contrast, the two northernmost populations of M. glareolus have a fixed mitotype that is shared with M. rutilus, likely due to introgressive hybridization. The analyses of phenotypic traits revealed that the body mass and whole-body, but not mass corrected, BMR are significantly reduced in M. glareolus females from northern Finland that also have the introgressed mitotype. Restricting the analysis to the single population where the mitotypes coexist, the association of mtDNA type with whole-body BMR remained but those with mass corrected BMR and body mass did not. Mitochondrial sequence variation in the introgressed haplotypes is compatible with demographic growth of the populations, but may also be a result of positive selection. Conclusion Our results show that the phenotypic traits vary markedly along the north-south axis of populations of M. glareolus. This variation may be related to adaptation to local environments and coincides with the gradient of genome reticulation between M. glareolus and M. rutilus, which was assessed by mtDNA introgression. Introgression of mtDNA may have affected morpho-physiological traits but do not show strong effects on either body mass or basal metabolic rate alone. We discuss the causes and biological meaning of our results and the means to clarify these questions in future research.peerReviewe