The independent variable is the drug, while patient blood pressure is the dependent variable. In some ways, this experiment resembles the one with breakfast and test scores. However, when comparing two different treatments, such as drug A and drug B, it’s usual to add another variable, called the control variable. The control variable, which in this case is a placebo that contains the same inactive ingredients as the drugs, makes it possible to tell whether either drug actually affects blood pressure. The independent variable is the condition that you change in an experiment.
- The slope tells us how the dependent variable (\(y\)) changes for every one unit increase in the independent (\(x\)) variable, on average.
- Even if you are still searching for a job that allows you to be economically self-sufficient, you can still take steps to work towards becoming financially independent.
- Collectively, these results revealed that combined inhibition of IKKε and TBK1 kinase activities caused myeloid cell expansion and T cell activation that were mediated by RIPK1 kinase activity-dependent and -independent pathways.
- For others, it may be expected that adult children will continue to live at home or receive assistance from their parents, even once they are working full-time.
- You have three independent variable levels, and each group gets a different level of treatment.
We found that IkkeK38A/K38A Tbk1fl/D135N Cx3cr1-Crewt/tg mice developed splenomegaly, granulocytosis, and monocytosis that were not observed in Tbk1fl/D135N Cx3cr1-Crewt/tg mice (Fig. 3b–e). Moreover, IkkeK38A/K38A Tbk1fl/D135N Cx3cr1-Crewt/tg mice showed a relative decrease in the percentage but not total number of splenic CD4+ and CD8 + T cells, which had an activated phenotype indicated by an increased CD69 to CD62L ratio (Fig. 3f, g). Importantly, homozygous expression of RIPK1-D138N prevented both the splenomegaly and expansion of myeloid cells as well as the activated T cell phenotype in IkkeK38A/K38A Tbk1fl/D135N Cx3cr1-Crewt/tg Ripk1D138N/D138N mice (Fig. 3b–g). Together, these results showed that IKKε and TBK1 share a redundant myeloid cell-intrinsic function that is essential to prevent RIPK1 kinase-dependent granulocytosis, monocytosis and T cell activation.
Independent vs. Dependent Variables Definition & Examples
IL-1β but also IL-18 and IL-33 have been shown to promote myelopoiesis and granulocytosis by stimulating G-CSF expression37,38,39. We therefore hypothesized that increased production of IL-1 family cytokines by TBK1-IKKε-deficient myeloid cells could be implicated in driving the expansion of granulocyte and monocyte compartments and cause systemic inflammation in these mice. Flow cytometry analysis confirmed the absence of IL-18R1 and IL-33R, while immunoblot analysis confirmed the loss of IL-1R1 in BM cells from Il1.18.33r-/- mice (Supplementary Fig. 4c, d). In addition, BM cells from Il1.18.33r-/- did not produce IL-6 in response to IL-1β, IL-18 and IL-33, but they produced normal levels of IL-6 after stimulation with IL-36β, functionally validating the specific deficiency of IL-1R1, IL-18R1, and IL-33R in these animals (Supplementary Fig. 4e, f).
IkkeK38A/K38A Tbk1fl/D135N Afp-Crewt/tg mice displayed normal spleen size and did not show liver pathology as judged by the absence of apoptotic cells and infiltrating immune cells as well as normal values of serum ALT, ALP and AST (Fig. 5a, c). Therefore, neither myeloid cell-specific nor liver parenchymal cell-specific IKKε and TBK1 inhibition were sufficient to cause liver damage, suggesting that combined inhibition of these kinases in both immune and parenchymal cells triggered cell death and inflammation in the liver. TBK1 and IKKε are IKK-related kinases that were first identified as critical mediators of type I IFN activation downstream of nucleic acid sensors14. The role of TBK1 in type I IFN activation, metabolic regulation, and TNFR1 signaling has been extensively studied11,26,27,40,41,42, however, the role of IKKε remains poorly understood. Here we employed genetic mouse models to study the in vivo role of IKKε and TBK1, particularly focusing on exploring potentially redundant functions of these kinases.
Cell death assay was performed using the Incucyte bioimaging platform (Essen); four images per well were captured with a lens that has a magnification of 10. Blood-cell-count analysis was performed using 40 µl of peripheral blood samples from mice using an Abacus Junior Vet analyzer according to the manufacturer’s instructions. So from this graph, you can see that the more dogs groomed, the higher the maintenance cost, and it is rising in a somewhat linear manner too.
In contrast, Tbk1D135N/D135N IkkeK38A/K38A Ripk1wt/D138N as well as Tbk1-/- Ikke-/- Ripk1wt/D138N mice showed a number of pathological features affecting multiple tissues, revealing an important role of IKKε in compensating for the loss of TBK1 to maintain tissue homeostasis and prevent disease. Combined loss of TBK1 and IKKε or their kinase activities in Ripk1wt/D138N genetic background caused transient alopecia, with 100% of these animals showing lack of hair at 3-4 weeks of age but fully recovering hair growth by the age of 7-8 weeks. The transient alopecia induced by combined loss of TBK1 and IKKε was entirely dependent on RIPK1 kinase activity as it was not observed in a homozygous Ripk1D138N/D138N genetic background. Interestingly, IkkeK38A/K38A Tbk1fl/D135N K14-CreTg/wt mice did not show hair loss arguing that TBK1 and IKKε act in cells other than keratinocytes to prevent alopecia. It is also noteworthy that keratinocyte-specific inhibition of TBK1 and IKKε did not cause skin pathology even in the presence of wild type RIPK1, showing that IKK-related kinases are not required to prevent RIPK1-mediated cell death and inflammation in the skin.
The dependent variable (height) depends on the independent variable (age). The target variable is used in supervised learning algorithms but not in unsupervised learning. An independent variable is the variable that is changed or controlled in a scientific experiment to test the effects on the dependent variable. The dependent variable is the condition that you measure in an experiment.
Combined inhibition of IKKε and TBK1 caused RIPK1-dependent liver inflammation
Importantly, inhibition of RIPK1 kinase activity by homozygous expression of RIPK1-D138N prevented the intestinal pathology of IkkeK38A/K38A Tbk1fl/D135N Villin-Crewt/tg mice (Fig. 8d). Taken together, these results showed that IKKε and TBK1 act in both IECs and myeloid cells to prevent cell death and inflammation in the gut. To study the physiological role of the kinase activity of TBK1 and IKKε in vivo, we generated mice expressing catalytically inactive versions of these kinases. Specifically, we introduced mutations substituting aspartic acid at position 135 of TBK1 with arginine (TBK1-D135N) and lysine at position 38 of IKKε with alanine (IKKε-K38A) in the respective endogenous genes using CRISPR/Cas9-mediated gene targeting (Fig. 1a, b).
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In an algebraic equation, an independent variable describes a variable whose values are independent of changes. If x and y are two variables in an algebraic equation and every value of x is linked with any other value of y, then ‘y’ value is said to be a function of x value known as an independent variable, and ‘y’ value is known as a dependent variable. Whether you’re conducting an experiment or learning algebra, understanding the relationship between independent and dependent variables is a valuable skill. Learning the difference between them can be tricky at first, but you’ll get the hang of it in no time.
Since the hair-colour could vary from person to person like for some it is blond, for some, it is black, etc. Most commonly, ‘a’,’b’,’c’, ‘x’,’y’ and ‘z’ are used as variables in equations. The variable is a quantity that can be changed or which is not fixed according to the mathematical operation performed. Usually, in algebra, we express an unknown number using the term ‘x’ and ‘y’. A researcher changes the version of a study guide given to students to see how it affects exam scores.
Taken together, our genetic studies revealed an important role of IKKε in compensating for the absence of TBK1 to prevent cell death and inflammation in multiple tissues. Importantly, RIPK1 kinase activity inhibition strongly suppressed, but could not fully prevent, the pathologies induced by combined inhibition of TBK1 and IKKε, showing that TBK1/IKKε also inhibit cell death and inflammation driven by RIPK1 kinase-independent mechanisms. In addition to its kinase activity-dependent cell death-inducing functions, RIPK1 also acts as a scaffold to promote proinflammatory signaling, which could be implicated in driving inflammation in mice lacking TBK1 and IKKε kinase activities. Moreover, TBK1 income taxes and IKKε are implicated in the regulation of multiple inflammatory signaling pathways2,3,4,5,7,8,9,10,54, metabolism42, mitochondrial homeostasis41,55,56 and autophagy57. While these functions of IKKε and TBK1 could be involved in driving the RIPK1 kinase-independent pathology caused by combined inhibition of TBK1 and IKKε, the specific underlying mechanisms remain elusive and remain to be elucidated in future studies. Our results also provide important insights into the cell-specific function of these kinases, that could also be relevant for the better understanding of the mechanisms driving the autoinflammatory pathology developing in humans with mutations disrupting TBK1 expression27.
The independent and dependent variables may be viewed in terms of cause and effect. If the independent variable is changed, then an effect is seen in the dependent variable. Remember, the values of both variables may change in an experiment and are recorded. The difference is that the value of the independent variable is controlled by the experimenter, while the value of the dependent variable only changes in response to the independent variable.