11 research outputs found
Fluid dynamics alter Caenorhabditis elegans body length via neuromuscular signaling with TGF-β/DBL-1
No full textThis is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record.Skeletal muscle wasting is a major obstacle for long-term space exploration. Similar to astronauts, the nematode Caenorhabditis elegans displays negative muscular and physical effects grown in space microgravity. However, it is still unclear what signal molecules and behavior affect the negative alterations. We here studied key signaling molecules involved in alterations of C. elegans physique in response to fluid-dynamics on the ground-based experiments. Like as spaceflight experiment with 1G accelerator onboard, a myosin heavy chain myo-3 and a TGF- dbl-1 gene expression altered increasing the fluid dynamic parameters viscosity/drag resistance or depth of liquid culture. These gene expression also drastically increased grown liquid medium as compared with moist agar surface. In addition, body length enhanced in WT and body-wall cuticle collagen mutants, rol-6 roller and dpy-5 dumpy, grown in liquid culture. On the other hand, in a TGF- gene dbl-1 and its signaling pathway sma-4/Smad mutants, their body lengths did not alter in liquid. Similarly, a D1-like dopamine receptor DOP-4 and a mechanosensory channel UNC-8 were required for altered physique in which DBL-1 signaling did not upregulated in liquid. Since C. elegans contraction rates are much higher in swimming mode in liquid than clawing mode on agar surface, we studied the relationship between body-length enhancement and contraction rate. Mutants significantly reduced contraction rate commonly show smaller size, although the rate in dop-4, dbl-1 and sma-4 mutants still increased in liquid. These results suggest that neuromuscular signaling via TGF-/DBL-1 to alter body physique in response to environmental conditions including fluid dynamics.We are grateful to the entire crew of the CERISE for their work on STS-129, STS-130, and the International Space Station. The CERISE was organized with the support of the JAXA. We also thank the Caenorhabditis elegans Genetic Center for kindly supplying the mutant strains. This work was also supported by JSPS KAKENHI grant numbers 26506029, 15H05937, the Cross-ministerial Strategic Innovation Promotion Program (J150000592), the Medical Research Council UK (G0801271), and National Institutes of Health (NIH NIAMS ARO54342). This work was supported by grants from the MEXT, the JSPS (15H05937, 26506029), the Cross-ministerial Strategic Innovation Promotion Program (J150000592), and the Cell Biology Experiment Project conducted by the Institute of Space and Astronautical Science in JAXA. TE was supported by the Medical Research Council of UK (G0801271). NJS was supported by the National Institutes of Health (NIH NIAMS ARO54342)
Validation of the OAKS prognostic model for acute kidney injury after gastrointestinal surgery
No full textBackground: Postoperative acute kidney injury (AKI) is a common complication of major gastrointestinal surgery with an impact on short- and long-term survival. No validated system for risk stratification exists for this patient group. This study aimed to validate externally a prognostic model for AKI after major gastrointestinal surgery in two multicentre cohort studies. Methods: The Outcomes After Kidney injury in Surgery (OAKS) prognostic model was developed to predict risk of AKI in the 7 days after surgery using six routine datapoints (age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker). Validation was performed within two independent cohorts: a prospective multicentre, international study (‘IMAGINE’) of patients undergoing elective colorectal surgery (2018); and a retrospective regional cohort study (‘Tayside’) in major abdominal surgery (2011–2015). Multivariable logistic regression was used to predict risk of AKI, with multiple imputation used to account for data missing at random. Prognostic accuracy was assessed for patients at high risk (greater than 20 per cent) of postoperative AKI. Results: In the validation cohorts, 12.9 per cent of patients (661 of 5106) in IMAGINE and 14.7 per cent (106 of 719 patients) in Tayside developed 7-day postoperative AKI. Using the OAKS model, 558 patients (9.6 per cent) were classified as high risk. Less than 10 per cent of patients classified as low-risk developed AKI in either cohort (negative predictive value greater than 0.9). Upon external validation, the OAKS model retained an area under the receiver operating characteristic (AUC) curve of range 0.655–0.681 (Tayside 95 per cent c.i. 0.596 to 0.714; IMAGINE 95 per cent c.i. 0.659 to 0.703), sensitivity values range 0.323–0.352 (IMAGINE 95 per cent c.i. 0.281 to 0.368; Tayside 95 per cent c.i. 0.253 to 0.461), and specificity range 0.881–0.890 (Tayside 95 per cent c.i. 0.853 to 0.905; IMAGINE 95 per cent c.i. 0.881 to 0.899). Conclusion: The OAKS prognostic model can identify patients who are not at high risk of postoperative AKI after gastrointestinal surgery with high specificity
Eine mikroskopische Übersicht intrazellulärer Transportprozesse
No full textDas Ziel dieser Arbeit ist die Entwicklung eines verbesserten Verständnisses von intrazellulären Transportprozessen in multizellulären Organismen. Für diese Zwecke wurde in diesen Studien die Vorzüge des Modelorgansimus Caenorhabditis elegans benutzt um dessen Familie der Rab-GTPasen zu untersuchen, da diese kleinen GTPasesn sämtliche Transportprozesse organisieren. Diese Arbeit umfasst eine morphologische und phenotypische Beschreibung der verfügbaren Mutanten dieser Rab-Genfamilie auf zellulärer und subzellulärer Ebene in 2D und 3D, mit Hilfe von elektronen- und röntgen-mikroskopischen Methoden. Zusätzlich wurde zur Bewahrung der zellulären Ultrastruktur die Methode des Hoch-Druck-Gefrierens angewendet, da diese Methode eine instantane, native Konservierung des gesamten Wurmes ermöglicht. Eine Einführung in die Thematik des intrazellulären Transport ist gegeben in Kapitel I währen alle benutzen Methoden in Kapitel II zu finden sind. Die Ergebnisse der morphologischen Studie mit Hilfe von elektronenmikroskopischen Methoden sowie die Verhaltensstudien von den Rab-Mutanten sind in einem Rab-Atlas zusammengefasst und werden in einem frei zugänglichen Rab-Wiki der Forschungsgemeinschaft zur Verfügung gestellt. Die Ergebnisse aus allen vom Author, für diese Studie, durchgeführten und analysierten Experimenten sind in Kapitel III aufgeführt und diskutiert. Weitere Fokus wurde auf die ultra-schnellen Transportprozesse in Nervenzellen gerichtet. Für die Auswertung der Vesikel Verteilungen in Neuronen wurde hierfür das semi-automatisches Programm XtraCOunt entwickelt. Die Ergebnisse dieser Studien sind in Kapitel IV zusammengefasst und die erste Anwendung dieses vielseitigen Programmes in weiterführenden Studien wird in Kapitel V präsentiert. Zuletzt wurden erste röntgen-mikroskopische Untersuchungen für die Untersuchung von Hoch-Druck-Gefrorenen Proben ausprobiert. Diese Tests umfassen die Untersuchung in der Phasenkontrast-Bildgebung, Holotomographie und Röntgenspektroskopie. In Kapitel VI werden die zugrundeliegenden mathematisch-physikalischen Hintergründe erörtert und die vielversprechenden Ergebnisse dieser Untersuchungen präsentiert. Im abschließenden Kapitel VII werden alle die Zusammenhänge der Untersuchungen dieser Studie diskutiert und deren Beitrag zum weiteren Verständnis im Dienste der Forschungsgemeinschaft erörtert.The general aim of this thesis work is to gain an encompassing insight into the intracellular trafficking machinery of multicellular organisms. For this purpose, the previously well-described model organism Caenorhabdits elegans is analyzed in our studies, with a focus on the family of small Rab-GTPases. These Rab-proteins (RABs) are the central players that orchestrate all intracellular trafficking events. An introduction to the current understandings in this field of science is given in the introductory chapter I. This thesis work began with a morphological description and a behavioral characterization of mutants of all members of rab-gene (rab) family. The major technique used for this anatomic investigation on the cellular- and subcellular level was two- as well as three-dimensional electron microscopy of high-pressure frozen nematode with a near-native sample-preservation. An atlas comprising all morphological data together with the results of additional behavioral studies, is the ultimate outcome of this thesis work. Among the descriptions of several tissues and organelles, the findings that the Golgi shapes seems to adapt to the activity in a tissue-specific manner is of central importance as it suggests that intracellular transport processes must also be investigated in a tissue-specific fashion. The generated tissue- and Rab-Atlas, along with all related results, is presented in chapter III, while a detailed description of used materials and methods is given in chapter II. During the entire investigation a special focus was directed towards the ultra-fast trafficking events that ensure the transmission at synapses. To aid these studies, the image analysis tool XtraCOunt was generated during this thesis work in order to semi-automates the analysis of these trafficking studies. Chapter IV describes this tool along with all its features. In the atlas studies the rab-10 mutant was identified as potentially neuronally impaired. In chapter IV, this mutant is examined for its synaptic features and it has been found to resemble the rab-2 mutant alterations in dense-core vesicle biogenesis. XtraCOunt was conceived for the analysis of electron micrographs of nematode synapses but was shown to be applicable in a vast range of other trafficking studies. Current collaborating studies, using this tool, led to the understanding of the phenotype of Sydney Brenner's first described mutant dpy-1 (dumpy), whose cuticular components are not able to maintain their network integrity. The fundamental findings of this study are presented in chapter V. To overcome imaging-constrains presented by the mostly electron microscopic nature of my study, I have furthermore tested the possibility of studying high-pressure frozen specimen with x-rays. High resolution phase contrast imaging, holo-tomography as well as micro-fluorescence investigations were tested for their applicability, feasibility and limitations. Their underlying mathematical theory and the obtained experimental results are presented and discussed in chapter VI. The major results of these investigations is a full-worm-tomogram with subcellular resolution and a map of tissue-specific elemental distributions within worm thin-slices. The concluding chapter VII briefly summarizes the results of all performed investigations in the context with one another and their possible meaning for the intracellular trafficking community
Price re-interpretations of the basic IO quantity models result in the ultimate input-output equations
No full textThis note shows that Leontief's well-known demand-driven input–output (IO) quantity model may also be interpreted as the almost unknown revenue-pull IO price model, but measured in value terms instead of in prices. It is also shown how these two demand-driven models may be combined into a single ultimate demand-driven IO equation. An analogous result holds for the supply-driven quantity model and the cost-push price model, which results in a single ultimate supply-driven IO equation. The new price interpretation of the Leontief quantity model opens up hitherto unused possibilities to simulate interindustry demand-driven inflation processes, just as the price interpretation of the Ghosh quantity model enables simulations of supply-driven inflation processes. KEYWORDS: Leontief modelGhosh modelSupply-driven inflationDemand-driven inflationUltimate input–output equations Previous article View latest articles Next article 1. Introduction The four basic input–output (IO) models are mathematically very similar, but economically they are worlds apart. The two quantity models are each other’s mirror image, as are their corresponding, two price models. The demand-driven IO quantity model (Leontief, 1941) and its cost-push IO price dual (Leontief, 1951) are well known. The supply-driven IO quantity model (Ghosh, 1958) is less known and – for good reasons – has hardly been used since the 1990s. Its revenue-pull IO price dual (Davar, 1989; Oosterhaven, 1989) is not known at all and has never been used, despite its potential. This note shows that this least known IO model can be rewritten such that it mimics the best known IO model, i.e. it mimics Leontief's quantity model, which therefor may also be interpreted as the Davar/Oosterhaven price model measured in value terms instead of in prices. As such, it may empirically be used to simulate demand-driven inflation processes, as opposed to supply-driven inflation processes that may be simulated with Leontief's cost-push price model. Before proving and explaining this new model interpretation, we briefly summarize the four basic IO models and present a more elegant proof for the re-interpretation of the Ghosh quantity model as the Leontief price model measured in values instead of in prices (Dietzenbacher, 1997). Besides, we show that the solution of both supply-driven models, as well as that of both demand-driven models, can be combined into one single, ultimate IO equation. 2. The four basic input–output models All four basic IO models are based on the accounting identities of the industry-by-industry type of input–output table (IOT) shown in , which also contains the definitions of the vectors and matrices used in this note. In and elsewhere, the symbol ∈ is used to indicate that the scalar or equation on its left-hand side represents the typical element or the typical equation of the matrix formulation on its right-hand side, e.g. yiq∈Y in indicates that the matrix with final outputs Y has yiq as its typical element, with i = 1, … , I and q = 1, … , Q, where I = the number of industries and Q = the number of final demand categories. Analogously, vpj=cpjxj∈Vi=Cx in the text just above (1) indicates how, in the Leontief model, primary inputs vpj∈V are determined by fixed primary input coefficients cpj∈C and total output xj∈x, with p = 1, … , P and j = 1, … , I, where P = number of primary input categories. Table 1. Input–output table with macro totals. Display Table IOTs are always expressed in monetary values. For IO modeling purposes, these monetary values are treated as quantities measured in unit prices with the value one, which is how the symbols in will be interpreted in this note. Consequently, prices in this note do not represent real prices but index prices that all have a value of one in the base year of the IOT. , by the way, also shows that an IOT essentially represents a double sectoral breakdown of the well-known macro-economic accounting identity for the Gross Domestic Product: Y = C + I + G + E – M. Italics are used to indicate scalars, whereas bold lower cases indicate vectors and bold capitals indicate matrices. A summation column with ones is indicated by i, while a summation row with ones is indicated by í. Both sets of input–output models may be given a microeconomic foundation, as both sets may be based on simplifications of the most general production function with multiple inputs and multiple outputs, as measured in 's columns and rows, respectively. The pair of Leontief models assumes single homogenous outputs across the rows of the IOT, each with a uniform price, along with heterogeneous inputs with different prices across its columns, whereas the Ghosh/Davar pair of models assumes single homogenous inputs across the columns of the IOT, each with a uniform price, along with heterogenous outputs with different prices across its rows (see the Appendix for all assumptions of both sets of models).1 In the classic demand-driven IO quantity model, along the rows of the IOT, total exogenous final demand quantities y=Yi, along with total endogenous intermediate demand quantities Zi, determines the size of total output, i.e. x=Zi+y. At constant prices, total output, in turn, backwardly along the columns of the IOT, determines the use of both intermediate and primary inputs by means of fixed intermediate input coefficients zij=aijxj∈Zi=Ax and fixed primary input coefficients vpj=cpjxj∈Vi=Cx, with i′A+i′C=i′. The changes in intermediate inputs subsequently lead to further and further backward effects on total output (see Figure 1). The solutions for total output, intermediate inputs, and primary inputs (i.e. imports and value added) then, respectively, read as follows: x=Ax+y⇒x=(I−A)−1y=Ly,Zi=ALyandVi=CLy(1) where L = the Leontief-inverse. Obviously, reality only comes close to this model when all markets are characterized by excess supply, i.e. around the bottom of the business cycle, but even then price reactions may dampen the predicted quantity changes (see further Oosterhaven, 2022, Ch. 7) Figure 1. Common causal structure of the demand-driven IO price and quantity model. Display full size The cost-push price dual of this classic IO model, along the columns of , assumes that exogenous primary input prices pp∈pv, along with endogenous intermediate input prices pi∈p, weighted with their respective cost shares C and A, determine the cost and price of total inputs pj=∑ipiaij+∑pppcpj∈p′=p′A+p′vC. At constant quantities, any change in the cost of total inputs is passed on uniformly, along the rows of the IOT, to all intermediate and final users of the outputs of the industry at hand. The changes in the prices of intermediate inputs are subsequently passed on further and further (see Figure 2). The solution for the prices of total output/input then reads as follows: p′=p′A+p′vC⇒p=p′vC(I−A)−1=p′vCL(2) Obviously, with constant quantities, this cost-push price model is suited to simulate the further forward, supply-driven price impacts of e.g. an increase in the import prices of oil and natural gas. More generally, it is able to simulate any kind of supply-driven inflation process.2 Figure 2. Common causal structure of the supply-driven IO price and quantity model. Display full size The duality of the two Leontief models may be illustrated by post-multiplying (2) with total final demand y. This gives: p′y=p′vCLy=p′vv(3) Although the values of the solutions of (1) and (2) are linked in (3), the variables of both models move independently. Exogenous final demand quantities y backwardly determine primary input quantities v in the quantity model, whereas exogenous primary supply prices pv forwardly determine final output prices p in the price model. On to the mirror images in the second pair of basic IO models. The supply-driven IO quantity model, along the columns of , at constant unit prices, assumes that the exogenous supply of primary input quantities v′=i′V, along with the endogenous supply of intermediate input quantities i′Z, determines the size of total input, and thus of total output, i.e. x′=i′Z+v′. In turn, the supply of total output, forwardly along the rows of the IOT, determines intermediate and final outputs by means of fixed intermediate output coefficients zij=xibij∈i′Z=x′B and fixed final output coefficients yiq=xidiq∈i′Y=x′D, with Bi+Di=i. The changes in intermediate outputs subsequently lead to further and further forward changes in total input and thus in total output (see Figure 2). The solutions for total input/output, intermediate output and final output (i.e. domestic final demand and exports) then, respectively, read as follows: x′=x′B+v′⇒x′=v′(I−B)−1=v′G,i′Z=v′GBandi′Y=v′GD(4) where G = the Ghosh-inverse. The assumption of a single homogenous input per column of the IOT, which is hidden in (4), implies the perfect substitutability of all inputs. This makes the model highly implausible, as it allows factories to work without labor and cars to drive without gas (see further Oosterhaven, 1988).3 In the revenue-pull price dual of this model, along the rows of the IOT, at constant quantities, exogenous prices for the single homogeneous final demands of category q, pq∈py′, along with endogenous prices for the single homogenous intermediate demands of industry j, pj∈p′, weighted with their respective revenue shares D and B, determine total output prices pi=∑jbijpj+∑qdiqpq∈p=Bp+Dpy′ and thus total revenue. In turn, any change in total revenue is fully passed on backwardly into the single price of intermediate and primary inputs per column of the IOT, with the intermediate input price changes subsequently being passed on further and further (see Figure 1). The solution for the prices of total output/input then reads as follows: p=Bp+Dpy′⇒p=(I−B)−1Dpy′=GDpy′(5) Obviously, at constant quantities, this model is suited to simulate the further backward, demand-driven price impacts of e.g. an increase in the export prices of particular industries. More generally, it is able to simulate any demand-driven inflation process. The duality of these last two basic IO models may be illustrated by pre-multiplying (5) with total primary input v′: v′p=v′GDpy′=y′py′(6) Again both model solutions (4) and (5) are linked by their values in (6), whereas their variables move independently: with exogenous primary supply quantities v′ forwardly determining the quantities of final output y′, and exogenous final output prices py′ backwardly determining the prices of primary inputs p. 3. Turning both quantity models into price models measured in values The above-explained supply-driven IO quantity model may be re-interpreted as the cost-push IO price model measured in value terms, instead of in prices (Dietzenbacher, 1997). The economic logic of this re-interpretation follows from Figure 2 that summarizes the identical causal structure of both supply-driven models. In the Ghosh quantity model, the exogenous quantity of primary inputs initiates a forward causal chain of quantity changes along the arrows of Figure 2, whereas in the case of the Leontief price model the exogenous price of primary inputs initiates a similar forward casual chain of price changes along the same arrows. The mathematical proof of the equivalence is simple. Substitute A=Zxˆ−1=xˆBxˆ−1 into the Leontief price model (2) and post-multiply the result with xˆ, where xˆ = a matrix with x on its diagonal and zerós elsewhere. This gives: p′xˆ=p′xˆBxˆ−1xˆ+p′vCxˆ(7) Next, substitute V=Cxˆ in (7), and simplify and solve the result as follows: p′xˆ=p′xˆB+p′vV⇒p′xˆ=p′vV(I−B)−1(8) Equation 8 shows that the Leontief price model (2) is identical to the Ghosh quantity model (4), except that the quantities of (4) are replaced with their corresponding values p′xˆ and p′vV in (8). 4 The economic logic of the comparable re-interpretation of the demand-driven IO quantity model (1) as the revenue-pull IO price model (5) measured in values, instead of in prices, follows from the common causal structure of the two models (see Figure 1). In both demand-driven models, any change in exogenous final demand, irrespective of whether it regards a price change or a quantity change, leads to a direct change in total output. Next, any change in total output backwardly leads to changes in both intermediate and primary inputs, again with the quantities changing in the quantity model and the prices changing in the price model. Finally, any change in intermediate inputs, in turn, leads to further and further backward changes in total output. Mathematically, the equivalence follows from substituting B=xˆ−1Z=xˆ−1Axˆ into the revenue-pull price model (5). Pre-multiplying the result with xˆ gives: xˆp=xˆxˆ−1Axˆp+xˆDpy′(9) Next, Y=xˆD is substituted into (7), and the result is simplified and solved as follows: xˆp=Axˆp+Ypy′⇒xˆp=(I−A)−1Ypy′(10) Equation 10 shows that the Leontief quantity model (1) may indeed be interpreted as the revenue-pull price model (5) wherein the price changes are evaluated in terms of the changes in value that accompany them, i.e. with xˆp and Ypy′. Note that the exogenous final output prices in (5) and (10) are defined per column of final output. In empirical applications of (5) and (10), however, it will often be more useful to assume that the prices of the cells of Ymove independently, e.g. because export price changes of food products will be different from those of chemicals. Note that this does not change the working of the model as final output prices are exogenous. If that more realistic assumption is applied to all the cells of Y in Figure 1, (5) and (10) change into: p=(I−B)−1(D⊗Py)iand(5alt) xˆp=(I−A)−1(Y⊗Py)i,(10alt) respectively, where ⊗ = the cell x cell multiplication of two matrices, and piq∈Py = the matrix with exogenous final output prices. In contrast to (5) and (10), (5alt) and (10alt) allow for an evaluation of the different backward impacts of a 10% increase in the export price of crude oil compared to a 10% increase in the export price of food products; with (5alt) showing the relative backward impact on total output prices and (10alt) showing the corresponding absolute backward impact in terms of changes in the values of total output due to the price change at hand. Dividing the new values by the base year values of (10alt) also gives the relative price changes. 4. Ultimate input–output equations Before concluding, it is worthwhile to look further at the price re-interpretations of both quantity models, as each combines the solutions of the two corresponding basic IO models, which is why we may call them the ultimate input–output equations. First, reconsider the solution of the re-interpretation of the Ghosh quantity model as the Leontief price model measured in values instead of in prices, which is derived in (8): p′xˆ=p′vV(I−B)−1(11) Obviously, we may label (11) the ultimate supply-driven IO equation, as it nicely combines the solution of the supply-driven quantity model and the supply-driven price model. If the quantities V and x are kept constant, (11) shows the impact of changing primary input prices on the prices of total input/output in terms of the absolute changes in the corresponding values, instead of in terms of the changes in the prices as in (2). Dividing the new values by the base year values gives the relative changes in all exogenous and endogenous prices. Alternatively, if the prices pv and p are kept constant at their base year values of one, (11) gives the impact of changing quantities of primary inputs on the quantities of total input/output according to the highly implausible supply-driven IO quantity model. Dividing the new values by the base year values gives the relative changes in total output. Subsequently, to get the changes in endogenous final output quantities and ditto prices (11) needs to be post-multiplied with the final output coefficientś matrix D. This delivers the ultimate IO equation for endogenous final outputs: p′Y=p′vV(I−B)−1D(12) Keeping the prices pv and p constant in (12) delivers the changes in the quantities of final output according to the Ghosh quantity model, whereas keeping the quantities V and Y constant in (12) delivers the changes in the (final) output prices according to the Leontief price model, as measured by the absolute changes in the corresponding values. Dividing by the base year values of one gives the relative price changes.5 Second, reconsider the solution of the re-interpretation of the Leontief quantity model as the Davar/Oosterhaven price model measured in values instead of in prices, as derived in (10): xˆp=(I−A)−1Ypy′(13) Obviously, we may label (13) the ultimate demand-driven IO equation, as it combines the solutions of the demand-driven price and quantity models. If the prices py′ and p are kept constant at their base year values of one, (13) gives the impact of absolute changes in the quantities of final demand on the quantities of total output according to the Leontief quantity model. Again, dividing the new values by the base year values gives the relative changes in the quantities of total output. Alternatively, holding the quantities Y and x constant, (13) gives the impact of changes in final output prices on the prices of total output according to the revenue-pull IO price model, but measured in terms of the effect on the corresponding absolute values, instead of in terms of prices as in (5). Again, dividing the new values by the old values gives the relative changes in all exogenous and endogenous prices. Subsequently, to get the changes in the endogenous primary input quantities and ditto prices, (13) needs to be pre-multiplied with the primary input coefficientś matrix C. This delivers the ultimate IO equation for endogenous primary inputs: Vp=C(I−A)−1Ypy′(14) Keeping prices py′ and p constant in (14) gives the changes in the quantities of primary inputs according to the Leontief quantity model, whereas keeping the quantities Y and V constant in (14) gives the changes in the (primary) input prices according to the Davar/Oosterhaven price model, as measured by the corresponding values of primary inputs. Dividing by the base year values again delivers the relative price changes.6 5. Conclusion This note reiterates and elegantly proves that the supply-driven input–output (IO) quantity model of Ghosh (1958) may be re-interpreted as the cost-push IO price model of Leontief (1951), but measured in value terms instead of in prices (Dietzenbacher, 1997). Additionally, it proves that the demand-driven IO quantity model of Leontief (1941) may similarly be re-interpreted as the almost unknown revenue-pull IO price model (Davar, 1989; Oosterhaven, 1989), again measured in value terms instead of in prices. Furthermore, it shows that the solution of the supply-driven quantity model may be combined in the single Equation 11 with that of the cost-push price model in what may be called: the ultimate supply-driven IO equation. Similarly, it is shown that the solution of the demand-driven quantity model may be combined in the single Equation 13 with that of the revenue-pull price model in what may be called: the ultimate demand-driven IO equation. The new price interpretation of the Leontief quantity model opens up hitherto unused opportunities to do all kinds of demand-driven inflation simulations of exogenous final output price changes. These may be done with the basic Leontief model, but of course also with extensions of this basic model. Interregional and international extensions would allow for simulations of demand-driven, backward price impacts along interregional and international interindustry supply chains, while extensions with endogenous household expenditures would allow for simulations of demand-driven interindustry price-wage-price spirals (see Oosterhaven, 2022, Ch. 7, for a combination of these two model extensions in case of the supply-driven inflation model). These are just two examples of the many possible applications of the price re-interpretation of the Leontief quantity model. Disclosure statement No potential conflict of interest was reported by the author(s). Notes 1 An alternative interpretation in which the Ghosh model is not the exact opposite of the Leontief model is presented by Mesnard (2009). His point of departure is a physical IO table that has homogeneous outputs along its rows and heterogeneous inputs along its columns. With this asymmetric base assumption naturally only asymmetric results can be derived. However, even tons of steel have different qualities with different prices, which is why they cannot sensibly be added in physical units. In real life, any IOT will have heterogeneous outputs along its rows as well as heterogeneous inputs along its columns, which is our point of departure, naturally leading to symmetric results. 2 Note that (2) uses the standard theoretical IO assumption that the prices of the primary inputs are uniform across the corresponding rows. In empirical applications, however, it is often more useful to assume that price changes may be different along the rows of the primary inputs, e.g. because import price changes will be different for different products. This does not change the working of the model, as these prices are exogenous. See Przybyliński and Gorzałczyński (2022) for a recent application of this model. See (5alt) and (10alt) for the analogous modification of the demand-driven price model. 3 See Gruver (1989) and Rose and Allision (1989) for attempts to defend the Ghosh quantity model, and Oosterhaven (1989) for a rebuff. After this exchange the Ghosh quantity model has hardly been used anymore. See Guerra and Sancho (2011) for an attempt to rescue the Type II Ghosh model in case of centrally planned economies, and Oosterhaven (2012) for a rebuff. In an otherwise fine article
Magrath Store News (November 30, 1967)
No full textAn archive of the Magrath Trading Store News.The University of Lethbridge Library received permission from the Wes Balderson to digitize and display this content.PHONES: OFFICE 758-3033 GROCERIES 758-3535 DRY GOODS 758-3252 HARDWARE 758-3065
STORE HOURS: MONDAY, THUESDAY, THURSDAY AND FRIDAY................................................. 8 A«M, to 6 P.M.
WEDNESDAY................ ¿.8 A.M. to 1 P.M............SATURDAY.....................8 A.M. to 7 P.M.
THURSDAY, NOVEMBER 30th, 1967 ......................................................................................................MAGRATH, ALBERTA.
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143,25» Plans were made for the Christmas festivities. Mrs. Isabel Holladay and Mrs. Morrow reported on hospital visitations. President Twila Steed announced the Regional Hospital Auxiliary meeting to be held in Medicine Hat December Sth. Mrs. Elsie Owens took the chair for election of officers for the coming two year term. The following were elected: President - Mrs. Ireta Matkin; 1st Vice President - Mrs, Pariel Tomlinson} 2nd Vice-President - Mrs, Annie Johns, Secretary—Treasurer Mrs. Isabel Holladay* Mrs. Matkin then appointed Mrs, Jfe-ry Nelson sewing «onvener, Mrs, Jean Dudley proposed a vote of thanks to Mrsi Steed for her untiring work during her term as president, especially for all the handwork she did appliquing the blocks on the Centennial quilt and for the amount of other sewing she did.
Retiring president Steed expressed her appreciation for all the encouragement and help she had received during her term of office.
The next meeting will be held January 12th at the home of Mrs, Twila Steed.
Funeral services for the late Roy Coleman who passed away November 19th at the age of 88 years were held in the Magrath LDS Chapel Thursday November 23rd with Bishop L.B, Tanner presiding, Elder Blair Sabey conducting. Prior to the service friends met with the family in the Relief Society Room at which time Smith Ackroyd offered the family prayer, Mrs, Maud -ttirie presided at the organ for the prelude and postlude. Opening hymn was ”0 Father” directed by Mrs. Inez Gibb, Invocation was offered by George Thomson, Eldred Hudson gave the biography of the deceased and J, H, Bridge was speaker, Mrs, Maud Ririe played as a special number an organ solo. Closing hymn was "Abide With Me” directed by Elden Coleman* Steele Blumel offered the benediction.
Ihllbearers were Garth Coleman, Herb Coleman, LaMar Bennett, Gordon Coleman, Vard Coleman, Bob Wright, Interment took place in the Jfegrath cemetery. Arlie Hudson offered the graveside prayer.
A resident of Fhgrath for many years Mrs. Flora Palmer, wife of J. Fred Palmer passed away in Lethbridge Wednesday, November 22nd at the age of 82 years, Born in England, Mrs. Palmer came to Magrath in 191®, was married that same year and resided in Magrath until 1954 when they moved to Lethbridge.
Survivors include her husband, one sone Grant of Lethbridge, four daughters Mrs. Phyllis Beane, Calgary, Mrs. Flora Gull, Bountiful, Utah, Mrs. Edna Nowlin, Lethbridge and Mrs. Grace Lybbert of Glenwood, 23 grandchildren and nine great grandchildren, two brothers in England.
Funeral services were held in the 10th Ave. L,D.S, Chapel, Lethbridge Saturday afternoon with Bishop Wm. Thompson officiating. Pallbearers were Tim Nowlin, Everett Nowlin, Gary Palmer, Don Palmer, larry and Barton Lybbert. Honorary pallbearers were Rickey Palmer and Doral Lybbert. Inteiment took place in the Magrath Cemetery.
A wedding of interest to Jfegrath resident took place in the Stirling L.D.S, Chapel Saturday, November 25th when Iinda Joyce Mertz, daughter of Mr, and Mrs. Wm. John Mertz of Stirling beeame the bride of Paul Eric Jensen, son of Mr, and Mrs. Svend A. Jensen of Ifegrath.
A wedding reception was held honoring the bride and groom in the Stirling Cultural Hall Saturday evening.
Friends will be sorry to hear Mr. George Coleman is a patient in a Lethbridge hospital, where he underwent surgery.
Mr, and Mrs. Ves Sabey had as their guests this weekend their son Jask and Miss Sue Degoyer, students at Rick’s College.
Mr, Marvin Miller and his fiance Miss Bernice Conrad of Calgary visited his parents Mr. and Mrs. Ken Miller during the weekend.
Mr. and Mrs, Carth Soleman had as their weekend guests Mr. Roas Coleman and Miss Irene Purser of Rexburg, Idaho and Miss Peggi- ann Coleman of Calgary.
Word was received Tuesday that Mrs. Emily (Buhler) Cassilias, formerly of Raymond, passed away in California Tuesday morning. She was a sister of Mrs. Ethel Miller and Mrs, Jennie Bone,
A THOUGHT TO LIVE BY
All I have seen teaches me to trust the Creator for all I have not seen. Emerson.
Mrs, Henning Andersen and two children accompanied by Mrs. Jerry Higgens all of Salt Lake City were Ifegrath weekend visitors. Mrs. Andersen visited her husband who is working here, and was the guest of her parents Mr. and Mrs. J. H, Bridge, Mrs. Higgens was the guest of Mr. and Mrs. •arth Coleman.
Melvin Blumell of Provo, Utah visited his parents Mr. and Mrs. Russel Blumell.
MaN’S TESTAMENT
Question not, but live and labor,
Till your goal be won.
Helping every feeble neighbor,
Seeking help from none.
Life is mostly froth and bubble,
Two things stand like stone,
Kindness in another’s trouble,
Courage in your own.
DO YOUR CHRISTMaS SHOPPING EARLY. VISIT THE HARDWARE DEPT, TOYWJD.MAGRATH TRADING COMPANY LTD.
Mr. and Mrs. Bert Gibb, Mr Mary Dudley, Mtb. Alberta Dudley and Mrs. Melba Hodking attended an Elder Family Reunion in Kettle Falls, Washington, recently. Eight sisters and one brother together -with their husbands and wife were present for the occasion.
MAGRATH PaRK jiTRE NEWS» Friday and Saturday December 1st and 2nd ’’FANTASTIC VOYAGE" starring Stephen Boyd, Raquel Welshi In color, cinemascope. Also cartoon and short. Family entertainment;
Mr; and Mrs, Norris Jackson and family of Stettler were Sunday visitors at the home of her parents Mr. and Mrs. Clyne Harker. Mr. and Mrs. Jackson are teaching school in Stettler»
Mr. and Mrs. Jim Heggie and family of Rexburg, Idaho spent the iunerican Thanksgiving holiday visiting her mother Mrs. ardella Bennett and his parents Mr. and Mrs. Albert Heggie in Raymond.
Miss Victoria Briggs of Salt ■Lake City has been visiting at the home of her parents Mr. and Mrs, Ernest Briggs,
Friends will be happy to hear Mrs, Briggs returned home Saturday after being a patient in the Calgary Foothills hospital for several weeks,
Mr. a nd Mrs. A. J, Sabey of Warner visited with friends and relatives in Mag- rath Saturday,
Mr, and Mrs, Martin Gurney of Orem, Utah are the proud parents of a baby daughter, Proud grandparents are Mr, and Mrs. Earl Gurney of Magrath and Mrs, Shaffer of Lethbridge,
Craig Tanner and David Tanner were among the students home from Rick’s College, Rexburg, Idaho to enjoy the Thanksgiving holida visiting family and friends including Mr. and Mrs. L. B. Tanner and Mr. and Mrs. Pingree Tanner.
Bryce Gurney was home from Rick’s College and spent the holiday visiting his parents Mr. and Mrs. Waldon Gurney.
Friends wishing to correspond and send greetings to Elder Brian Bennett, son of Mr, and Mrs. Ray Bennett, Spring Coulee, may do so by contacting him at the following address - Elder Brian Bennett/ 3 rue Renkinj Verviers (liege) Belgique.
Mr. and Mrs. Wm. Wocknitz and Mr. and Mrs. Earl wocknitz were among the relatives who attended the wedding of their niece in Three Hills during the weekend-.
Mrs; Donelda Navratil has reutnred home from Creston B. C. where she visited her parents Mr; and Mrs. Wm. Veale.
Mr, and Mrs. Ted Haines are receiving congratulations on the birth of a daughter last week in the Magrath Municipal Hospital.
Mr. and Mrs. Jay Hamilton were visitors in Dillon, Montana during the weekend.
FOR SUE» Wiener pigs, H. Frenseli 758-3535
N0TI0E» Milk River Ridge AOTS Men’s Club will hold the regular supper meeting in the thgrath United Church Hall Tuesday, December 12th at 7 P.M, A program will follow,u . '1 .
NOTICE» Mrs, Ann Oampbell will present her "Expo" Choir in a short program Sunday, December 3rd at 12:15 P»M. in the Magrath United Church following the regular worship service. The public is invited to attend* Ushers will be in attendance, A silver collection will be taken to aid Mrs, Oampbell in taking her choir to the woJtíld competitions in V/ales this summer. The choir will perform this same Sunday in Del Bonita United Church at 3 P«M.
WANTED» Propane heater - 40,OJO - *>0,000 B,T,U, Suitable for garage.
Contact Trading Co. Hardware Dept,
PaNlRX SALE - The Youth Organizations of the Magrath United Church will hold a joint Pantry Sale in the Lions Hall Saturday, December 9th from 2»30 - 5 P»M, Your support will be most appreciated.
ROD «ND GUN CLUB BINGO — Monday night tec, ¿th,Lions Hall at 8 P,M. Everyone welcome,
ARRIVING ANY DhY - Recliner chairs.
Hardware Dept.
CHRISTMAS LIGHT CLIPS — quick, secure permanent clip on - clip off - for your outdoor lights. Set of 15 - 1,49, Hardware Dept,
Patients in the Magrath Municipal Hospital included Mrs, Alvira Bridge, Mrs, Leora Christensen, Mrs. Delecta Wilde, Mr, Fred Chin, Mr. Frank Hufnagel, Joanne Perry, Jack Bengry, Isaac Waldner, John Waldner Jr,, Ruben D, Entz, Mrs, Katie Mandel, Mrs, Rodney Bly and daughter, Mrs, Mary Jfexwell and DallAft Beazer,
♦•*••••
Mr* Frank Heinish is leaving this Friday, December 1st for Europe where he will join his wife, his daughter, her husband and three children in his native Vienna, Austria.
Mr. Heinish came to Magrath forty years ago and has not returned to his homeland since his arrival here.
He wishes to take this opportunity to wish everyone in Ifegrath and district continued health and happiness and would like to thank everyone for their many kindnesses extended to him and the pleasant association he has had through his forty years in Migra th.
FOR SaLE» 4 roomed house cheap for cash. Esther McVey. Ph 758-3254.MAGRATH GRADING CON'RANY LTD.
Upstairs
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NOTICE; I will do : .roning in my home.
Carol McCoy.
LOST; Man's gold wrist watch on bracelet
L, A. Harrison.
NOTICE; BaZAAR AND BAKE SALE - Magrath 1st
Ward Relief Society will be having a Bazaar,
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the Lions Hall at 2 P.M. Chocolates and
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1st Ward Relief Society.
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Del Bonita School Auxiliary.
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Signaling Mechanisms Behind the Benefits of Sleep
No full textHintergrund: Schlaf ist ein streng regulierter Zustand körperlicher Ruhe und reduzierten Bewusstseins, der evolutionär im ganzen Tierreich konserviert ist. Schlafmangel ist in der modernen Gesellschaft weit verbreitet und betrifft 10 – 30 % der Erwachsenen. Dies stellt ein ernstes gesundheitliches Problem dar, da Schlafmangel mit vielen Krankheiten assoziiert ist, darunter Depressionen, Krebs und Herz-Kreislauf-Erkrankungen. Umgekehrt beeinflussen auch Krankheiten und das Immunsystem das Schlafverhalten. Trotz der fundamentalen Rolle dieser Wechselbeziehung sind grundlegende molekulare Mechanismen, die Funktionen des Immunsystems und Schlafkontrolle verbinden, bisher kaum verstanden. Da die Schlafregulation in Säugetieren sehr komplex ist, ist es sinnvoll konservierte Mechanismen zuerst in einfacheren Modellorganismen zu untersuchen. Der Rundwurm C. elegans ist ein solcher etablierter, simpler und vielseitiger Modellorganismus für die Schlafforschung. Er schläft sowohl im Rhythmus seiner Larvenentwicklung immer jeweils während des Lethargus kurz vor der Häutung, als auch nach besonderem Stress, wie zum Beispiel Hunger oder Hitze. C. elegans besitzt ein invariantes Nervensystem, in dem eine rapide Depolarisation des einzelnen RIS-Interneurons genügt, um Schlaf zu induzieren. Eine Mutation des AP2 Transkriptionsfaktors APTF-1 verhindert die Expression von FLP-11, dem schlafinduzierenden Neuropeptid von RIS. Dies führt praktisch zu völliger Schlaflosigkeit, die in C. elegans in der Regel nicht tödlich ist, und deshalb ein nützliches Modell für genetisch-chronischen Schlafmangel darstellt. Unser Labor fand heraus, dass eine Gain-of-function-Mutation in der Kollagenase NAS-38 über Signalwege der angeborenen Immunität und RIS-Aktivierung zu vermehrtem Schlaf während des Lethargus führt. Gleichzeitig wird dabei die Expression einer ganzen Familie antimikrobieller Peptide (AMP) hochreguliert. Derselbe Signalweg, einschließlich der AMP, sowie das Schlafverhalten werden auch durch Verletzungen induziert. Interessanterweise sterben nicht-schlafende Würmer nach einer Verletzung häufiger. Insgesamt deutet dies darauf hin, dass AMP als Signalmoleküle fungieren könnten, die Schlaf als Teil einer globalen Schutzreaktion vom peripheren Gewebe zum Nervensystem signalisieren. Für diese Hypothese fehlten bisher jedoch die Beweise. Fragestellungen und Hypothesen: Mein Ziel war es, den molekularen Mechanismus zu entschlüsseln, durch den verschiedene Reize der angeborenen Immunität, das heißt NAS-38 sowie epidermale Verletzungen, Schlaf induzieren. Zwei Fragen habe ich hierbei im Speziellen adressiert: Welche Domänen des NAS 38-Proteins sind an der Schlafregulation beteiligt? Da die Astacin-Domäne als aktive Proteasedomäne von NAS-38 angesehen wird, erwartete ich eine Schlüsselrolle dieser Domäne auch in der Schlafinduktion. Zweitens, welche Rolle spielen AMP bei der Signalisierung von immunitätsinduziertem Schlaf? Da gezeigt wurde, dass AMP während des NAS-38 Schlafes und auch nach Verwundung hochreguliert sind, erwartete ich, dass AMP an der Signalisierung von Schlaf von der Epidermis zum Nervensystem beteiligt sind. In einem zweiten Schritt untersuchte ich die molekularen Mechanismen, die den Vorteilen von Schlaf für das Überleben von Verletzungen zugrunde liegen. Auch hier habe ich speziell zwei Fragestellungen untersucht: Verändert genetischer Schlafentzug die transkriptionelle Reaktion auf epidermale Verletzungen? Da Schlaf für viele fundamentale Prozesse wichtig ist und Schlaflosigkeit die Sterblichkeit nach Verletzungen erhöht, vermutete ich, dass genetischer Schlafentzug die transkriptionelle Reaktion auf Verletzungen beeinträchtigt. Zweitens, ist Schlaf wichtig für die Entwicklung von Robustheit, um im Falle einer Verletzung weniger Schaden zu nehmen? Während der Larvenentwicklung fällt die Cuticula-Synthese mit Schlaf zeitlich zusammen. Daher stellte ich die Hypothese auf, dass Schlafentzug die korrekte Bildung einer Cuticula beeinträchtigt. Methoden: Zur Analyse der Signalmechanismen, durch die sowohl NAS-38 als auch Verletzungen Schlaf induzieren, filmte ich das Schlafverhalten von C. elegans mittels Langzeit-Bildgebung in Agarose-Mikrokammern. So führte ich eine Struktur-Funktions-Analyse mit verschiedenen nas-38 Mutanten durch, in denen jeweils eine andere NAS-38 Domäne deletiert war. Darüber hinaus testete ich verschiedene Suppressoren für immunvermittelten Schlaf, der durch NAS 38 oder Verletzungen induziert war. Die Redundanz des Suppressionseffektes der verschiedenen Mitglieder der AMP-Familie auf immunvermittelten Schlaf testete ich, indem ich den Suppressionsphänotyp einer CRISPR/Cas9-editierten Multi-Knockout-Mutante analysierte, in der insgesamt 19 AMP deletiert waren. Um Effektoren zu identifizieren, die den AMP nachgeschaltet sind, induzierte ich Schlaf durch Überexpression des AMP NLP 29 unter der Kontrolle eines Hitzeschock-Promotors und analysierte die Sschlafsuppression durch verschiedene Knockout-Mutanten. Im zweiten Projekt beschäftigte ich mich mit der Frage, wie genau Schlaf das Überleben nach Verletzungen unterstützt. Ich verglich die Expression von literaturbekannten Reportern für verschiedene Aspekte der Verwundungsreaktion mittels Langzeit-Fluoreszenzmikroskopie im Wildtyp sowie dem Modell für chronisch-genetischen Schlafmangel. Darüber hinaus habe ich die Transkriptome zwischen jeweils adulten verwundeten und unverwundeten Wildtypen und schlaflosen Mutanten verglichen. Um die Struktur der Cuticula des Wildtyps und der schlaflosen Mutante zu vergleichen, analysierte ich außerdem rasterelektronen-mikroskopische Aufnahmen. Ergebnisse: Im ersten Projekt konnte ich zeigen, dass NAS-38 Schlaf durch seine Astacin-Domäne verlängert. Dieser Prozess wird moderiert durch die TSP-1-Domäne. Weiterhin konnte ich zeigen, dass viele AMP redundant wirken um immunvermittelten Schlaf, verursacht durch NAS-38 oder Verletzungen, zu signalisieren. Ich konnte zeigen, dass das AMP NLP-29 über den Neuropeptidrezeptor NPR-12 wirkt. Dieser kann NLP-29-induzierten Schlaf vermitteln, wenn er in einem neuronalen Netzwerk exprimiert wird, welches nachweislich RIS aktiviert. Interessanterweise fand ich außerdem heraus, dass für NLP-29-vermittelten Schlaf der EGFR Signalweg notwendig ist. Im zweiten Projekt entdeckte ich, dass Schlaflosigkeit die transkriptionelle Reaktion auf Verletzungen nicht dramatisch verändert. Allerdings ist das Transkriptionsprofil bereits in der unverletzten schlaflosen Mutante verändert. Dies betraf unter anderem eine Gruppe oszillierender Gene, die Cuticula-assoziierte Proteine codieren, und deren Expression normalerweise ihren Höhepunkt gegen Ende des Lethargus erreicht. Da angenommen wird, dass der Zeitpunkt der Kollagenexpression entscheidend für eine fehlerfreie Cuticula-Bildung ist, analysierte ich die Cuticula der schlaflosen Mutante. Ich konnte zeigen, dass die Cuticula des adulten Tieres tatsächlich einen strukturellen Defekt aufweist. Dieser betrifft speziell Furchen in der Region nahe den Alae und könnte möglicherweise die Strapazierfähigkeit der Cuticula gegenüber bestimmten Belastungen verringern. Daher könnte Schlaf erforderlich sein, Robustheit in Form einer strukturierten Cuticula zu fördern. Schlussfolgerungen: In diesem Dissertationsprojekt vollendete ich die Charakterisierung eines neuentdeckten Mechanismus in C. elegans, durch den Verwundungen Schlaf als Teil der Immunantwort aus der Peripherie zum Nervensystem signalisieren. Ich konnte zeigen, dass AMP gewebeübergreifend Signale von der Epidermis an ein neuronales Netz vermitteln, welches wiederum RIS aktiviert und dadurch Schlaf induziert. Da Komponenten dieses Signalweges konserviert sind, könnten AMP auch in anderen Tieren, einschließlich des Menschen, Schlaf zur Genesung fördern. Darüber hinaus habe ich die Grundlagen für die Analyse molekularer Mechanismen geschaffen, die den essentiellen Funktionen des Schlafes für Heilung und Überleben zugrunde liegen. Obwohl Schlaflosigkeit die transkriptionelle Reaktion auf Verletzungen nicht drastisch zu verändern scheint, deuten meine Ergebnisse auf eine Rolle des Schlafes bei der richtigen Cuticula-Bildung und möglicherweise sogar auf eine vielfältigere Rolle bei der zeitlichen Regulierung der Genexpression hin.:Summary I
Zusammenfassung IV
Contents VII
List of Figures XII
List of Tables XIV
Abbreviations XV
1. Introduction 1
1.1. Sleep is fascinating 1
1.1.1. The origin and basic features of sleep 1
1.1.2. Regulation of sleep in higher animals 3
1.1.2.1. Neuronal control of sleep 3
1.1.2.2. Molecular control of sleep 5
1.1.3. The functions of sleep 6
1.2. The immune system and its relationship to sleep 7
1.3. Wound healing and its relationship to sleep 10
1.4. Caenorhabditis elegans is a well-studied model organism 12
1.4.1. Sleep in C. elegans 15
1.4.2. The C. elegans cuticle 18
1.4.3. Immunity in C. elegans 19
1.4.4. Wound healing response in C. elegans 22
2. Previous results 25
2.1. A strong gain-of-function mutation in the astacin metallo-proteinase NAS 38 increases lethargus duration and movement quiescence in C. elegans 25
2.2. NAS-38 increases sleep mostly through the RIS neuron 25
2.3. NAS-38 is expressed in the epidermis and oscillates with the developmental rhythm 25
2.4. nas-38(ok3407) acts via innate immunity pathways to increase lethargus duration and AMP expression 27
2.5. Overexpression of AMPs induces RIS dependent quiescence 30
2.6. Epidermal wounding induces RIS-dependent sleep, which is beneficial for survival 31
3. Thesis Aims 34
3.1. Aim 1 – Characterizing the molecular mechanism through which NAS-38, innate immunity, and wounding induce sleep 34
3.2. Aim 2 – Analyzing how sleep promotes survival after wounding 35
4. Materials and Methods 36
4.1. C. elegans maintenance 36
4.2. C. elegans crossing and genotyping 41
4.3. Creation of transgenic animals 45
4.3.1. Creating the npr-12 rescue in nmr-1 expressing neurons 45
4.3.2. Microparticle bombardment 45
4.3.3. CRISPR/Cas9 system 46
4.4. Synchronizing worm cultures by hypochlorite treatment 48
4.5. Imaging 49
4.5.1. Imaging setups 49
4.5.2. DIC Imaging of worm development, lethargus, and sleep behavior 50
4.5.2.1. Imaging of heterozygous mutants 50
4.5.3. DIC imaging in the temperature control device 51
4.5.4. Fluorescent imaging experiments 51
4.5.4.1. nas-38p::d1GFP and nlp-29p::GFP during L1 development 51
4.5.4.2. nlp-29p::GFP in L4 larvae 52
4.5.4.3. nlp-29p::GFP after heat shock-induced lin-3 overexpression 52
4.5.4.4. Imaging fluorescent markers in (wounded) young adults 52
4.5.4.5. Functional Ca2+ imaging in young adults 52
4.5.4.6. Fluorescence imaging across the whole developmental time 54
4.5.4.7. Nuclear decompaction assays 55
4.5.4.8. Transcription factor localization with spinning disc confocal microscopy 55
4.5.4.9. Imaging DPY-13::mKate2 in young adults 56
4.6. Image analysis 56
4.6.1. Assessment of developmental time and lethargus detection 56
4.6.2. Sleep detection in DIC mode 56
4.6.3. Analyzing functional Ca2+ images 57
4.6.4. Fluorescent reporter analysis during long-term imaging 57
4.7. RNAi-by-feeding 58
4.8. Transcriptome analysis 59
4.8.1. Analysis of the nas-38(ok3407) transcriptome 59
4.8.2. Analysis of the wounding transcriptome 59
4.9. Epidermal wounding 62
4.9.1. Laser wounding 62
4.9.2. Needle wounding 62
4.9.3. Survival assay 63
4.10. Scanning Electron Microscopy (SEM) 63
4.11. Histamine-inducible hyperpolarization of RIS 64
4.12. Cuticle integrity test with Sodium hypochlorite 64
4.13. NPR-12 receptor modeling 64
4.14. Quantification and statistical analysis 65
5. Results 66
5.1. Aim 1 – Characterizing the pathway through which NAS 38, wounding and innate immunity induce sleep 66
5.1.1. The loss of function mutation nas-38(tm2655) shows the opposite phenotype to the gain of function mutation nas-38(ok3407) 66
5.1.2. nas-38 gain-of-function mutants act through their astacin protease domain and are semi-dominant 66
5.1.3. Transcriptome analysis of nas-38(ok3407) reveals upregulation of genes associated with secretion, innate immunity and cuticle formation 69
5.1.4. nas-38(knu568) increased movement quiescence can be suppressed by mutations of innate immunity pathways 72
5.1.5. Multiple NLPs and CNCs act in parallel to mediate nas-38(ok3407) induced sleep 75
5.1.6. Wounding-induced sleep requires RIS, ALA, EGFR and immune signaling 77
5.1.7. NLP-29 signals via the NPR-12 receptor in neurons upstream of RIS 80
5.1.8. NLP-29 requires neuronal EGFR signaling to induce sleep 81
5.1.9. Simple in silico models suggest that many different NLPs can bind to NPR-12 83
5.1.10. AMPs contribute to the survival after wounding 85
5.2. Aim 2 – Identifying the advantages sleep provides that help to survive harmful conditions 87
5.2.1. Wounding decreases the lifespan in the wild type and the aptf 1(gk794) mutant 87
5.2.2. Histamine-inducible RIS hyperpolarization suppresses wounding sleep 87
5.2.3. Genetic sleep deprivation decreases translocation of DAF-16 into the nucleus immediately after wounding 89
5.2.4. Genetic sleep deprivation hardly changes the transcriptional wounding response 95
5.2.5. Genetic sleep deprivation and wounding increase nuclear PHA 4 101
5.2.6. Oscillating genes and genes associated with the cuticle and the unfolded protein response are upregulated in young adult aptf 1(gk794) mutants 106
5.2.7. Genetic sleep deprivation leads to a malformation of cuticular furrows 109
5.2.8. Genetic sleep deprivation leads to an increased transcription of lethargus specific oscillating genes in young adults 114
5.2.9. Genetic sleep deprivation does not significantly affect development time or body size 120
5.2.10. Expression of fluorescent reporters of oscillating genes is not phase-shifted in the aptf-1(gk794) mutant 122
6. Discussion and Outlook 128
6.1. NAS-38 acts through its astacin domain to increase sleep via innate immunity pathways 128
6.2. NAS-38 during larval lethargus and epidermal wounding in the adult signal sleep via many AMPs as part of a peripheral immune response 130
6.3. Epidermal AMPs activate a neuronal circuit to induce sleep 131
6.4. Genetically sleep deprived worms can mount a proper wounding response in many ways, except for DAF-16/FOXO regulation 132
6.5. Genetic sleep deprivation alters cuticle formation 135
6.6. The role of PHA-4/FOXA in genetically sleep-deprived animals 137
6.7. Conclusion 139
7. References 140
8. Acknowledgements 163
9. Appendix 166
9.1. Standard reagents 166
9.2. Sequence summary of PHX3754 167
9.3. MATLAB script to analyze the intensity of fluorescent reporters over time 171
9.4. Permissions to reprint figures 174
9.5. Experimental author contributions 175
9.6. Predicted interactions between the NPR-12 receptor and peptides of the nlp and cnc families 176
9.7. Overlap of the adult wounding transcriptome with other data sets 179
9.8. Curriculum Vitae – Marina Patricia Sinner 181Background: Sleep is a tightly regulated state of behavioral quiescence and reduced consciousness, which is conserved throughout the animal kingdom. In modern societies 10 – 30 % of the adult population suffer from insufficient sleep, which poses a serious health problem as sleep deprivation is associated with a variety of diseases including depression, cancer, and cardiovascular diseases. Conversely, sickness and the immune system also influence sleep patterns. Despite the important role of this interrelationship between sleep and immunity, basic molecular mechanisms that link both vital functions are only poorly understood yet. As sleep regulation is complex in mammals and is thus difficult to address experimentally, it is reasonable to investigate its basic conserved mechanisms in simpler models first. The nematode C. elegans is such a well-established, simple, and powerful model organism for sleep research. It displays stress-induced sleep, for example upon starvation or heat shock, but also developmentally-timed sleep during lethargus prior to each larval molt. C. elegans possesses an invariant nervous system in which rapid depolarization of the single RIS interneuron is sufficient to induce sleep. Mutation of the AP2 transcription factor APTF 1 deprives RIS of its sleep-inducing neuropeptide FLP-11 and thus virtually abolishes sleep. This is not per se lethal in C. elegans, thereby presenting a powerful model for genetic sleep deprivation. Our lab found that a gain-of-function mutation in the collagenase NAS-38 strongly increases RIS-dependent sleep during lethargus with a concomitant upregulation of a large family of antimicrobial peptides (AMPs) via immunity pathways. Epidermal wounding also triggers AMP expression via immune signaling and induces sleep in the adult worm. Moreover, genetic sleep deprivation increases mortality upon epidermal injury. Together, this suggests AMPs to act as somnogens from peripheral tissues to the nervous system as part of a protective response. This hypothesis, however, was hitherto lacking final evidence and pathway components.
Research questions and hypotheses: I aimed to characterize the molecular mechanism by which separate triggers of innate immunity, i. e. NAS-38 and wounding, induce sleep. I specifically addressed two questions: Firstly, which domains of the NAS-38 protein are involved in sleep regulation? As the astacin domain is predicted to be the active protease domain of NAS-38, I expected a role for it also in sleep induction by NAS-38. Secondly, what is the role of AMPs in signaling immunity-induced sleep? As they have been shown to be upregulated during times of increased sleep in the nas-38 mutant and after wounding, I expected AMPs to be involved in signaling sleep from the epidermis to the nervous system. In a second step, I investigated the molecular mechanisms underlying the benefits of sleep for surviving injury. Again, I addressed two questions: Firstly, does genetic sleep deprivation alter the transcriptional wounding response? As sleep has a role in many fundamental processes and sleeplessness increases mortality upon wounding, I hypothesized that genetic sleep deprivation impairs wounding-induced changes of transcriptional activity. Secondly, does sleep help building robustness before encountering injury? During larval development the synthesis of a new cuticle coincides with sleep. Thus, I hypothesized that genetic sleep deprivation impairs proper cuticle formation. Methods: To dissect the signaling mechanisms by which NAS-38 and wounding induced sleep, I followed sleep behavior of C. elegans by long-term imaging in agarose microchambers. I performed a structure-function analysis with different nas-38 mutants, each carrying a deletion of a different domain. Moreover, I screened for suppressors of sleep induced by NAS 38 or wounding. To test for redundancy of the AMP family, I investigated the suppression-phenotype of a CRISPR/Cas9 edited multi-knockout mutant lacking 19 AMPs. To identify downstream effectors of the AMP NLP 29, I induced sleep by overexpressing NLP 29 from a heat-shock promoter and analyzed the suppression-phenotype of different knockout mutants. For the second project, I addressed the question how sleep aids recovery from injury. I followed fluorescent reporters of previously described wounding response pathways by fluorescent long-term imaging in wild-type and genetically sleep-deprived animals. Moreover, I compared the transcriptomes of adult wild-type and genetically sleep-deprived worms both wounded and unwounded. To investigate the structure of the cuticle, I analyzed scanning electron microscopy images. Results: In the first project, I could show that NAS-38 indeed increases sleep via its astacin domain in a process that is modulated by the TSP-1 domain. Moreover, I could show that many AMPs act redundantly in mediating immunity-induced sleep downstream of NAS-38 and after wounding. I demonstrated that the AMP NLP-29 signals sleep via the neuropeptide receptor NPR 12. This receptor can mediate sleep when it is specifically expressed in command interneurons of a circuit that has been shown to activate RIS. Interestingly, I also found that EGFR signaling is required to mediate NLP-29-induced sleep.
In the second project, I found that sleeplessness does not dramatically alter the transcriptional wounding response. However, I could show that transcription is altered already in the unwounded non-sleeping mutant. This affects, among others, a specific subset of oscillating collagen-coding genes, whose expression usually peaks around the end of lethargus. As the timing of expression of collagens is thought to be highly important for proper cuticle formation, I characterized the cuticle of the aptf-1(gk794) mutant. I could show that young adult aptf 1(gk794) worms indeed have a structural defect affecting cuticular furrows in the region adjacent to the alae, which could potentially decrease specific aspects of resilience of the cuticle. Thus, sleep might be required to build robustness in the form of a properly structured cuticle. Conclusion: In this PhD project, I completed the characterization of a novel mechanism by which wounding signals sleep from the periphery to the nervous system as part of the immune response in C. elegans. I could show that AMPs act as cross-tissue signals from the epidermis to a neuronal RIS-controlling circuit that ultimately leads to sleep induction. As components of this molecular pathway are highly conserved, AMPs might also induce sleep to promote recovery from injury in other organisms, including humans. Moreover, I laid the foundations for dissecting the molecular mechanisms behind the functions of sleep for healing and survival. Even though the disability to sleep did not seem to drastically change the transcriptional response to wounding, my results indicate a role for
Association between peri-operative angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers and acute kidney injury in major elective non-cardiac surgery: a multicentre, prospective cohort study
No full textThis manuscript was drafted as part of a STARSurg ‘HackDay’ event, held on 3 March 2017. We thank C. Shaw, R.Ots and the University of Edinburgh for their provision offacilities and support for the preparation and analysis ofthis paper. STARSurg are supported by a PlatinumPartnership with the BJS Society
Validation of the OAKS prognostic model for acute kidney injury after gastrointestinal surgery
No full textBackground: Postoperative acute kidney injury (AKI) is a common complication of major gastrointestinal surgery with an impact on short- and long-term survival. No validated system for risk stratification exists for this patient group. This study aimed to validate externally a prognostic model for AKI after major gastrointestinal surgery in two multicentre cohort studies. Methods: The Outcomes After Kidney injury in Surgery (OAKS) prognostic model was developed to predict risk of AKI in the 7 days after surgery using six routine datapoints (age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker). Validation was performed within two independent cohorts: a prospective multicentre, international study (‘IMAGINE’) of patients undergoing elective colorectal surgery (2018); and a retrospective regional cohort study (‘Tayside’) in major abdominal surgery (2011–2015). Multivariable logistic regression was used to predict risk of AKI, with multiple imputation used to account for data missing at random. Prognostic accuracy was assessed for patients at high risk (greater than 20 per cent) of postoperative AKI. Results: In the validation cohorts, 12.9 per cent of patients (661 of 5106) in IMAGINE and 14.7 per cent (106 of 719 patients) in Tayside developed 7-day postoperative AKI. Using the OAKS model, 558 patients (9.6 per cent) were classified as high risk. Less than 10 per cent of patients classified as low-risk developed AKI in either cohort (negative predictive value greater than 0.9). Upon external validation, the OAKS model retained an area under the receiver operating characteristic (AUC) curve of range 0.655–0.681 (Tayside 95 per cent c.i. 0.596 to 0.714; IMAGINE 95 per cent c.i. 0.659 to 0.703), sensitivity values range 0.323–0.352 (IMAGINE 95 per cent c.i. 0.281 to 0.368; Tayside 95 per cent c.i. 0.253 to 0.461), and specificity range 0.881–0.890 (Tayside 95 per cent c.i. 0.853 to 0.905; IMAGINE 95 per cent c.i. 0.881 to 0.899). Conclusion: The OAKS prognostic model can identify patients who are not at high risk of postoperative AKI after gastrointestinal surgery with high specificity
Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.
No full textBACKGROUND: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. METHODS: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. RESULTS: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). DISCUSSION: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability
Efecto del uso de prebiótico y probióticos en la resistencia bacteriana de escherichia coli spp y klebsiella spp en ponedoras hy line brown
No full textEl uso de aditivos prebióticos, probióticos y simbióticos han sido de gran interés debido al aumento de restricción de los promotores de crecimiento causado por la resistencia bacteriana obtenida en los últimos años. Se realizará un estudio en 240 gallinas ponedoras Hy Line Brown, El diseño será completamente al azar (CRD, complete randomized design). Se distribuirán de manera aleatorizada 8 grupos, cada uno con 10 repeticiones donde se sustituirá antibióticos promotores de crecimiento en la dieta por diferentes niveles de prebióticos en combinación con probióticos. Se les otorgara 110g diariamente de alimento con los siguientes aditivos VitaCAN, Poultrystar, Vitasym DFM y Enramicina 8% con diferentes unidades de inclusión y combinación obtenido 8 tratamientos donde se tomaran muestras del contenido intestinal y se llevaran al laboratorio de microbiología para realizar cultivos y antibiograma a razón de analizar el crecimiento y resistencia bacteriano Escherichia coli spp y klebsiella spp en las gallinas ponedoras; los resultados obtenidos en el estudio arrojan que la Dieta H (Oligosaccharides y Bacillus subtilis) presento el menor porcentaje de crecimiento del 10% Klebsiella spp y no presento crecimiento de Escherichia coli spp por otra parte los antibióticos con mayor resistencia para las bacterias analizadas en el estudio fueron la ampicilina sulbactam y las tetraciclinas, finalmente el uso de prebióticos, probióticos y simbióticos nos permite obtener mejores resultados en la inmunidad de los animales igualmente nos permite no utilizar promotores de crecimiento en las producciones avícolas teniendo en cuenta que se obtiene mejores resultados y contribuimos a disminuir la resistencia bacteriana.The use of prebiotic, probiotic and synbiotics additives has been of great interest due to the increase in restriction of growth promoters caused by bacterial resistance obtained in recent years. A study will be carried out on 240 Hy Line Brown laying hens. The design will be completely randomized (CRD). 8 groups will be randomly distributed, each with 10 repetitions where growth-promoting antibiotics in the diet will be replaced by different levels of prebiotics in combination with probiotics. They will be given 110g of food daily with the following additives VitaCAN, Poultrystar, Vitasym DFM and Enramycin 8% with different inclusion and combination units, obtaining 8 treatments where samples of the intestinal contents will be taken and taken to the microbiology laboratory to perform cultures and antibiogram. by analyzing the bacterial growth and resistance Escherichia coli spp and klebsiella spp in laying hens; The results obtained in the study show that Diet H (Oligosaccharides and Bacillus subtilis) presented the lowest percentage of growth of 10% Klebsiella spp and did not present growth of Escherichia coli spp, on the other hand, the antibiotics with the greatest resistance to the bacteria analyzed in the study. study was ampicillin sulbactam and tetracyclines, finally the use of prebiotics, probiotics and synbiotics allows us to obtain better results in the immunity of animals, it also allows us not to use growth promoters in poultry production taking into account that better results are obtained and We contribute to reducing bacterial [email protected]
