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Food waste has been described as a global problem with numerous root causes (Minor et al., 2019; Narvanen et al., 2020; Niina et al., 2022; Weber and Khademian, 2008). Food waste has reached alarming proportions, with approximately one-third of all food produced going to waste (FAO, 2014; Gustavsson et al., 2011). Food waste accounts for 20% of all food produced in the European Union(EU), costing 143 billion EUR annum (Stenmarck et al., 2016). A study was done by Future Directions International (FDI) in 2016 found that 25% of the globe's food waste happens in South and Southeast Asia. Food waste prevention at the source must be the main priority. Still, the EU's food waste hierarchy puts redistribution of surplus food for human consumption as the second-best option when food waste cannot be avoided (European Commission, 2020). Some Southeast Asia countries managed 64% of avoidable food waste by redistributing it to those in need (Tech Collective, 2019). Most food waste is managed via lower-priority methods, including composting, incineration, or landfill (European Comission, 2020; Eurostat, 2020; Obersteiner et al., 2021). Redistribution of surplus food or food donation to a marginalised community can be advantageous. Aside from the environmental, economic and social benefits, using the food for its intended purpose preserves its energy and nutrient content. Furthermore, surplus food redistribution is increasingly recognised to address food insecurity and food waste (Schneider, 2013). In Malaysia, the government is concerned with redistributing surplus food operated by a food bank or charity organisation via donations from the food retail industry (Hamik et al., 2021). Keywords: Redistribution, Surplus Food, Food Donor, Government Policy and Practices

We used monthly precipitation and temperature data to give early warning of years with higher West Nile Virus (WNV) risk in Nebraska. We used generalized additive models with a negative binomial distribution and smoothing curves to identify combinations of extremes and timing that had the most influence, experimenting with all combinations of temperature and drought data, lagged by 12, 18, 24, 30, and 36 months. We fit models on data from 2002 through 2011, used Akaike's Information Criterion (AIC) to select the best‐fitting model, and used 2012 as out‐of‐sample data for prediction, and repeated this process for each successive year, ending with fitting models on 2002–2017 data and using 2018 for out‐of‐sample prediction. We found that warm temperatures and a dry year preceded by a wet year were the strongest predictors of cases of WNV. Our models did significantly better than random chance and better than an annual persistence naïve model at predicting which counties would have cases. Exploring different scenarios, the model predicted that without drought, there would have been 26% fewer cases of WNV in Nebraska through 2018; without warm temperatures, 29% fewer; and with neither drought nor warmth, 45% fewer. This method for assessing the influence of different combinations of extremes at different time intervals is likely applicable to diseases other than West Nile, and to other annual outcome variables such as crop yield., Key Points A dry year preceded by a wet year in combination with warm temperatures increases the number of human cases of West Nile Virus in NebraskaWe found that drought accounted for 26% of WNV cases 2002–2018, and drought and temperature together accounted for 45% of cases

Rationale: Lymphatic vessels function to drain interstitial fluid from a variety of tissues. Although shear stress generated by fluid flow is known to trigger lymphatic expansion and remodeling, the molecular basis underlying flow-induced lymphatic growth is unknown. Objective: We aimed to gain a better understanding of the mechanism by which laminar shear stress activates lymphatic proliferation. Methods and Results: Primary endothelial cells from dermal blood and lymphatic vessels (blood vascular endothelial cells and lymphatic endothelial cells [LECs]) were exposed to low-rate steady laminar flow. Shear stress–induced molecular and cellular responses were defined and verified using various mutant mouse models. Steady laminar flow induced the classic shear stress responses commonly in blood vascular endothelial cells and LECs. Surprisingly, however, only LECs showed enhanced cell proliferation by regulating the vascular endothelial growth factor (VEGF)-A, VEGF-C, FGFR3, and p57/CDKN1C genes. As an early signal mediator, ORAI1, a pore subunit of the calcium release–activated calcium channel, was identified to induce the shear stress phenotypes and cell proliferation in LECs responding to the fluid flow. Mechanistically, ORAI1 induced upregulation of Krüppel-like factor (KLF)-2 and KLF4 in the flow-activated LECs, and the 2 KLF proteins cooperate to regulate VEGF-A, VEGF-C, FGFR3, and p57 by binding to the regulatory regions of the genes. Consistently, freshly isolated LECs from Orai1 knockout embryos displayed reduced expression of KLF2, KLF4, VEGF-A, VEGF-C, and FGFR3 and elevated expression of p57. Accordingly, mouse embryos deficient in Orai1 , Klf2 , or Klf4 showed a significantly reduced lymphatic density and impaired lymphatic development. Conclusions: Our study identified a molecular mechanism for laminar flow–activated LEC proliferation.

Background In collaboration with state, tribal, local, and territorial health departments, CDC established the U.S. Zika Pregnancy Registry (USZPR) in early 2016 to monitor pregnant women with laboratory evidence of possible recent Zika virus infection and their infants. Methods This report includes an analysis of completed pregnancies (which include live births and pregnancy losses, regardless of gestational age) in the 50 U.S. states and the District of Columbia (DC) with laboratory evidence of possible recent Zika virus infection reported to the USZPR from January 15 to December 27, 2016. Birth defects potentially associated with Zika virus infection during pregnancy include brain abnormalities and/or microcephaly, eye abnormalities, other consequences of central nervous system dysfunction, and neural tube defects and other early brain malformations. Results During the analysis period, 1,297 pregnant women in 44 states were reported to the USZPR. Zika virus-associated birth defects were reported for 51 (5%) of the 972 fetuses/infants from completed pregnancies with laboratory evidence of possible recent Zika virus infection (95% confidence interval [CI] = 4%-7%); the proportion was higher when restricted to pregnancies with laboratory-confirmed Zika virus infection (24/250 completed pregnancies [10%, 95% CI = 7%-14%]). Birth defects were reported in 15% (95% CI = 8%-26%) of fetuses/infants of completed pregnancies with confirmed Zika virus infection in the first trimester. Among 895 liveborn infants from pregnancies with possible recent Zika virus infection, postnatal neuroimaging was reported for 221 (25%), and Zika virus testing of at least one infant specimen was reported for 585 (65%). Conclusions and implications for public health practice These findings highlight why pregnant women should avoid Zika virus exposure. Because the full clinical spectrum of congenital Zika virus infection is not yet known, all infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy should receive postnatal neuroimaging and Zika virus testing in addition to a comprehensive newborn physical exam and hearing screen. Identification and follow-up care of infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy and infants with possible congenital Zika virus infection can ensure that appropriate clinical services are available.

OBJECTIVE To determine the relationships between Kruppel-like factors (KLF) 2 and 4, immune-activation, and subclinical vascular disease in HIV-infected patients on antiretroviral therapy (ART). DESIGN Double-blind, randomized, placebo-controlled trial. METHODS We studied 74 HIV-infected adults on ART enrolled in a randomized clinical trial of statin therapy. KLF2 and KLF4 gene expression was measured by quantitative PCR from peripheral blood mononuclear cells (PBMCs) at baseline and after 24 weeks of 10 mg daily rosuvastatin or placebo. At the same time points, T-cell and monocyte activation were assessed by flow cytometry and vascular health was assessed by cardiac computed tomography and carotid ultrasound. RESULTS KLF4 expression was negatively correlated with duration of ART (r = -0.351, P = 0.004) and positively correlated with measures of immune activation: proinflammatory monocytes [CD14CD16 (r = 0.343, P = 0.003)], patrolling monocytes [CD14CD16 (r = 0.276, P = 0.017)], and activated CD8 T-lymphocytes [CD8DRCD38 (r = 0.264, P = 0.023)]. KLF2 expression was negatively correlated with subclinical atherosclerosis: mean-mean common carotid artery intima-media thickness (r = -0.231, P = 0.048), mean-max carotid artery intima-media thickness (r = -0.271, P = 0.020), and coronary artery calcium score (r = -0.254, P = 0.029). There were no statistically significant changes in KLF2/4 expression in PBMCs after 24 weeks of rosuvastatin. CONCLUSION Expression of KLF4 in PBMCs positively correlates with cellular markers of immune activation, whereas KLF2 expression negatively correlates with markers of subclinical atherosclerosis in this HIV-infected population on ART. Additional studies are needed to determine if targeted interventions might alter KLF2/4 expression to reduce inflammation and vascular risk in humans.

This study describes the design process and implementation of video media in learning the electrical and electronic measuring instruments principles.The purpose of making this media to improve students understanding of the principles of electrical and electronic measuring instruments, include teaching materials about the gauge multimeters, the voltmeter and amperemeter. Research procedure followed the steps of research and development. Data collection was done by assigning kuersioner and structured interviews. The results showed that the learning conditions is still conventional, the use of video-based learning media has been tested and positive impact on student responses and help students and teachers in the learning process. The implication is expected to have an impact on teachers increased innovation in the use of instructional media.

Krüppel-like factor 4 (KLF4) is a transcription factor expressed in the vascular endothelium, where it promotes anti-inflammatory and anticoagulant states, and increases endothelial nitric oxide synthase expression. We examined the role of endothelial KLF4 in pulmonary arterial (PA) hypertension (PAH). Mice with endothelial KLF4 knockdown were exposed to hypoxia for 3 weeks, followed by measurement of right ventricular and PA pressures, pulmonary vascular muscularization, and right ventricular hypertrophy. The effect of KLF4 on target gene expression was assessed in lungs from these mice, verified in vitro by small interfering RNA (siRNA) knockdown of KLF4, and further studied at the promoter level with cotransfection experiments. KLF4 expression was measured in lung tissue from patients with PAH and normal control subjects. We found that, after hypoxia, right ventricular and PA pressures were significantly higher in KLF4 knockdown animals than controls. Knockdown animals also had more severe pulmonary vascular muscularization and right ventricular hypertrophy. KLF4 knockdown resulted in increased pulmonary expression of endothelin-1 and decreased expression of endothelial nitric oxide synthase, endothelin receptor subtype B, and prostacyclin synthase. Concordant findings were observed in vitro, both with siRNA knockdown of KLF4 and promoter activity assays. Finally, KLF4 expression was reduced in lungs from patients with PAH. In conclusion, endothelial KLF4 regulates the transcription of genes involved in key pathways implicated in PAH, and its loss exacerbates pulmonary hypertension in response to chronic hypoxia in mice. These results introduce a novel transcriptional modulator of PAH, with the potential of becoming a new therapeutic target.

Loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans, and also modulate mammalian vascular age-associated phenotypes. Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models. Conversely, Kruppel-like family of transcription factor overexpression extends nematode lifespan in an autophagy-dependent manner. Furthermore, we show the mammalian vascular factor Kruppel-like family of transcription factor 4 has a conserved role in augmenting autophagy and improving vessel function in aged mice. Kruppel-like family of transcription factor 4 expression also decreases with age in human vascular endothelium. Thus, Kruppel-like family of transcription factors constitute a transcriptional regulatory point for the modulation of autophagy and longevity in C. elegans with conserved effects in the murine vasculature and potential implications for mammalian vascular aging., KLF family transcription factors (KLFs) regulate many cellular processes, including proliferation, survival and stress responses. Here, the authors position KLFs as important regulators of autophagy and lifespan in C. elegans, a role that may extend to the modulation of age-associated vascular phenotypes in mammals.

Historically, the relationship between exercise and the cardiovascular system was viewed as unidirectional, with a disease resulting in exercise limitation and hazard. This article reviews and explores the bidirectional nature, delineating the effects, generally positive, on the cardiovascular system and atherosclerosis. Exercise augments eNOS, affects redox potential, and favorably affects mediators of atherosclerosis including lipids, glucose homeostasis, and inflammation. There are direct effects on the vasculature as well as indirect benefits related to exercise-induced changes in body composition and skeletal muscle. Application of aerobic exercise to specific populations is described, with the hope that this knowledge will move the science forward and improve individual patient outcome.

A complex and diverse vascular system is requisite for the survival of higher organisms. The process of vascular development is highly regulated, involving the de novo formation of vessels (vasculogenesis), followed by expansion and remodeling of the primitive vasculature (angiogenesis), culminating in differentiation of endothelial phenotypes, as found in the mature vascular system. Over the last decade, significant advances have been made in understanding the molecular regulation of endothelial cell development and differentiation. Endothelial development, in particular the mechanisms in play during vasculogenesis and angiogenesis, is discussed in a sister review to this article. This review highlights the key pathways governing in endothelial differentiation, with a focus on the major molecular mechanisms of endothelial specification and heterogeneity.

The vascular endothelium plays a critical role in vascular homeostasis. Inflammatory cytokines and non-laminar blood flow induce endothelial dysfunction and confer a pro-adhesive and pro-thrombotic phenotype. Therefore, identification of factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Kruppel-like factor 4 expression has been documented in endothelial cells, but a function has not been described. In this communication we describe the expression in vitro and in vivo of Kruppel-like factor 4 in human and mouse endothelial cells. Furthermore, we demonstrate that endothelial Kruppel-like factor 4 is induced by pro-inflammatory stimuli and shear stress. Overexpression of Kruppel-like factor 4 induces expression of multiple anti-inflammatory and anti-thrombotic factors including endothelial nitric-oxide synthase and thrombomodulin, whereas knockdown of Kruppellike factor 4 leads to enhancement of tumor necrosis factor alpha-induced vascular cell adhesion molecule-1 and tissue factor expression. The functional importance of Kruppel-like factor 4 is verified by demonstrating that Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface and prolongs clotting time under inflammatory states. Kruppel-like factor 4 differentially regulates the promoter activity of pro- and anti-inflammatory genes in a manner consistent with its anti-inflammatory function. These data implicate Kruppel-like factor 4 as a novel regulator of endothelial activation in response to pro-inflammatory stimuli.

Endothelial cell phenotypes markedly differ, depending upon function and vascular bed of origin. Differences might account for specific susceptibility to pathological conditions. As leukocyte adhesion to activated endothelium is the initiating event in a range of diseases, we compared the influence of vascular bed-specific flow patterns on adhesion molecule expression in human saphenous vein (HSVEC) and coronary artery endothelial cells (HCAEC). In vitro, immune cell attachment was increased 1.6-fold when tumor necrosis factor (TNF)-α-stimulated HSVEC were exposed to coronary artery flow in place of physiological venous flow and 1.9-fold higher compared with attachment to cytokine-stimulated HCAEC exposed to coronary artery flow. This was associated with increased concentrations of soluble E-selectin, VCAM-1, and ICAM-1 in supernatants of HSVEC exposed to coronary artery flow compared with HCAEC exposed to the same flow pattern. Venous and coronary artery flow both increased TNF-α-induced E-selectin and ICAM-1 expression on HSVEC, but only coronary artery flow increased VCAM-1 expression. In marked contrast to HSVEC, venous and coronary artery flow attenuated TNF-α-induced E-selectin and VCAM-1 expression on HCAEC, whereas coronary artery flow further induced ICAM-1 on cytokine-stimulated HCAEC. With the exception of cytokine-induced ICAM-1, adhesion molecule expression on HSVEC exposed to coronary artery flow exceeded expression on HCAEC. Thus ICAM-1 expression involves complex flow-dependent and -independent pathways with marked dissimilarities between the two endothelial cell types studied. Interestingly, Kruppel-like factor (KLF) 4 overexpression in HCAEC and HSVEC significantly reduced TNF-α-induced E-selectin and VCAM-1 expression in static conditions, while ICAM-1 expression remained constant. Furthermore, both flow patterns induced KLF2 and KLF4 expression in HCAEC and HSVEC. Venous and coronary artery flow differentially influence endothelial adhesion molecule and transcription factor expression, depending on the vascular bed of origin. Differences in adhesion molecule expression and subsequent immune cell adhesion between HSVEC and HCAEC may contribute to different susceptibility to pathological conditions.

Angiogenesis, the process by which new blood vessels develop from a pre-existing vascular network, is essential for normal development and in certain physiological states. Inadequate or excessive angiogenesis has been incriminated in a number of pathologic states. For example, vaso-occlusive disease arising from atherosclerosis can lead to ischemia, a situation in which enhanced angiogenesis would be beneficial. Conversely, overzealous angiogenesis can contribute to tumor development and in this case inhibition of angiogenesis is desirable. Thus, strategies to induce or inhibit angiogenesis are of considerable therapeutic interest.

Background— Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to modulate endothelial function, the transcriptional mechanisms underlying these effects are incompletely understood. We hypothesized that Lung-Kruppel–like factor (LKLF/KLF2), a novel and potent regulator of endothelial gene expression, may mediate the downstream effects of statins. Here we report that statin-induced expression of endothelial NO synthase (eNOS) and thrombomodulin is KLF2 dependent. Methods and Results— KLF2 mRNA was induced by treatment with multiple statins in a concentration-dependent manner. Multiple lines of evidence suggest that this induction is dependent on inhibition of the Rho pathway and requires de novo transcription. Furthermore, promoter deletion and mutational analyses suggest that mevastatin induced KLF2 promoter activity through a single myocyte enhancer factor binding site. Finally, small-interfering RNA–mediated knockdown of KLF2 strongly attenuated the ability of mevastatin to increase eNOS and thrombomodulin accumulation in endothelial cells. Conclusions— Taken together, these observations indicate that statin-dependent induction of eNOS and thrombomodulin requires KLF2 and thereby provides a novel molecular target for modulating endothelial function in vascular disease.

Die vorliegende Arbeit befasst sich mit Aspekten der Wirkungsgradverbesserung an thermischen Turbomaschinen durch Reduktion von Spaltverlusten mittels Einblasung von der Schaufelspitze in den Schaufelspalt. Dazu wird eine Drallstr��mung herangezogen. Unterschiedliche Methoden zur Herstellung einer Drallstr��mung werden diskutiert. Dabei stellt sich heraus, dass nicht alle ��blicherweise zur Entwicklung von Drallstr��mungen eingesetzten Methoden auch f��r den gegebenen Fall der verdrallten Einblasung relevant sind. Es erfolgt eine analytische Modellbildung, um den Erfolg der Ma��nahme a priori im Groben absch��tzen zu k��nnen. Dies ist ein wichtiger Schritt, um insbesondere in fr��hen Entwicklungsphasen rasche und zielf��hrende Entscheidungen treffen zu k��nnen und l��ngere zeit- und kostenintensive Irrwege vermeiden zu k��nnen. Die analytische Modellbildung wird mittels Massenbilanz, Impulsbilanz, Bernoulligleichung, Reibungsverlustber��cksichtigung und Betrachtung von Carnot'schem Sto��verlust angegeben. Weiters werden die Ergebnisse des analytischen Modells mittels einer dreidimensionalen numerischen Str��mungssimulation verglichen, die im Sinne einer kartesischen Geometrie einen senkenf��rmigen Einlaufbereich umfasst, der von dem Schaufelspalt komplettiert wird. Diesbez��gliche Berechnungen werden unter Verwendung von zwei charakteristischen Reynoldszahlen ausgef��hrt. Dabei erfolgen umfassende Parametervariationen, die sowohl unterschiedliche Winkelgeschwindigkeiten als auch unterschiedliche Einblasewinkel umfassen. Die Ergebnisse der verdrallten Zustr��mung der Einblasestr��mung werden sowohl mit einer nichtverdrallten Einblasestr��mung als auch mit den korrespondierenden F��llen ohne Einblasung verglichen. Die Str��mungssimulationen werden f��r einen sinnvollen Vergleich der Spaltstr��mung in Bezug auf ihren statischen Druckabfall mittels voller Wandaufl��sung durchgef��hrt. Dabei wird festgestellt, dass im Gegensatz zur Einblasung ohne Rotation, bei der eine Einblaserichtung entgegen der Spaltstr��mung vorteilhafter war, nun eine Einblasung in Richtung der Spaltstr��mung sinnvoller erscheint, wenn die Winkelgeschwindigkeit eine gewisse Mindestst��rke ��berschreitet. Insbesondere im Bereich hoher Winkelgeschwindigkeiten bei Einblasung in Richtung der Spaltstr��mung k��nnen bedeutende Verbesserungen des Wirkungsgrades erzielt werden. Eine verdrallte Einblasung entgegen der Richtung der Spaltstr��mung stellt sich als kontraproduktiv heraus. Eine Einblasung normal zur Spaltstr��mung kann zwar durch zus��tzliche Reibungserscheinungen zu einer Reduktion des Spaltmassenstromes beitragen, aber die zur Herstellung der Drallstr��mung erforderliche Energie nicht rechtfertigen. Der Vergleich zwischen analytischem Modell und numerischer Str��mungssimulation kann in weiten relevanten Arbeitsbereichen eine zufriedenstellende ��bereinstimmung erbringen, wodurch sowohl die Qualit��t der analytischen Modellbildung als auch der numerischen Str��mungssimulation und somit auch die Wirksamkeit der verdrallten Einblasung zus��tzlich abgesichert werden. Dieser Vergleich erfolgt schlie��lich nicht nur in Bezug auf den CD-Wert sondern auch auf den Wirkungsgrad, um einen ganzheitlichen Vergleich zu erm��glichen., The present work considers aspects of efficiency improvement of thermal turbomachinery by reducing tip gap losses by injection from the blade tip to the blade gap. For this purpose, a swirling flow is used. Different methods for producing a swirling flow are discussed. It turns out that not all methods normally used for the development of swirling flows are also relevant for the particular case of swirling injection. An analytic modeling is used to get a rough impression of the success of the action a priori. This is an important step in order to make rapid and goal-oriented decisions, especially in early stages of development and to be able to avoid long time and cost intensive actions without success. Analytical modeling is given by mass balance, momentum balance, Bernoulli equation, friction loss account and consideration of Carnot shock loss. Furthermore, the results of the analytical model are compared by means of a three-dimensional computational fluid dynamics simulation, which includes a sink shaped inlet area in terms of a Cartesian geometry, which is completed by the tip gap area. Calculations are carried out using two characteristic Reynolds numbers. Comprehensive parameter variations, including both different angular velocities and injection angles, are carried out. The results of the swirling injection are compared with both a non swirling injection as well as with the corresponding cases without tip gap injection. For a meaningful comparison of the gap flow in relation to its static pressure drop the flow simulations are performed by full wall resolution. It is found that in contrast to the injection without swirl, in which an injection against the direction of the gap flow was more advantageous, now an injection usefully appears in the direction of the gap flow, when the angular velocity exceeds a certain minimum strength. Especially in the field of high angular velocities with injection in the direction of the gap flow significant improvements in efficiency can be achieved. A swirling injection against the direction of the gap flow turns out to be counterproductive. An injection normal to the gap flow can contribute to a reduction of the tip gap mass flow through additional friction losses, but cannot justify the energy necessary to produce the swirling flow. The comparison between the analytical model and the computational fluid dynamics simulation stays in satisfactory agreement in relevant work areas, whereby both the quality of the analytical modeling and the computational fluid dynamics simulation, and thus the efficiency of the swirling injection are additionally ensured. This comparison is carried out not only with respect to the CD value but also with respect to efficiency, to enable a holistic comparison.

Regulation of endothelial cell biology by the Notch signaling pathway (Notch) is essential to vascular development, homeostasis, and sprouting angiogenesis. Although Notch determines cell fate and differentiation in a wide variety of cells, the molecular basis of upstream regulation of Notch remains poorly understood. Our group and others have implicated the Kruppel-like factor family of transcription factors as critical regulators of endothelial function. Here, we show that Kruppel-like factor 4 (KLF4) is a central regulator of sprouting angiogenesis via regulating Notch. Using a murine model in which KLF4 is overexpressed exclusively in the endothelium, we found that sustained expression of KLF4 promotes ineffective angiogenesis leading to diminished tumor growth independent of endothelial cell proliferation or cell cycling effects. These tumors feature increased vessel density yet are hypoperfused, leading to tumor hypoxia. Mechanistically, we show that KLF4 differentially regulates expression of Notch receptors, ligands, and target genes. We also demonstrate that KLF4 limits cleavage-mediated activation of Notch1. Finally, we rescue Notch target gene expression and the KLF4 sprouting angiogenesis phenotype by supplementation of DLL4 recombinant protein. Identification of this hitherto undiscovered role of KLF4 implicates this transcription factor as a critical regulator of Notch, tumor angiogenesis, and sprouting angiogenesis.

This invited review summarizes work presented in the Russell Ross lecture delivered at the 2012 proceedings of the American Heart Association. We begin with a brief overview of the structural, cellular, and molecular biology of Krüppel-like factors. We then focus on discoveries during the past decade, implicating Krüppel-like factors as key determinants of vascular cell function in atherosclerotic vascular disease.

We report the formation of stable bound wave packets in a modified Belousov−Zhabotinsky reaction. These densely stacked structures arise from an attractive interaction between oxidation pulses that is not known from the classical Belousov−Zhabotinsky system. The characteristic stacking period increases with the initial concentration of bromate but decreases with cyclohexanedione. Wave stacking can also induce cascades of bunching events in which internally dense but mutually well segregated wave clusters are formed. For different initial concentrations, we observed the apparent merging of waves in front-to-back collisions. All three modes of wave dynamics are analyzed in terms of their dispersion behavior. The dispersion relations proved to be anomalous in each case and revealed the existence of an attractor which induces the formation of stable wave packets. The underlying mechanism has a pure reaction−diffusion character since wave propagation is not affected by fluid convection. At high initial concent...

In this issue of Blood , Zhang et al identify the Src-PLD1-PKCγ axis as critically involved in the process that causes ROP, highlighting new potential targets for therapy.[1][1] Vascular endothelial growth factor (VEGF) is acknowledged as the predominant regulator of angiogenesis; blockade of VEGF

The inhibitory effect of molecular oxygen on chemical oscillations in a semiclosed Belousov−Zhabotinsky system is investigated. Comparison of experimental results obtained from anaerobic and aerobic reactions shows that the oxygen-induced increase of oscillation periods is most pronounced at low concentrations of sulfuric acid or bromate and at high concentrations of malonic acid. Under the given experimental conditions, oxygen inhibition is negligible for [H2SO4] > 0.35 M, [BrO3-] > 0.15 M, and [CH2(COOH)2] < 0.07 M. Based on the classical Oregonator, we propose an extended model that accounts for the observed concentration dependencies. This model treats oxygen as a dynamic variable and is capable of describing oxygen oscillations as well as the striking increase in oxygen concentration for conditions in which oscillations are fully suppressed. The rate equations of the extended Oregonator model are presented in a dimensionless form and are, for anaerobic conditions, in exact correspondence to the class...

Renal clearance of insulin is achieved by glomerular filtration and by passage from the postglomerular peritubular circulation into the renal interstitium. In the proximal tubule, filtered insulin binds to the apical membrane and is internalized and degraded, while insulin in the interstitium is taken up by receptor-mediated endocytosis and degraded. To study these processes we have utilized cultured opossum kidney cells. These cells have proximal-like features and process insulin in a manner consistent with that described in vivo. To study apical and basolateral uptake and metabolism of insulin independently, cells were grown on filters suspended in culture wells. Insulin was degraded to large insulin-size intermediates and low-molecular-weight products. This occurred whether the protein was internalized from the apical or basolateral pole of the cell. Analysis of the intermediate products by reverse-phase high-performance liquid chromatography revealed that products formed after apical or basolateral internalization were similar. Since products were preferentially released from the side of uptake, it is likely that apically and basolaterally internalized insulin is degraded in comparable organelles located in different regions of the cell. Most of the internalized insulin traversed the degradative pathway but some insulin followed a retroendocytic or minor transcytotic pathway. Degradation was inhibited by chloroquine, which also selectively increased the release of internalized insulin from the apical pole irrespective of the side of uptake. Thus while the polar degradative processes appear to be similar in nature, the polar exocytotic processes appear to be different.

Antibodies to CD44 have been used to inhibit a variety of processes which include lymphohemopoiesis, lymphocyte migration, and tumor metastasis. Some, but not all, CD44-mediated functions derive from its ability to serve as a receptor for hyaluronan (HA). However, sites on CD44 that interact with either ligands or antibodies are poorly understood. Interspecies rat/mouse CD44 chimeras were used to analyze the specificity of 25 mAbs and to determine that they recognize at least seven epitopes. Amino acid substitutions that resulted in loss of antibody recognition were all located in the region of homology to other cartilage link family proteins. While at least five epitopes were eliminated by single amino acid replacements, multiple residues had to be changed to destroy binding by other antibodies. One antibody was sensitive to changes in any of three separate parts of the molecule and some antibodies to distinct epitopes cross-blocked each other. Certain antibodies had the ability to increase HA binding by lymphocytes but this did not correlate absolutely with antibody specificity and was only partially attributable to CD44 cross-linking. Antibodies that consistently blocked HA recognition were all sensitive to amino acid changes within a short stretch of CD44. Such blocking antibodies interacted with CD44 more strongly than ligand in competition experiments. One large group of antibodies blocked ligand binding, but only with a particular cell line. This detailed analysis adds to our understanding of functional domains within CD44 and requirements for antibodies to influence recognition of one ligand.

The endothelium regulates vascular homeostasis, and endothelial dysfunction is a proximate event in the pathogenesis of atherothrombosis. Stimulation of the endothelium with proinflammatory cytokines or exposure to hemodynamic-induced disturbed flow leads to a proadhesive and prothrombotic phenotype that promotes atherothrombosis. In contrast, exposure to arterial laminar flow induces a gene program that confers a largely antiadhesive, antithrombotic effect. The molecular basis for this differential effect on endothelial function remains poorly understood. While recent insights implicate Kruppel-like factors (KLFs) as important regulators of vascular homeostasis, the in vivo role of these factors in endothelial biology remains unproven. Here, we show that endothelial KLF4 is an essential determinant of atherogenesis and thrombosis. Using in vivo EC-specific KLF4 overexpression and knockdown murine models, we found that KLF4 induced an antiadhesive, antithrombotic state. Mechanistically, we demonstrated that KLF4 differentially regulated pertinent endothelial targets via competition for the coactivator p300. These observations provide cogent evidence implicating endothelial KLFs as essential in vivo regulators of vascular function in the adult animal.