Cardiac fibrosis represents a significant health burden, with endothelial dysfunction and damaged perivascular microenvironment increasingly recognized as key contributors to fibrotic remodeling. The urokinase plasminogen activator receptor (uPAR), a critical component of the urokinase system, plays a pivotal role in vascular remodeling and fibrosis. While prior evidence indicates that uPAR deficiency leads to microvascular dysfunction and perivascular fibrosis, the underlying mechanisms remain poorly defined. This study investigates how uPAR deficiency contributes to fibrotic remodeling of the cardiac perivascular-like microenvironment. Single-cell RNA sequencing data analysis and immunofluorescence staining on mouse heart cryosections were performed to characterize uPAR expression within the cardiac perivascular microenvironment. To model this microenvironment in vitro, cardiospheres (CSs) were generated from non-myocyte cardiac cells of wild-type and uPAR-knockout mice. CRISPR/Cas9-generated Plaur knockout (KO) 3T3 fibroblasts (FBs) were employed as model stromal cells. Pro-fibrotic activation of FBs was induced by TGFβ1 treatment. Comparative analyses of extracellular matrix (ECM) deposition, fibrotic cell transformation, and comprehensive secretome profiling was conducted using western blotting. Our findings demonstrated that uPAR was expressed by endothelial cells (ECs) and FBs within the cardiac perivascular microenvironment. uPAR deficiency exacerbated profibrotic stimuli in CSs, including elevated active TGFβ1, impaired integrin functions, and altered cell secretome. These alterations collectively disrupt critical cell-cell and cell-matrix interactions, leading to increased ECM deposition, EC loss and decreased cell viability. Using Plaur KO FBs, we demonstrated that uPAR deficiency amplified TGFβ1-mediated Akt signaling pathway and ECM deposition. Our study reveals that uPAR loss drives fibrotic remodeling of the cardiac perivascular-like microenvironment and exacerbates TGFβ1-mediated effects, highlighting its potential as a therapeutic target for cardiac fibrosis.

Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.

The rational use of wild reindeer (Rangifer tarandus L., 1758) based on reliable data on the number, distribution, age-sex composition, and herd size of the population is a challenging problem for hunting management. The purpose of this study was to characterize the current state of the Lena-Olenek tundra wild reindeer (LOWR) population. The counting of LOWR was based on the aerial census conducted from July 10 to 12, 2018; coordinate data from the GLONASS/Argos satellite tracker collars; stock materials from previous aerial surveys in the tundra of Yakutia. From the data obtained, the livestock of the LOWR was estimated to be 83,260. We specified that deer are housed in three distinct groups: broodstock, mixed, and male. The main livestock in the LOWR were females (44.2 %), calves (22.4 %), and juvenile animals 1–2 years old (17.5 %). Over 32 years, there was a decrease in 62.2% in the number of adult males and an increase in the number of fingerlings and juvenile animals. Since the middle of the last century, there has been a gradual increase in the number of LOWR from 21,000 to 95,000 deer in 2009 and a slight decrease to 83,200 deer in the last decade due to the exclusion of Taimyr reindeer migrants. The results of this study can be used to rationalize the use of wild reindeer resources and the allocation of quotas for production. Further census work will make it possible to monitor the state of the population over time.

Recently, the social transformations have occurred more frequently due to changes in the world such as the crisis caused by COVID‐19, and ongoing social tensions caused by income gap, and changes in traditional values under the influence of digitalization of all spheres of life. The article covers issues of place and role of mining companies, ESG‐transformation, the social values creation and the social expenditures in the system of social risk protection of the Northern regions of Russia. Theoretical approaches were analyzed to understand the process of design social risk protecting strategies with the focus not only on the micro‐level of firms or companies, but on the meso‐level of a region and description of social issues which have arisen in a region. Literature review shows that companies operated play a significant role in the risk protection systems of the territory where they operate. In turn, the place of social values in the system of risk protection is determined by the stage of transformation period. The analysis of corporate social activities is made on companies contributed the most to the economic development of the Northern region such as «Karelsky Okatysh» (the subsidiary of Public Joint Stock Company (PJSC) «Severstal»), Public Joint Stock Company «ALROSA» (hereinafter PJSC «ALROSA») and its subsidiary company “Severalmaz”, Limited liability company «LUKOIL‐Komi» (hereinafter LLC «LUKOIL‐Komi»). The methodological frame is based on garnering corporate activities and calculation share of corporate expenditures in risk protection systems. It was found that the features of the Northern regions should be taken into account when company chooses the directions of social policy and plans the budget for social programs. For example, it is noted that expenses on support of the Indigenous people of the North are more significant and constant than other categories. At the same time, the following controversial issue of the social activity of companies was identified: corporate activities and social expenses have a sinusoidal waveform which is determined by the stage of ESG‐transformation and by the main actor in the risk protection system such as governments or companies operated in the Northern regions. The research result shows that social role of extractive companies is currently on “possible” or “desirable” stages and has not yet become absolutely “necessary”. Moreover, any of social activities can be “undesirable” after its legitimization. A balance of interests must occur between the state, companies and the communities to strengthen the role of social values and distribute the responsibility for risks.

Fibrinolytics delivered into the general circulation lack selectivity for nascent thrombi, reducing efficacy and increasing the risk of bleeding. Urokinase-type plasminogen activator (uPA) transgenically expressed within murine platelets provided targeted thromboprophylaxis without causing bleeding but is not clinically feasible. Recent advances in generating megakaryocytes prompted us to develop a potentially clinically relevant means to produce "antithrombotic" platelets from CD34+ hematopoietic stem cell-derived in vitro-grown megakaryocytes. CD34+ megakaryocytes internalize and store in alpha granules (alpha-granules) single-chain uPA (scuPA) and a plasmin-resistant thrombinactivatable variant (uPAT). Both uPAs colocalized with internalized factor V (FV), fibrinogen and plasminogen, low-density lipoprotein receptor-related protein 1 (LRP1), and interferoninduced transmembrane protein 3, but not with endogenous von Willebrand factor (VWF). Endocytosis of uPA by CD34+ megakaryocytes was mediated, in part, via LRP1 and alpha IIb beta 3. scuPA-containing megakaryocytes degraded endocytosed intragranular FV but not endogenous VWF in the presence of internalized plasminogen, whereas uPATmegakaryocytes did not significantly degrade either protein. We used a carotid artery injury model in nonobese diabetic-severe combined immunodeficiency IL2r gamma null (NSG) mice homozygous for VWFR1326H(a mutation switching binding VWF specificity from mouse to human glycoprotein Ib alpha) to test whether platelets derived from scuPA- or uPATmegakaryocytes would prevent thrombus formation. NSG/VWFR1326H mice exhibited a lower thrombotic burden after carotid artery injury compared with NSG mice unless infused with human platelets or megakaryocytes, whereas intravenous injection of uPAmegakaryocytes generated sufficient uPA-containing human platelets to lyse nascent thrombi. These studies describe the use of in vitro-generated megakaryocytes as a potential platform for delivering uPA or other ectopic proteins within platelet alpha-granules to sites of vascular injury.

Our prior finding that uPA endogenously expressed and stored in the platelets of transgenic mice prevented thrombus formation without causing bleeding, prompted us to develop a potentially clinically relevant means of generating anti-thrombotic human platelets in vitro from CD34 + hematopoietic cell-derived megakaryocytes. CD34 + -megakaryocytes internalize and store in α-granules single-chain uPA (scuPA) and a uPA variant modified to be plasmin-resistant, but thrombin-activatable, (uPAT). Both uPAs co-localized with internalized factor V (FV), fibrinogen and plasminogen, low-density lipoprotein receptor-related protein 1 (LRP1), and interferon-induced transmembrane protein 3 (IFITM3), but not with endogenous von Willebrand factor (VWF). Endocytosis of uPA by CD34 + -\megakaryocytes was mediated in part via LRP1 and αIIbβ3. scuPA-containing megakaryocytes degraded endocytosed intragranular FV, but not endogenous VWF, in the presence of internalized plasminogen, whereas uPAT-megakaryocytes did not significantly degrade either protein. We used a carotid-artery injury model in NOD-scid IL2rγnull (NSG) mice homozygous for VWF R1326H (a mutation switching binding VWF specificity from mouse to human glycoprotein IbmlIX) to test whether platelets derived from scuPA-MKs or uPAT-Mks would prevent thrombus formation. NSG/VWF R1326H mice exhibited a lower thrombotic burden after carotid artery injury compared to NSG mice unless infused with human platelets or MKs, whereas intravenous injection of either uPA-containing megakaryocytes into NSG/VWF R1326H generated sufficient uPA-containing human platelets to lyse nascent thrombi. These studies suggest the potential to deliver uPA or potentially other ectopic proteins within platelet α-granules from in vitro- generated megakaryocytes. Key points:Unlike platelets, in vitro-grown megakaryocytes can store exogenous uPA in its α-granules.uPA uptake involves LRP1 and αIIbβ3 receptors and is functionally available from activated platelets.

The focus of this study is labor legislation in Russia and Great Britain. The period of the late XIX - early XX centuries became a time of transition of new labor standards, which had both positive and negative consequences for the working class, but at the same time reflected interests of big capital. The laws discussed in the article (the Russian law «On minors working in factories, factories and manufactories», the English law «Factory and Workshop Act 1878» and others) haven’t only historical, but also social significance, since they raise important issues of ensuring rights of children and young people, and also lay the foundation for the further development of legislative initiatives. The development of the legislative framework on child labor in England begins somewhat earlier than in Russia. However, further changes made to the regulatory framework of the two countries have a general tendency to increase the age threshold for children’s involvement in labor activity and the requirements for primary education. At the same time, the legislations of these countries also have common problems associated with numerous exceptions for the use of child labor in production. The author of the article proposes a new approach to the analysis of comparative aspects of the legislation of Great Britain and Russia, which will allow us to identify and generalize the factors and conditions that shaped the labor legal environment during the transition period. The results of this article contribute to a better understanding of the processes that underlie the development of modern labor law and can be used for further research in the field of labor law in the 21st century.

Background and Aims: To assess lipid metabolic disorders and right and left ventricular strain in young people with metabolic syndrome to identify early markers of myocardial dysfunction. Methods: 50 young people (18–44 years old) were examined; 26 of them had a newly established clinical and laboratory diagnosis of MS. The control group consisted of 24 young healthy people. Anthropometric data included height, body weight, waist circumference (WC), waist-to-height ratio, body mass index (BMI). Lipid profile was assessed including total cholesterol (TC), triglycerides (TG), high and low density lipoprotein cholesterol (HDL and LDL cholesterol), as well as glucose levels. Longitudinal (GLS), circular (GCS), and radial (GRS) strain were measured using 4D echocardiography. Results: In individuals with MS, the mean values of circular (GCS), radial (GRS) strain and area strain (GAS) of the LV were also significantly lower compared to the control group (p1=0.002, p2=0.002, p3=0.001). Mean RV GLS values of 20.4% in the main group were lower compared to the control group (24.3%, p=0.02), although they were at the lower limit of the norm. The TC level had a strong direct correlation with tLV GLS in 2D and 4D, GAS, GCS, GRS; direct moderate correlation with LV EF in 4D. LDL-C was correlated with 2D and 4D LV GLS (r1=0.63, r2=0.69), GAS (r=0.81), GRS (r=0.77). Conclusions: In young people with MS, 2D and 4D RV and LV strain is an earliest marker of myocardial dysfunction associated with changes in the lipid profile, namely, an increase in the level of total cholesterol and low-density lipoprotein cholesterol . 3

The purpose of this article is to evaluate the systolic function of the left and right ventricles and measure myocardial Strain in young people (from 18 to 44 years old) with a newly established clinical and laboratory diagnosis of metabolic syndrome (MS) according to the criteria of the International Diabetes Federation (IDF), to identify possible early markers of myocardial dysfunction. All patients underwent standard transthoracic echocardiography (EchoCG) with assessment of systolic function of the left and right ventricles (LV and RV). The work detects early markers of ventricular myocardial dysfunction using speckle tracking 2D and 4D EchoCG, and also investigates the relationship between the main components of MS and echocardiographic parameters. With the help of a comparative analysis, statistical data were revealed on the low global longitudinal strain of the left and right ventricle in 2D and 4D in the main group compared with the control group. In individuals with MS, the mean values of global circular strain (GCS), radial (GRS) strain and global area strain (GAS) of the left ventricle were also significantly lower than the control group. Indicators obesity diseases (body weight and waist circumference) had a negative correlation with the ejection fraction (EF) and parameters of ventricular strain.

The article presents data on the morphology, range and number of the American mink in Yakutia, gives materials on its morpho- and craniometry. Data on the dynamics of the range and number of the American mink in Yakutia from the moment of its introduction in the early 1960s to the present time are shown. The range of the mink has expanded in the north-east direction from Southern Yakutia to Central Yakutia for half a century, and new mink settlement sites from the eastern side of the Magadan region have been noted. After naturalization of the American mink during 25 years, there was a gradual increase in its number from 686 individuals to 4-5 thousand individuals. Over the next 35 years, the number of the species has stabilized and remains at this level with some fluctuations over the years, excluding 2005-2006, when there was a sharp increase in the number of mink.

The authors consider conceptual approaches to determining the impact of digital transformation on the spatial development of the northern territories and propose their own understanding of assessing the potential of digitalization, which makes it possible to obtain a fairly verifiable picture of the localization of digitalization opportunities at the regional level. In the course of the study, territorial differentiation was revealed in terms of the level of implementation of digital technologies, and a number of characteristics of the types of regions were determined in this context. Based on the obtained assessment of the potential, the authors present promising areas of digitalization that can affect the spatial development of the northern (Arctic) territories. The carried out assessment showed that in most of the subjects of the Russian Federation, the selected areas correspond to those identified as promising economic specializations in the Spatial Development Strategy. At the same time, those regions were identified in which these positions do not coincide. The authors believe that the implementation of a reliable assessment of the potential of digitalization on the basis of the proposed methodology will allow to implement more effective management solutions in solving the problems of spatial planning of the northern territories of Russia and will allow using the specific features of the North as an advantage in its development.

We wish to develop a clinically relevant strategy to deliver anti-thrombotic urokinase plasminogen activator (uPA)-carrying platelets (uPA-PLTs) as a targeted thromboprophylaxis that can be administered to patients with a concurrent high risk of bleeding. This intent was based on our previous data showing that transgenic mice, ectopically expressing uPA in megakaryocytes (MKs), released PLTs, containing uPA in α granules, that were effective as a thromboprophylaxis agent (PMID12689937). We faced two major challenges in further developing uPA-containing PLTs for clinical application: (1) How to get uPA into PLTs as human Plts do not take up uPA, and (2) α-granular uPA led to proteolysis of other α-granule proteins. To diminish degradation of α-granular proteins by uPA, we generated a plasmin-insensitive, but thrombin-activatable, truncated uPA mutant (uPA-T, bottom, Fig. 2). We found that both native single-chain uPA (scuPA) and uPA-T can be taken up by human MKs into the same α granules whereby they co-localize with endocytosed Factor V (FV) and/or fibrinogen (FBGN), as evidenced by confocal microscopy, suggesting that the uPA variants use the same endocytic receptor pathway, also utilized by FV and FBGN (Fig. 1). To delineate what receptor system(s) mediate uPA uptake by CD34+ MK, we found that FV (known to be partially internalized via low-density lipoprotein receptor-related protein 1 (LRP1) competed with both uPA variants for uptake, and that uptake of uPA variants and FV was partially inhibited by the LRP1 antagonist, receptor-associated protein (RAP), further supporting that LRP1 mediates internalization of the uPAs. We also found that uPA and FBGN uptake was partially inhibited by αIIbβ3 integrin antagonist ReoPro. Since we observed that LRP1 protein expression and extent of uPA uptake by MKs declines upon maturation, whereas αIIbβ3 expression does not, we tested if targeting of uPA to αIIbβ3 would facilitate its uptake by CD34+ MKs. We generated a chimeric prodrug composed of a single-chain version of the variable region (scFv) of an anti-αIIbβ3 monoclonal antibody fused to uPA-T (PLT/uPA-T, bottom Fig. 2) which binds human αIIbβ3 on both quiescent and activated PLTs, and is enzymatically activated specifically by thrombin. We have previously shown that in two murine injury models, PLT/uPA-T did not lyse preexisting clots, while it concurrently prevented the development of nascent thrombi (PMC4731161). However, direct infusion of PLT/uPA-T in mice caused significant thrombocytopenia. Now, we found that CD34+ MK internalized PLT/uPA-T into the same α granules of MKs, but with significantly higher efficiency than uPA-T protein (top Fig. 2) which will optimize loading of MKs by uPA-T for subsequent use as a source of uPA-PLTs. We found that scuPA-loaded platelets released from infused MKs prevent thrombus formation in a Rose Bengal photochemical injury model. These studies were done using immunocompromised NOD-scid IL2rγnull (NSG) mice homozygous for VWFR1326H (a VWF mutation switching binding specificity from mouse to human GPIb/IX). NSG/VWFR1326H mice had impaired clotting after vascular injury compared to NSG mice unless infused with human PLTs or MKs. We found that MKs that endocytosed uPA-T can also prevent thrombi formation in this model. Future studies will test whether PLTs released from PLT/uPA-T-loaded MKs would further enhance efficacy of this thromboprophylactic strategy, while avoiding thrombocytopenia, and can become a point-of-care thromboprophylaxis therapeutic in the clinical setting of high-risk of developing thrombi with concurrent concerns of inducing significant bleeding. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Registration of moose lithophagy by means of photo traps was carried out on six salt lick in the protected territo-ries of Southern and Central Yakutia. The duration of moose lithophagy is up to 132 min, with an average of 9-12 min. Females salted longer than males. In Southern Yakutia, half of the visits to lick occur at the darkest time of the day from midnight to 4 am (50.5%), and in Central Yakutia from 8 pm to 12 pm (42.5%). The lowest attendance of lick was ob-served in both cases during daylight hours from 8 am to 8 pm (5.6% and 8.6%). In both parts of the range, females are more likely than males to visit lick at dawn from 4 am to 8 am. The highest activity of salting in both areas is observed in June: in Southern Yakutia - 5.7 moose per day, in Central Yakutia - 2.1 moose per day. This circumstance is explained by the period of calving in females and the development of horns in males. For the entire observation period, the average number of visits per day by animals was: in Southern Yakutia - 3.7 (in the period from May to July), in Central Yakutia - 1.0 (in the period from June to August). In southern Yakutia, there is a sharp increase in male visits to lick in the month of June, which falls sharply in July. In Central Yakutia, this is not observed. The sex ratio of individuals who visited salt lick was: in Central Yakutia males - 60.9%, females - 39.1%; in Southern Yakutia males - 45.7%, females - 54.3%. The percentage of calves was: in Southern Yakutia - 10.2%, in Central Yakutia - 30.3%. In Southern Yakutia, females with moose calves accounted for 3.4% of all visits, and in Central Yakutia - 11.2%

Endothelial cells (ECs) degrade the extracellular matrix of vessel walls and contact surrounding cells to facilitate migration during angiogenesis, leading to formation of an EC-tubular network (ETN). Mesenchymal stromal cells (MSC) support ETN formation when co-cultured with ECs, but the mechanism is incompletely understood. We examined the role of the urokinase-type plasminogen activator (uPA) system, i.e. the serine protease uPA, its inhibitor PAI-1, receptor uPAR/CD87, clearance by the low-density lipoprotein receptor-related protein (LRP1) and their molecular partners, in the formation of ETNs supported by adipose tissue-derived MSC. Co-culture of human umbilical vein ECs (HUVEC) with MSC increased mRNA expression levels of uPAR, MMP14, VEGFR2, TGFβ1, integrin β3 and Notch pathway components (Notch1 receptor and ligands: Dll1, Dll4, Jag1) in HUVECs and uPA, uPAR, TGFβ1, integrin β3, Jag1, Notch3 receptor in MSC. Inhibition at several steps in the activation process indicates that uPA, uPAR and LRP1 cross-talk with αv-integrins, VEGFR2 and Notch receptors/ligands to mediate ETN formation in HUVEC-MSC co-culture. The urokinase system mediates ETN formation through the coordinated action of uPAR, uPA's catalytic activity, its binding to uPAR and its nuclear translocation. These studies identify potential targets to help control aberrant angiogenesis with minimal impact on healthy vasculature.

N-methyl-D-aspartate (NMDA) receptors are widely expressed in the central nervous system. However, their presence and function at extraneuronal sites is less well characterized. In the present study, we examined the expression of NMDA receptor subunit mRNA and protein in human pulmonary artery (HPA) by quantitative polymerase chain reaction (PCR), immunohistochemistry and immunoblotting. We demonstrate that both GluN1 and GluN2 subunit mRNAs are expressed in HPA. In addition, GluN1 and GluN2 (A-D) subunit proteins are expressed by human pulmonary artery smooth muscle cells (HPASMCs) in vitro and in vivo. These subunits localize on the surface of HPASMCs and form functional ion channels as evidenced by whole-cell patch-clamp electrophysiology and reduced phenylephrine-induced contractile responsiveness of human pulmonary artery by the NMDA receptor antagonist MK801 under hypoxic condition. HPASMCs also express high levels of serine racemase and vesicular glutamate transporter 1, suggesting a potential source of endogenous agonists for NMDA receptor activation. Our findings show HPASMCs express functional NMDA receptors in line with their effect on pulmonary vasoconstriction, and thereby suggest a novel therapeutic target for pharmacological modulations in settings associated with pulmonary vascular dysfunction.

In order to determine the clinical significance of exercise stress echocardiography in patients with severe to moderate aortic stenosis, a stress-induced increase in the mean pressure gradient across the aortic valve was recorded and myocardial contractile reserve was assessed using a number of parameters (ejection fraction, global longitudinal strain, elasticity index). It was found that, with normal values of EF at rest in patients with severe and moderate aortic stenosis, the deficit in contractile function was revealed using the GLS index, which demonstrated a decrease in both groups at the peak of exercise. A decrease in contractile reserve by both parameters (EF and GLS) was found in the group of patients with severe AS, which, combined with a significant stress-induced increase in the gradient on the aortic valve (≥18–20 mm Hg), an increase in pulmonary artery pressure (> 60 mm Hg) and decrease in systemic systolic blood pressure (>20 mm Hg) should be considered as a predictors of a poor prognosis of the natural course of aortic valve disease, and patients with similar stress test results should be possible candidates for surgical aortic valve replacement. A decrease in the in the LV elasticity index augmentation at the peak of exercise, strongly correlated with changes in other considered parameters of contractility and the metabolic power of exercise (MET), significantly complements the functional characteristics of the lesion for choosing the optimal management strategy. Consequently, exercise stress echocardiography is an indispensable diagnostic tool for determining the prognosis and timing of surgery in patients with aortic stenosis.

Alpha granules in megakaryocytes contain a mixture of endogenously expressed proteins as well as proteins taken up from the intramedullar fluid. Both pools are thought to be found in all alpha granules in the megakaryocytes and released platelets. We have been studying the ectopic expression of urokinase (uPA) in platelets as a targeting strategy for fibrinolysis of nascent thrombi without causing fibrinolysis of established thrombi. These studies also demonstrated that there are two distinct pools of alpha granules, an endogenous cargo pool of granules and an exogenous uptake cargo pool of granules.