An Analytical Solution for Stress Transfer between a Broken Prestressing Wire and Mortar Coating in PCCP.

A prestressed concrete cylinder pipe (PCCP) consists of a concrete core, a steel cylinder, prestressing wires, and a mortar coating. Most PCCP failures are related to the breakage of prestressing wires. It is thus expected that the load-bearing capacity of PCCP is significantly affected by the length of the prestress loss zone and the stress distribution in the broken wire. Based on a tri-linear bond-slip model, the length of prestress loss zone and the stress transfer mechanism between a broken wire and a mortar coating are analysed in this paper. During the breaking (unloading) process of a prestressing wire, the interfacial bondline exhibits the following three stages: elastic stage, elastic-softening stage, and elastic-softening-debonding stage. The closed-form solutions for the interfacial slip, the interfacial shear stress, and the axial stress in the broken wire are derived for each stage. The solutions are verified by the finite element predictions. A parametric study is presented to investigate the effects of the size of the prestressing wires, the prestressing level, the interfacial shear strength, and the residual interfacial shear strength on the interfacial stress transfer. For an example PCCP with an inner diameter of 4 m, the length of prestress loss zone increases from 500 mm to 3300 mm as the radius of prestressing wire increases from 1 mm to 7 mm. It increases from 2700 mm to 7700 mm when the interfacial shear strength reduces from 3.94 MPa to 0.62 MPa and reduces from 13,200 mm to 7300 mm as the residual interfacial shear stress factor increases from 0.1 to 0.9.

Enantioselective Pd-catalyzed dearomative reductive Heck and domino Heck-Suzuki reactions of 2-CF3-indoles.

Highly enantioselective palladium-catalyzed dearomative reductive Heck reaction and domino Heck-Suzuki reaction of 2-CF3-indoles have been developed. Using Pd(OAc)2/(R)-Synphos as the catalyst and Et3SiH as a hydride source, a variety of indolines bearing a 2-trifluoromethyl quaternary stereocenter were obtained via a dearomative reductive Heck reaction. Alternatively, using Pd(dba)2/phosphoramidite as the catalyst and Ar4BNa as a coupling partner, structurally diverse indolines containing two vicinal carbon stereocenters were afforded through the domino dearomative Heck-Suzuki reaction.

Whole-Genome Resequencing of Worldwide Wild and Domestic Sheep Elucidates Genetic Diversity, Introgression, and Agronomically Important Loci.

Domestic sheep and their wild relatives harbor substantial genetic variants that can form the backbone of molecular breeding, but their genome landscapes remain understudied. Here, we present a comprehensive genome resource for wild ovine species, landraces and improved breeds of domestic sheep, comprising high-coverage (∼16.10×) whole genomes of 810 samples from 7 wild species and 158 diverse domestic populations. We detected, in total, ∼121.2 million single nucleotide polymorphisms, ∼61 million of which are novel. Some display significant (P < 0.001) differences in frequency between wild and domestic species, or are private to continent-wide or individual sheep populations. Retained or introgressed wild gene variants in domestic populations have contributed to local adaptation, such as the variation in the HBB associated with plateau adaptation. We identified novel and previously reported targets of selection on morphological and agronomic traits such as stature, horn, tail configuration, and wool fineness. We explored the genetic basis of wool fineness and unveiled a novel mutation (chr25: T7,068,586C) in the 3'-UTR of IRF2BP2 as plausible causal variant for fleece fiber diameter. We reconstructed prehistorical migrations from the Near Eastern domestication center to South-and-Southeast Asia and found two main waves of migrations across the Eurasian Steppe and the Iranian Plateau in the Early and Late Bronze Ages. Our findings refine our understanding of genome variation as shaped by continental migrations, introgression, adaptation, and selection of sheep.

Recovery of a hypolipidemic polysaccharide from artificially cultivated Sanghuangporus vaninii with an effective method.

In this study, an effective method was developed to extract the polysaccharide from Sanghuangporus vaninii (PFSV) by destroying the cell wall. Box-Behnken design was employed to determine the optimal processing conditions as follows: processing temperature (80°C), processing time (0.81 h) and amount of HCl (1.5 ml). Under these conditions, the yield of PFSV reached 5.94 ± 0.16%. The purified polysaccharide (PFSV-2) was found to be a hetero-polysaccharide with an average molecular weight of 20.377 kDa. The backbone of PFSV-2 was composed of an →6)-α-Galp-(1→ and →2,6)-ß-Manp-(1→ and →2)-α-Fucp-(1→ and was branched of t-α-Manp-(1→ at position 2 of residue B. PFSV-2 showed hypolipidemic activity by decreasing lipid accumulation and the levels of total cholesterol and triglycerides in zebrafish larvae. Furthermore, PFSV-2 downregulated the pparg, fasn, and HMGCRb genes and upregulated the pparab and acaca genes. These findings suggested PFSV-2 may be a promising candidate in lipid regulation therapy.

The onset of sleep disturbances and their associations with anxiety after acute high-altitude exposure at 3700 m.

Sleep disturbances and psychiatric repercussions pose great challenges at high altitude; however, few studies have investigated sleep disturbance and anxiety profiles and their associations after acute exposure in consecutive patients. Thus, we aimed to study the profiles of sleep disturbances in consecutive patients after high-altitude exposure and the association of such disturbances with anxiety. A total of 668 participants were recruited at sea level and 3700 m. The trials were performed at sea level (1 week prior to a 2-h flight to a high-altitude destination) and at 3700 m (24, 72, and 168 h). Sleep disturbances were assessed by self-reported sleep patterns and scores on the Athens Insomnia Scale (AIS). State anxiety was assessed using the Self-Rating Anxiety Scale (SAS). In our study, the incidence of sleep disturbances increased significantly after acute high-altitude exposure (65.3%, 434/668) and then gradually decreased after 72 h (50%, 141/282) and 168 h (44%, 124/282). The sleep assessments AIS [2.0 (4.0) vs. 4.0 (5.0)] and ESS [4.0 (4.0) vs. 5.0 (5.0)] increased significantly (p < 0.05). Also, the SAS increased significantly from 26.25 (3.75) to 28.75 (7.5). The SAS was significantly high in sleep disturbance group [31.25 (7.5) vs. 27.5 (5), p < 0.001] than in the non-sleep- disturbance group. The baseline SAS and AIS scores were significantly higher in participants with sleep disturbances than in those without (p < 0.01). Age, baseline insomnia, sleepiness, fatigue, and higher SAS were predictors of sleep disturbances in univariate regression (all p values < 0.05). However, only an older age (p = 0.045) and a higher baseline SAS (p = 0.018) remained independent predictors of sleep disturbances. Our findings indicated that acute high-altitude exposure triggers the onset of sleep disturbances, which are closely associated with anxiety. Furthermore, baseline state anxiety and age are independent predictors of sleep disturbances at high altitude.

MTF2 Induces Epithelial-Mesenchymal Transition and Progression of Hepatocellular Carcinoma by Transcriptionally Activating Snail.

BACKGROUND: Metal regulatory transcription factor 2 (MTF2) has been previously reported as a protein binding to the metal response element of the mouse metallothionein promoter, which is involved in chromosome inactivation and pluripotency. However, the function of MTF2 in tumor formation and progression has not yet been completely elucidated. METHODS: The expression of MTF2 and clinicopathological characteristics were evaluated by hepatocellular carcinoma (HCC) tissue microarray of 240 specimens. The role of MTF2 on HCC progression was determined using MTT, crystal violet, and transwell assays. Tumor growth was monitored in a xenograft model, and intrahepatic metastasis models were established. RESULTS: The expression of MTF2 was increased in HCC and strongly associated with the clinical characteristics and prognosis. Forced expression of MTF2 in HCC cells significantly promoted cell growth, migration, and invasion in vitro. In contrast, downregulation of MTF2 inhibited cell growth, migration, and invasion in vitro. Moreover, knock down of MTF2 suppressed tumorigenesis and intrahepatic metastasis of HCC cells in vivo. Mechanistically, MTF2 overexpression may promote growth and epithelial-mesenchymal transition processes of HCC cells by facilitating Snail transcription. CONCLUSION: MTF2 promotes the proliferation, migration, and invasion of HCC cells by regulating Snail transcription, providing a potential therapeutic candidate for patients with HCC.

Anti-atherosclerotic effect of hesperidin in LDLr-/- mice and its possible mechanism.

Hesperidin, a citrus bioflavonoid, exerts numerous pharmacological activities. However, its protective effect against atherosclerosis in vivo remains poorly understood. In the present study, we aimed to observe the effects of hesperidin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr-/-) mice. After 12 weeks of treatment, the animals were sacrificed. The blood samples were collected for further analysis. Mouse peritoneal macrophages were collected. Hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation, gene expressions were performed on liver and aorta samples. The data showed that hesperidin ameliorated HFD-induced weight gain, improved insulin resistance and ameliorated hyperlipidemia. Hesperidin suppressed HFD-induced hepatic steatosis, atherosclerotic plaque area and macrophage foam cell formation. Further study showed that hesperidin down-regulated expressions of acetyl coenzyme A carboxylase alpha (ACCα) and fatty acid synthase (FAS) which are two key enzymes in fatty acid and triglyceride synthesis in liver; and upregulated expression of hepatic ATP-binding cassette transporters G8 (ABCG8), macrophage ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) which are transporters involved in the process of reverse cholesterol transport. Hesperidin also reduced oxidative stress by normalizing activities of antioxidant enzymes and inflammation in HFD-fed LDLr-/- mice. These findings suggest that hesperidin reduced atherosclerosis via its pleiotropic effects, including improvement of insulin resistance, amelioration of lipid profiles, inhibition of macrophage foam cell formation, anti-oxidative effect and anti-inflammatory action.

Physiological and psychological factors associated with onset of high-altitude headache in Chinese men upon acute high-altitude exposure at 3700 m.

Aim We aimed to identify clinical characteristics and risk factors associated with onset of high-altitude headache (HAH) after acute exposure at 3700 m. Method In two hours, 163 individuals ascended by plane to 3700 m. Demographic information, physiological and psychological measurements, cognitive function, physical work capacity tests and profile of mood states within one week prior to the departure and within 24 hours after arrival were examined. Results HAH patients featured significantly higher vertebral artery diastolic velocity (Vd), heart rate (HR) and pulmonary artery diameter. HAH was also associated with a more negative mood state, including scores for tension anxiety, depression, hostility, fatigue and confusion, as well as lower vigor (all p values <0.05). Furthermore, negative emotions were positively related to HAH severity. HAH slightly decreased cognitive functioning. HR, Vd, lack of vigor, confusion and self-reported anxiety (all p values <0.05) were independent risk factors for HAH. We have identified three independent baseline predictors for HAH including internal diameter of the left ventricle (LVD), Athens Insomnia Scale (AIS) and confusion score. Conclusions Higher HR, Vd, confusion and self-reported anxiety and insufficient vigor were independent risk factors for HAH. Furthermore, higher baseline LVD, AIS and confusion score are independent predictors of HAH.

Principal Component Analysis and Risk Factors for Acute Mountain Sickness upon Acute Exposure at 3700 m.

OBJECTIVE: We aimed to describe the heterogeneity in the clinical presentation of acute mountain sickness (AMS) and to identify its primary risk factors. METHODS: The participants (n = 163) received case report form questionnaires, and their heart rate (HR), oxygen saturation (SpO2), echocardiographic and transcranial Doppler variables, ability to perform mental and physical work, mood and psychological factors were assessed within 18 to 22 hours after arriving at 3700 m from sea level (500 m) by plane. First, we examined the differences in all variables between the AMS-positive and the AMS-negative groups. Second, an adjusted regression analysis was performed after correlation and principal component analyses. RESULTS: The AMS patients had a higher diastolic vertebral artery velocity (Vd; p = 0.018), a higher HR (p = 0.006) and a lower SpO2. The AMS subjects also experienced poorer sleep quality, as quantified using the Athens Insomnia Scale (AIS). Moreover, the AMS population exhibited more negative mood states, including anxiety, depression, hostility, fatigue and confusion. Five principal components focused on diverse aspects were also found to be significant. Additionally, more advanced age (p = 0.007), a higher HR (p = 0.034), a higher Vd (p = 0.014), a higher AIS score (p = 0.030), a decreased pursuit aiming capacity (p = 0.035) and decreased vigor (p = 0.015) were risk factors for AMS. CONCLUSIONS: Mood states play critical roles in the development of AMS. Furthermore, an elevated HR and Vd, advanced age, elevated AIS sores, insufficient vigor and decreased mental work capacity are independent risk factors for AMS.

Lack of association of CYP11B2-344C/T polymorphism with essential hypertension: a meta-analysis.

OBJECTIVE: A meta-analysis was carried out to evaluate the correlation between CYP11B2-344C/T polymorphism and essential hypertension susceptibility. METHODS: By retrieving relevant databases and collecting domestic and international literatures about the correlation between CYP11B2-344C/T polymorphism and essential hypertension, the quality of literature were evaluated according to NEWCASTLE-OTTAWA case-control study quality rating scale (NOS). RevMan 5.0 was used to select the best genetic model, analysis the heterogeneity, calculate combined OR and the 95% CI. RESULTS: 8532 subjects were included in this study. Compared with the control group, the OR (95% CI) values of dominant model, recessive model, and additive model were 1.01 (95% CI: 0.81~1.25), 1.03 (95% CI: 0.83~1.19) and 1.10 (95% CI: 0.93-1.29). CONCLUSION: There is no evidence to confirm that CYP11B2 (-344C/T) polymorphism is associated with susceptibility of essential hypertension.

Cerebral hemodynamic characteristics of acute mountain sickness upon acute high-altitude exposure at 3,700 m in young Chinese men.

PURPOSE: We aimed at identifying the cerebral hemodynamic characteristics of acute mountain sickness (AMS). METHODS: Transcranial Doppler (TCD) sonography examinations were performed between 18 and 24 h after arrival at 3,700 m via plane from 500 m (n = 454). A subgroup of 151 subjects received TCD examinations at both altitudes. RESULTS: The velocities of the middle cerebral artery, vertebral artery (VA) and basilar artery (BA) increased while the pulsatility indexes (PIs) and resistance indexes (RIs) decreased significantly (all p < 0.05). Velocities of BA were higher in AMS (AMS+) individuals when compared with non-AMS (AMS-) subjects (systolic velocity: 66 ± 12 vs. 69 ± 15 cm/s, diastolic velocity: 29 ± 7 vs. 31 ± 8 cm/s and mean velocity, 42 ± 9 vs. 44 ± 10 cm/s). AMS was characterized by higher diastolic velocity [V d_VA (26 ± 4 vs. 25 ± 4, p = 0.013)] with lower PI and RI (both p = 0.004) in VA. Furthermore, the asymmetry index (AI) of VAs was significantly lower in the AMS + group [-5.7 % (21.0 %) vs. -2.5 % (17.8 %), p = 0.016]. The AMS score was closely correlated with the hemodynamic parameters of BA and the V d_VA, PI, RI and AI of VA. CONCLUSION: AMS is associated with alterations in cerebral hemodynamics in the posterior circulation rather than the anterior one, and is characterized by higher blood velocity with lower resistance. In addition, the asymmetry of VAs may be involved in AMS.

Correlation between blood pressure changes and AMS, sleeping quality and exercise upon high-altitude exposure in young Chinese men.

BACKGROUND: Excessive elevation of arterial blood pressure (BP) at high altitude can be detrimental to our health due to acute mountain sickness (AMS) or some AMS symptoms. This prospective and observational study aimed to elucidate blood pressure changes induced by exposure to high-altitude hypoxia and the relationships of these changes with AMS prevalence, AMS severity, sleep quality and exercise condition in healthy young men. METHODS: A prospective observational study was performed in 931 male young adults exposed to high altitude at 3,700 m (Lhasa) from low altitude (LA, 500 m). Blood pressure measurement and AMS symptom questionnaires were performed at LA and on day 1, 3, 5, and 7 of exposure to high altitude. Lake Louise criteria were used to diagnose AMS. Likewise, the Athens Insomnia Scale (AIS) and the Epworth Sleepiness Scale (ESS) were filled out at LA and on day 1, 3, and 7 of exposure to high altitude. RESULTS: After acute exposure to 3,700 m, diastolic blood pressure (DBP) and mean arterial blood pressure (MABP) rose gradually and continually (P < 0.05). Analysis showed a relationship with AMS for only MABP (P < 0.05) but not for SBP and DBP (P > 0.05). Poor sleeping quality was generally associated with higher SBP or DBP at high altitude, although inconsistent results were obtained at different time (P < 0.05). SBP and Pulse BP increased noticeably after high-altitude exercise (P < 0.05). CONCLUSIONS: Our data demonstrate notable blood pressure changes under exposure to different high-altitude conditions: 1) BP increased over time. 2) Higher BP generally accompanied poor sleeping quality and higher incidence of AMS. 3) SBP and Pulse BP were higher after high-altitude exercise. Therefore, we should put more effort into monitoring BP after exposure to high altitude in order to guard against excessive increases in BP.

Identification of cellular proteome using two-dimensional difference gel electrophoresis in ST cells infected with transmissible gastroenteritis coronavirus.

BACKGROUND: Transmissible gastroenteritis coronavirus (TGEV) is an enteropathogenic coronavirus that causes diarrhea in pigs, which is correlated with high morbidity and mortality in suckling piglets. Information remains limited about the comparative protein expression of host cells in response to TGEV infection. In this study, cellular protein response to TGEV infection in swine testes (ST) cells was analyzed, using the proteomic method of two-dimensional difference gel electrophoresis (2D DIGE) coupled with MALDI-TOF-TOF/MS identification. RESULTS: 33 differentially expressed protein spots, of which 23 were up-regulated and 10 were down-regulated were identified. All the protein spots were successfully identified. The identified proteins were involved in the regulation of essential processes such as cellular structure and integrity, RNA processing, protein biosynthesis and modification, vesicle transport, signal transduction, and the mitochondrial pathway. Western blot analysis was used to validate the changes of alpha tubulin, keratin 19, and prohibitin during TGEV infection. CONCLUSIONS: To our knowledge, we have performed the first analysis of the proteomic changes in host cell during TGEV infection. 17 altered cellular proteins that differentially expressed in TGEV infection were identified. The present study provides protein-related information that should be useful for understanding the host cell response to TGEV infection and the underlying mechanism of TGEV replication and pathogenicity.

Effects of angiotensin II receptor antagonist olmesartan on renal hemodynamic variables and vascular structural properties in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetic nephropathy is a major cause of renal failure in diabetes mellitus (DM). It has been known that renin-angiotensin system (RAS) blockers have a renal protective effect. This study aimed to investigate whether treatment with angiotensin II receptor blocker, olmesartan, could modify renal hemodynamic variables and vascular structural properties, then attenuate renal injury in streptozotocin (STZ)-induced DM rats. METHODS: DM was induced in male Wistar rats by intraperitoneal administration of STZ. The rats were then randomized to a DM group and an olmesartan treatment (OLM + DM) group. The normal group (non-DM) were administered only citrate buffer. At the end of the 14th week, blood glucose, kidney weight/body weight and urinary protein-to-creatinine ratio were determined. Further, the flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated, perfused kidneys. From the relationship, 3 indices of vascular structural properties were estimated: slope of flow-pressure (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of pressure-GFR (glomerular filtration capacity against pressure) and threshold pressure for beginning filtration at pressure-GFR (preglomerular to postglomerular vascular resistance ratio). Kidneys were then perfusion fixed for histological analysis. The renal histopathology was observed by light microscopy. RESULTS: The body weight of DM rats was lower than that of non-DM rats. Blood glucose, kidney weight/body weight, urinary protein-to-creatinine ratio were significantly greater in DM rats than in non-DM rats. The parameters such as kidney weight/body weight, urinary protein-to-creatinine ratio in OLM + DM rats had dramatically decreased compared with those in DM rats. However, the treatment with olmesartan had no effect on blood glucose levels. The slope of flow-pressure relationship was greater in DM rats than that in non-DM rats (P < 0.05). But the slope of the pressure-GFR relationship was lower in DM rats than that in non-DM rats (P < 0.05) with the x-intercept of the line similar between the two groups. The slope of the flow-pressure relationship was decreased in DM rats group treated with olmesartan (P < 0.05). Moreover, olmesartan significantly increased the slope of the pressure-GFR relationship in DM rats (P < 0.05). The x-intercept of the pressure-GFR relationship reduced following olmesartan in DM rats. CONCLUSIONS: Treatment with olmesartan reduced urinary protein-to-creatinine ratio independent of blood glucose and increased average renal vessel lumen diameter in the perfused kidneys of STZ-induced DM rats, predominantly in preglomerular vessels, and then improved renal excretory capability. These findings were consistent with remodeling of the preglomerular vasculature in our hisological measurements.

CCN1 promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury.

Endothelial progenitor cells (EPCs) contribute to the process of reendothelialization and prevent neointimal formation after vascular injury. The present study was designed to investigate whether the cysteine-rich 61 (CYR61, CCN1), an important matricellular component of local vascular microenvironment, has effect on EPCs differentiation and reendothelialization in response to vascular injury in rat. Following balloon injury, CCN1 was rapidly induced and dynamically changed at vascular lesions. Overexpression of CCN1 by adenovirus (Ad-CCN1) accelerated reendothelialization and inhibited neointimal formation in the early phase (day 14) after vascular injury (p < 0.05), while no effect was shown on day 21. Ad-CCN1 treatment increased the adhering EPCs on the surface of injured vessels on day 7, and the ratio of GFP- and vWF-positive area to the total luminal length on day 14 was 2.3-fold higher in the Ad-CCN1-EPC-transplanted group than in controls. Consistent with these findings, CCN1-stimulated EPC differentiation in vitro and 20 genes were found differentially expressed during CCN1-induced EPC differentiation, including Id1, Vegf-b, Vegf-c, Kdr, Igf-1, Ereg, Tgf, Mdk, Ptn, Timp2, etc. Among them, negative transcriptional regulator Id1 was associated with CCN1 effect on EPC differentiation. Our data suggest that CCN1, from the microenvironment of injured vessels, enhances reendothelialization via a direct action on EPC differentiation, revealing a possible new mechanism underlying the process of vascular repair.

CD4+Foxp3+ regulatory T cells converted by rapamycin from peripheral CD4+CD25(-) naive T cells display more potent regulatory ability in vitro.

BACKGROUND: Rapamycin (RAPA) is a relatively new immunosuppressant drug that functions as a serine/threonine kinase inhibitor to prevent rejection in organ transplantation. RAPA blocks activation of T-effector (Teff) cells by inhibiting the response to interleukin-2. Recently, RAPA was also shown to selectively expand the T-regulator (Treg) cell population. To date, no studies have examined the mechanism by which RAPA converts Teff cells to Treg cells. METHODS: Peripheral CD4(+)CD25(-) naive T cells were cultivated with RAPA and B cells as antigen-presenting cells (APCs) in vitro. CD4(+)CD25(-) T cells were harvested after 6 days and analyzed for expression of forkhead box protein 3 (Foxp3) using flow cytometry. CD4(+)CD25(+)CD127(-) subsets as the converted Tregs were isolated from the mixed lymphocyte reactions (MLR) with CD127 negative selection, followed by CD4 and CD25 positive selection using microbeads and magnetic separation column (MSC). Moreover, mRNA was extracted from converted Tregs and C57BL/6 naive CD4(+)CD25(+) T cells and Foxp3 levels were examined by quantitative real-time polymerase chain reaction (rt-PCR). A total of 1 x 10(5) carboxyfluorescein succinimidyl ester (CFSE)-labeled naive CD4(+)CD25(-) T cells/well from C57BL/6 mice were cocultured with DBA/2 or C3H maturation of dendritic cells (mDCs) (0.25 x 10(5)/well) in 96-well round-bottom plates for 6 days. Then 1 x 10(5) or 0.25 x 10(5) converted Treg cells were added to every well as regulatory cells. Cells were harvested after 6 days of culture and analyzed for proliferation of CFSE-labeled naive CD4(+)CD25(-) T cells using flow cytometry. Data were analyzed using CellQuest software. RESULTS: We found that RAPA can convert peripheral CD4(+)CD25(-) naive T Cells to CD4(+)Foxp3(+) Treg cells using B cells as APCs, and this subtype of Treg can potently suppress Teff proliferation and maintain antigenic specificity. CONCLUSION: Our findings provide evidence that RAPA induces Treg cell conversion from Teff cells and uncovers an additional mechanism for tolerance induction by RAPA.

Inhibitor of DNA binding-1 promotes the migration and proliferation of endothelial progenitor cells in vitro.

Migration and proliferation of endothelial progenitor cells (EPCs) are the key mechanisms in re-endothelialization after vascular injury. Inhibitor of DNA binding-1 (Id1) function has been linked to the proliferation, migration, and senescence of cells, and studies have shed light on the relationship between Id1 and the biological functions of EPCs. On the basis of the available data concerning Id1 and the behavior of EPCs, we hypothesized that Id1 was an important regulator in modulating the migration and proliferation of EPCs. Culture of spleen-derived EPCs was done as previously described. Id1 was presented at low levels in EPCs. Id1 was localized predominantly in the cytoplasm, and was rapidly upregulated by stimulation with serum and vascular endothelial growth factor. The migration and proliferation of EPCs were extensively improved by overexpression of adenovirus-mediated exogenous Id1 and inhibited by silencing of endogenous Id1 in EPCs. These results suggest that Id1 has a direct role in regulation of the migration and proliferation in EPCs.

Transfection of HGF gene enhances endothelial progenitor cell (EPC) function and improves EPC transplant efficiency for balloon-induced arterial injury in hypercholesterolemic rats.

Risk factors for coronary heart disease can reduce the number of endothelial progenitor cells (EPCs) and impair EPC function, thus hindering their utility in the treatment of cardiovascular diseases. In the present study, we began exploring the feasibility of genetic modification of EPCs with hepatocyte growth factor (HGF) to counter the effects of these risk factors and enhance the biological functions of EPCs. The effects of HGF transfection on proliferation, migration and angiogenesis of EPCs were investigated. Additionally, the role of ERK1/2 in this process was evaluated through the observation of ERK1/2 and ERK1/2 phosphorylation as well as by pharmacological analysis. Finally, we evaluated the effect of HGF-transfected EPCs (HGF-EPCs) on neointima formation after balloon-induced arterial injury in hypercholesterolemic rats. Our data showed that EPCs transfected with the HGF gene released high levels of soluble HGF protein, which were maintained for at least nine days. Transfection with HGF also enhanced the proliferative, migratory and angiogenic capabilities of EPCs, and promoted the activation of ERK1/2 without affecting its expression. ERK1/2 blockade by the chemical inhibitor PD98059 partially inhibited these effects. In hypercholesterolemic rats, HGF-EPCs homed to the site of vascular injury at a significantly higher rate than did EPCs without the exogenous HGF gene. Furthermore, systemically applied HGF-EPCs were more effective in decreasing neointima formation and increasing re-endothelialization. These data suggest that gene delivery combined with EPC transplant may be a practical and promising therapy for the prevention of neointimal formation after vascular injury.

A meprin inhibitor suppresses atherosclerotic plaque formation in ApoE-/- mice.

Meprin is a member of the astacin family of zinc metalloendopeptidases. It is widely distributed in the body, and hydrolyzes and inactivates several endogenous vasoactive peptides, some of which could alter various functions of cells in the arterial wall. We assessed the influence of chronic meprin inhibition by daily administration of actinonin (5mg/kg body weight per day; i.p.) on the development of atherosclerotic changes in ApoE(-/-) mice. Mice were fed a high-fat (21% fat), cholesterol-rich (1% cholesterol) Western-type diet for 16 weeks starting at 10 weeks of age. At 20 weeks of age, randomly selected ApoE(-/-) mice were treated with Western-type diet chow pellets supplemented with commercially available actinonin (meprin-I group) for 6 weeks; the diet of control ApoE(-/-) mice was supplemented with saline (placebo group). There was no difference in body weight, hemodynamic data and serum lipids between the two groups at the end of the dietary period. Meprin-I treatment was found to elevate levels of natriuretic peptides (NPs) in plasma and the vascular wall by radioimmunoassay. Meprin-I treatment also decreased plaque volume and suppressed lipid deposition in carotid arteries. Meprin-I treatment reduced production of reactive oxygen species (ROS) and apoptosis (which are associated with atherosclerosis) in the vascular wall. In in vitro experiments, meprin-I treatment increased NP function on cell apoptosis, proliferation, and intracellular ROS generation in the THP-1 cell line and primary vascular smooth muscle cells (VSMC). These results suggest that the meprin inhibitor actinonin may have a protective role in atherosclerosis, and that meprin inhibition may be therapeutically useful in atherosclerosis prevention. Suppression of degradation in the arteries of endogenously released NPs (particularly atrial natriuretic peptide and brain natriuretic peptide), or other kinins known to have anti-atherosclerotic actions, may at least partially contribute to the inhibitory effects of meprin-I on atherosclerotic changes.