A new dynamical mechanism of incomplete fusion in heavy-ion collision

The incomplete fusion has been proved as the formation and emission of the $\alpha$ particle by the increase in the rotational energy of the very mass-asymmetric dinuclear system. The results of the dinuclear system model have confirmed that the incomplete fusion in heavy-ion collisions occurs at a large orbital angular momentum ($L > 30 \hbar$) due to the strong increase of the intrinsic fusion barrier.Comment: 6 pages, 11 figure

Розробка цільового профілю якості капсул із вмістом сухого екстракту Salvia sclarea L., вирощеної в Таджикистані

Aim. To work out the concept of scientific research on the pharmaceutical development of capsules based on the substance of a dry extract of Salvia sclarea L. (clary sage) grown in Tajikistan by developing a target drug quality profile. Materials and methods. During the research, methods of a systematic approach, scientific analysis, comparison, analogy, and generalization of information on the pharmaceutical development of herbal medicines were used. Tabular and schematic tools for visual presentation of the data obtained were also applied. Results. The pharmacological studies of a dry extract of Salvia sclarea L. grown in Tajikistan using the “elevated plus maze” test indicate the prospects of its use as an active substance of a moderate anxiolytic action in the dose of 300 mg/kg. The results obtained served as the basis for developing a target quality profile for capsules containing a dry extract as the first stage of the pharmaceutical development, implementing the programmable quality concept “Quality by Design”. When developing the target quality profile for capsules, a set of complementary provisions, recommendations, and methods of the State Pharmacopoeia of Ukraine and the Eurasian Economic Union concerning the issues of technological, chemical, and microbiological requirements for the development of pharmaceutical products was analyzed. Conclusions. Thus, the development of a target quality profile for capsules containing a dry extract of Salvia sclarea L. will make it possible to rationally use material resources and implement the programmable quality concept. Мета наукового дослідження – розробити цільовий профіль якості капсул на основі субстанції сухого екстракту Salvia sclarea L. (шавлії мускатної), вирощеної в Таджикистані. Матеріали та методи. Під час виконання досліджень використовували метод системного підходу, наукового аналізу, порівняння, аналогії та узагальнення відомостей про фармацевтичну розробку лікарських рослинних засобів. Також застосовували табличні та схематичні засоби наочної презентації отриманих даних. Результати досліджень. Проведені фармакологічні дослідження сухого екстракту шавлії мускатної, вирощеної в Таджикистані за допомогою тесту «припіднятий хрестоподібний лабіринт», доводять перспективність його використання як активної субстанції помірної анксіолітичної дії в дозі 300 мг/кг. Отримані результати стали основою цільового профілю якості капсул із вмістом сухого екстракту як першого етапу фармацевтичної розробки, реалізуючи концепцію програмованої якості «Quality by Design». Розробляючи  цільовий профіль якості капсул, проаналізували комплекс взаємодоповняльних положень, рекомендацій та методик Державної фармакопеї України та Євразійського економічного союзу щодо питань технологічних, хімічних та мікробіологічних вимог до розробки фармацевтичних препаратів. Висновки. Отже, розробка цільового профілю якості капсул із вмістом сухого екстракту шавлії мускатної дозволить раціонально використовувати матеріальні ресурси й реалізувати концепцію програмованої якості

Clinical Effectiveness of the Fixed‐Dose vs Free‐Dose Triple Combinations in Patients with Uncontrolled Arterial Hypertension

Background: The purpose of our study was a comparative assessment of the antihypertensive effectiveness of 2 triple combination antihypertensive therapy (AHT) regimens in a free-dose and fixed-dose combination of perindopril, indapamide, and amlodipine in hypertensive patients with high cardiovascular risk and a poor response to the 2-drug combinations in the clinic practice. Methods and Results: Our study included 143 patients (79 men and 88 women) with arterial hypertension (AH) Grades 1-3 (ESC/ESH, 2018) and high cardiovascular risk who did not achieve the target blood pressure (TBP) on dual combination AHT. The mean age of patients was 55.76±9.35 years; the average duration of AH was 10.69±6.61 years. All patients underwent the examinations according to the 2018 ESC/ESH Guidelines for the management of arterial hypertension. Patients included in the study were divided into 2 groups using the envelope method: Group 1 (n=84) received a fixed-dose, triple combination of perindopril, indapamide, and amlodipine; Group 2 (n=83) received a free-dose combination of these drugs. In both groups, treatment began after discontinuation of previous therapy, with a low dose of a triple combination of antihypertensive drugs (perindopril [5 mg/day], indapamide [1.25 mg/day], amlodipine [5 mg/day]) in the form of a fixed or free combination. The initial doses of perindopril/indapamide/amlodipine in both groups were not statistically different: 6.9±2.4/1.74±0.6/7.1±2.4mg/day in Group 1 and 6.9±2.7/1.95±0.6/7.1±2.5 mg/day in Group 2. After 4 weeks of therapy, if necessary, the doses of drugs were increased, starting with perindopril; the next adjustment of drug doses was carried out after 12 weeks of therapy. The final treatment results were determined after 24 weeks of AHT. Target blood pressure (TBP) of <140/90 mmHg was reached by 94.4% of patients in Group 1 and 83.3% in Group 2 (χ²=7.471, Р=0,006); TBP of <130/80 mmHg was reached by 70% of patients in Group 1 and 42% in Group 2 (χ²=11.61, Р=0,0001). A significant improvement in the diurnal BP profile was also revealed during treatment. According to ABPM data, both groups achieved TBP in terms of the average 24-h and average daytime systolic blood pressure (SBP) and diastolic blood pressure (DBP). Regarding average nighttime SBP and DBP and normalization of average nighttime diastolic blood pressure variability, target values were achieved only in Group 1(P=0.028). In both groups, 24-week triple-combination therapy led to a significant decrease in central SBP, central DBP, and pulse wave velocity (PWV). At the same time, the positive dynamics of central SBP were more pronounced in Group 1 than in Group 2 (Table 4), and PWV in Group 1 reached standard values. Conclusion: The results of our study showed that in the treatment of uncontrolled hypertension on previous therapy in AH patients with high cardiovascular risk, a single-pill triple combination of the ACEI perindopril, the CCB amlodipine, and the thiazide-like diuretic indapamide contributed to the effective daily blood pressure control, the improvement of diurnal blood pressure profile, and a positive effect on central blood pressure and PWV, thereby having a positive impact on the prognosis and quality of life of AH patients with high cardiovascular risk

Insulin Resistance Impairs Circulating Angiogenic Progenitor Cell Function and Delays Endothelial Regeneration

OBJECTIVE Circulating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration. RESEARCH DESIGN AND METHODS We quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion. RESULTS IRKO mice, although glucose tolerant, had fewer circulating Sca-1+/Flk-1+ APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor–stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit+ bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial repair. CONCLUSIONS Insulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals

Novel Role of the IGF-1 Receptor in Endothelial Function and Repair: Studies in Endothelium-Targeted IGF-1 Receptor Transgenic Mice

We recently demonstrated that reducing IGF-1 receptor (IGF-1R) numbers in the endothelium enhances nitric oxide (NO) bioavailability and endothelial cell insulin sensitivity. In the present report, we aimed to examine the effect of increasing IGF-1R on endothelial cell function and repair. To examine the effect of increasing IGF-1R in the endothelium, we generated mice overexpressing human IGF-1R in the endothelium (human IGF-1R endothelium-overexpressing mice [hIGFREO]) under direction of the Tie2 promoter enhancer. hIGFREO aorta had reduced basal NO bioavailability (percent constriction to NG-monomethyl-l-arginine [mean (SEM) wild type 106% (30%); hIGFREO 48% (10%)]; P < 0.05). Endothelial cells from hIGFREO had reduced insulin-stimulated endothelial NO synthase activation (mean [SEM] wild type 170% [25%], hIGFREO 58% [3%]; P = 0.04) and insulin-stimulated NO release (mean [SEM] wild type 4,500 AU [1,000], hIGFREO 1,500 AU [700]; P < 0.05). hIGFREO mice had enhanced endothelium regeneration after denuding arterial injury (mean [SEM] percent recovered area, wild type 57% [2%], hIGFREO 47% [5%]; P < 0.05) and enhanced endothelial cell migration in vitro. The IGF-1R, although reducing NO bioavailability, enhances in situ endothelium regeneration. Manipulating IGF-1R in the endothelium may be a useful strategy to treat disorders of vascular growth and repair. Insulin-resistant type 2 diabetes characterized by perturbation of the insulin/IGF-1 system is a multisystem disorder of nutrient homeostasis, cell growth, and tissue repair (1). As a result, type 2 diabetes is a major risk factor for the development of a range of disorders of human health, including occlusive coronary artery disease (2), peripheral vascular disease (3), stroke (4), chronic vascular ulcers (5), proliferative retinopathy (6), and nephropathy (7). A key hallmark of these pathologies is endothelial cell dysfunction characterized by a reduction in bioavailability of the signaling radical nitric oxide (NO). In the endothelium, insulin binding to its tyrosine kinase receptor stimulates release of NO (8). Insulin resistance at a whole-body level (9,10) and specific to the endothelium (11) leads to reduced bioavailability of NO, indicative of a critical role for insulin in regulating NO bioavailability. The insulin receptor (IR) and IGF-1 receptor (IGF-1R) are structurally similar—both composed of two extracellular α and two transmembrane β subunits linked by disulfide bonds (12). As a result, IGF-1R and IR can heterodimerize to form insulin-resistant hybrid receptors composed of one IGF-1R-αβ complex and one IR-αβ subunit complex (13,14). We recently demonstrated that reducing IGF-1R (by reducing the number of hybrid receptors) enhances insulin sensitivity and NO bioavailability in the endothelium (15). To examine the effect of increasing IGF-1R specifically in the endothelium on NO bioavailability, endothelial repair, and metabolic homeostasis, we generated a transgenic mouse with targeted overexpression of the human IGF-1R in the endothelium (hIGFREO)

Orai3 Surface Accumulation and Calcium Entry Evoked by Vascular Endothelial Growth Factor

Objective: Vascular endothelial growth factor (VEGF) acts, in part, by triggering calcium ion (Ca2+) entry. Here, we sought understanding of a Synta66-resistant Ca2+ entry pathway activated by VEGF. Approach and Results: Measurement of intracellular Ca2+ in human umbilical vein endothelial cells detected a Synta66-resistant component of VEGF-activated Ca2+ entry that occurred within 2 minutes after VEGF exposure. Knockdown of the channel-forming protein Orai3 suppressed this Ca2+ entry. Similar effects occurred in 3 further types of human endothelial cell. Orai3 knockdown was inhibitory for VEGF-dependent endothelial tube formation in Matrigel in vitro and in vivo in the mouse. Unexpectedly, immunofluorescence and biotinylation experiments showed that Orai3 was not at the surface membrane unless VEGF was applied, after which it accumulated in the membrane within 2 minutes. The signaling pathway coupling VEGF to the effect on Orai3 involved activation of phospholipase Cγ1, Ca2+ release, cytosolic group IV phospholipase A2α, arachidonic acid production, and, in part, microsomal glutathione S-transferase 2, an enzyme which catalyses the formation of leukotriene C4 from arachidonic acid. Shear stress reduced microsomal glutathione S-transferase 2 expression while inducing expression of leukotriene C4 synthase, suggesting reciprocal regulation of leukotriene C4–synthesizing enzymes and greater role of microsomal glutathione S-transferase 2 in low shear stress. Conclusions: VEGF signaling via arachidonic acid and arachidonic acid metabolism causes Orai3 to accumulate at the cell surface to mediate Ca2+ entry and downstream endothelial cell remodeling

Piezo1 integration of vascular architecture with physiological force

The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic¹⁻⁵. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca²⁺-permeable non-selective cationic channels for detection of noxious mechanical impact⁶⁻⁸. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology. Global or endothelial-specific disruption of mouse Piezo1 profoundly disturbed the developing vasculature and was embryonic lethal within days of the heart beating. Haploinsufficiency was not lethal but endothelial abnormality was detected in mature vessels. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear-stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells. Downstream of this calcium influx there was protease activation and spatial reorganization of endothelial cells to the polarity of the applied force. The data suggest that Piezo1 channels function as pivotal integrators in vascular biology

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell–specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling