Porous structure of nano-dimensional boraso-graphenic powders

The structural features of surface of the nano-dimensional bor-azo-graphenic powders (t-BNg) after previous washing in boiling water were researched. The results showed that after process of purifier (washing) the powder’s surface of t-BNg characterized as slit-like micro-, mesoporous (monodispersed) structure with a narrow porous distribution in the range of 3.82 - 4.17 nm. The outer surface specific area of the powders of t-BNg according to “t - method” is 28.3 m²/g. The inner specific surface area of the mesopores is 141 m²/g (BJH method). The residues of boron oxonitride in the form of a purified sublimate, a white powder, extracted from a washed and dried sample of t-BNg at a temperature of 540 K and a pressure of ≤ 1.0 Pa. The sublimate, according to chemical analysis and infrared spectroscopy, was identified on the assumption of the cyclic dimer of di-hydro-di-hydroxo-di-bor-ox-azole of the composition of H(OH)[(BON)₂](OH)H. The model of carbamide synthesis of boron nitride, as a sequence of chemical transformations of borate-carbamide precursors in a freely radical boron-pair (> B - N В - N В – N <)

Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium.

The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1ΔEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function

Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels.

The lymphatic system is composed of a hierarchical network of fluid absorbing lymphatic capillaries and transporting collecting vessels. Despite distinct functions and morphologies, molecular mechanisms that regulate the identity of the different vessel types are poorly understood. Through transcriptional analysis of murine dermal lymphatic endothelial cells (LECs), we identified Foxp2, a member of the FOXP family of transcription factors implicated in speech development, as a collecting vessel signature gene. FOXP2 expression was induced after initiation of lymph flow in vivo and upon shear stress on primary LECs in vitro. Loss of FOXC2, the major flow-responsive transcriptional regulator of lymphatic valve formation, abolished FOXP2 induction in vitro and in vivo. Genetic deletion of Foxp2 in mice using the endothelial-specific Tie2-Cre or the tamoxifen-inducible LEC-specific Prox1-CreER &lt;sup&gt;T2&lt;/sup&gt; line resulted in enlarged collecting vessels and defective valves characterized by loss of NFATc1 activity. Our results identify FOXP2 as a new flow-induced transcriptional regulator of collecting lymphatic vessel morphogenesis and highlight the existence of unique transcription factor codes in the establishment of vessel-type-specific endothelial cell identities

Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2.

The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5-Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling

EXERTIONAL ANGINA AND DISSEMINATED INTRAVASCULAR COAGULATION

Patients with III f.c. exertional angina display the signs of chronic DIC. I stage incipient characters are revealed in 42,6% of patients, II stage characters - in 57,4% of patients. Soluble fibrin monomer complexes are initial markers of the chronic DIC. In identical angina pectoris clinical presentation the degree of activity and the DIC syndrome stage can be diverse. The DIC syndrome stage depends on the coronary heart disease duration, angina pectoris and the duration of the accompanied cardiac insufficiency

Патология верхних конечностей у детей с мукополисахаридозами

Background. Despite the success in the treatment of children with mucopolysaccharidoses (MPS) as a result of the widespread of  enzyme  replacement  therapy  and  hematopoietic  stem  cells  transplantation,  orthopedic  manifestations  continue  to  be a  significant  problem,  while  the  pathology  of  the  upper  limbs  in  children  with  MPS  is  not  sufficiently  represented  in  the literature. The aim of this studywas to analyze orthopedic and neurological manifestations in the upper extremities of children with  mucopolysaccharidosis  based  on  a  sequential  case  series. Materials  and  Methods. We  carried  out  a  comprehensive analysis of clinical and radiological involvement of the upper extremities in 49 patients with MPS. Results. The most common complaints reated to the upper extremities were difficulties in the daily activities (dressing, self-care, playing), impairment of the fine motor skills, and muscle weakness. The most frequent clinical manifestations related to the upper extremities were limited active shoulder abduction, impaired hand grip, flexion contractures of the elbow joint, ulnar deviation of the hand. All patients with MPS types I, II, and VI had limited active and passive extension and flexion of the metacarpophalangeal and interphalangeal joints. In patients with MPS IV, hypermobility of the hand joints prevailed. We noticed minimal presence of typical clinical manifestations related to compression of the median nerve secific for carpal tunnel syndrome. The majority of patients showed a decrease in tendon and periosteal reflexes. The most pronounced decrease in muscle strength was observed in to extensors (elbow, fingers) and shoulder abductors, which may contribute to the predominant formation of a flexion pattern of contractures. On radiographs of the hand, the “melting sugar” symptom and shortening of the metacarpal bones were observed in most patients. Conclusion.Clinical and radiological manifestations related to the upper extremities take  place  in  all  types  of  the  mPS,  and  lead  to  functional  disorders  that  complicate  daily  life  and  self-care.  Upper  limb pathology in children with MPS requires earlier detection and more active treatment after comprehensive risk assessment.Актуальность. Несмотря на успехи в лечении детей с мукополисахаридозами (МПС) в результате широкого внедрения ферментзаместительной терапии и трансплантации гематопоэтических стволовых клеток, ортопедические проявления продолжают оставаться значительной проблемой, при этом патология верхних конечностей у детей с МПС отражена в литературе недостаточно.Материалы и методы Нами проведен комплексный анализ клинических и рентгенологических проявлений со стороны верхних конечностей у 49 пациентов с МПС.Результаты. Наиболее частыми жалобами со стороны верхних конечностей были неловкость при выполнении повседневных движений (одевание, самообслуживание, пользование предметами), нарушение мелкой моторики, мышечная слабость. Наиболее частым клиническим проявлением со стороны верхних конечностей было ограничение активного отведения плеча, нарушение кистевого схвата, сгибательные контрактуры в локтевом суставе, ульнарная девиация кисти. У всех пациентов с МПС I, II и VI типов имело место ограничение активного и пассивного разгибания и сгибания пястнофаланговых и межфаланговых суставов. У пациентов с МПС IV преобладала гипермобильность суставов кисти. При оценке симптомов, характерных для синдрома карпального канала отмечено отсутствие типичных клинических проявлений, обусловленных компрессией срединного нерва. У большинства пациентов отмечалось снижение сухожильных и периостальных рефлексов. Наиболее выраженное снижение силы мышц отмечалось в отношении разгибания пальцев кисти, отведения плеча и разгибания в локтевом суставе, что может способствовать формировании флексионного паттерна контрактур суставов верхних конечностей. На рентгенограммах кисти симптом «тающего сахара» и укорочение пястных костей наблюдались у большинства пациентов.Заключение. Клинические и рентгенологические проявления со стороны верхних конечностей наблюдаются при всех изученных нами типах заболевания, и приводят к функциональным нарушениям, затрудняющим повседневную жизнь и самообслуживание. Патология верхних конечностей у детей с МПС требует более раннего выявления и более активной лечебной тактики после всесторонней оценки рисков

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma

Pkd1 Regulates Lymphatic Vascular Morphogenesis during Development.

Lymphatic vessels arise during development through sprouting of precursor cells from veins, which is regulated by known signaling and transcriptional mechanisms. The ongoing elaboration of vessels to form a network is less well understood. This involves cell polarization, coordinated migration, adhesion, mixing, regression, and shape rearrangements. We identified a zebrafish mutant, lymphatic and cardiac defects 1 (lyc1), with reduced lymphatic vessel development. A mutation in polycystic kidney disease 1a was responsible for the phenotype. PKD1 is the most frequently mutated gene in autosomal dominant polycystic kidney disease (ADPKD). Initial lymphatic precursor sprouting is normal in lyc1 mutants, but ongoing migration fails. Loss of Pkd1 in mice has no effect on precursor sprouting but leads to failed morphogenesis of the subcutaneous lymphatic network. Individual lymphatic endothelial cells display defective polarity, elongation, and adherens junctions. This work identifies a highly selective and unexpected role for Pkd1 in lymphatic vessel morphogenesis during development

FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure.

The mechanisms maintaining adult lymphatic vascular specialization throughout life and their role in coordinating inter-organ communication to sustain homeostasis remain elusive. We report that inactivation of the mechanosensitive transcription factor Foxc2 in adult lymphatic endothelium leads to a stepwise intestine-to-lung systemic failure. Foxc2 loss compromised the gut epithelial barrier, promoted dysbiosis and bacterial translocation to peripheral lymph nodes, and increased circulating levels of purine metabolites and angiopoietin-2. Commensal microbiota depletion dampened systemic pro-inflammatory cytokine levels, corrected intestinal lymphatic dysfunction, and improved survival. Foxc2 loss skewed the specialization of lymphatic endothelial subsets, leading to populations with mixed, pro-fibrotic identities and to emergence of lymph node-like endothelial cells. Our study uncovers a cross-talk between lymphatic vascular function and commensal microbiota, provides single-cell atlas of lymphatic endothelial subtypes, and reveals organ-specific and systemic effects of dysfunctional lymphatics. These effects potentially contribute to the pathogenesis of diseases, such as inflammatory bowel disease, cancer, or lymphedema

Endothelial Calcineurin Signaling Restrains Metastatic Outgrowth by Regulating Bmp2.

Calcineurin/NFAT signaling is active in endothelial cells and is proposed to be an essential component of the tumor angiogenic response. Here, we investigated the role of endothelial calcineurin signaling in vivo in physiological and pathological angiogenesis and tumor metastasis. We show that this pathway is dispensable for retinal and tumor angiogenesis, but it is implicated in vessel stabilization. While ablation of endothelial calcineurin does not affect the progression of primary tumors or tumor cell extravasation, it does potentiate the outgrowth of lung metastases. We identify Bmp2 as a downstream target of the calcineurin/NFAT pathway in lung endothelium, potently inhibiting cancer cell growth by stimulating differentiation. We reveal a dual role of calcineurin/NFAT signaling in vascular regression or stabilization and in the tissue-specific production of an angiocrine factor restraining cancer cell outgrowth. Our results suggest that, besides targeting the immune system, post-transplantation immunosuppressive therapy with calcineurin inhibitors directly targets the endothelium, contributing to aggressive cancer progression