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

Multiple roles of lymphatic vessels in peripheral lymph node development.

The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-β signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development

The origins and spread of domestic horses from the Western Eurasian steppes

Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region.Domestication of horses fundamentally transformed long-range mobility and warfare(1). However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling(2-4) at Botai, Central Asia around 3500 bc(3). Other longstanding candidate regions for horse domestication, such as Iberia(5) and Anatolia(6), have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association(7) between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc(8,9) driving the spread of Indo-European languages(10). This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture(11,12).Descriptive and Comparative Linguistic

The origins and spread of domestic horses from the Western Eurasian steppes

Domestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 bc. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture

IFN-γ-dependent tumor-antigen cross-presentation by lymphatic endothelial cells promotes their killing by T cells and inhibits metastasis.

Tumor-associated lymphatic vessels promote metastasis and regulate antitumor immune responses. Here, we assessed the impact of cytotoxic T cells on the local lymphatic vasculature and concomitant tumor dissemination during an antitumor response. Interferon-γ (IFN-γ) released by effector T cells enhanced the expression of immunosuppressive markers by tumor-associated lymphatic endothelial cells (LECs). However, at higher effector T cell densities within the tumor, T cell-based immunotherapies induced LEC apoptosis and decreased tumor lymphatic vessel density. As a consequence, lymphatic flow was impaired, and lymph node metastasis was reduced. Mechanistically, T cell-mediated tumor cell death induced the release of tumor antigens and cross-presentation by tumor LECs, resulting in antigen-specific LEC killing by T cells. When LECs lacked the IFN-γ receptor expression, LEC killing was abrogated, indicating that IFN-γ is indispensable for reducing tumor-associated lymphatic vessel density and drainage. This study provides insight into how cytotoxic T cells modulate tumor lymphatic vessels and may help to improve immunotherapeutic protocols

CHILDREN'S ARTERIAL HYPERTENSION: DRUG CHOICE. THE RESULTS OF THE PHARMACOEPIDEMIOLOGICAL STUDY RIFAGD

The multicentered pharmacoepidemiological study «Rifagd» (prevalence and pharmacotherapy of arterial hypertension in children) in 13 cities of Russia was conducted with the purpose of analyzing of pediatricians' approach to the treatment of children's arterial hypertension, including drug choice. This allowed to estimate their experience, knowledge, as well as to direct the way to improvements of quality in medical treatment of patients with arterial hypertension. The majority of pediatricians (83,1%) encounter difficulties in hypertension treatment in connection with guidelines absence (37,3%), medical practice absence (30,4%) and «absence of indications for the application of antihypertensive drugs in pediatrics» (31,9%). for arterial hypertension treatment pediatricians use AgE-inhibitors, diuretics and beta blockers.Key words: rifagd, arterial hypertension, pharmacoepidemiology, questioning of pediatricians, ace inhibitors, diuretics, beta blockers

CHILDREN'S ARTERIAL HYPERTENSION: DRUG CHOICE. THE RESULTS OF THE PHARMACOEPIDEMIOLOGICAL STUDY RIFAGD

The multicentered pharmacoepidemiological study «Rifagd» (prevalence and pharmacotherapy of arterial hypertension in children) in 13 cities of Russia was conducted with the purpose of analyzing of pediatricians' approach to the treatment of children's arterial hypertension, including drug choice. This allowed to estimate their experience, knowledge, as well as to direct the way to improvements of quality in medical treatment of patients with arterial hypertension. The majority of pediatricians (83,1%) encounter difficulties in hypertension treatment in connection with guidelines absence (37,3%), medical practice absence (30,4%) and «absence of indications for the application of antihypertensive drugs in pediatrics» (31,9%). for arterial hypertension treatment pediatricians use AgE-inhibitors, diuretics and beta blockers.Key words: rifagd, arterial hypertension, pharmacoepidemiology, questioning of pediatricians, ace inhibitors, diuretics, beta blockers

HYPERPIESIS OF CHILDREN AND TEENAGERS: REAL PROBLEM FOR A PEDIATRICIAN

The authors have conducted multicentric epidemiological research in 13 cities of russia to examine approaches of pediatricians to diagnostics and treatment hyperpiesis in childhood, which allowed the researchers to estimate their experience and knowledge. It has turned out that most pediatricians can not apply the knowledge in hyperpiesis diagnostics due to the absence of the agebdependent cuffs to measure hyperpiesis, as well as the skills to assess the hyperpiesis measurement findings along with centile tables use. Quality improvement of hyperpiesis diagnostics in childhood is possible by means of implementation of educational programs for the pediatricians on diagnostics and treatment of children, suffering from hyperpiesis.Key words: child's hyperpiesis, epidemiology, diagnostics, children

Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization.

The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine