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Background: Diagnostic and treatment delays have caused significant impacts on the physical and emotional well-being of adolescents with endometriosis, though such research is limited. This study aimed to assess the effects of one-year dienogest therapy on the clinical picture, pain patterns, psycho-emotional status, and quality-of-life indicators in adolescents with endometriosis after surgical treatment. Methods: The study enrolled 32 girls aged 13–17 with peritoneal endometriosis to analyze one-year dynamics of the Visual Analog Scale (VAS), McGill Pain Questionnaire, Beck Depression Scale (BDI), Hospital Anxiety and Depression Scale (HADS), Spielberger State-Trait Anxiety Inventory (STAI) and SF-36 quality-of-life survey scores along with clinical and laboratory indicators before surgery and after one-year dienogest therapy. Results. The therapy provided a significant alleviation of endometriosis-associated clinical symptoms, including dysmenorrhea, pelvic pain, gastrointestinal/dysuria symptoms, decreased everyday activity (

The author develops the concept of global bifurcation shaped by a number of dangerous planetary factors, primarily by ecological crisis of mankind. The analysis showed that global bifurcation is objectively inevitable and the option of a general planetary catastrophe is most likely. Nevertheless, in general, historical alternatives still remain uncertain, contradictory, unclear, thus allowing us to hope that humanity still has a fragile chance for future development in the post-bifurcation period. From the standpoint of the structural-synergetic theory of sociodynamics and taking into account new empirical data, the general planetary problems and historical alternatives of the era of global bifurcation are clarified and analyzed. According to the author, four bifurcation scenarios are possible: 1) Global ecological catastrophe, the death of mankind; 2) Global ecological crisis, long-term degradation of mankind and social regression; 3) Global nuclear-missile catastrophe, the death of mankind; 4) Restructuring of world society and its entry onto the trajectory of sustainable historical development.

Recombinant chymosins (rСhns) of the cow and the camel are currently considered as standard milk coagulants for cheese-making. The search for a new type of milk-clotting enzymes that may exist in nature and can surpass the existing "cheese-making" standards is an urgent biotechnological task. Within this study, we for the first time constructed an expression vector allowing production of a recombinant analog of moose chymosin in the expression system of Escherichia coli (strain SHuffle express). We built a model of the spatial structure of moose chymosin and compared the topography of positive and negative surface charges with the correspondent structures of cow and camel chymosins. We found that the distribution of charges on the surface of moose chymosin has common features with that of cow and camel chymosins. However, the moose enzyme carries a unique positively charged patch, which is likely to affect its interaction with the substrate. Biochemical and technological properties of the moose rChn were studied. Commercial rСhns of cow and camel were used as comparison enzymes. In some technological parameters, the moose rChn proved to be superior to the reference enzymes. Сompared with the cow and camel rСhns, the moose chymosin specific activity is less dependent on the changes in CaCl2 concentration in the range of 1-5 mM and pH in the range of 6-7, which is an attractive technological property. The total proteolytic activity of the moose rСhn occupies an intermediate position between the rСhns of cow and camel. The combination of biochemical and technological properties of the moose rСhn argues for further study of this enzyme.Эталонными коагулянтами молока для сыроделия в настоящее время считаются рекомбинантные химозины (рХн) коровы и верблюда. Нахождение молокосвертывающих ферментов, способных превзойти эталонные коагулянты молока, является актуальной биотехнологической задачей. Нами сконструирован экспрессирующий вектор, который позволил впервые получить рекомбинантный аналог химозина лося в системе экспрессии Escherichia coli (штамм SHuffle Express). Построена модель пространственной структуры химозина лося, и проведено сравнение топографии положительных и отрицательных поверхностных зарядов с соответствующими структурами химозинов коровы и верблюда. Обнаружено, что распределение зарядов на поверхности химозина лося имеет общие черты с распределением зарядов химозинов коровы и верблюда. Отличительная особенность химозина лося – наличие положительно заряженного поверхностного участка, который, вероятно, влияет на его взаимодействие с субстратом. Исследованы основные биохимические и технологические свойства рХн лося. В качестве ферментов сравнения использовали коммерческие рХн коровы и верблюда. Установлено, что по некоторым технологическим показателям рХн лося превосходил ферменты сравнения. По сравнению с рХн коровы и верблюда специфическая активность рХн лося в меньшей степени зависит от изменения концентрации CaCl2 в диапазоне 1–5 мМ и рН в диапазоне 6–7, что является привлекательным технологическим свойством. По общей протеолитической активности рХн лося занимает промежуточное положение между ферментами коровы и верблюда. Совокупность биохимических и технологических свойств рХн лося свидетельствует о необходимости дальнейшего изучения этого фермента.

Creation of scaffold-based tissue-engineered constructs (SB TECs) is costly and requires coordinated qualified efforts. Cryopreservation enables longer shelf-life for SB TECs while enormously enhancing their availability as medical products. Regenerative treatment with cryopreserved SB TECs prepared in advance (possibly prêt-à-porter) can be started straight away on demand. Animal studies and clinical trials indicate similar levels of safety for cryopreserved and freshly prepared SB TECs. Although cryopreservation of such constructs is more difficult than that of cell suspensions or tissues, years of research have proved the principal possibility of using ready-to-transplant SB TECs after prolonged cryostorage. Cryopreservation efficiency depends not only on the sheer viability of adherent cells on scaffolds after thawing, but largely on the retention of proliferative and functional properties by the cells, as well as physical and mechanical properties by the scaffolds. Cryopreservation protocols require careful optimization, as their efficiency depends on multiple parameters including cryosensitivity of cells, chemistry and architecture of scaffolds, conditions of cell culture before freezing, cryoprotectant formulations, etc. In this review we discuss recent achievements in SB TEC cryopreservation as a major boost for the field of tissue engineering and biobanking.

One of the main causes of cell death in neurodegenerative diseases is excitotoxicity. Today the potential directions of treatment neurodegenerative diseases are including cell therapy, the purpose of which is to replace lost nerve tissue with donor cells. Transplanted cells along with replaced lost tissues have a paracrine effect, which requires careful study. The aim of this work was to study the effect of conditioned media, obtaining from neuronal and glial progenitor cells, on a primary culture of cerebellar neurons in a model of glutamate excitotoxicity. The cell viability, expression of marker genes for apoptosis and neuritogenesis, and the number of necrotic and apoptotic cells were determined in the culture of cerebellar neurons. The composition of the studied conditioned media was analyzed for the content of neurotrophins. A comparative analysis was revealed differences in the secretion of neurotrophins between the obtained cultures: the amount of brain-derived neurotrophic factor, nerve growth factor, ciliary neurotrophic factor and glial neurotrophic factor was higher in the secretion of glial progenitors. It was shown that the addition of conditioned media from neuronal cells does not significantly affect the viability of cerebellar neurons, whereas preincubation with media from glial progenitors has a neuroprotective effect by increasing the viability of cerebellar neurons, and during long-term cultivation promotes the growth of neurites by increasing the expression level of MAP2 and GAP43 genes.

The aim of study was to evaluate the immunophenotype of resident macrophages of the liver, Kupffer cells, in rats in the norm.Material and methods. The study included male Wistar rats’ samples (n=6) that presented fragments of the middle lobe of the liver taken under ether anesthesia. The obtained samples were fixed in liquid nitrogen, after that cryosections 5–7 μm thick were prepared. Histological slides were used to detect the expression of a number of macrophage markers with an antibody kit: CD68, CD206, CD 163, CD86. After the first antibodies, sections were stained with antibodies conjugated to FITC, cell nuclei were detected using DAPI, the obtained preparations were studied using a fluorescence microscope.Results. When analyzing the expression of CD68 in the rat liver, it was found that normally about 20% of the cells in the field of vision appeared to be CD68+ cells, which was consistent with the earlier study results of the authors. The number of CD163+ and CD206+ cells coincided with the number of CD68+ macrophages, while CD86+ macrophages were significantly less.Conclusions. Under normal conditions, the population of resident macrophages of the rat liver is represented by cells with pronounced expression of CD68, CD163 and CD206. A large number of CD163+ and CD206+ macrophages allows concluding that Kupffer cells are close to the M2 pro-regenerative phenotype. However, the detection of CD86+ resident macrophages indicates the presence of M1 macrophages, or the presence of normal macrophages with an intermediate M1 and M2 phenotype, in the rat liver. The revealed high content of macrophages expressing CD163 and CD206 in the liver evidences not only pro-regenerative properties of Kupffer cells, but also the close connection of macrophages with liver functions, since these receptors are involved in the utilization of hemoglobin and a number of hormones.

At the normal physiological conditions, hepatocytes predominantly reside in G0 phase of cell cycle; they actively proceed to G1 phase upon damage to the organ. As it was shown in experiments with restoration of liver mass in rats after subtotal hepatectomy (resection of 80% of the organ mass may be considered as a model of the 'small for size' liver syndrome), the growth inhibition is due to prolonged arrest of hepatocyte proliferation, molecular mechanisms of which remain understudied. In a rat model of liver regeneration after surgical removal of 80% of its mass, we observe a delayed onset of hepatocyte proliferation: Ki67+ hepatocytes begin to appear as late as at 30 h after liver subtotal resection. Their appearance coincides with the beginning of transcription of genes for cyclins A2, B1, D 1 , and E 1 at 24-30 h after surgery. The corresponding increase in concentrations of cyclin D 1 and E proteins is further delayed till 48 h after liver resection. We have also observed a prolonged decrease in the expression of proto-oncogene c-met (the hepatocyte growth factor receptor-encoding gene Met), an increase in expression of the transforming growth factor β1 (TGFβ 1 ) receptor-encoding gene Tgfbr2. At the same time, irreversible block of hepatocyte proliferation is prevented by expression of certain factors, notably of the TWEAK/Fn14 signaling pathway: concentrations of the corresponding proteins in remnant livers have peaked from 24 to 48 h after liver subtotal resection.

In the central nervous system and in the liver, the macrophage populations are represented exclusively by descendants of the hematopoietic progenitor cells of the yolk sac. The reasons for such differential distribution of macrophages are not fully understood. We found that, as can be judged by corresponding changes in the expression of CD86 and CD163 markers, the transient macrophages of monocytic lineage are more sensitive to activating stimuli. The two macrophage populations have distinct patterns of gene expression, which is particularly noticeable for M1- and M2-associated genes. For instance, Kupffer cells more readily develop and longer maintain the elevated expression levels of Il4, Il10, and Il13 upon the activation; by contrast, the macrophages of monocytic lineage express Il1b, Il12a, and Tnfα upon the activation. The obtained results allow us to conclude that the in vitro activated Kupffer cells of the liver are committed to M2 phenotype, whereas the in vitro activated monocyte-derived macrophages show a typical M1 behavior. These observations are likely to reflect the situation in the in vivo microenvironments.

In the Kluyveromyces lactis expression system, recombinant elk chymosin with milk-clotting activity of 150,6 ± 2,1 AU/ml was obtained. The threshold of thermal inactivation of the enzyme was 52,5°C, the temperature optimum was 55°C. The change in MA depending on pH and Ca2+ concentration corresponded to the requirements for milk coagulants for cheese making.

Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells.

Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity.

Background: Stem cell secretomes hold great promise for regenerative medicine. This study is focused on the secretome-mediated neuroprotective effects of the human induced pluripotent stem cell-derived neuronal and glial progenitor cells. Therapeutic properties of the secretomes were assessed under conditions of the hypoxia-induced neuronal damage in vitro and in vivo. Methods: Secretory activity of the cultured neuronal and glial progenitor cells was analyzed by proteomic and immunosorbent-based approaches. Conditioned media collected from the cultures was tested for neuroprotective properties in vitro and in vivo.In vitro experiments involved exposure of SH-SY5Y cells to the conditioned media during the recovery from the cobalt chloride-induced hypoxia. Neuroprotective effects were assessed by cell survival and neurite outgrowth. Cell survival indicators included MTT and LDH tests, vital staining with propidium iodide and Hoechst 33342, and polymerase chain reaction assay for the expression of apoptosis-related genes. Neurite outgrowth was assessed by alterations in SH-SY5Y cell morphology and MAP2/GAP43 gene expression dynamics. In vivo experiments involved intra-arterial administration of the conditioned media to laboratory rats during the recovery from experimental ischemic stroke. Neuroprotective effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration, and the numbers of newly formed blood vessels in the affected area of the brain. Results: Secretomes of glial and neuronal progenitor cells partially overlapped, with specific proteins (found in secretome of one of the studied cultures and absent from the other) constituting, respectively, 31% and 45%. The glial progenitor cell-conditioned media showed higher content of neurotrophins (BDNF, GDNF, CNTF and NGF).Moreover, the glial progenitor cell-conditioned media was superior to the neuronal progenitor cell-conditioned media in facilitating neurite outgrowth and increasing SHSY-5Y cell survival after the cobalt dichloride-induced hypoxia. In addition, intra-arterial infusion of the glial progenitor cell-conditioned media to the animals after experimental ischemic stroke significantly enhanced functional recovery and promoted tissue repair at the site of brain damage, as indicated by reduced microglia/macrophage infiltration, decreased expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13), and increased numbers of newly formed blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. Conclusions: The results indicate pronounced cytoprotective, anti-inflammatory and angionenic properties of soluble factors secreted by glial progenitor cells.

We studied the influence of sucrose applied in combination with different concentrations of penetrating cryoprotectants (DMSO, ethylene glycol, and glycerol) on the efficiency of cryopreservation of umbilical cord-derived multipotent stromal cells (MSC). The results indicate that these cells can be cryopreserved with the use of 5-10% DMSO or ethylene glycol with equal efficiency; addition of 0.2 M sucrose does not affect cell survival after thawing. The efficiency of glycerol as a cryoprotectant increases with increasing its concentration from 5 to 10%, but remains significantly lower than the efficiency of DMSO or ethylene glycol. Addition of sucrose to a final concentration of 0.2 M increases the efficiency of glycerol. The efficiency of combination of 10% glycerol and sucrose was comparable with that of combinations of DMSO and ethylene glycol with sucrose. The mechanism of the observed enhancement is apparently related to the influence of sucrose on the dynamic properties of the lipid membranes and facilitation of glycerol diffusion into the cells.

Macrophages are a central component of innate immunity that play an important role in the defense of the organism. Macrophages are highly plastic and are activated by interaction with other cells and environmental factors. In this work, we study the effect of lipopolysaccharide on macrophages derived from the two most polar (CD14+ and CD16+ monocytes) as well as the intermediate subset of blood monocytes from healthy donors and assess what happens to the subset most prone to polarization on the transcriptomic and proteomic level. It has been shown that, according to primary pro-inflammatory polarization markers, their cytokine profile, and their phagocytic activity, macrophages derived from CD14+ monocytes exhibit higher sensitivity to inducers of pro-inflammatory polarization. Flow cytometry analysis revealed increased levels of CD86, while secretome analysis demonstrated significant increase of pro-inflammatory and anti-inflammatory cytokines observed in CD14+-derived macrophages, as compared to CD16+-derived macrophages in conditioned media. Assessment of the transcriptome and proteome of CD14+-derived macrophages with further bioinformatic analysis identified the most significant differences after polarization towards the pro-inflammatory phenotype. Immune-, membrane-, IFN-γ-, cytokine-, and defense-associated pathways were found significantly prevalent, while downregulated pathways were represented by RNA binding-, housekeeping-, exocytosis-, intracellular transport-, peptide and amide metabolic-related signaling. This data could be useful for macrophage-based cell therapeutics of cancer, as it provides additional background for the manipulation of donor monocytes intended for back transplantation.

Macrophage populations in most mammalian organs consist of cells of different origin. Resident macrophages originate from erythromyeloid precursors of the yolk sac wall, maintenance of the numbers of such macrophages in postnatal ontogenesis is practically independent of bone marrow haematopoiesis. The largest populations of the resident macrophages of embryonic origin are found in the central nervous system (microglia) and liver (Kupffer cells). In contrast, skin dermis and mucous membranes become predominantly colonized by bone marrow-derived monocytes that show pronounced functional and phenotypic plasticity. In the present study, we compared Kupffer cells and monocytes using the immunophenotype, gene expression profile, proteome, and pool of microRNA. The observed differences did not consider the resident liver macrophages as purely M2 macrophages or state that monocytes have purely M1 features. Monocytes show signs of high plasticity and sensitivity to pathogen-associated molecular patterns (e.g., high levels of transcription for Tlr 2, 4, 7, and 8). In contrast, the resident liver macrophages were clearly involved in the regulation of specific organ functions (nitrogen metabolism, complement system protein synthesis).

The conditions of electron flow generation during heating and cooling of a cylindrical lithium niobate crystal with a diameter of 13 mm and a height of 7 mm with a Z-oriented axis of polarization were studied. Studies were conducted at a pressure of 105–1 Pa. It was found that the discharge begins to form in the sub nanosecond range. At a pressure of more than 1 Pa, a gas breakdown on the crystal surface contributes to the discharge current. The preparation of the crystal and the coordination of the indication system made it possible to develop a pyroelectric source of electrons, designed for a discharge voltage of ∼100 kV with a discharge current of ∼400 mA for the microsecond and nanosecond ranges.

Macrophages, important cells of innate immunity, are known for their phagocytic activity, capability for antigen presentation, and flexible phenotypes. Macrophages are found in all tissues and therefore represent an attractive therapeutic target for the treatment of diseases of various etiology. Genetic programming of macrophages is an important issue of modern molecular and cellular medicine. The controllable activation of macrophages towards desirable phenotypes in vivo and in vitro will provide effective treatments for a number of inflammatory and proliferative diseases. This review is focused on the methods for specific alteration of gene expression in macrophages, including the controllable promotion of the desired M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes in certain pathologies or model systems. Here we review the strategies of target selection, the methods of vector delivery, and the gene editing approaches used for modification of macrophages.

The project on the organization of trade relations between China and other countries arose in the second half of the II century BC. The caravan road connecting East Asia with the Mediterranean in the ancient time and to the Middle Ages was used, first of all, for export of silk from China. Therefore in 1877 the German geographer F.F. von Richtgofen called this route giving the chance for establishment of business contacts, cultural dialogue, promoting to mutual enrichment of large civilizations,—“A Silk Road”. By XV century the overland Silk Road fell into decay, sea trade and navigation began to develop. At the present stage of its development the mankind realized need of restitution of the interstate and international interaction inherent in the period of existence of the Great Silk Road. At the XXIV session of the UNESCO General conference in 1987 the project on complex studying of the Great Silk Road was developed. This international project worked according to two large programs of UNESCO: “The environment surrounding the person, resources of the ground and sea” and “The culture and the future”. In the next years development of the idea of reconstruction and expansion of the opportunities put in the ancient times in the Great Silk Road continued. In 2013 the Chinese President Xi Jinping put forward the concept of “A New Silk Road” under the slogan “One Belt – One Road” including the “Economic Belt of the Silk Road” and “Sea Silk Road of the XXI Century” projects. The strategy of “A New Silk Road” included the project of development of the Northern Sea Route. The Northern Sea Route—the major navigable main passing across the seas of Arctic Ocean, connecting the European and Far East ports and also mouths of the navigable Siberian rivers into the unified transport system of the Arctic. The history of the Northern Sea Route began with the first voyages of the Pomors. Development, studying and the description of sea routes of the Russian Arctic continued further. Development of the Arctic navigation promoted the beginning of the industrial development of natural resources of the region. The large-scale industrial development of the Arctic territories began in the 1930s. During the Great Patriotic War of 1941–1945 ice breakers played a large role in conducting of northern convoys. The existing ports were specially converted, new polar stations are built and also additional airfields are developed. In post-war years the Arctic navigation gained further development thanks to the commissioning of icebreaking vessels of new classes. The map of the Northern Sea Route on which the objects built in the 1930–1940s are shown is presented in the article. In July, 2017 during the visit to Russia the chairman Xi Jinping with the president V.V. Putin reached the important agreement on development and use of the Arctic Sea Route and creation of the Ice Silk Road, the sea way uniting North America, East Asia and Western Europe. Within the project of “The Ice Silk Road” tankers with production of Yamal LNG for the first time in the history went the Arctic Sea Route without icebreaking maintenance in the summer of 2018 and arrived from the Arctic port Sabbeta to the Chinese port Jiangsu Zhudong. By these flights the beginning of the regular supply of LNG across the Northern Sea Route is opened.

Functional and anatomical connection between the liver and the spleen is most clearly manifested in various pathological conditions of the liver (cirrhosis, hepatitis). The mechanisms of the interaction between the two organs are still poorly understood, as there have been practically no studies on the influence exerted by the spleen on the normal liver. Mature male Sprague-Dawley rats of 250-260 g body weight, 3 months old, were splenectomized. The highest numbers of Ki67+ hepatocytes in the liver of splenectomized rats were observed at 24 h after the surgery, simultaneously with the highest index of Ki67-positive hepatocytes. After surgical removal of the spleen, expression of certain genes in the liver tissues increased. A number of genes were upregulated in the liver at a single time point of 24 h, including Ccne1, Egf, Tnfa, Il6, Hgf, Met, Tgfb1r2 and Nos2. The expression of Ccnd1, Tgfb1, Tgfb1r1 and Il10 in the liver was upregulated over the course of 3 days after splenectomy. Monitoring of the liver macrophage populations in splenectomized animals revealed a statistically significant increase in the proportion of CD68-positive cells in the liver (as compared with sham-operated controls) detectable at 24 h and 48 h after the surgery. The difference in the liver content of CD68-positive cells between splenectomized and sham-operated animals evened out by day 3 after the surgery. No alterations in the liver content of CD163-positive cells were observed in the experiments. A decrease in the proportion of CD206-positive liver macrophages was observed at 48 h after splenectomy. The splenectomy-induced hepatocyte proliferation is described by us for the first time. Mechanistically, the effect is apparently induced by the removal of spleen as a major source of Tgfb1 (hepatocyte growth inhibitor) and subsequently supported by activation of proliferation factor-encoding genes in the liver.