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•Cumulative recording of proliferation and differentiation in situ shows that primitive HSCs are not activated by inflammation or blood loss.

The most well-known example of an ordered quantum state—superconductivity—is caused by the formation and condensation of pairs of electrons. Fundamentally, what distinguishes a superconducting state from a normal state is a spontaneously broken symmetry corresponding to the long-range coherence of pairs of electrons, leading to zero resistivity and diamagnetism. Here we report a set of experimental observations in hole-doped Ba1−xKxFe2As2. Our specific-heat measurements indicate the formation of fermionic bound states when the temperature is lowered from the normal state. However, when the doping level is x≈ 0.8, instead of the characteristic onset of diamagnetic screening and zero resistance expected below the superconducting phase transition, we observe the opposite effect: the generation of self-induced magnetic fields in the resistive state, measured by spontaneous Nernst effect and muon spin rotation experiments. This combined evidence indicates the existence of a bosonic metal state in which Cooper pairs of electrons lack coherence, but the system spontaneously breaks time-reversal symmetry. The observations are consistent with the theory of a state with fermionic quadrupling, in which long-range order exists not between Cooper pairs but only between pairs of pairs.

Strontium ruthenate (Sr2RuO4) continues to present an important test of our understanding of unconventional superconductivity, because while its normal-state electronic structure is known with precision, its superconductivity remains unexplained. There is evidence that its order parameter is chiral, but reconciling this with recent observations of the spin part of the pairing requires an order parameter that is either finely tuned or implies a new form of pairing. Therefore, a definitive resolution of whether the superconductivity of Sr2RuO4is chiral is important for the study of superconductivity. Here we report the measurement of zero-field muon spin relaxation—a probe sensitive to weak magnetism—on samples under uniaxial stresses. We observe stress-induced splitting between the onset temperatures of superconductivity and time-reversal symmetry breaking—consistent with the qualitative expectations for a chiral order parameter—and argue that this observation cannot be explained by conventional magnetism. In addition, we report the appearance of bulk magnetic order under higher uniaxial stress, above the critical pressure at which a Lifshitz transition occurs in Sr2RuO4.

In general, magnetism and superconductivity are antagonistic to each other. However, there are several families of superconductors in which superconductivity coexists with magnetism, and a few examples are known where the superconductivity itself induces spontaneous magnetism. The best known of these compounds are Sr2RuO4and some non-centrosymmetric superconductors. Here, we report the finding of a narrow dome of an s+is′superconducting phase with apparent broken time-reversal symmetry (BTRS) inside the broad s-wave superconducting region of the centrosymmetric multiband superconductor Ba1 − xKxFe2As2(0.7 ≲ x≲ 0.85). We observe spontaneous magnetic fields inside this dome using the muon spin relaxation (μSR) technique. Furthermore, our detailed specific heat study reveals that the BTRS dome appears very close to a change in the topology of the Fermi surface. With this, we experimentally demonstrate the likely emergence of a novel quantum state due to topological changes of the electronic system.

Although bone marrow niche cells are essential for hematopoietic stem cell (HSC) maintenance, their interaction in response to stress is not well defined. Here, we used a mouse model of acute thrombocytopenia to investigate the cross talk between HSCs and niche cells during restoration of the thrombocyte pool. This process required membrane-localized stem cell factor (m-SCF) in megakaryocytes, which was regulated, in turn, by vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB). HSCs and multipotent progenitors type 2 (MPP2), but not MPP3/4, were subsequently activated by a dual-receptor tyrosine kinase (RTK)–dependent signaling event, m-SCF/c-Kit and VEGF-A/vascular endothelial growth factor receptor 2 (VEGFR-2), contributing to their selective and early proliferation. Our findings describe a dynamic network of signals in response to the acute loss of a single blood cell type and reveal the important role of 3 RTKs and their ligands in orchestrating the selective activation of hematopoietic stem and progenitor cells (HSPCs) in thrombocytopenia.

Although bone marrow niche cells are essential for hematopoietic stem cell (HSC) maintenance, their interaction in response to stress is not well defined. Here, we used a mouse model of acute thrombocytopenia to investigate the cross talk between HSCs and niche cells during restoration of the thrombocyte pool. This process required membrane-localized stem cell factor (m-SCF) in megakaryocytes, which was regulated, in turn, by vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB). HSCs and multipotent progenitors type 2 (MPP2), but not MPP3/4, were subsequently activated by a dual-receptor tyrosine kinase (RTK)–dependent signaling event, m-SCF/c-Kit and VEGF-A/vascular endothelial growth factor receptor 2 (VEGFR-2), contributing to their selective and early proliferation. Our findings describe a dynamic network of signals in response to the acute loss of a single blood cell type and reveal the important role of 3 RTKs and their ligands in orchestrating the selective activation of hematopoietic stem and progenitor cells (HSPCs) in thrombocytopenia.

Southern Tuscany (central Italy) is a mining district with epithermal stibnite (Hg and Au) mineralisation, an area characterized by a marked geothermal anomaly with underlying magmatic bodies, geothermal fluids feeding geothermal wells and springs depositing travertine. This study deals with the actual to subrecent relation between high temperature geothermal fluids and epithermal stibnite (gold and cinnabar) mineralisation in Southern Tuscany on the basis of chemical and stable isotope (C, O, H, S) data, of ore samples showing the paragenesis stibnite, calcite, fluorite, gypsum and of geothermal fluids tapped by the geothermal wells in the upper and lower aquifer of the Piancastagnaio geothermal field (Monte Amiata geothermal area). δ13CPDBdata between +5.6 to +7.1 ‰ and δ 18O values ranging from 13.8 to 23 ‰, suggest that the CO2in the fluids that deposited the calcite gangue of the stibnite ores at 100 to 250 °C, predominantly at 120 to 160 °C, are produced by thermometamorphic fluid/rock interaction in the aquifer. Negative Eu and Ce anomaly in der REE distribution pattern of calcite, fluorite and gypsum are produced by a thermochemical reduction of Eu3+to Eu2+and the oxidation of Ce3+to Ce4+, respectively, that prohibits the substitution of Eu and Ce in the calcite, fluorite and gypsum lattice. Oxygen and hydrogen isotope data of the fluids produced in the Piancastagnaio geothermal field reveal with δ18OSMOWfrom +6.66 to +7.68 ‰, δ2HSMOWfrom –41.4 to –34.3 ‰ and 3H from 0.7 to 1.2 TU that those fluids are a mixture of a dominating deep-seated uprising high-temperature fluid and a subordinate amount of recent shallow-seated cool groundwater. The isotopic composition of sulphur of the geothermal fluids close to 0 ‰ suggests that most of the sulphur derives from the underlying magmatic intrusions or, alternatively, from the sulphides disseminated in the Paleozoic rocks of the Tuscan crystalline basement. The difference in δ18O between H2O and SO4–2in the deep-seated fluids of the Piancastagnaio geothermal field gives an equilibrium temperature of about 300°C. This temperature corresponds to the measured bottom-hole temperature determined in the geothermal wells. High temperature, isotopic data and elevated Sb, As, Au, Na, K, Cl, B, ammonium, H2S, sulphate and CO2load makes the high temperature geothermal fluid of the Piancastagnaio geothermal field a model for the fluid that deposited the stibnite mineralisation of southern Tuscany in a temperature range from 120 to 300°C and the travertines at a temperature of about 120°C. The migration of the geothermal fluids was driven by fracture zones produced by extensional tectonics and the consequent series of earthquakes that characterize until now the study area. The strata-bound character of the stibnite mineralisation is due to the preferential deposition of the stibnite ores in the very porous and fractured evaporitic strata of the Calcare Cavernoso formation.

Glioblastoma multiforme is a fast-growing malignant brain tumor with poor prognosis and low survival rate. Here we investigated the potential use of anticancer drug dioxadet loaded into nanogels for glioma treatment. We used block copolymer of polyethylene glycol and polymethacrylic acid for synthesis of dioxadet carriers and two types of cross-linking agents: non-degradable ethylenediamine and biodegradable cystamine, containing disulfide bond. We analyzed physicochemical properties of nanoparticles, their loading capacity, cytotoxicity of drug-loaded nanogels, and also their internalization into glioma cells. We found the optimal conditions that promote the efficient loading of the drug. We demonstrated that dioxadet loaded nanogels have relatively high level of loading capacity (>35% w/w) and loading efficiency (>75%). We shown that nanogels with the biodegradable cross-links prone to dissociate under reducing conditions (glutathione) that allow to decrease IC50values of the drug compared to the nanogels with ethylendiamine cross-links. This stimuli-sensitive behavior of nanogels could be beneficial for tumor treatment. Confocal analysis of glioma cells demonstrated that both types of nanogels accumulate in cells and localize in lysosomes. These results indicate that loading of dioxadet into nanoparticles can improve its performance; such formulation has a potential for further studies and practical applications.

Long-term repopulating (LT) hematopoietic stem cells (HSCs) are the most undifferentiated cells at the top of the hematopoietic hierarchy. The regulation of HSC pool size and its contribution to hematopoiesis are incompletely understood. We depleted hematopoietic stem and progenitor cells (HSPCs) in adult mice in situ and found that LT-HSCs recovered from initially very low levels (<1%) to below 10% of normal numbers but not more, whereas progenitor cells substantially recovered shortly after depletion. In spite of the persistent and massive reduction of LT-HSCs, steady-state hematopoiesis was unaffected and residual HSCs remained quiescent. Hematopoietic stress, although reported to recruit quiescent HSCs into cycle, was well tolerated by HSPC-depleted mice and did not induce expansion of the small LT-HSC compartment. Only upon 5-fluorouracil treatment was HSPC-depleted bone marrow compromised in reconstituting hematopoiesis, demonstrating that HSCs and early progenitors are crucial to compensate myeloablation. Hence, a contracted HSC compartment cannot recover in situ to its original size, and normal steady-state blood cell generation is sustained with <10% of normal LT-HSC numbers without increased contribution of the few residual cells.

Long-term repopulating (LT) hematopoietic stem cells (HSCs) are the most undifferentiated cells at the top of the hematopoietic hierarchy. The regulation of HSC pool size and its contribution to hematopoiesis are incompletely understood. We depleted hematopoietic stem and progenitor cells (HSPCs) in adult mice in situ and found that LT-HSCs recovered from initially very low levels (<1%) to below 10% of normal numbers but not more, whereas progenitor cells substantially recovered shortly after depletion. In spite of the persistent and massive reduction of LT-HSCs, steady-state hematopoiesis was unaffected and residual HSCs remained quiescent. Hematopoietic stress, although reported to recruit quiescent HSCs into cycle, was well tolerated by HSPC-depleted mice and did not induce expansion of the small LT-HSC compartment. Only upon 5-fluorouracil treatment was HSPC-depleted bone marrow compromised in reconstituting hematopoiesis, demonstrating that HSCs and early progenitors are crucial to compensate myeloablation. Hence, a contracted HSC compartment cannot recover in situ to its original size, and normal steady-state blood cell generation is sustained with <10% of normal LT-HSC numbers without increased contribution of the few residual cells.

Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/hr) in 26 ethanol-dependent inpatients who were sober for at least one month prior to testing. This study found that nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception, dysphoria, verbal fluency impairment, and learning deficits. Nimodipine improved memory function, but had no other intrinsic behavioral activity in this patient group. Nimodipine pretreatment attenuated the perceived similarity of ketamine effects to ethanol as well as ketamine-induced euphoria and sedation. However, nimodipine did not reduce the stimulant effects of ketamine. These data suggest that antagonism of L-type VSCCs attenuates the behavioral effects of NMDA antagonists in humans. They support the continued evaluation of nimodipine in the treatment of neuropsychiatric disorders. They also suggest that drugs, such as ethanol, that combine NMDA and L-type VSCC antagonism may have enhanced tolerability without attenuation of their stimulant effects.

Maintenance of stem cell properties is associated with reduced proliferation. However, in mouse hematopoietic stem cells (HSCs), loss of quiescence results in a wide range of phenotypes, ranging from functional failure to extensive self-renewal. It remains unknown whether the function of human HSCs is controlled by the kinetics of cell cycle progression. Using human HSCs and human progenitor cells (HSPCs), we report here that elevated levels of CCND1–CDK4 complexes promoted the transit from G0 to G1 and shortened the G1 cell cycle phase, resulting in protection from differentiation-inducing signals in vitro and increasing human leukocyte engraftment in vivo. Further, CCND1–CDK4 overexpression conferred a competitive advantage without impacting HSPC numbers. In contrast, accelerated cell cycle progression mediated by elevated levels of CCNE1–CDK2 led to the loss of functional HSPCs in vivo. Collectively, these data suggest that the transition kinetics through the early cell cycle phases are key regulators of human HSPC function and important for lifelong hematopoiesis.

Isotopic composition of sulfur was determined in more than 150 samples of sulfides and sulfates from the Levikha ore field. On the basis of the results so obtained, we are discussing the sources of sulfur in the sulfide ores and in sulfates of the ore deposits, physicochemical conditions of their deposition, and their genetic connections with sulfides in the overburden. -- Authors.

Long-term hematopoietic stem cells (HSCs [LT-HSCs]) are well known to display unpredictable differences in their clonal expansion capacities after transplantation. Here, by analyzing the cellular output after transplantation of stem cells differing in surface expression levels of the Kit receptor, we show that LT-HSCs can be systematically subdivided into two subtypes with distinct reconstitution behavior. LT-HSCs expressing intermediate levels of Kit receptor (Kitint) are quiescent in situ but proliferate extensively after transplantation and therefore repopulate large parts of the recipient’s hematopoietic system. In contrast, metabolically active Kithi LT-HSCs display more limited expansion capacities and show reduced but robust levels of repopulation after transfer. Transplantation into secondary and tertiary recipient mice show maintenance of efficient repopulation capacities of Kitint but not of Kithi LT-HSCs. Initiation of differentiation is marked by the transit from Kitint to Kithi HSCs, both of which precede any other known stem cell population.

Hypoxia is a prominent feature in the maintenance of hematopoietic stem cell (HSC) quiescence and multipotency. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain proteins (PHDs) serve as oxygen sensors and may therefore regulate this system. Here, we describe a mouse line with conditional loss of HIF prolyl hydroxylase 2 (PHD2) in very early hematopoietic precursors that results in self-renewal of multipotent progenitors under steady-state conditions in a HIF1α- and SMAD7-dependent manner. Competitive bone marrow (BM) transplantations show decreased peripheral and central chimerism of PHD2-deficient cells but not of the most primitive progenitors. Conversely, in whole BM transfer, PHD2-deficient HSCs replenish the entire hematopoietic system and display an enhanced self-renewal capacity reliant on HIF1α. Taken together, our results demonstrate that loss of PHD2 controls the maintenance of the HSC compartment under physiological conditions and causes the outcompetition of PHD2-deficient hematopoietic cells by their wild-type counterparts during stress while promoting the self-renewal of very early hematopoietic progenitors.

Hypoxia is a prominent feature in the maintenance of hematopoietic stem cell (HSC) quiescence and multipotency. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain proteins (PHDs) serve as oxygen sensors and may therefore regulate this system. Here, we describe a mouse line with conditional loss of HIF prolyl hydroxylase 2 (PHD2) in very early hematopoietic precursors that results in self-renewal of multipotent progenitors under steady-state conditions in a HIF1α- and SMAD7-dependent manner. Competitive bone marrow (BM) transplantations show decreased peripheral and central chimerism of PHD2-deficient cells but not of the most primitive progenitors. Conversely, in whole BM transfer, PHD2-deficient HSCs replenish the entire hematopoietic system and display an enhanced self-renewal capacity reliant on HIF1α. Taken together, our results demonstrate that loss of PHD2 controls the maintenance of the HSC compartment under physiological conditions and causes the outcompetition of PHD2-deficient hematopoietic cells by their wild-type counterparts during stress while promoting the self-renewal of very early hematopoietic progenitors.

The transcription factor runt-related transcription factor 1 (Runx1) is essential for the establishment of definitive hematopoiesis during embryonic development. In adult blood homeostasis, Runx1 plays a pivotal role in the maturation of lymphocytes and megakaryocytes. Furthermore, Runx1 is required for the regulation of hematopoietic stem and progenitor cells. However, how Runx1 orchestrates self-renewal and lineage choices in combination with other factors is not well understood. In the present study, we describe a genome-scale RNA interference screen to detect genes that cooperate with Runx1 in regulating hematopoietic stem and progenitor cells. We identify the polycomb group protein Pcgf1 as an epigenetic regulator involved in hematopoietic cell differentiation and show that simultaneous depletion of Runx1 and Pcgf1 allows sustained self-renewal while blocking differentiation of lineage marker–negative cells in vitro. We found an up-regulation of HoxA cluster genes on Pcgf1 knock-down that possibly accounts for the increase in self-renewal. Moreover, our data suggest that cells lacking both Runx1 and Pcgf1 are blocked at an early progenitor stage, indicating that a concerted action of the transcription factor Runx1, together with the epigenetic repressor Pcgf1, is necessary for terminal differentiation. The results of the present study uncover a link between transcriptional and epigenetic regulation that is required for hematopoietic differentiation.

We study Fano threefolds birationally equivalent to a quartic containing a plane. We prove that linear systems that have no maximal singularities at a singular point of the variety can have maximal singularities only along curves of degree one. We construct corresponding birational automorphisms. Bibliography: 10 titles.

Background: Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up‐regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N‐methyl‐d‐aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate.

Different methods for measurement of strong underwater shock waves pressure pulses with peak pressures of up to 200 MPa and rise time of tens to hundreds of nanoseconds are described and compared. The experimental techniques include direct methods of pressure measurement using various electromechanical gauges such as quartz, carbon-based, and commercially available PCB gauges, and nondirect methods based on measurement of the velocity of the shock wave such as time-of-flight and fast-streak photography. Advantages and disadvantages of the used gauges and methods are discussed. The shock waves were produced by underwater electrical discharge (discharge current amplitude ≤100 kA, pulse duration ≤5 μs) initiated by an exploding wire. A good correspondence between the pressure amplitudes measured by the various gauges and methods was observed. The obtained dependence of the shock wave pressure on the distance from the discharge channel was found to be best fitted by a r−0.7law. It is also shown that none of these methods can be used to determine the time evolution of the pressure behind the front of the shock wave.Different methods for measurement of strong underwater shock waves pressure pulses with peak pressures of up to 200 MPa and rise time of tens to hundreds of nanoseconds are described and compared. The experimental techniques include direct methods of pressure measurement using various electromechanical gauges such as quartz, carbon-based, and commercially available PCB gauges, and nondirect methods based on measurement of the velocity of the shock wave such as time-of-flight and fast-streak photography. Advantages and disadvantages of the used gauges and methods are discussed. The shock waves were produced by underwater electrical discharge (discharge current amplitude ≤100 kA, pulse duration ≤5 μs) initiated by an exploding wire. A good correspondence between the pressure amplitudes measured by the various gauges and methods was observed. The obtained dependence of the shock wave pressure on the distance from the discharge channel was found to be best fitted by a r−0.7law. It is also shown that none of these methods can be used to determine the time evolution of the pressure behind the front of the shock wave.

Immune response to allogenic tumor cells is associated with the appearance of long-living CD8+ memory cells capable of rapid restimulation and lysis of tumor cells in case of repeated injection of these cells. In order to acquire the effector function, allorestricted memory cells need antigen restimulation for 2 days, which is a specific feature of central memory cell population. These cells can suppress proliferation of naive splenocytes in vitro. In mixed lymphocyte cultures containing memory cells, antigen stimulation induces more intensive IL-10 production and deeper suppression of IL-2 production in comparison with cultures containing naive cells. The conditions for activation of naive cells during secondary immune response are not optimal.

The combined cytostatic effect of doxorubicin and gestagens progesterone, medroxyprogesterone acetate, mecigestone, and butagest on doxorubicin-resistant and doxorubicin-sensitive human breast cancer MCF-7 cells was studied by the MTT assay. On the 6th day of incubation progesterone, medroxyprogesterone acetate, mecigestone, and butagest in high concentrations (10-5M) potentiated the cytostatic action of doxorubicin in sensitive and resistant cells by 30-50%. Potentiation of the cytostatic effect produced by doxorubicin in sensitive cells is related to intrinsic cytotoxic activity of gestagens. In resistant cells these changes are associated with potentiation of the effect of doxorubicin.

It is proved that certain types of fibring on del Pezzo surfaces of degree 2 are birationally rigid.

We study the birational geometry of a Fano threefold that is a double covering of a cone over a Veronese surface with ramification at a non-singular section by a cubic. In particular, we consider the set of Mori structures and possible types of maximal singularities of linear systems.

The scorpion toxin BeKm-1 is unique among a variety of known short scorpion toxins affecting potassium channels in its selective action on ether-a-go-go-related gene (ERG)-type channels. BeKm-1 shares the common molecular scaffold with other short scorpion toxins. The toxin spatial structure resolved by NMR consists of a short alpha-helix and a triple-stranded antiparallel beta-sheet. By toxin mutagenesis study we identified the residues that are important for the binding of BeKm-1 to the human ERG K+ (HERG) channel. The most critical residues (Tyr-11, Lys-18, Arg-20, Lys-23) are located in the alpha-helix and following loop whereas the "traditional" functional site of other short scorpion toxins is formed by residues from the beta-sheet. Thus the unique location of the binding site of BeKm-1 provides its specificity toward the HERG channel.

Reduction by Birch procedure of 3-methoxy-B-nor-8-isoestra-1,3,5(10)-trienes followed by hydrolysis of reaction products furnished 19,B-bisnor-8,10-isoanalogs of steroid androgens. With the use of the correlation NMR spectroscopy a complete assignment of signals in the 1H and 13C NMR spectra was performed for two representatives of this steroid group, and their prevailing conformations in solution were established.

The problem of birational rigidity for three-dimensional algebraic varieties fibered over rational curves into del Pezzo surfaces of degree 1 is discussed. A criterion for the rigidity of such fibrations in the Mori category is suggested and the inverse implication is proved (Theorem 3.3). Surgeries on fibers in fibrations of this type, which turn out to be closely related to the rigidity problem, are considered. In particular, an important result on the uniqueness of a smooth model in a class of maps over a base is stated (Corollary 4.5).

Abstract: In this note, we discuss birational properties of some three-dimensional Del Pezzo fibrations of degree two.

The problem of birational rigidity is investigated for smooth Mori fibre spaces representable as a pencil of del Pezzo surfaces of degree 1 or 2.