Prolonged use of temozolomide leads to increased anxiety and decreased content of aggrecan and chondroitin sulfate in brain tissues of aged rats.

Chemotherapy with temozolomide (TMZ) is an essential part of anticancer therapy used for malignant tumors (mainly melanoma and glioblastoma); however, the long-term effects on patient health and life quality are not fully investigated. Considering that tumors often occur in elderly patients, the present study was conducted on long-term (4 months) treatment of adult Wistar rats (9 months old, n=40) with TMZ and/or dexamethasone (DXM) to investigate potential behavioral impairments or morphological and molecular changes in their brain tissues. According to the elevated plus maze test, long-term use of TMZ affected the anxiety of the adult Wistar rats, although no significant deterioration of brain morphology or cellular composition of the brain tissue was revealed. The expression levels of all studied heparan sulfate (HS) proteoglycans (HSPGs) (syndecan-1, syndecan-3, glypican-1 and HSPG2) and the majority of the studied chondroitin sulfate (CS) proteoglycans (CSPGs) (decorin, biglycan, lumican, brevican, neurocan aggrecan, versican, Cspg4/Ng2, Cspg5 and phosphacan) were not affected by TMZ/DXM, except for neurocan and aggrecan. Aggrecan was the most sensitive proteoglycan to TMZ/DXM treatment demonstrating downregulation of its mRNA and protein levels following TMZ (-10-fold), DXM (-45-fold) and TMZ-DXM (-80-fold) treatment. HS content was not affected by TMZ/DXM treatment, whereas CS content was decreased 1.5-2.5-fold in the TMZ- and DXM-treated brain tissues. Taken together, the results demonstrated that treatment of adult Wistar rats with TMZ had long-term effects on the brain tissues, such as decreased aggrecan core protein levels and CS chain content and increased anxiety of the experimental animals.

In-Plane Magnetic Penetration Depth in Sr_{2}RuO_{4}: Muon-Spin Rotation and Relaxation Study.

We report on measurements of the in-plane magnetic penetration depth (λ_{ab}) in single crystals of Sr_{2}RuO_{4} down to ≃0.015 K by means of muon-spin rotation-relaxation. The linear temperature dependence of λ_{ab}^{-2} for T≲0.7 K suggests the presence of nodes in the superconducting gap. This statement is further substantiated by observation of the Volovik effect, i.e., the reduction of λ_{ab}^{-2} as a function of the applied magnetic field. The experimental zero-field and zero-temperature value of λ_{ab}=124(3) nm agrees with λ_{ab}≃130 nm, calculated based on results of electronic structure measurements reported in A. Tamai et al. [High-resolution photoemission on Sr_{2}RuO_{4} reveals correlation-enhanced effective spin-orbit coupling and dominantly local self-energies, Phys. Rev. X 9, 021048 (2019)PRXHAE2160-330810.1103/PhysRevX.9.021048]. Our analysis reveals that a simple nodal superconducting energy gap, described by the lowest possible harmonic of a gap function, does not capture the dependence of λ_{ab}^{-2} on T, so the higher angular harmonics of the energy gap function need to be introduced.

Probing Momentum-Dependent Scattering in Uniaxially Stressed Sr_{2}RuO_{4} through the Hall Effect.

The largest Fermi surface sheet of the correlated metal Sr_{2}RuO_{4} can be driven through a Lifshitz transition between an electronlike and an open geometry by uniaxial stress applied along the [100] lattice direction. Here, we investigate the effect of this transition on the longitudinal resistivity ρ_{xx} and the Hall coefficient R_{H}. ρ_{xx}(T), when Sr_{2}RuO_{4} is tuned to this transition, is found to have a T^{2}logT form, as expected for a Fermi liquid tuned to a Lifshitz transition. R_{H} is found to become more negative as the Fermi surface transitions from an electronlike to an open geometry, opposite to general expectations from this change in topology. The magnitude of the change in R_{H} implies that scattering changes throughout the Brillouin zone, not just at the point in k space where the transition occurs. In a model of orbital-dependent scattering, the electron-electron scattering rate on sections of Fermi surface with xy orbital weight is found to decrease dramatically.

Dexamethasone Inhibits Heparan Sulfate Biosynthetic System and Decreases Heparan Sulfate Content in Orthotopic Glioblastoma Tumors in Mice.

Glioblastoma (GB) is an aggressive cancer with a high probability of recurrence, despite active chemoradiotherapy with temozolomide (TMZ) and dexamethasone (DXM). These systemic drugs affect the glycosylated components of brain tissue involved in GB development; however, their effects on heparan sulfate (HS) remain unknown. Here, we used an animal model of GB relapse in which SCID mice first received TMZ and/or DXM (simulating postoperative treatment) with a subsequent inoculation of U87 human GB cells. Control, peritumor and U87 xenograft tissues were investigated for HS content, HS biosynthetic system and glucocorticoid receptor (GR, Nr3c1). In normal and peritumor brain tissues, TMZ/DXM administration decreased HS content (5-6-fold) but did not affect HS biosynthetic system or GR expression. However, the xenograft GB tumors grown in the pre-treated animals demonstrated a number of molecular changes, despite the fact that they were not directly exposed to TMZ/DXM. The tumors from DXM pre-treated animals possessed decreased HS content (1.5-2-fold), the inhibition of HS biosynthetic system mainly due to the -3-3.5-fold down-regulation of N-deacetylase/N-sulfotransferases (Ndst1 and Ndst2) and sulfatase 2 (Sulf2) expression and a tendency toward a decreased expression of the GRalpha but not the GRbeta isoform. The GRalpha expression levels in tumors from DXM or TMZ pre-treated mice were positively correlated with the expression of a number of HS biosynthesis-involved genes (Ext1/2, Ndst1/2, Glce, Hs2st1, Hs6st1/2), unlike tumors that have grown in intact SCID mice. The obtained data show that DXM affects HS content in mouse brain tissues, and GB xenografts grown in DXM pre-treated animals demonstrate attenuated HS biosynthesis and decreased HS content.

Hierarchy of Lifshitz Transitions in the Surface Electronic Structure of Sr_{2}RuO_{4} under Uniaxial Compression.

We report the evolution of the electronic structure at the surface of the layered perovskite Sr_{2}RuO_{4} under large in-plane uniaxial compression, leading to anisotropic B_{1g} strains of ϵ_{xx}-ϵ_{yy}=-0.9±0.1%. From angle-resolved photoemission, we show how this drives a sequence of Lifshitz transitions, reshaping the low-energy electronic structure and the rich spectrum of van Hove singularities that the surface layer of Sr_{2}RuO_{4} hosts. From comparison to tight-binding modeling, we find that the strain is accommodated predominantly by bond-length changes rather than modifications of octahedral tilt and rotation angles. Our study sheds new light on the nature of structural distortions at oxide surfaces, and how targeted control of these can be used to tune density of state singularities to the Fermi level, in turn paving the way to the possible realization of rich collective states at the Sr_{2}RuO_{4} surface.

Natural Killer Cell Derived Microvesicles Affect the Function of Trophoblast Cells.

The interaction of natural killer (NK) and trophoblast cells underlies the formation of immune tolerance in the mother-fetus system and the maintenance of the physiological course of pregnancy. In addition, NK cells affect the function of trophoblast cells, interacting with them via the receptor apparatus and through the production of cytokines. Microvesicles (MVs) derived from NK cells are able to change the function of target cells. However, in the overall pattern of interactions between NK cells and trophoblasts, the possibility that both can transmit signals to each other via MVs has not been taken into account. Therefore, the aim of this study was to assess the effect of NK cell-derived MVs on the phenotype, proliferation, and migration of trophoblast cells and their expression of intracellular messengers. We carried out assays for the detection of content transferred from MV to trophoblasts. We found that NK cell-derived MVs did not affect the expression of CD54, CD105, CD126, CD130, CD181, CD119, and CD120a receptors in trophoblast cells or lead to the appearance of CD45 and CD56 receptors in the trophoblast membrane. Further, the MVs reduced the proliferation but increased the migration of trophoblasts with no changes to their viability. Incubation of trophoblast cells in the presence of MVs resulted in the activation of STAT3 via pSTAT3(Ser727) but not via pSTAT3(Tyr705). The treatment of trophoblasts with MVs did not result in the phosphorylation of STAT1 and ERK1/2. The obtained data indicate that NK cell-derived MVs influence the function of trophoblast cells, which is accompanied by the activation of STAT3 signaling.

Deep Semantic Segmentation of Angiogenesis Images.

Angiogenesis is the development of new blood vessels from pre-existing ones. It is a complex multifaceted process that is essential for the adequate functioning of human organisms. The investigation of angiogenesis is conducted using various methods. One of the most popular and most serviceable of these methods in vitro is the short-term culture of endothelial cells on Matrigel. However, a significant disadvantage of this method is the manual analysis of a large number of microphotographs. In this regard, it is necessary to develop a technique for automating the annotation of images of capillary-like structures. Despite the increasing use of deep learning in biomedical image analysis, as far as we know, there still has not been a study on the application of this method to angiogenesis images. To the best of our knowledge, this article demonstrates the first tool based on a convolutional Unet++ encoder-decoder architecture for the semantic segmentation of in vitro angiogenesis simulation images followed by the resulting mask postprocessing for data analysis by experts. The first annotated dataset in this field, AngioCells, is also being made publicly available. To create this dataset, participants were recruited into a markup group, an annotation protocol was developed, and an interparticipant agreement study was carried out.

Observation of a robust and active catalyst for hydrogen evolution under high current densities.

Despite the fruitful achievements in the development of hydrogen production catalysts with record-breaking performances, there is still a lack of durable catalysts that could work under large current densities (>1000 mA cm-2). Here, we investigated the catalytic behaviors of Sr2RuO4 bulk single crystals. This crystal has demonstrated remarkable activities under the current density of 1000 mA cm-2, which require overpotentials of 182 and 278 mV in 0.5 M H2SO4 and 1 M KOH electrolytes, respectively. These materials are stable for 56 days of continuous testing at a high current density of above 1000 mA cm-2 and then under operating temperatures of 70 °C. The in-situ formation of ferromagnetic Ru clusters at the crystal surface is observed, endowing the single-crystal catalyst with low charge transfer resistance and high wettability for rapid gas bubble removal. These experiments exemplify the potential of designing HER catalysts that work under industrial-scale current density.

The superconductivity of Sr2RuO4 under c-axis uniaxial stress.

Applying in-plane uniaxial pressure to strongly correlated low-dimensional systems has been shown to tune the electronic structure dramatically. For example, the unconventional superconductor Sr2RuO4 can be tuned through a single Van Hove point, resulting in strong enhancement of both Tc and Hc2. Out-of-plane (c axis) uniaxial pressure is expected to tune the quasi-two-dimensional structure even more strongly, by pushing it towards two Van Hove points simultaneously. Here, we achieve a record uniaxial stress of 3.2 GPa along the c axis of Sr2RuO4. Hc2 increases, as expected for increasing density of states, but unexpectedly Tc falls. As a first attempt to explain this result, we present three-dimensional calculations in the weak interaction limit. We find that within the weak-coupling framework there is no single order parameter that can account for the contrasting effects of in-plane versus c-axis uniaxial stress, which makes this new result a strong constraint on theories of the superconductivity of Sr2RuO4.

Elastocaloric determination of the phase diagram of Sr2RuO4.

One of the main developments in unconventional superconductivity in the past two decades has been the discovery that most unconventional superconductors form phase diagrams that also contain other strongly correlated states. Many systems of interest are therefore close to more than one instability, and tuning between the resultant ordered phases is the subject of intense research1. In recent years, uniaxial pressure applied using piezoelectric-based devices has been shown to be a particularly versatile new method of tuning2,3, leading to experiments that have advanced our understanding of the fascinating unconventional superconductor Sr2RuO4 (refs. 4-9). Here we map out its phase diagram using high-precision measurements of the elastocaloric effect in what we believe to be the first such study including both the normal and the superconducting states. We observe a strong entropy quench on entering the superconducting state, in excellent agreement with a model calculation for pairing at the Van Hove point, and obtain a quantitative estimate of the entropy change associated with entry to a magnetic state that is observed in proximity to the superconductivity. The phase diagram is intriguing both for its similarity to those seen in other families of unconventional superconductors and for extra features unique, so far, to Sr2RuO4.

Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell-Trophoblast Interactions.

During pregnancy, uterine NK cells interact with trophoblast cells. In addition to contact interactions, uterine NK cells are influenced by cytokines, which are secreted by the cells of the decidua microenvironment. Cytokines can affect the phenotypic characteristics of NK cells and change their functional activity. An imbalance of pro- and anti-inflammatory signals can lead to the development of reproductive pathology. The aim of this study was to assess the effects of cytokines on NK cells in the presence of trophoblast cells in an in vitro model. We used TNFα, IFNγ, TGFß and IL-10; the NK-92 cell line; and peripheral blood NK cells (pNKs) from healthy, non-pregnant women. For trophoblast cells, the JEG-3 cell line was used. In the monoculture of NK-92 cells, TNFα caused a decrease in CD56 expression. In the coculture of NK cells with JEG-3 cells, TNFα increased the expression of NKG2C and NKG2A by NK-92 cells. Under the influence of TGFß, the expression of CD56 increased and the expression of NKp30 decreased in the monoculture. After the preliminary cultivation of NK-92 cells in the presence of TGFß, their cytotoxicity increased. In the case of adding TGFß to the PBMC culture, as well as coculturing PBMCs and JEG-3 cells, the expression of CD56 and NKp44 by pNK cells was reduced. The differences in the effects of TGFß in the model using NK-92 cells and pNK cells may be associated with the possible influence of monocytes or other lymphoid cells from the mononuclear fraction.

Non-Fermi liquid behavior below the Néel temperature in the frustrated heavy fermion magnet UAu2.

The term Fermi liquid is almost synonymous with the metallic state. The association is known to break down at quantum critical points (QCPs), but these require precise values of tuning parameters, such as pressure and applied magnetic field, to exactly suppress a continuous phase transition temperature to the absolute zero. Three-dimensional non-Fermi liquid states, apart from superconductivity, that are unshackled from a QCP are much rarer and are not currently well understood. Here, we report that the triangular lattice system uranium diauride (UAu2) forms such a state with a non-Fermi liquid low-temperature heat capacity [Formula: see text] and electrical resistivity [Formula: see text] far below its Néel temperature. The magnetic order itself has a novel structure and is accompanied by weak charge modulation that is not simply due to magnetostriction. The charge modulation continues to grow in amplitude with decreasing temperature, suggesting that charge degrees of freedom play an important role in the non-Fermi liquid behavior. In contrast with QCPs, the heat capacity and resistivity we find are unusually resilient in magnetic field. Our results suggest that a combination of magnetic frustration and Kondo physics may result in the emergence of this novel state.

Multiple Irradiation Affects Cellular and Extracellular Components of the Mouse Brain Tissue and Adhesion and Proliferation of Glioblastoma Cells in Experimental System In Vivo.

Intensive adjuvant radiotherapy (RT) is a standard treatment for glioblastoma multiforme (GBM) patients; however, its effect on the normal brain tissue remains unclear. Here, we investigated the short-term effects of multiple irradiation on the cellular and extracellular glycosylated components of normal brain tissue and their functional significance. Triple irradiation (7 Gy*3 days) of C57Bl/6 mouse brain inhibited the viability, proliferation and biosynthetic activity of normal glial cells, resulting in a fast brain-zone-dependent deregulation of the expression of proteoglycans (PGs) (decorin, biglycan, versican, brevican and CD44). Complex time-point-specific (24-72 h) changes in decorin and brevican protein and chondroitin sulfate (CS) and heparan sulfate (HS) content suggested deterioration of the PGs glycosylation in irradiated brain tissue, while the transcriptional activity of HS-biosynthetic system remained unchanged. The primary glial cultures and organotypic slices from triple-irradiated brain tissue were more susceptible to GBM U87 cells' adhesion and proliferation in co-culture systems in vitro and ex vivo. In summary, multiple irradiation affects glycosylated components of normal brain extracellular matrix (ECM) through inhibition of the functional activity of normal glial cells. The changed content and pattern of PGs and GAGs in irradiated brain tissues are accompanied by the increased adhesion and proliferation of GBM cells, suggesting a novel molecular mechanism of negative side-effects of anti-GBM radiotherapy.

Effects of Microvesicles Derived from NK Cells Stimulated with IL-1ß on the Phenotype and Functional Activity of Endothelial Cells.

Microvesicles (MVs) are plasma extracellular vesicles ranging from 100 (150) to 1000 nm in diameter. These are generally produced by different cells through their vital activity and are a source of various protein and non-protein molecules. It is assumed that MVs can mediate intercellular communication and modulate cell functions. The interaction between natural killer cells (NK cells) and endothelial cells underlies multiple pathological conditions. The ability of MVs derived from NK cells to influence the functional state of endothelial cells in inflammatory conditions has yet to be studied well. In this regard, we aimed to study the effects of MVs derived from NK cells of the NK-92 cell line stimulated with IL-1ß on the phenotype, caspase activity, proliferation and migration of endothelial cells of the EA.hy926 cell line. Endothelial cells were cultured with MVs derived from cells of the NK-92 cell line after their stimulation with IL-1ß. Using flow cytometry, we evaluated changes in the expression of endothelial cell surface molecules and endothelial cell death. We evaluated the effect of MVs derived from stimulated NK cells on the proliferative and migratory activity of endothelial cells, as well as the activation of caspase-3 and caspase-9 therein. It was established that the incubation of endothelial cells with MVs derived from cells of the NK-92 cell line stimulated with IL-1ß and with MVs derived from unstimulated NK cells, leads to the decrease in the proliferative activity of endothelial cells, appearance of the pan leukocyte marker CD45 on them, caspase-3 activation and partial endothelial cell death, and reduced CD105 expression. However, compared with MVs derived from unstimulated NK cells, a more pronounced effect of MVs derived from cells of the NK-92 cell line stimulated with IL-1ß was found in relation to the decrease in the endothelial cell migratory activity and the intensity of the CD54 molecule expression on them. The functional activity of MVs is therefore mediated by the conditions they are produced under, as well as their internal contents.

Definitions of acute renal dysfunction: an evolving clinical and biomarker paradigm.

PURPOSE OF REVIEW: The current definition and classification of acute kidney injury (AKI) has limitations and shortcomings, which impact clinical management. The aim of this review is to highlight recent advances in our understanding of the pathophysiology and epidemiology of AKI, which impacts management and offers opportunities. RECENT FINDINGS: Kidney damage varies according to the type of primary insult, secondary effects and mitigating responses and leads to distinct molecular, cellular and functional changes. Different sub-types of AKI with varying clinical phenotypes, recovery patterns and responses to therapeutic interventions have been identified. New tools to identify and characterize these AKI sub-types are available with the potential opportunity for individualized timely aetiology-based management of AKI. SUMMARY: The identification of different sub-phenotypes of AKI based on genetic, molecular, cellular and functional pathophysiological changes following potential nephrotoxic exposures is possible with new technologies. This offers opportunities for personalized management of AKI and supports the call for a refinement of the existing AKI criteria.

Evidence for even parity unconventional superconductivity in Sr2RuO4.

Unambiguous identification of the superconducting order parameter symmetry in [Formula: see text] has remained elusive for more than a quarter century. While a chiral p-wave ground state analogue to superfluid 3He-A was ruled out only very recently, other proposed triplet-pairing scenarios are still viable. Establishing the condensate magnetic susceptibility reveals a sharp distinction between even-parity (singlet) and odd-parity (triplet) pairing since the superconducting condensate is magnetically polarizable only in the latter case. Here field-dependent 17O Knight shift measurements, being sensitive to the spin polarization, are compared to previously reported specific heat measurements for the purpose of distinguishing the condensate contribution from that due to quasiparticles. We conclude that the shift results can be accounted for entirely by the expected field-induced quasiparticle response. An upper bound for the condensate magnetic response of <10% of the normal state susceptibility is sufficient to exclude all purely odd-parity candidates.

High-sensitivity heat-capacity measurements on Sr2RuO4 under uniaxial pressure.

A key question regarding the unconventional superconductivity of [Formula: see text] remains whether the order parameter is single- or two-component. Under a hypothesis of two-component superconductivity, uniaxial pressure is expected to lift their degeneracy, resulting in a split transition. The most direct and fundamental probe of a split transition is heat capacity. Here, we report measurement of heat capacity of samples subject to large and highly homogeneous uniaxial pressure. We place an upper limit on the heat-capacity signature of any second transition of a few percent of that of the primary superconducting transition. The normalized jump in heat capacity, [Formula: see text], grows smoothly as a function of uniaxial pressure, favoring order parameters which are allowed to maximize in the same part of the Brillouin zone as the well-studied van Hove singularity. Thanks to the high precision of our measurements, these findings place stringent constraints on theories of the superconductivity of [Formula: see text].

Long-Term Exposure to Temozolomide Affects Locomotor Activity and Cartilage Structure of Elderly Experimental Rats.

Chemotherapy with temozolomide (TMZ) is an essential part of anticancer therapy of various malignant tumours; however, its long-term effects on patients' health and life quality need to be further investigated. Here, we studied the effects of TMZ and/or companion drug dexamethasone (DXM) on the locomotor activity and cartilage structure of elderly Wistar rats (n = 40). Long-term TMZ treatment selectively inhibited the horizontal, but not vertical locomotor activity of the rats (6.7-fold, p < 0.01) and resulted in delamination of the superficial epiphyseal cartilage of the femoral epiphysis of knee joints, a 2-fold decrease in mean thickness of epiphyseal cartilage (p < 0.001), and changes in the proliferative and maturation cartilage zones ratio. The simultaneous use of DXM attenuated TMZ-induced changes in cartilage thickness and integrity and compensated the decrease in horizontal locomotor activity of experimental animals. Nevertheless, combined TMZ/DXM treatment still significantly affected the structure of proximal tibial, but not distal femoral epiphysis of knee joints of the rats. These changes were accompanied by the increased content of total glycosaminoglycans (GAGs) and their partial re-localisation from chondrocytes into tissue matrix, as well as the decrease in sulfated GAGs content in both compartments. Taken together, the results demonstrate that long-term treatment with TMZ results in a significant decrease in locomotor activity of elderly Wistar rats and the reorganisation of their knee joint cartilage structure, while DXM treatment attenuates those effects. So, use of DXM or chondroprotective drugs might be beneficial to maintain quality of life for TMZ-treated cancer patients.

Nanotoxicity of ZrS3 Probed in a Bioluminescence Test on E. coli Bacteria: The Effect of Evolving H2S.

Materials from a large family of transition metal trichalcogenides (TMTCs) attract considerable attention because of their potential applications in electronics, optoelectronics and energy storage, but information on their toxicity is lacking. In this study, we investigated the toxicity of ZrS3, a prominent TMTC material, toward photoluminescent E. coli bacteria in a bioluminescence test. We found that freshly prepared ZrS3 suspensions in physiological saline solution with concentrations as high as 1 g/L did not exhibit any toxic effects on the bacteria. However, ZrS3 suspensions that were stored for 24 h prior to the bioluminescence tests were very toxic to the bacteria and inhibited their emission, even at concentrations down to 0.001 g/L. We explain these observations by the aqueous hydrolysis of ZrS3, which resulted in the formation of ZrOx on the surface of ZrS3 particles and the release of toxic H2S. The formation of ZrOx was confirmed by the XPS analysis, while the characteristic H2S smell was noticeable for the 24 h suspensions. This study demonstrates that while ZrS3 appears to be intrinsically nontoxic to photoluminescent E. coli bacteria, it may exhibit high toxicity in aqueous media. The results of this study can likely be extended to other transition metal chalcogenides, as their toxicity in aqueous solutions may also increase over time due to hydrolysis and the formation of H2S. The results of this study also demonstrate that since many systems involving nanomaterials are unstable and evolve over time in various ways, their toxicity may evolve as well, which should be considered for relevant toxicity tests.