A study of turbulence and interacting inertial modes in a differentially-rotating spherical shell experiment

We present a study of inertial modes in a differentially rotating spherical shell (spherical Couette flow) experiment with a radius ratio of $\eta = 1/3$. Inertial modes are Coriolis-restored linear wave modes which often arise in rapidly rotating fluids. Recent experimental work has shown that inertial modes exist in a spherical Couette flow for $\Omega_{i}<\Omega_{o}$, where $\Omega_i$ and $\Omega_o$ is the inner and outer sphere rotation rate. A finite number of particular inertial modes has previously been found. By scanning the Rossby number from $-2.5 < Ro = (\Omega_{i}-\Omega_{o})/\Omega_{o} < 0$ at two fixed $\Omega_{o}$, we report the existence of similar inertial modes. However, the behavior of the flow described here differs much from previous spherical Couette experiments. We show that the kinetic energy of the dominant inertial mode dramatically increases with decreasing Rossby number that eventually leads to a wave-breaking and an increase of small-scale structures at a critical Rossby number. Such a transition in a spherical Couette flow has not been described before. The critical Rossby number scales with the Ekman number as0 $E^{1/5}$. Additionally, the increase of small-scale features beyond the transition transfers energy to a massively enhanced mean flow around the tangent cylinder. In this context, we discuss an interaction between the dominant inertial modes with a geostrophic Rossby mode exciting secondary modes whose frequencies match the triadic resonance condition

Renal Ischemia/Reperfusion Injury in Soluble Epoxide Hydrolase-Deficient Mice

Aim 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-dependent eicosanoids that play opposite roles in the regulation of vascular tone, inflammation, and apoptosis. 20-HETE aggravates, whereas EETs ameliorate ischemia/reperfusion (I/R)-induced organ damage. EETs are rapidly metabolized to dihydroxyeicosatrienoic acids (DHETs) by the soluble epoxide hydrolase (sEH). We hypothesized that sEH gene (EPHX2) deletion would increase endogenous EET levels and thereby protect against I/R-induced acute kidney injury (AKI). Methods Kidney damage was evaluated in male wildtype (WT) and sEH-knockout (KO)-mice that underwent 22-min renal ischemia followed by two days of reperfusion. CYP-eicosanoids were analyzed by liquid chromatography tandem mass spectrometry. Results Contrary to our initial hypothesis, renal function declined more severely in sEH-KO mice as indicated by higher serum creatinine and urea levels. The sEH-KO-mice also featured stronger tubular lesion scores, tubular apoptosis, and inflammatory cell infiltration. Plasma and renal EET/DHET-ratios were higher in sEH-KO than WT mice, thus confirming the expected metabolic consequences of sEH deficiency. However, CYP-eicosanoid profiling also revealed that renal, but not plasma and hepatic, 20-HETE levels were significantly increased in sEH-KO compared to WT mice. In line with this finding, renal expression of Cyp4a12a, the murine 20-HETE-generating CYP-enzyme, was up-regulated both at the mRNA and protein level, and Cyp4a12a immunostaining was more intense in the renal arterioles of sEH-KO compared with WT mice. Conclusion These results indicate that the potential beneficial effects of reducing EET degradation were obliterated by a thus far unknown mechanism leading to kidney-specific up- regulation of 20-HETE formation in sEH-KO-mice

Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats

mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their clinical use particularly early after transplantation. Interference with vascular endothelial growth factor (VEGF)-A, important for physiologic functioning of renal endothelial cells and tubular epithelium, has been implicated in detrimental renal effects of mTOR inhibitors. Low doses of Rapamycin (loading dose 3 mg/kg bodyweight, daily doses 1.5 mg/kg bodyweight) were administered in an allogenic rat kidney transplantation model resulting in a mean through concentration of 4.30 ng/mL. Glomerular and peritubular capillaries, tubular cell proliferation, or functional recovery from preservation/reperfusion injury were not compromised in comparison to vehicle treated animals. VEGF-A, VEGF receptor 2, and the co-receptor Neuropilin-1 were upregulated by Rapamycin within 7 days. Rat proximal tubular cells (RPTC) responded in vitro to hypoxia with increased VEGF-A and VEGF-R1 expression that was not suppressed by Rapamycin at therapeutic concentrations. Rapamycin did not impair proliferation of RPTC under hypoxic conditions. Low-dose Rapamycin early posttransplant does not negatively influence the VEGF network crucial for recovery from preservation/reperfusion injury. Enhancement of VEGF signaling peritransplant holds potential to further improve outcomes

Food effects on statolith composition of the common cuttlefish (Sepia officinalis)

The concentration of trace elements within cephalopod statoliths can provide a record of the environmental characteristics at the time of calcification. To reconstruct accurately the environmental characteristics at the time of calcification, it is important to understand the influence of as many factors as possible. To test the hypothesis that the elemental composition of cuttlefish statoliths could be influenced by diet, juvenile Sepia officinalis were fed either shrimp Crangon sp. or fish Clupea harengus under equal temperature and salinity regimes in laboratory experiments. Element concentrations in different regions of the statoliths (core–lateral dome–rostrum) were determined using laser ablation inductively coupled plasma mass spectrometry (LA- ICPMS). The ratios of Sr/Ca, Ba/Ca, Mn/Ca and Y/Ca in the statolith’s lateral dome of shrimp-fed cuttlefish were significantly higher than in the statolith’s lateral dome of fish-fed cuttlefish. Moreover, significant differences between statolith regions were found for all analysed elements. The fact that diet adds a considerable variation especially to Sr/Ca and Ba/Ca must be taken into account in future micro-chemical statolith studies targeting cephalopod’s life history

The mTOR inhibitor Rapamycin protects from premature cellular senescence early after experimental kidney transplantation

Interstitial fibrosis and tubular atrophy, a major cause of kidney allograft dysfunction, has been linked to premature cellular senescence. The mTOR inhibitor Rapamycin protects from senescence in experimental models, but its antiproliferative properties have raised concern early after transplantation particularly at higher doses. Its effect on senescence has not been studied in kidney transplantation, yet. Rapamycin was applied to a rat kidney transplantation model (3 mg/kg bodyweight loading dose, 1.5 mg/kg bodyweight daily dose) for 7 days. Low Rapamycin trough levels (2.1-6.8 ng/mL) prevented the accumulation of p16(INK4a) positive cells in tubules, interstitium, and glomerula. Expression of the cytokines MCP-1, IL-1 beta, and TNF-alpha, defining the proinflammatory senescence-associated secretory phenotype, was abrogated. Infiltration with monocytes/macrophages and CD8(+) T-lymphocytes was reduced and tubular function was preserved by Rapamycin. Inhibition of mTOR was not associated with impaired structural recovery, higher glucose levels, or weight loss. mTOR inhibition with low-dose Rapamycin in the immediate posttransplant period protected from premature cellular senescence without negative effects on structural and functional recovery from preservation/reperfusion damage, glucose homeostasis, and growth in a rat kidney transplantation model. Reduced senescence might maintain the renal regenerative capacity rendering resilience to future injuries resulting in protection from interstitial fibrosis and tubular atrophy

Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes

Abstract Background Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections. Methods Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined. Results In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations. Conclusions Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients

Associated factors and comorbidities in patients with pyoderma gangrenosum in Germany: a retrospective multicentric analysis in 259 patients

Background: Pyoderma gangrenosum (PG) is a rarely diagnosed ulcerative neutrophilic dermatosis with unknown origin that has been poorly characterized in clinical studies so far. Consequently there have been significant discussions about its associated factors and comorbidities. The aim of our multicenter study was to analyze current data from patients in dermatologic wound care centers in Germany in order to describe associated factors and comorbidities in patients with PG. Methods: Retrospective clinical investigation of patients with PG from dermatologic wound care centers in Germany. Results: We received data from 259 patients with PG from 20 different dermatologic wound care centers in Germany. Of these 142 (54.8\%) patients were female, 117 (45.2\%) were male; with an age range of 21 to 95 years, and a mean of 58 years. In our patient population we found 45.6\% with anemia, 44.8\% with endocrine diseases, 12.4\% with internal malignancies, 9.3\% with chronic inflammatory bowel diseases and 4.3\% with elevated creatinine levels. Moreover 25.5\% of all patients had a diabetes mellitus with some aspects of potential association with the metabolic syndrome. Conclusions: Our study describes one of the world's largest populations with PG. Beside the well-known association with chronic bowel diseases and neoplasms, a potentially relevant new aspect is an association with endocrine diseases, in particular the metabolic syndrome, thyroid dysfunctions and renal disorders. Our findings represent clinically relevant new aspects. This may help to describe the patients' characteristics and help to understand the underlying pathophysiology in these often misdiagnosed patients

Molecular Predictors of 3D Morphogenesis by Breast Cancer Cell Lines in 3D Culture

Correlative analysis of molecular markers with phenotypic signatures is the simplest model for hypothesis generation. In this paper, a panel of 24 breast cell lines was grown in 3D culture, their morphology was imaged through phase contrast microscopy, and computational methods were developed to segment and represent each colony at multiple dimensions. Subsequently, subpopulations from these morphological responses were identified through consensus clustering to reveal three clusters of round, grape-like, and stellate phenotypes. In some cases, cell lines with particular pathobiological phenotypes clustered together (e.g., ERBB2 amplified cell lines sharing the same morphometric properties as the grape-like phenotype). Next, associations with molecular features were realized through (i) differential analysis within each morphological cluster, and (ii) regression analysis across the entire panel of cell lines. In both cases, the dominant genes that are predictive of the morphological signatures were identified. Specifically, PPARγ has been associated with the invasive stellate morphological phenotype, which corresponds to triple-negative pathobiology. PPARγ has been validated through two supporting biological assays