Rare glutamic acid methyl ester peptaibols from Sepedonium ampullosporum Damon KSH 534 exhibit promising antifungal and anticancer activity

Fungal species of genus Sepedonium are rich sources of diverse secondary metabolites (e.g., alkaloids, peptaibols), which exhibit variable biological activities. Herein, two new peptaibols, named ampullosporin F (1) and ampullosporin G (2), together with five known compounds, ampullosporin A (3), peptaibolin (4), chrysosporide (5), c(Trp-Ser) (6) and c(Trp-Ala) (7), have been isolated from the culture of Sepedonium ampullosporum Damon strain KSH534. The structures of 1 and 2 were elucidated based on ESI-HRMS(n) experiments and intense 1D and 2D NMR analyses. The sequence of ampullosporin F (1) was determined to be Ac-Trp(1)-Ala(2)-Aib(3)-Aib(4)-Leu(5)-Aib(6)-Gln(7)-Aib(8)-Aib(9)-Aib(10)-GluOMe(11)-Leu(12)-Aib(13)-Gln(14)-Leuol(15), while ampullosporin G (2) differs from 1 by exchanging the position of Gln(7) with GluOMe(11). Furthermore, the total synthesis of 1 and 2 was carried out on solid-phase to confirm the absolute configuration of all chiral amino acids as L. In addition, ampullosporin F (1) and G (2) showed significant antifungal activity against B. cinerea and P. infestans, but were inactive against S. tritici. Cell viability assays using human prostate (PC-3) and colorectal (HT-29) cancer cells confirmed potent anticancer activities of 1 and 2. Furthermore, a molecular docking study was performed in silico as an attempt to explain the structure-activity correlation of the characteristic ampullosporins (1–3)

Anthelmintic activity and cytotoxic effects of compounds isolated from the fruits of Ozoroa insignis del. (Anacardiaceae)

Ozoroa insignis Del. is an ethnobotanical plant widely used in traditional medicine for various ailments, including schistosomiasis, tapeworm, and hookworm infections. From the so far not investigated fruits of Ozoroa insignis, the anthelmintic principles could be isolated through bioassay-guided isolation using Caenorhabditis elegans and identified by NMR spectroscopic analysis and mass spectrometric studies. Isolated 6-[8(Z)-pentadecenyl] anacardic (1), 6-[10(Z)-heptadecenyl] anacardic acid (2), and 3-[7(Z)-pentadecenyl] phenol (3) were evaluated against the 5 parasitic organisms Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum, which mainly infect humans and other mammals. Compounds 1-3 showed good activity against Schistosoma mansoni, with compound 1 showing the best activity against newly transformed schistosomula with 50% activity at 1microM. The isolated compounds were also evaluated for their cytotoxic properties against PC-3 (human prostate adenocarcinoma) and HT-29 (human colorectal adenocarcinoma) cell lines, whereby compounds 2 and 3 showed antiproliferative activity in both cancer cell lines, while compound 1 exhibited antiproliferative activity only on PC-3 cells. With an IC50 value of 43.2 microM, compound 3 was found to be the most active of the 3 investigated compounds

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well

Mikroskalige Elementzusammensetzung von in situ gewonnenen organo-mineralischen Assoziationen einer Kalkmarsch

Die Erforschung zeitlicher Dynamiken der Elementzusammensetzungen als auch der räumlichen Verteilungen von organo-mineralischen Assoziationen ist entscheidend für das Verständnis ihrer Funktion bei der Stabilisierung organischer Bodensubstanz (OBS). Insbesondere Fe-Oxide und -Hydroxide spielen aufgrund ihrer hohen Reaktivität eine wichtige Rolle bei der langfristigen Stabilisierung der OBS. In redoximorphen Böden findet die Ausfällung von Fe-Oxiden direkt an der Grenzfläche zwischen Bodenmatrix und Bodenlösung von Grobporen statt. Daher sind diese Böden besonders geeignet, die Interaktionen von Fe-Oxiden mit gelöster organischer Substanz, sowie redox-induzierte Alterungsprozesse von anfänglich schlechter kristallinen Fe-Oxiden zu untersuchen. Wir haben dazu eine Kalkmarsch (nahe Büsum, Schleswig-Holstein) für die Gewinnung von sowohl frisch gefällten als auch gealterten Fe-Oxiden ausgewählt. Die Probenentnahme erfolgte in situ ohne physikalische oder chemische Störung. Hierzu verwendeten wir spezielle Kollektoren, die über längere Zeiträume im Boden verbleiben können und auf welchen Glas- oder Siliziumscheiben zur Nachbildung der Bodenmatrixoberfläche angebracht wurden (1). Die Kollektoren wurden für ein halbes Jahr, ein Jahr und für zweieinhalb Jahre installiert. Mittels Rasterelektronenmikroskopie wurden auf ausgewählten Glas/Si-Scheiben geeignete Stellen für die nachfolgende Messung der Sekundärionenverteilung via NanoSIMS ausgesucht. Im ersten Schritt der Auswertung steht die Implementierung eines geeigneten statistischen Verfahrens zur Auswertung der NanoSIMS-Messungen. Hierzu entwickeln wir innerhalb von Look@NanoSIMS (2) eine Möglichkeit zur überwachten Klassifikation von ROIs (Regions Of Interest) und eine anschließende Clusteranalyse aller Kanäle. Die Auswertung der Daten ermöglicht Aussagen über die Genese und Alterung von organo-mineralischen Assoziationen in Redoxzyklen. Gleichermaßen lassen sich Aussagen über die zeitlich variable Bedeutung der Assoziationen von OBS mit Fe-Oxiden im Vergleich zu Assoziationen von OBS mit Tonmineralen für die Langzeitstabilisierung von OBS treffen

Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer

Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Results: Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Conclusion: Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC

Change in cervical length after arrested preterm labor and the risk of preterm birth

ACKNOWLEDGMENTS B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds stock options for ObsEva. B.W.J.M. has received research funding from Guerbet and Merck.Peer reviewedPublisher PD

Severe COVID-19 pneumonia: Perfusion analysis in correlation with pulmonary embolism and vessel enlargement using dual-energy CT data

Background Gas exchange in COVID-19 pneumonia is impaired and vessel obstruction has been suspected to cause ventilation-perfusion mismatch. Dual-energy CT (DECT) can depict pulmonary perfusion by regional assessment of iodine uptake. Objective The purpose of this study was the analysis of pulmonary perfusion using dual-energy CT in a cohort of 27 consecutive patients with severe COVID-19 pneumonia. Method We retrospectively analyzed pulmonary perfusion with DECT in 27 consecutive patients (mean age 57 years, range 21–73; 19 men and 8 women) with severe COVID-19 pneumonia. Iodine uptake (IU) in regions-of-interest placed into normally aerated lung, ground-glass opacifications (GGO) and consolidations was measured using a dedicated postprocessing software. Vessel enlargement (VE) within opacifications and presence of pulmonary embolism (PE) was assessed by subjective analysis. Linear mixed models were used for statistical analyses. Results Compared to normally aerated lung 106/151 (70.2%) opacifications without upstream PE demonstrated an increased IU, 9/151 (6.0%) an equal IU and 36/151 (23.8%) a decreased IU. The estimated mean iodine uptake (EMIU) in opacifications without upstream PE (GGO 1.77 mg/mL; 95%-CI: 1.52–2.02; p = 0.011, consolidations 1.82 mg/mL; 95%-CI: 1.56–2.08, p = 0.006) was significantly higher compared to normal lung (1.22 mg/mL; 95%-CI: 0.95–1.49). In case of upstream PE, EMIU of opacifications (combined GGO and consolidations) was significantly decreased compared to normal lung (0.52 mg/mL; 95%-CI: -0.07–1.12; p = 0.043). The presence of VE in opacifications correlated significantly with iodine uptake (p<0.001). Conclusions DECT revealed the opacifications in a subset of patients with severe COVID-19 pneumonia to be perfused non-uniformly with some being hypo- and others being hyperperfused. Mean iodine uptake in opacifications (both ground-glass and consolidation) was higher compared to normally aerated lung except for areas with upstream pulmonary embolism. Vessel enlargement correlated with iodine uptake: In summary, in a cohort of 27 consecutive patients with severe COVID-19 pneumonia, dual-energy CT demonstrated a wide range of iodine uptake in pulmonary ground-glass opacifications and consolidations as a surrogate marker for hypo- and hyperperfusion compared to normally aerated lung. Applying DECT to determine which pathophysiology is predominant might help to tailor therapy to the individual patient´s needs