Uredinorubellins and caeruleoramularin, photodynamically active anthraquinone derivatives produced by two species of the genus ramularia

Both the phytopathogenic fungus Ramularia collo-cygni and the hyperparasite R. uredinicola biosynthesize a number of red and yellow anthraquinone derivatives called rubellins. The new compounds uredinorubellins I and II, which were isolated from R. uredinicola, contribute to understanding the biosynthesis pathway that leads from simple anthraquinones to the rubellins. In addition, we isolated for the first time such simple compounds as chrysophanol and helminthsporin from both Ramularia species. A blue compound isolated from the mycelium of R. collo-cygni was revealed to be a unique 9,4-anthracenedione derivative. Structure elucidation by (1)H and (13)C NMR of the new but unstable compound caeruleoramularin was possible only by feeding the fungus different labeled (13)C acetates. The photodynamic activity of the uredinorubellins was comparable to rubellin D, whereas chrysophanol and caeruleoramularin did not display such activity.     

First-trimester combined screening for Down syndrome: prediction of low birth weight, small for gestational age and pre-term delivery in a cohort of non-selected women

OBJECTIVE: To establish the relationship between the first-trimester screening markers [pregnancy-associated plasma protein A (PAPP-A), free human chorionic gonadotrophin-beta (beta-hCG), nuchal translucency (NT)], the Down syndrome (DS) risk estimate, and the adverse outcomes such as low birth weight, small for gestational age (SGA) and pre-term delivery. METHODS: A retrospective cohort study including 1,734 non-selected singleton pregnancies consecutively enrolled into the programme of first-trimester combined screening for DS in a 12-month period at a single centre. Data from the Prenatal Patient Registry in ASTRAIA were combined with the Danish National Newborn Screening Registry and Danish Birth Registry. RESULTS: There was a significant relation between low PAPP-A MoM, low beta-hCG MoM, increased risk estimate for DS and low birth weight and SGA. Low PAPP-A MoM and increased NT showed a significant relation to pre-term and spontaneous pre-term delivery. Low PAPP-A MoM showed a significant relation to early pre-term delivery. CONCLUSION: First-trimester screening markers exhibited a significant relation to low birth weight, SGA and to some extent, to pre-term and early pre-term delivery. The screening performance of individual markers was poor.     

A polymorphism of the interleukin-1 beta gene is associated with sperm pathology in humans

In a prospective case-control study of 127 normozoospermic and 435 non-normozoospermic Caucasian men, the genotype frequencies of a polymorphism of the interleukin-1 beta gene (IL-1beta Taq C-->T) were statistically significantly different between groups (homozygous wild-type C/C [57%], heterozygous C/T [42%], and homozygous mutant T/T [1%] vs. C/C [57%], C/T [36%], T/T [7%] for normozoospermic and non-normozoospermic men, respectively; odds ratio, 4.8; 95% confidence interval, 1.13 to 20.28). This association was restricted to men with the oligoasthenoteratozoospermia (OAT) syndrome. We conclude that the investigated polymorphism is associated with sperm pathology in Caucasians.     

Fatigue Analysis and Defect Size Evaluation of Filled NBR including Temperature Influence

The fatigue behavior of a filled non-crystallizing elastomer was investigated on axisymmetric dumbbell specimens. By plotting relevant Wöhler curves, a power law behavior was found. In addition, temperature increases due to heat build-up were monitored. In order to distinguish between initiation and crack growth regimes, hysteresis curves, secant and dynamic moduli, dissipated and stored energies, and normalized minimum and maximum forces were analyzed. Even though indications related to material damaging were observed, a clear trend to recognize the initiation was not evident. Further details were revealed by considering a fracture mechanics. The analysis of the fracture surfaces evidenced the presence of three regions, associated to initiation, fatigue striation, and catastrophic failure. Additional fatigue tests were performed with samples in which a radial notch was introduced. This resulted in a reduction in lifetime by four orders of magnitude; nevertheless, the fracture surfaces revealed similar failure mechanisms. A fracture mechanics approach, which considered the effect of temperature, was adopted to calculate the critical defect size for fatigue, which was found to be approximately 9 μm. This value was then compared with the particle size distribution obtained through X-ray microcomputed tomography (μ-CT) of undamaged samples and it was found that the majority of the initial defects were indeed smaller than the calculated one. Finally, the evaluation of J-integral for both unnotched and notched dumbbells enabled the assessment of a geometry-independent correlation with fatigue life.     

Photon efficient orientation estimation using polarization modulation in single-molecule localization microscopy

Combining orientation estimation with localization microscopy opens up the possibility to analyze the underlying orientation of biomolecules on the nanometer scale. Inspired by the recent improvement of the localization precision by shifting excitation patterns (MINFLUX, SIMFLUX), we have adapted the idea towards the modulation of excitation polarization to enhance the orientation precision. For this modality two modes are analyzed: i) normally incident excitation with three polarization steps to retrieve the in-plane angle of emitters and ii) obliquely incident excitation with p-polarization with five different azimuthal angles of incidence to retrieve the full orientation. Firstly, we present a theoretical study of the lower precision limit with a Cramér-Rao bound for these modes. For the oblique incidence mode we find a favorable isotropic orientation precision for all molecular orientations if the polar angle of incidence is equal to arccos⁡2/3≈35 degrees. Secondly, a simulation study is performed to assess the performance for low signal-to-background ratios and how inaccurate illumination polarization angles affect the outcome. We show that a precision, at the Cramér-Rao bound (CRB) limit, of just 2.4 and 1.6 degrees in the azimuthal and polar angles can be achieved with only 1000 detected signal photons and 10 background photons per pixel (about twice better than reported earlier). Lastly, the alignment and calibration of an optical microscope with polarization control is described in detail. With this microscope a proof-of-principle experiment is carried out, demonstrating an experimental in-plane precision close to the CRB limit for signal photon counts ranging from 400 to 10,000.     

Individual Response to Botulinum Toxin Therapy in Movement Disorders: A Time Series Analysis Approach

On a group level, satisfaction with botulinum neurotoxin (BoNT) treatment in neurological indications is high. However, it is well known that a relevant amount of patients may not respond as expected. The aim of this study is to evaluate the BoNT treatment outcome on an individual level using a statistical single-case analysis as an adjunct to traditional group statistics. The course of the daily perceived severity of symptoms across a BoNT cycle was analyzed in 20 cervical dystonia (CD) and 15 hemifacial spasm (HFS) patients. A parametric single-case autoregressive integrated moving average (ARIMA) time series analysis was used to detect individual responsiveness to BoNT treatment. Overall, both CD and HFS patients significantly responded to BoNT treatment with a gradual worsening of symptom intensities towards BoNT reinjection. However, only 8/20 CD patients (40%) and 5/15 HFS patients (33.3%) displayed the expected U-shaped curve of BoNT efficacy across a single treatment cycle. CD (but not HFS) patients who followed the expected outcome course had longer BoNT injection intervals, showed a better match to objective symptom assessments, and were characterized by a stronger certainty to control their somatic symptoms (i.e., internal medical locus of control). In addition to standard evaluation procedures, patients should be identified who do not follow the mean course-of-treatment effect. Thus, the ARIMA single-case time series analysis seems to be an appropriate addition to clinical treatment studies in order to detect individual courses of subjective symptom intensities.