Identification of plant-derived alkaloids with therapeutic potential for myotonic dystrophy type I

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3 UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of availableMBNL1leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequesteredMBNL1from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1.We identified several alkaloids, including the -carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of theDM1pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases

Administration of Silver Fir (Abies alba Mill.) to goats and its potential to control gastro-intestinal parasites

Gastrointestinal nematodes (GIN) substantially impact on goat health. Because of the widespread development of GIN, resistant to allopathic drugs, further research into alternative parasite control methods is required [1]. Silver fir, Abies alba MILL (SF), is traditionally used by Swiss farmers in order to control GIN infections of goats but also to improve animal welfare. A survey among goat farmers revealed that goat farmers use SF in winter during a period of approximately five months. The SF-ration per animal and day differ between approximately 8.2 g dry matter (DM) to 600 g DM [2]. As there is scientific evidence neither for an anthelmintic potential nor for the feed intake and milk performance of SF, we conducted a study with 30 goats. For a 20 days feeding experiment one group of 15 goats (A) was, additionally to their basic ration, daily fed with SF. The remaining 15 goats (group B) were fed with the basic ration only. Individual faecal egg counts (FEC) were conducted of all goats. Furthermore the effects of SF on the intake of the basic ration, milk yield and ingredients were tested. Total phenols (TP) and essential oils (EO) of 12 representative samples of the administered SF were determined by steam distillation and GS-MS-Analytic, respectively. SF contained 1,8 % TP. Limonene, bornyl acetate and beta caryophyllene were identified as the main EO. SF-feeding did not result in a reduction of GIN FEC (Fig 1). The intake of SF per animal and day was 261 +/- 0.22 g DM. Although SF reduced the basic forage intake significantly, SF increased the total DM intake significantly (A: 1948 +/- 93 g DM; B: 1797 +/- 93 g DM). SF feeding showed no effect on milk yield and milk components (Tab 1) [2]. Although farmers are convinced of the anthelmintic potential of SF, our short term study could not point to such an effect. It is possible that a prolonged period of SF administration is necessary in order for such effects to become apparent. [1] Jackson, N. F. und Coop, R. L. (2000). The development of anthelmintic resistance in sheep nematodes. Parasitology, 120(07):95 [2] Giebler-Schubert, Frauke (2013). Einsatz von Weißtanne zur Reduktion des Magen-Darm-Strongyliden-Befalls bei Ziegen: In-vivo-Versuche und Erfahrungswissen, Universität Hohenhei

First Operational Experience from the LHCb Silicon Tracker

The LHCb Silicon Tracker is a silicon micro-strip detector covering a sensitive area of 12 m2 with a total of 272k readout channels. The installation of the detector is complete and commissioning is making excellent progress. The detector has recorded first beam-induced events during LHC synchronization tests in August 2008 and in June 2009. These events have allowed the performance to be studied, and adjustments to the operational parameters to be made. In this contribution, we will draw first lessons from the in-situ commissioning of the Silicon Tracker, and present results from the reconstruction of data collected during the LHC synchronization tests

Performance of the LHCb Silicon Tracker with first data

The LHCb Silicon Tracker consists of two sub-detectors the Tracker Turicensis and Inner Tracker that are constructed from silicon microstrip technology. Performance studies of both sub-detectors using data taken during the LHC synchronization tests are described

Commissioning of the LHCb Silicon Tracker using data from the LHC injection tests

LHCb is a single-arm forward spectrometer dedicated to the study of the CP-violation and rare decays in the b-quark sector. An efficient and high precision tracking system is a key requirement of the experiment. The LHCb Silicon Tracker Project consists of two sub-detectors that make use of silicon micro-strip technology: the Tracker Turicensis located upstream of the spectrometer magnet and the Inner Tracker which covers the innermost part of the tracking stations after the magnet. In total an area of 12 m^2 is covered by silicon. In September 2008 and June 2009, injection tests from the SPS to the LHC were performed. Bunches of order 5x10^9 protons were dumped onto a beam stopper (TED) located upstream of LHCb. This produced a spray of ~10 GeV muons in the LHCb detector. Though the occupancy in this environment is relatively large, these TED runs have allowed a first space and time alignment of the tracking system. Results of these studies together and the overall detector performance obtained in the TED running will be discussed

Differential branching fraction and angular analysis of the decay B0→K∗0μ+μ−

The angular distribution and differential branching fraction of the decay B 0→ K ∗0 μ + μ − are studied using a data sample, collected by the LHCb experiment in pp collisions at s√=7 TeV, corresponding to an integrated luminosity of 1.0 fb−1. Several angular observables are measured in bins of the dimuon invariant mass squared, q 2. A first measurement of the zero-crossing point of the forward-backward asymmetry of the dimuon system is also presented. The zero-crossing point is measured to be q20=4.9±0.9GeV2/c4 , where the uncertainty is the sum of statistical and systematic uncertainties. The results are consistent with the Standard Model predictions

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

Model-independent search for CP violation in D0→K−K+π−π+ and D0→π−π+π+π− decays

A search for CP violation in the phase-space structures of D0 and View the MathML source decays to the final states K−K+π−π+ and π−π+π+π− is presented. The search is carried out with a data set corresponding to an integrated luminosity of 1.0 fb−1 collected in 2011 by the LHCb experiment in pp collisions at a centre-of-mass energy of 7 TeV. For the K−K+π−π+ final state, the four-body phase space is divided into 32 bins, each bin with approximately 1800 decays. The p-value under the hypothesis of no CP violation is 9.1%, and in no bin is a CP asymmetry greater than 6.5% observed. The phase space of the π−π+π+π− final state is partitioned into 128 bins, each bin with approximately 2500 decays. The p-value under the hypothesis of no CP violation is 41%, and in no bin is a CP asymmetry greater than 5.5% observed. All results are consistent with the hypothesis of no CP violation at the current sensitivity

Search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓

A search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓ is performed with a data sample, corresponding to an integrated luminosity of 1.0  fb-1 of pp collisions at √s=7  TeV, collected by the LHCb experiment. The observed number of Bs0→e±μ∓ and B0→e±μ∓ candidates is consistent with background expectations. Upper limits on the branching fractions of both decays are determined to be B(Bs0→e±μ∓)101  TeV/c2 and MLQ(B0→e±μ∓)>126  TeV/c2 at 95% C.L., and are a factor of 2 higher than the previous bounds

Production, Commissioning and First Data of the LHCb Silicon Tracker

We give here a short review of the LHCb Silicon Tracker, the main points of the module production and quality control, followed by the commissioning of the detector. Problems that were found during production or commissioning are described and the first performance assessment of the installed detector with “beam data” is given