Methicillin-resistant Staphylococcus aureus ST398 in Humans and Animals, Central Europe

Isolates found in persons and animals in Germany and Austria show a genetic relationship

Mission Qatabān. Rapport de la 4e campagne de fouille sur le site de Ḥaṣī (Yémen)

Preliminary report of the 4th campaign of excavations in the site of Hasî by the French Mission in the ancient kingdom of Qataban (Yemen), in 2007-08. Plan of the site; archaeological excavation; survey of the surrounding.Rapport non publié des résultats obtenus lors de la 4e campagne de la mission archéologique dans le royaume antique de Qataban (Yémen) en 2007-08 sur le site de Hasi : relevé topographique du site, fouille archéologique, prospection du territoire alentour

Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds

Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites

Discovery of a small molecule probe that post-translationally stabilizes the survival motor neuron protein for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA

SDS-200 : a Swiss German speech to Standard German text corpus

We present SDS-200, a corpus of Swiss German dialectal speech with Standard German text translations, annotated with dialect, age, and gender information of the speakers. The dataset allows for training speech translation, dialect recognition, and speech synthesis systems, among others. The data was collected using a web recording tool that is open to the public. Each participant was given a text in Standard German and asked to translate it to their Swiss German dialect before recording it. To increase the corpus quality, recordings were validated by other participants. The data consists of 200 hours of speech by around 4000 different speakers and covers a large part of the Swiss German dialect landscape. We release SDS-200 alongside a baseline speech translation model, which achieves a word error rate (WER) of 30.3 and a BLEU score of 53.1 on the SDS-200 test set. Furthermore, we use SDS-200 to fine-tune a pre-trained XLS-R model, achieving 21.6 WER and 64.0 BLEU

The two-pore channel TPCN2 mediates NAADP-dependent Ca2+-release from lysosomal stores

Second messenger-induced Ca2+-release from intracellular stores plays a key role in a multitude of physiological processes. In addition to 1,4,5-inositol trisphosphate (IP3), Ca2+, and cyclic ADP ribose (cADPR) that trigger Ca2+-release from the endoplasmatic reticulum (ER), nicotinic acid adenine dinucleotide phosphate (NAADP) has been identified as a cellular metabolite that mediates Ca2+-release from lysosomal stores. While NAADP-induced Ca2+-release has been found in many tissues and cell types, the molecular identity of the channel(s) conferring this release remained elusive so far. Here, we show that TPCN2, a novel member of the two-pore cation channel family, displays the basic properties of native NAADP-dependent Ca2+-release channels. TPCN2 transcripts are widely expressed in the body and encode a lysosomal protein forming homomers. TPCN2 mediates intracellular Ca2+-release after activation with low-nanomolar concentrations of NAADP while it is desensitized by micromolar concentrations of this second messenger and is insensitive to the NAADP analog nicotinamide adenine dinucleotide phosphate (NADP). Furthermore, TPCN2-mediated Ca2+-release is almost completely abolished when the capacity of lysosomes for storing Ca2+ is pharmacologically blocked. By contrast, TPCN2-specific Ca2+-release is unaffected by emptying ER-based Ca2+ stores. In conclusion, these findings indicate that TPCN2 is a major component of the long-sought lysosomal NAADP-dependent Ca2+-release channel

The seasonal nitrogen cycle in Wilkinson Basin, Gulf of Maine, as estimated by 1-D biological model optimization

Author Posting. © Elsevier B.V., 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Marine Systems 78 (2009): 77-93, doi:10.1016/j.jmarsys.2009.04.001.The objective of this study was to fit a simple ecosystem model to climatological nitrogen cycle data in the Gulf of Maine, in order to calibrate the biological model for use in future 3-D modelling studies. First depth-dependent monthly climatologies of nitrate, ammonium, chlorophyll, zooplankton, detritus and primary production data from Wilkinson Basin, Gulf of Maine, were created. A 6-box nitrogen-based ecosystem model was objectively fitted to the data through parameter optimization. Optimization was based on weighted least squares with model-data misfits nondi- mensionalized by assigned uncertainties in the monthly climatological estimates. These uncertainties were estimated as the standard deviations of the raw data from the 6-meter and monthly bin averages. On average the model fits the monthly means almost within their assigned uncertainties. Several statistics are examined to assess model-data misfit. Pattern statistics such as the correlation coefficient lack practical significance when data errors are large relative to the signal, as in this application. Thus Taylor diagrams were not found to be useful. The RMSE and model bias normalized by the data error were found to be the most useful skill metrics as they indicate whether the model fits the data within its estimated error. The optimal simulated nitrogen cycle budgets are presented, as an estimate of the seasonal nitrogen cycle in Wilkinson Basin, and discussed in context of the available data.Wilkinson Basin has spring and fall phytoplankton blooms, and strong summer stratification with a deep chlorophyll maximum near 21 m, just above the nitracline. The mean euphotic zone depth is estimated to be 25 m, relatively constant with season. The model estimates annual primary production as 176 g C m−2 yr−1, annual new production as 71 g C m−2 yr−1 and sinking PON fluxes of 9.7 and 4.7 g N m−2 yr−1 at 24 and 198 m respectively. Areas for improvement in the biological model, the model optimization method, and significant data gaps are identified.This work was supported by ONR, NSF, and NOAA grant to Dennis McGillicuddy

Satisfaction with care after total hip or knee replacement predicts self-perceived health status after surgery

<p>Abstract</p> <p>Background</p> <p>Inpatient satisfaction with care is a standard indicator of the quality of care delivered during hospitalization. Total hip and knee replacement (THR/TKR) for osteoarthritis (OA) are among the most successful orthopaedic interventions having a positive impact on health-related quality of life (HRQoL). The aim was to evaluate the effect of satisfaction shortly after hospital discharge on 1-month, 6-month and 1-year Medical Outcomes Study 36-item Short Form (SF-36) scores for OA patients after THR and TKR, controlling for patient characteristics, clinical presentation and preoperative SF-36 scores.</p> <p>Methods</p> <p>A multicenter prospective cohort study recruited 231 patients with OA scheduled to receive THR or TKR. Satisfaction was assessed by the Patients Judgment of Hospital Quality (PJHQ) questionnaire and HRQoL by the SF-36 questionnaire. Linear models for repeated measures assessed the relation between satisfaction (scores were dichotomized) and postoperative SF-36 scores.</p> <p>Results</p> <p>Of 231 participants, 189 were followed up 12 months after discharge (mean age 69 SD = 8; 42.6% male). The mean length of hospital stay was 13.5 (SD = 4) days. After adjustment for preoperative SF-36 scores, sociodemographic and clinical patient characteristics, satisfied patients (PJHQ score > 70) had higher SF-36 scores 1 year after surgery than did less-satisfied patients. Admission, medical care, and nursing and daily care scores mainly predicted bodily pain, mental health, social functioning, vitality and general health scores of the SF-36.</p> <p>Conclusion</p> <p>Besides being a quality-of-care indicator, immediate postoperative patient satisfaction with care may bring a new insight into clinical practice, as a predictor of self-perceived health status after surgery.</p