Highly tunable thiosulfonates as a novel class of cysteine protease inhibitors with anti-parasitic activity against Schistosoma mansoni

The development of a new class of cysteine protease inhibitors utilising the thiosulfonate moiety as an SH specific electrophile is described. This moiety has been introduced into suitable amino acid derived building blocks, which were incorporated into peptidic sequences leading to very potent i.e. sub micromolar inhibitors of the cysteine protease papain in the same range as the vinyl sulfone based inhibitor K11777. Therefore, their inhibitory effect on Schistosoma mansoni, a human blood parasite, that expresses several cysteine proteases, was evaluated. The homophenylalanine side chain containing compounds 27 - 30 and especially 36 showed promising activities compared with K11777 and warrant further investigations of these peptidic thiosulfonate inhibitors as new potential anti-parasitic compounds

Activation of stress-activated protein kinase in osteoarthritic cartilage: evidence for nitric oxide dependence

AbstractObjective We have demonstrated in bovine chondrocytes that nitric oxide (NO) mediates IL1 dependent apoptosis under conditions of oxidant stress. This process is accompanied by activation of c-Jun NH2-terminal kinase (JNK; also called stress-activated protein kinase). In these studies we examined activation of JNK in explant cultures of human osteoarthritic cartilage obtained at joint replacement surgery and we characterized the role of peroxynitrite to act as an upstream trigger.Design A novel technique to isolate chondrocyte proteins (<10% of total cartilage protein) from cartilage specimens was developed. It was used to analyse JNK activation by a western blot technique. To examine the hypothesis that chondrocyte JNK activation is a result of increased peroxynitrite, in vitro experiments were performed in which cultured chondrocytes were incubated with this oxidant.Results Activated JNK was detected in the cytoplasm of osteoarthritis (OA) affected chondrocytes but not in that of controls. In vitro, chondrocytes produce NO and superoxide anion. IL-1 (48h), which induces nitric oxide synthase, resulted in an activation of JNK; this effect was reversed by N-monomethylarginine (NMA). TNFα treated chondrocytes at 48h produce superoxide anion (EPR method). Exposure of cells to peroxynitrite led to an accumulation of intracellular oxidants, in association with JNK activation and cell death by apoptosis.Conclusion We suggest that JNK activation is among the IL-1 elicited responses that injure articular chondrocytes and this activation of JNK is dependent on intracellular oxidant formation (including NO peroxynitrite). In addition, the extraction technique here described is a novel method that permits the quantitation and study of proteins such as JNK involved in the signaling pathways of chondrocytes within osteoarthritic cartilage

Scientific and Technological Approaches to Searching for Extant Life in the Solar System

Future directions for investigations and measurements identified in the decadal survey Vision and Voyages for Planetary Science in the Decade 2013-2022 include direct methods to search for extant life. Within the framework a 35-year science vision for future decades extending into the 2020s and beyond, "Ocean Worlds" of the outer Solar System (e.g., Enceladus and Europa), as well as Mars, represent accessible targets that likely provide habitable environments that may support extant life. NASA Ames Research Center (ARC) is currently developing a multi-dimensional approach, led by astrobiology scientists in the ARC Space Sciences Division, technologists in the ARC Exploration Technology Directorate, and small payload engineers in the ARC Mission Design Division, to enable the definitive detection of extant extraterrestrial life in future NASA missions

High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep

SUMMARY: Chronic environmental fluoride exposure under calcium stress causes fragility fractures due to osteoporosis and bone quality deterioration, at least in sheep. Proof of skeletal fluorosis, presenting without increased bone density, calls for a review of fracture incidence in areas with fluoridated groundwater, including an analysis of patients with low bone mass. INTRODUCTION: Understanding the skeletal effects of environmental fluoride exposure especially under calcium stress remains an unmet need of critical importance. Therefore, we studied the skeletal phenotype of sheep chronically exposed to highly fluoridated water in the Kalahari Desert, where livestock is known to present with fragility fractures. METHODS: Dorper ewes from two flocks in Namibia were studied. Chemical analyses of water, blood and urine were executed for both cohorts. Skeletal phenotyping comprised micro-computer tomography (μCT), histological, histomorphometric, biomechanical, quantitative backscattered electron imaging (qBEI) and energy-dispersive X-ray (EDX) analysis. Analysis was performed in direct comparison with undecalcified human iliac crest bone biopsies of patients with fluoride-induced osteopathy. RESULTS: The fluoride content of water, blood and urine was significantly elevated in the Kalahari group compared to the control. Surprisingly, a significant decrease in both cortical and trabecular bones was found in sheep chronically exposed to fluoride. Furthermore, osteoid parameters and the degree and heterogeneity of mineralization were increased. The latter findings are reminiscent of those found in osteoporotic patients with treatment-induced fluorosis. Mechanical testing revealed a significant decrease in the bending strength, concurrent with the clinical observation of fragility fractures in sheep within an area of environmental fluoride exposure. CONCLUSIONS: Our data suggest that fluoride exposure with concomitant calcium deficit (i) may aggravate bone loss via reductions in mineralized trabecular and cortical bone mass and (ii) can cause fragility fractures and (iii) that the prevalence of skeletal fluorosis especially due to groundwater exposure should be reviewed in many areas of the world as low bone mass alone does not exclude fluorosis

Does the Constitution Provide More Ballot Access Protection for Presidential Elections Than for U.S. House Elections?

Both the U.S. Constitution and The Federalist Papers suggest that voters ought to have more freedom to vote for the candidate of their choice for the U.S. House of Representatives than they do for the President or the U.S. Senate. Yet, strangely, for the last thirty-three years, the U.S. Supreme Court and lower courts have ruled that the Constitution gives voters more freedom to vote for the candidate of their choice in presidential elections than in congressional elections. Also, state legislatures, which have been writing ballot access laws since 1888, have passed laws that make it easier for minor-party and independent candidates to get on the ballot for President than for the U.S. House. As a result, voters in virtually every state invariably have far more choices on their general election ballots for the President than they do for the House. This Article argues that the right of a voter to vote for someone other than a Democrat or a Republican for the House is just as important as a voter’s right to do so for President, and that courts should grant more ballot access protection to minor-party and independent candidates for the House

Wnt1 promotes cementum and alveolar bone growth in a time-dependent manner

The WNT/β-catenin signaling pathway plays a central role in the biology of the periodontium, yet the function of specific extracellular WNT ligands remains poorly understood. By using a Wnt1-inducible transgenic mouse model targeting Col1a1-expressing alveolar osteoblasts, odontoblasts, and cementoblasts, we demonstrate that the WNT ligand WNT1 is a strong promoter of cementum and alveolar bone formation in vivo. We induced Wnt1 expression for 1, 3, or 9 wk in Wnt1Tg mice and analyzed them at the age of 6 wk and 12 wk. Micro–computed tomography (CT) analyses of the mandibles revealed a 1.8-fold increased bone volume after 1 and 3 wk of Wnt1 expression and a 3-fold increased bone volume after 9 wk of Wnt1 expression compared to controls. In addition, the alveolar ridges were higher in Wnt1Tg mice as compared to controls. Nondecalcified histology demonstrated increased acellular cementum thickness and cellular cementum volume after 3 and 9 wk of Wnt1 expression. However, 9 wk of Wnt1 expression was also associated with periodontal breakdown and ectopic mineralization of the pulp. The composition of this ectopic matrix was comparable to those of cellular cementum as demonstrated by quantitative backscattered electron imaging and immunohistochemistry for noncollagenous proteins. Our analyses of 52-wk-old mice after 9 wk of Wnt1 expression revealed that Wnt1 expression affects mandibular bone and growing incisors but not molar teeth, indicating that Wnt1 influences only growing tissues. To further investigate the effect of Wnt1 on cementoblasts, we stably transfected the cementoblast cell line (OCCM-30) with a vector expressing Wnt1-HA and performed proliferation as well as differentiation experiments. These experiments demonstrated that Wnt1 promotes proliferation but not differentiation of cementoblasts. Taken together, our findings identify, for the first time, Wnt1 as a critical regulator of alveolar bone and cementum formation, as well as provide important insights for harnessing the WNT signal pathway in regenerative dentistry

FACT - The First G-APD Cherenkov Telescope: Status and Results

The First G-APD Cherenkov telescope (FACT) is the first telescope using silicon photon detectors (G-APD aka. SiPM). It is built on the mount of the HEGRA CT3 telescope, still located at the Observatorio del Roque de los Muchachos, and it is successfully in operation since Oct. 2011. The use of Silicon devices promises a higher photon detection efficiency, more robustness and higher precision than photo-multiplier tubes. The FACT collaboration is investigating with which precision these devices can be operated on the long-term. Currently, the telescope is successfully operated from remote and robotic operation is under development. During the past months of operation, the foreseen monitoring program of the brightest known TeV blazars has been carried out, and first physics results have been obtained including a strong flare of Mrk501. An instantaneous flare alert system is already in a testing phase. This presentation will give an overview of the project and summarize its goals, status and first results

Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract

[[abstract]]Both gemcitabine and weekly 24-h infusion of high-dose 5-fluorouracil/leucovorin (HDFL) have shown promising antitumour activity for patients with locally advanced or metastatic carcinoma of the biliary tract (CBT). From April 1999 through December 2002, 30 patients with inoperable CBT were treated with gemcitabine 800 mg m(-2), intravenous infusion for 30 min, followed by 5-FU, 2000 mg m(-2) and leucovorin, 300 mg m(-2), intravenous infusion for 24 h, on day 1, 8 and 15, every 4 weeks. A total of 166 cycles were given (median of four cycles per patient, range 1-24 cycles). Response was evaluable in 28 patients and toxicity in 29 patients. Partial response was obtained in six patients, stable disease in 13, while progressive disease occurred in nine. The objective response rate was 21.4% (95% CI: 5.2-37.6%). The most common grade 3 or 4 toxicity was infection (nine patients). Other types of grade 3 or 4 toxicity included leucopenia (four patients), thrombocytopenia (three patients), anaemia (three patients), nausea/vomiting (two patients) and elevation of liver transaminases (three patients). As of 30 September 2003, the median progression-free survival was 3.7 months (95% CI: 2.8-4.6 months) and the median overall survival was 4.7 months (95% CI: 0.8-8.6 months). Our data suggest that weekly gemcitabine plus HDFL is modestly active with acceptable treatment-related toxicity for patients with advanced CBT

Effect of a low-cost, behaviour-change intervention on latrine use and safe disposal of child faeces in rural Odisha, India: a cluster-randomised controlled trial.

BACKGROUND: Uptake of Government-promoted sanitation remains a challenge in India. We aimed to investigate a low-cost, theory-driven, behavioural intervention designed to increase latrine use and safe disposal of child faeces in India. METHODS: We did a cluster-randomised controlled trial between Jan 30, 2018, and Feb 18, 2019, in 66 rural villages in Puri, Odisha, India. Villages were eligible if not adjacent to another included village and not designated by the Government to be open-defecation free. All latrine-owning households in selected villages were eligible. We assigned 33 villages to the intervention via stratified randomisation. The intervention was required to meet a limit of US$20 per household and included a folk performance, transect walk, community meeting, recognition banners, community wall painting, mothers' meetings, household visits, and latrine repairs. Control villages received no intervention. Neither participants nor field assessors were masked to study group assignment. We estimated intervention effects on reported latrine use and safe disposal of child faeces 4 months after completion of the intervention delivery using a difference-in-differences analysis and stratified results by sex. This study is registered at ClinicalTrials.gov, NCT03274245. FINDINGS: We enrolled 3723 households (1807 [48·5%] in the intervention group and 1916 [51·5%] in the control group). Analysis included 14 181 individuals (6921 [48·8%] in the intervention group and 7260 [51·2%] in the control group). We found an increase of 6·4 percentage points (95% CI 2·0-10·7) in latrine use and an increase of 15·2 percentage points (7·9-22·5) in safe disposal of child faeces. No adverse events were reported. INTERPRETATION: A low-cost behavioural intervention achieved modest increases in latrine use and marked increases in safe disposal of child faeces in the short term but was unlikely to reduce exposure to faecal pathogens to a level necessary to achieve health gains. FUNDING: The Bill & Melinda Gates Foundation and International Initiative for Impact Evaluation