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921.
Uli Hacksell Ethan S. Burstein Krista McFarland Roger G. Mills Hilde Williams 《Neurochemical research》2014,39(10):2008-2017
Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP. 相似文献
922.
Jaclyn Ellis Ethan M. Lange Jin Li Josee Dupuis Jens Baumert Jeremy D. Walston Brendan J. Keating Peter Durda Ervin R. Fox Cameron D. Palmer Yan A. Meng Taylor Young Deborah N. Farlow Renate B. Schnabel Carola S. Marzi Emma Larkin Lisa W. Martin Joshua C. Bis Paul Auer Vasan S. Ramachandran Stacey B. Gabriel Monte S. Willis James S. Pankow George J. Papanicolaou Jerome I. Rotter Christie M. Ballantyne Myron D. Gross Guillaume Lettre James G. Wilson Ulrike Peters Wolfgang Koenig Russell P. Tracy Susan Redline Alex P. Reiner Emelia J. Benjamin Leslie A. Lange 《Human genetics》2014,133(8):985-995
C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women’s Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10?6) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10?6; CRP, p = 4.2 × 10?71; APOE, p = 1.6 × 10?6). The fourth significant locus, CD36 (p = 1.6 × 10?6), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10?5) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10?10). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10?6; CD36, p = 1.4 × 10?6). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent. 相似文献
923.
Liver transplants have their highest technical failure rate in the first two weeks following surgery. Currently, there are limited devices for continuous, real-time monitoring of the graft. In this work, a three wavelengths system is presented that combines near-infrared spectroscopy and photoplethysmography with a processing method that can uniquely measure and separate the venous and arterial oxygen contributions. This strategy allows for the quantification of tissue oxygen consumption used to study hepatic metabolic activity and to relate it to tissue stress. The sensor is battery operated and communicates wirelessly with a data acquisition computer which provides the possibility of implantation provided sufficient miniaturization. In two in vivo porcine studies, the sensor tracked perfusion changes in hepatic tissue during vascular occlusions with a root mean square error (RMSE) of 0.135 mL/min/g of tissue. We show the possibility of using the pulsatile wave to measure the arterial oxygen saturation similar to pulse oximetry. The signal is also used to extract the venous oxygen saturation from the direct current (DC) levels. Arterial and venous oxygen saturation changes were measured with an RMSE of 2.19% and 1.39% respectively when no vascular occlusions were induced. This error increased to 2.82% and 3.83% when vascular occlusions were induced during hypoxia. These errors are similar to the resolution of a commercial oximetry catheter used as a reference. This work is the first realization of a wireless optical sensor for continuous monitoring of hepatic hemodynamics. 相似文献
924.
Bin Li Colin A. Flaveny Camilla Giambelli Dennis Liang Fei Lu Han Brian I. Hang Feng Bai Xin-Hai Pei Vania Nose Oname Burlingame Anthony J. Capobianco Darren Orton Ethan Lee David J. Robbins 《PloS one》2014,9(7)
Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. 相似文献
925.
926.
S. Akin O.I. Soliman A.A. Constantinescu F. Akca O. Birim R.T. van Domburg O. Manintveld K. Caliskan 《Netherlands heart journal》2016,24(2):134-142
Background
Despite advances in pump technology, thromboembolic events/acute pump thrombosis remain potentially life-threatening complications in patients with continuous-flow left ventricular assist devices (CF-LVAD). We sought to determine early signs of thromboembolic event/pump thrombosis in patients with CF-LVAD, which could lead to earlier intervention.Methods
We analysed all HeartMate II recipients (n = 40) in our centre between December 2006 and July 2013. Thromboembolic event/pump thrombosis was defined as a transient ischaemic attack (TIA), ischaemic cerebrovascular accident (CVA), or pump thrombosis.Results
During median LVAD support of 336 days [IQR: 182–808], 8 (20 %) patients developed a thromboembolic event/pump thrombosis (six TIA/CVA, two pump thromboses). At the time of the thromboembolic event/pump thrombosis, significantly higher pump power was seen compared with the no-thrombosis group (8.2 ± 3.0 vs. 6.4 ± 1.4 W, p = 0.02), as well as a trend towards a lower pulse index (4.1 ± 1.5 vs. 5.0 ± 1.0, p = 0.05) and a trend towards higher pump flow (5.7 ± 1.0 vs. 4.9 ± 1.9 L m, p = 0.06).The thrombosis group had a more than fourfold higher lactate dehydrogenase (LDH) median 1548 [IQR: 754–2379] vs. 363 [IQR: 325–443] U/L, p = 0.0001). Bacterial (n = 4) or viral (n = 1) infection was present in 5 out of 8 patients. LDH > 735 U/L predicted thromboembolic events/pump thrombosis with a positive predictive value of 88 %.Conclusions
In patients with a CF-LVAD (HeartMate II), thromboembolic events and/or pump thrombosis are associated with symptoms and signs of acute haemolysis as manifested by a high LDH, elevated pump power and decreased pulse index, especially in the context of an infection. 相似文献927.
The Bahamian archipelago consists of approximately 2,400 islands occurring in the Atlantic Ocean off the coasts of Florida, Cuba, and Hispaniola. In 1982 Donovan Correll and Helen Correll published the most current synopsis of the floristic diversity of this island chain. Their publication cited a total of 1,371 vascular plant species of which 114 seed plants were listed as endemic to the archipelago (~8 % of the native flora). In the last 30 years, additional herbarium collections and taxonomic studies have shown that a number of species previously indicated to be endemic to these islands also occur in other regions or have been taxonomically merged into other species. The current number of species considered endemic to the Bahamian archipelago is 89 (~6 % of the total flora). There are 50 endemic species that have a known distribution on one (31 species) or two island groupings (19 species). Biogeographical analyses of endemic plant distributions shows three distinct clusters of species: southern, central, and the northern islands, with a fourth cluster that includes islands with a small area and one medium size island that seems that has been underexplored (i.e., Little Inagua). We anticipate that understanding the conservation status of endemic species and their distributions will help to develop legislation to preserve this Bahamian natural heritage. 相似文献
928.
Eric Carey Lynn Gape B. Naqqi Manco Dion Hepburn Ross L. Smith Lindy Knowles David Knowles Mark Daniels Michael A. Vincent Ethan Freid Brett Jestrow M. Patrick Griffith Michael Calonje Alan W. Meerow Dennis W. Stevenson Javier Francisco-Ortega 《The Botanical review》2014,80(3):265-282
The Bahamian archipelago has a rich flora with 89 endemic species. An international symposium held at Nassau in October 2012 to celebrate the 30th anniversary of the publication of the “Flora of the Bahama Archipelago” provided a forum to discuss plant conservation issues on these islands. This article builds on conclusions from this symposium and results from joint plant conservation research projects among the authors. The two main conservation challenges for these islands are: (1) environmental uncertainties derived from global warming and associated sea level changes and (2) the need for increased plant conservation awareness among the predominant urban population of the archipelago. Legal tools and biodiversity international agreements in place for The Commonwealth of the Bahamas can facilitate mechanisms for effective plant conservation. Further legal developments need to be established in The United Kingdom Overseas Territory of The Turks and Caicos Islands. There is an urgent need to redevelop the Botanic Garden of Nassau and designate it as the national botanic garden of The Bahamas. Further research related to the taxonomy, biology, conservation status, and distribution of the endemic species is urgently needed. Research initiatives pertinent to the detrimental effect and biology of invasive species are also lacking. The heterogeneous environments and uneven distribution of human populations across the archipelago are major challenges for conservation. Finally because of the political and economic status of The Bahamas and The Turks and Caicos, conservation agencies from the archipelago do not have easy access to international or British/European Union funds for global conservation initiatives. 相似文献
929.
Benjamin L. de Bivort Ethan O. Perlstein Sam Kunes Stuart L. Schreiber 《Journal of molecular evolution》2009,68(5):490-497
The metabolic cycle of Saccharomyces cerevisiae consists of alternating oxidative (respiration) and reductive (glycolysis) energy-yielding reactions. The intracellular concentrations
of amino acid precursors generated by these reactions oscillate accordingly, attaining maximal concentration during the middle
of their respective yeast metabolic cycle phases. Typically, the amino acids themselves are most abundant at the end of their
precursor’s phase. We show that this metabolic cycling has likely biased the amino acid composition of proteins across the
S. cerevisiae genome. In particular, we observed that the metabolic source of amino acids is the single most important source of variation
in the amino acid compositions of functionally related proteins and that this signal appears only in (facultative) organisms
using both oxidative and reductive metabolism. Periodically expressed proteins are enriched for amino acids generated in the
preceding phase of the metabolic cycle. Proteins expressed during the oxidative phase contain more glycolysis-derived amino
acids, whereas proteins expressed during the reductive phase contain more respiration-derived amino acids. Rare amino acids
(e.g., tryptophan) are greatly overrepresented or underrepresented, relative to the proteomic average, in periodically expressed
proteins, whereas common amino acids vary by a few percent. Genome-wide, we infer that 20,000 to 60,000 residues have been
modified by this previously unappreciated pressure. This trend is strongest in ancient proteins, suggesting that oscillating
endogenous amino acid availability exerted genome-wide selective pressure on protein sequences across evolutionary time.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Benjamin L. de Bivort and Ethan O. Perlstein have contributed equally to this work. 相似文献
930.
In an alternate reading frame overlapping the viral envelope gene, HIV-1 has been shown to encoded a truncated glutathione peroxidase (GPx) module. Essential active site residues of the catalytic core regions of mammalian GPx sequences are conserved in the putative viral GPx (vGPx, encoded by the env-fs gene). Cells transfected with an HIV-1 env-fs construct show up to a 100% increase in GPx enzyme activity, and are protected against the loss of mitochondrial transmembrane potential and subsequent cell death induced by exogenous oxidants or mitochondrial reactive oxygen species. An intact vGPx gene was observed to be more common in HIV-1-infected long-term non-progressors, as compared to HIV-1 isolates from patients developing AIDS. An antioxidant/antiapoptotic protective role of the vGPx is also consistent with the observation that -1 frameshifting induced by the HIV-1 env-fs sequence AAAAAGA (which contains a potential "hungry" arginine codon, AGA) increases during arginine deficiency, which has been associated with increased oxidative stress. Under arginine-limited conditions, nitric oxide synthase generates superoxide, which rapidly combines with NO to form peroxynitrite, which can cause activated T-cells to undergo apoptosis. Thus, biosynthesis of the HIV-1 GPx as an adaptive response to low arginine conditions might delay oxidant-induced apoptotic cell death, providing an enhanced opportunity for viral replication. 相似文献