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51.
Ingo V. Hartung Marion Hitchcock Florian Pühler Roland Neuhaus Arne Scholz Stefanie Hammer Kirstin Petersen Gerhard Siemeister Dominic Brittain Roman C. Hillig 《Bioorganic & medicinal chemistry letters》2013,23(8):2384-2390
Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed—despite being orally bioavailable and not a P-glycoprotein substrate—much lower brain/plasma exposure ratios than PD325901. 相似文献
52.
Markus Ernstberger Pascal Boeswetter Tobias Baselt Frank Ebert Fabiola Basan Hanno Steinke Niels Hammer Ronny Grunert Peter Hartmann 《Journal of biophotonics》2013,6(4):310-313
Thin slices of human tissues are characterized concerning reflection and transmission in a wavelength range from 400 to 1700 nm. The results are primarily useful to find a wavelength for the detection of subjacent blood vessels during surgical procedures, especially neurological surgery. The measurements have been conducted using a customized measuring station, utilizing two halogen bulb lamps and two spectrometers. This paper focuses on creating a data base with the optical properties of artery, brain, bone, nasal mucosa, and nerve. The spectral distributions are compared among each other, similarities and differences are pointed out. Each tissue has got unique spectral characteristics, whereas typical absorption bands can be found in the overall tissues, especially hemoglobin and water absorption bands. The reflectivity maxima are typically located in the red or near‐infrared. All the transmission maxima are located between 1075 nm and 1100 nm. The measurements have been conducted at the Institute of Anatomy at the University of Leipzig. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) 相似文献
53.
Geoffrey Guest Francesco Cherubini Anders Hammer Strømman 《Global Change Biology Bioenergy》2013,5(4):459-466
Bioenergy makes up a significant portion of the global primary energy pie, and its production from modernized technology is foreseen to substantially increase. The climate neutrality of biogenic CO2 emissions from bioenergy grown from sustainably managed biomass resource pools has recently been questioned. The temporary change caused in atmospheric CO2 concentration from biogenic carbon fluxes was found to be largely dependent on the length of biomass rotation period. In this work, we also show the importance of accounting for the unutilized biomass that is left to decompose in the resource pool and how the characterization factor for the climate impact of biogenic CO2 emissions changes whether residues are removed for bioenergy or not. With the case of Norwegian Spruce biomass grown in Norway, we found that significantly more biogenic CO2 emissions should be accounted towards contributing to global warming potential when residues are left in the forest. For a 100‐year time horizon, the global warming potential bio factors suggest that between 44 and 62% of carbon‐flux, neutral biogenic CO2 emissions at the energy conversion plant should be attributed to causing equivalent climate change potential as fossil‐based CO2 emissions. For a given forest residue extraction scenario, the same factor should be applied to the combustion of any combination of stem and forest residues. Life cycle analysis practitioners should take these impacts into account and similar region/species specific factors should be developed. 相似文献
54.
Catherine R. M. Attard Chris J. Brauer Jacob D. Van Zoelen Minami Sasaki Michael P. Hammer Leslie Morrison James O. Harris Luciana M. Möller Luciano B. Beheregaray 《Conservation Genetics》2016,17(6):1469-1473
Maintaining genetic diversity within captive breeding populations is a key challenge for conservation managers. We applied a multi-generational genetic approach to the captive breeding program of an endangered Australian freshwater fish, the southern pygmy perch (Nannoperca australis). During previous work, fish from the lower Murray-Darling Basin were rescued before drought exacerbated by irrigation resulted in local extinction. This endemic lineage of the species was captive-bred in genetically designed groups, and equal numbers of F1 individuals were reintroduced to the wild with the return of favourable habitat. Here, we implemented a contingency plan by continuing the genetic-based captive breeding in the event that a self-sustaining wild population was not established. F1 individuals were available as putative breeders from the subset of groups that produced an excess of fish in the original restoration program. We used microsatellite-based parentage analyses of these F1 fish to form breeding groups that minimized inbreeding. We assessed their subsequent parental contribution to F2 individuals and the maintenance of genetic diversity. We found skewed parental contribution to F2 individuals, yet minimal loss of genetic diversity from their parents. However, the diversity was substantially less than that of the original rescued population. We attribute this to the unavoidable use of F1 individuals from a limited number of the original breeding groups. Alternative genetic sources for supplementation or reintroduction should be assessed to determine their suitability. The genetic fate of the captive-bred population highlights the strong need to integrate DNA-based tools for monitoring and adaptive management of captive breeding programs. 相似文献
55.
Theresa L. Cole Michael P. Hammer Peter J. Unmack Peter R. Teske Chris J. Brauer Mark Adams Luciano B. Beheregaray 《Conservation Genetics》2016,17(6):1377-1391
Distinguishing the relative influence of historic (i.e. natural) versus anthropogenic factors in metapopulation structure is an important but often overlooked step in management programs of threatened species. Biotas in freshwater wetlands and floodplains, such as those in the Murray–Darling Basin (MDB)—one of Australia’s most impacted ecosystems, are particularly susceptible to anthropogenic fragmentation. Here we present a comprehensive multilocus assessment of genetic variation in the threatened southern pygmy perch Nannoperca australis (578 individuals; 45 localities; microsatellite, allozyme and mitochondrial DNA datasets), an ecological specialist with low dispersal potential. We assess patterns of spatial structure and genetic diversity in populations spanning the highly fragmented MDB and test whether recent anthropogenic modification has disrupted range-wide connectivity. We detected strong and hierarchical population structure, very low genetic diversity and lack of contemporary gene flow across the MDB. In contrast, the apparent absence of pronounced or long-term phylogeographic structure suggests that observed population divergences generally do not reflect deeply historic natural fragmentation. Coalescent-based analyses supported this inference, revealing that divergence times between populations from the upper and lower MDB fall into the period of European settlement. It appears that the observed contemporary isolation of populations is partly explained by the severe modification of the MDB post-dating the onset of European settlement. Our integrated approach substantially improves the interpretation of how fragmentation impacts present-day biodiversity. It also provides novel contributions for risk-assessing management actions in the context of captive breeding and translocations of small freshwater fishes, a group of increasing global conservation concern. 相似文献
56.
Stefan Schleifenbaum Torsten Prietzel Gabriela Aust Andreas Boldt Sebastian Fritsch Isabel Keil Holger Koch Robert M?bius Holger A. Scheidt Martin F. X. Wagner Niels Hammer 《PloS one》2016,11(3)
Introduction
Though xenogeneic acellular scaffolds are frequently used for surgical reconstruction, knowledge of their mechanical properties is lacking. This study compared the mechanical, histological and ultrastructural properties of various native and acellular specimens.Materials and Methods
Porcine esophagi, ureters and skin were tested mechanically in a native or acellular condition, focusing on the elastic modulus, ultimate tensile stress and maximum strain. The testing protocol for soft tissues was standardized, including the adaption of the tissue’s water content and partial plastination to minimize material slippage as well as templates for normed sample dimensions and precise cross-section measurements. The native and acellular tissues were compared at the microscopic and ultrastructural level with a focus on type I collagens.Results
Increased elastic modulus and ultimate tensile stress values were quantified in acellular esophagi and ureters compared to the native condition. In contrast, these values were strongly decreased in the skin after acellularization. Acellularization-related decreases in maximum strain were found in all tissues. Type I collagens were well-preserved in these samples; however, clotting and a loss of cross-linking type I collagens was observed ultrastructurally. Elastins and fibronectins were preserved in the esophagi and ureters. A loss of the epidermal layer and decreased fibronectin content was present in the skin.Discussion
Acellularization induces changes in the tensile properties of soft tissues. Some of these changes appear to be organ specific. Loss of cross-linking type I collagen may indicate increased mechanical strength due to decreasing transverse forces acting upon the scaffolds, whereas fibronectin loss may be related to decreased load-bearing capacity. Potentially, the alterations in tissue mechanics are linked to organ function and to the interplay of cells and the extracellular matrix, which is different in hollow organs when compared to skin. 相似文献57.
Glenda E. Gray Fatima Laher Tanya Doherty Salim Abdool Karim Scott Hammer John Mascola Chris Beyrer Larry Corey 《PLoS biology》2016,14(3)
In the last 15 years, antiretroviral therapy (ART) has been the most globally impactful life-saving development of medical research. Antiretrovirals (ARVs) are used with great success for both the treatment and prevention of HIV infection. Despite these remarkable advances, this epidemic grows relentlessly worldwide. Over 2.1 million new infections occur each year, two-thirds in women and 240,000 in children. The widespread elimination of HIV will require the development of new, more potent prevention tools. Such efforts are imperative on a global scale. However, it must also be recognised that true containment of the epidemic requires the development and widespread implementation of a scientific advancement that has eluded us to date—a highly effective vaccine. Striving for such medical advances is what is required to achieve the end of AIDS.In the last 15 years, antiretroviral therapy (ART) has been the most globally impactful life-saving development of medical research. Antiretrovirals (ARVs) are used with great success for both the treatment and prevention of HIV infection. In the United States, the widespread implementation of combination ARVs led to the virtual eradication of mother-to-child transmission of HIV from 1,650 cases in 1991 to 110 cases in 2011, and a turnaround in AIDS deaths from an almost 100% five-year mortality rate to a five-year survival rate of 91% in HIV-infected adults [1]. Currently, the estimated average lifespan of an HIV-infected adult in the developed world is well over 40 years post-diagnosis. Survival rates in the developing world, although lower, are improving: in sub-Saharan Africa, AIDS deaths fell by 39% between 2005 and 2013, and the biggest decline, 51%, was seen in South Africa [2].Furthermore, the association between ART, viremia, and transmission has led to the concept of “test and treat,” with the hope of reducing community viral load by testing early and initiating treatment as soon as a diagnosis of HIV is made [3]. Indeed, selected regions of the world have begun to actualize the public health value of ARVs, from gains in life expectancy to impact on onward transmission, with a potential 1% decline in new infections for every 10% increase in treatment coverage [2]. In September 2015, WHO released new guidelines removing all limitations on eligibility for ART among people living with HIV and recommending pre-exposure prophylaxis (PrEP) to population groups at significant HIV risk, paving the way for a global onslaught on HIV [4].Despite these remarkable advances, this epidemic grows relentlessly worldwide. Over 2.1 million new infections occur each year, two-thirds in women and 240,000 in children [2]. In heavily affected countries, HIV infection rates have only stabilized at best: the annualized acquisition rates in persons in their first decade of sexual activity average 3%–5% yearly in southern Africa [5–7]. These figures are hardly compatible with the international health community’s stated goal of an “AIDS-free generation” [8,9]. In highly resourced settings, microepidemics of HIV still occur, particularly among gays, bisexuals, and men who have sex with men (MSM) [10]. HIV epidemics are expanding in two geographic regions in 2015—the Middle East/North Africa and Eastern Europe/Central Asia—largely due to challenges in implementing evidence-based HIV policies and programmes [2]. Even for the past decade in the US, almost 50,000 new cases recorded annually, two-thirds among MSM, has been a stable figure for years and shows no evidence of declining [1].While treatment scale-up, medical male circumcision [11], and the implementation of strategies to prevent mother-to-child transmission [12] have received global traction, systemic or topical ARV-based biomedical advances to prevent sexual acquisition of HIV have, as yet, made limited impressions on a population basis, despite their reported efficacy. Factors such as their adherence requirements, cost, potential for drug resistance, and long-term feasibility have restricted the appetite for implementation, even though these approaches may reduce HIV incidence in select populations.Already, several trials have shown that daily oral administration of the ARV tenofovir disoproxil fumarate (TDF), taken singly or in combination with emtricitabine, as PrEP by HIV-uninfected individuals, reduces HIV acquisition among serodiscordant couples (where one partner is HIV-positive and the other is HIV-negative) [13], MSM [14], at-risk men and women [15], and people who inject drugs [16,17] by between 44% and 75%. Long-acting injectable antiretroviral agents such as rilpivirine and cabotegravir, administered every two and three months, respectively, are also being developed for PrEP. All of these PrEP approaches are dependent on repeated HIV testing and adherence to drug regimens, which may challenge effectiveness in some populations and contexts.The widespread elimination of HIV will require the development of new, more potent prevention tools. Because HIV acquisition occurs subclinically, the elimination of HIV on a population basis will require a highly effective vaccine. Alternatively, if vaccine development is delayed, supplementary strategies may include long-acting pre-exposure antiretroviral cocktails and/or the administration of neutralizing antibodies through long-lasting parenteral preparations or the development of a “genetic immunization” delivery system, as well as scaling up delivery of highly effective regimens to eliminate mother-to-child HIV transmission (Fig 1).Open in a separate windowFig 1Medical interventions required to end the epidemic of HIV.Image credit: Glenda Gray. 相似文献
58.
A review of studies on the X-pinch as a radiation source for X-ray projection shadow radiography (XPSR) and X-ray absorption spectroscopy (XAS) is presented. The ultimate capabilities of the techniques and ways of their achievement are considered. XPSR has been successfully used to study high-energy-density plasma objects, in particular, exploding wires and wire arrays. Using XPSR, the internal structure and dynamics of a wire explosion and wire array implosion have been investigated for the first time, which has made it possible to develop an adequate consistent theory of the processes occurring in the wire loads of generators with currents from several units of kiloamperes to a few tens of megamperes. The use of XAS for diagnostics of wire loads has allowed one for the first time to measure the parameters of matter in the wire core and plasma corona of the load. X-ray images of various biological objects have obtained, including those with the use of the phase contrast method. This review is a logical continuation of the review “Х-Pinch” [Plasma Phys. Rep. 41, 319, 493 (2015)], in which the Х-pinch as a physical object was considered. 相似文献
59.
Kyle T. Whiddon Ravindra Gudneppanavar Theodore J. Hammer Destiny A. West Michael C. Konopka 《Microbial biotechnology》2019,12(5):1024-1033
Most methanotrophic bacteria maintain intracytoplasmic membranes which house the methane-oxidizing enzyme, particulate methane monooxygenase. Previous studies have primarily used transmission electron microscopy or cryo-electron microscopy to look at the structure of these membranes or lipid extraction methods to determine the per cent of cell dry weight composed of lipids. We show an alternative approach using lipophilic membrane probes and other fluorescent dyes to assess the extent of intracytoplasmic membrane formation in living cells. This fluorescence method is sensitive enough to show not only the characteristic shift in intracytoplasmic membrane formation that is present when methanotrophs are grown with or without copper, but also differences in intracytoplasmic membrane levels at intermediate copper concentrations. This technique can also be employed to monitor dynamic intracytoplasmic membrane changes in the same cell in real time under changing growth conditions. We anticipate that this approach will be of use to researchers wishing to visualize intracytoplasmic membranes who may not have access to electron microscopes. It will also have the capability to relate membrane changes in individual living cells to other measurements by fluorescence labelling or other single-cell analysis methods. 相似文献
60.