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| 2. |
- Miethke, Marcus, et al.
(författare)
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Towards the sustainable discovery and development of new antibiotics
- 2021
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Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 5:10, s. 726-749
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Forskningsöversikt (refereegranskat)abstract
- An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
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| 3. |
- Barreca, Maria Letizia, et al.
(författare)
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Structure-Based Discovery of Pyrazolobenzothiazine Derivatives As Inhibitors of Hepatitis C Virus Replication
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:6, s. 2270-2282
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Tidskriftsartikel (refereegranskat)abstract
- The NS5B RNA-dependent RNA polymerase is an attractive target for the development of novel and selective inhibitors of hepatitis C virus replication. To identify novel structural hits as anti-HCV agents, we performed structure based virtual screening of our in-house library followed by rational drug design, organic synthesis, and biological testing. These studies led to the identification of pyrazolobenzothiazine scaffold as a suitable template for obtaining novel anti-HCV agents targeting the NS5B polymerase. The best compound of this series was the meta-fluoro-N-1-phenyl pyrazolobenzothiazine derivative 4a, which exhibited an EC50 = 3.6 mu M, EC90 = 25.6 mu M, and CC50 > 180 mu M in the Huh 9-13 replicon system, thus providing a good starting point for further hit evolution.
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| 4. |
- Graco-Roza, Caio, et al.
(författare)
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Distance decay 2.0 – A global synthesis of taxonomic and functional turnover in ecological communities
- 2022
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 31:7, s. 1399-1421
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Understanding the variation in community composition and species abundances (i.e., beta-diversity) is at the heart of community ecology. A common approach to examine beta-diversity is to evaluate directional variation in community composition by measuring the decay in the similarity among pairs of communities along spatial or environmental distance. We provide the first global synthesis of taxonomic and functional distance decay along spatial and environmental distance by analysing 148 datasets comprising different types of organisms and environments.Location: Global.Time period: 1990 to present.Major taxa studied: From diatoms to mammals.Method: We measured the strength of the decay using ranked Mantel tests (Mantel r) and the rate of distance decay as the slope of an exponential fit using generalized linear models. We used null models to test whether functional similarity decays faster or slower than expected given the taxonomic decay along the spatial and environmental distance. We also unveiled the factors driving the rate of decay across the datasets, including latitude, spatial extent, realm and organismal features.Results: Taxonomic distance decay was stronger than functional distance decay along both spatial and environmental distance. Functional distance decay was random given the taxonomic distance decay. The rate of taxonomic and functional spatial distance decay was fastest in the datasets from mid-latitudes. Overall, datasets covering larger spatial extents showed a lower rate of decay along spatial distance but a higher rate of decay along environmental distance. Marine ecosystems had the slowest rate of decay along environmental distances.Main conclusions: In general, taxonomic distance decay is a useful tool for biogeographical research because it reflects dispersal-related factors in addition to species responses to climatic and environmental variables. Moreover, functional distance decay might be a cost-effective option for investigating community changes in heterogeneous environments.
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| 5. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 6. |
- Li, Shanghuo, et al.
(författare)
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The ALMA Survey of 70 μm Dark High-mass Clumps in Early Stages (ASHES). VII. Chemistry of Embedded Dense Cores
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 939:2
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Tidskriftsartikel (refereegranskat)abstract
- We present a study of the chemistry toward 294 dense cores in 12 molecular clumps, using data obtained from the ALMA Survey of 70 μm dark High-mass clumps in Early Stages. We identified 97 protostellar cores and 197 prestellar core candidates, based on the detection of outflows and molecular transitions of high upper-energy levels (E u /k > 45 K). The detection rate of the N2D+ emission toward the protostellar cores is 38%, which is higher than 9% for the prestellar cores, indicating that N2D+ does not exclusively trace prestellar cores. The detection rates of the DCO+ emission are 35% for the prestellar cores and 49% for the protostellar cores, which are higher than those for N2D+, implying that DCO+ appears more frequently than N2D+ in both prestellar and protostellar cores. Both the N2D+ and DCO+ abundances appear to decrease from the prestellar to the protostellar stage. The DCN, C2D, and 13CS emission lines are rarely seen in the dense cores of early evolutionary phases. The detection rate of the H2CO emission toward dense cores is 52%, three times higher than that for CH3OH (17%). In addition, the H2CO detection rate, abundance, line intensities, and line widths increase with the core evolutionary status, suggesting that the H2CO line emission is sensitive to protostellar activity.
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| 7. |
- Manfroni, Giuseppe, et al.
(författare)
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The Versatile Nature of the 6-Aminoquinolone Scaffold : Identification of Submicromolar Hepatitis C Virus NS5B Inhibitors
- 2014
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:5, s. 1952-1963
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported that the 6-aminoquinolone chemotype is a privileged scaffold to obtain antibacterial and antiviral agents. Herein we describe the design, synthesis, and enzymatic and cellular characterization of new 6-aminoquinolone derivatives as potent inhibitors of NS5B polymerase, an attractive and viable therapeutic target to develop safe anti-HCV agents. The 6-amino-7-[4-(2-pyridinyl)-1-piperazinyl]quinolone derivative 8 proved to be the best compound of this series, exhibiting an IC50 value of 0.069 mu M against NS5B polymerase and selective antiviral effect (EC50 = 3.03 mu M) coupled with the absence of any cytostatic effect (CC50 > 163 mu M; SI > 54) in Huh 9-13 cells carrying a HCV genotype 1b, as measured by MTS assay. These results indicate that the 6-aminoquinolone scaffold is worthy of further investigation in the context of NS5B-targeted HCV drug discovery programs.
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| 8. |
- Sabatini, Giovanni, et al.
(författare)
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The ALMA Survey of 70 μm Dark High-mass Clumps in Early Stages (ASHES). VI. The Core-scale CO Depletion
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 936:1
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Tidskriftsartikel (refereegranskat)abstract
- Studying the physical and chemical properties of cold and dense molecular clouds is crucial for the understanding of how stars form. Under the typical conditions of infrared dark clouds, CO is removed from the gas phase and trapped onto the surface of dust grains by the so-called depletion process. This suggests that the CO-depletion factor (f D ) can be a useful chemical indicator for identifying cold and dense regions (i.e., prestellar cores). We have used the 1.3 mm continuum and C18O (2-1) data observed at the resolution of ∼5000 au in the ALMA Survey of 70 μm Dark High-mass Clumps in Early Stages (ASHES) to construct averaged maps of f D in 12 clumps to characterize the earliest stages of the high-mass star formation process. The average f D determined for 277 of the 294 ASHES cores follows an unexpected increase from the prestellar to the protostellar stage. If we exclude the temperature effect due to the slight variations in the NH3 kinetic temperature among different cores, we explain this result as a dependence primarily on the average gas density, which increases in cores where protostellar conditions prevail. This shows that f D determined in high-mass star-forming regions at the core scale is insufficient to distinguish among prestellar and protostellar conditions for the individual cores and should be complemented by information provided by additional tracers. However, we confirm that the clump-averaged f D values correlate with the luminosity-to-mass ratio of each source, which is known to trace the evolution of the star formation process.
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