Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design.

The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads

Response of terrestrial net primary productivity (NPPT) in the Wujiang catchment (China) to the construction of cascade hydropower stations

The damming of rivers results in hydrological modifications that not only affect the aquatic ecosystem but also adjoining terrestrial systems. Thirteen dams commissioned along the Wujiang River have induced ecological problems, including decreased water turbidity and loss of biodiversity, which potentially influence ecosystem net primary production (NPP) and hence the sequestration, transformation, and storage of carbon. We used terrestrial NPP (NPPT) as a bioindicator to assess the impact of dams on carbon storage in the Wujiang catchment. MODIS satellite and meteorological data were used as inputs to the CASA model to calculate annual NPPT from 2000 to 2014. NPPT was calculated at the catchment and landscape scale to quantify the impact of dams on surrounding terrestrial ecosystems. Mean NPPT was calculated for concentric buffer zones covering a range of spatial extents (0–10 km) from the reservoir shoreline. We found a negligible impact from construction of a single dam on NPPT at the catchment scale. By contrast, the impact of dam construction was scale-dependent, with a stronger landscape-scale effect observed at short distances (i.e., 0–1 km) from the reservoir. Decreases in NPPT were mainly ascribed to the loss of vegetated land resulting from dam impoundment and subsequent urbanization of the surrounding area

Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and β-interferon production during pseudomonas aeruginosa infection

Bacterial infection can trigger autophagy and inflammasome activation, but the effects of inflammasome activation on autophagy are unknown. We examined this in the context of Pseudomonas aeruginosa macrophage infection, which triggers NLRC4 inflammasome activation. P. aeruginosa induced autophagy via TLR4 and its adaptor TRIF. NLRC4 and caspase-1 activation following infection attenuated autophagy. Caspase-1 directly cleaved TRIF to diminish TRIF-mediated signaling, resulting in inhibition of autophagy and in reduced type I interferon production. Expression of a caspase-1 resistant TRIF mutant enhanced autophagy and type I interferon production following infection. Preventing TRIF cleavage by caspase-1 in an in vivo model of P. aeruginosa infection resulted in enhanced bacterial autophagy, attenuated IL-1β production, and increased bacterial clearance. Additionally, TRIF cleavage by caspase-1 diminished NLRP3 inflammasome activation. Thus, caspase-1 mediated TRIF cleavage is a key event in controlling autophagy, type I interferon production, and inflammasome activation with important functional consequences

Keck/Palomar Cosmic Web Imagers (KCWI/PCWI) Reveal an Enormous Lyα\alpha Nebula in an Extremely Overdense QSO Pair Field at z=2.45z=2.45

Enormous Ly$\alpha$ nebulae (ELANe) represent the extrema of Ly$\alpha$ nebulosities. They have detected extents of $>200$ kpc in Ly$\alpha$ and Ly$\alpha$ luminosities $>10^{44}$ erg s$^{-1}$. The ELAN population is an ideal laboratory to study the interactions between galaxies and the intergalactic/circumgalactic medium (IGM/CGM) given their brightness and sizes. The current sample size of ELANe is still very small, and the few $z\approx2$ ELANe discovered to date are all associated with local overdensities of active galactic nuclei (AGNs). Inspired by these results, we have initiated a survey of ELANe associated with QSO pairs using the Palomar and Keck Cosmic Web Imagers (PCWI/KCWI). In this letter, we present our first result: the discovery of ELAN0101+0201 associated with a QSO pair at $z=2.45$. Our PCWI discovery data shows that, above a 2-$\sigma$ surface brightness of $1.2\times10^{-17}$ \sbunit, the end-to-end size of ELAN0101+0201 is $\gtrsim 232$ kpc. We have conducted follow-up observations using KCWI, resolving multiple Ly$\alpha$ emitting sources within the rectangular field-of-view of $\approx 130\times165$ projected kpc$^2$, and obtaining their emission line profiles at high signal-to-noise ratios. Combining both KCWI and PCWI, our observations confirm that ELAN0101+0201 resides in an extremely overdense environment. Our observations further support that a large amount of cool ($T\sim10^4$K) gas could exist in massive halos (M$\gtrsim10^{13}$M$_\odot$) at $z\approx2$. Future observations on a larger sample of similar systems will provide statistics of how cool gas is distributed in massive overdensities at high-redshift and strongly constrain the evolution of the intracluster medium (ICM).Comment: Submitted to Astrophysical Journal Letter, 9 pages, 4 figures, Comments Welcom

Acceptance and commitment therapy for symptom interference in metastatic breast cancer patients: a pilot randomized trial

PURPOSE: Breast cancer is the leading cause of cancer mortality in women worldwide. With medical advances, metastatic breast cancer (MBC) patients often live for years with many symptoms that interfere with activities. However, there is a paucity of efficacious interventions to address symptom-related suffering and functional interference. Thus, this study examined the feasibility and preliminary efficacy of telephone-based acceptance and commitment therapy (ACT) for symptom interference with functioning in MBC patients. METHODS: Symptomatic MBC patients (N = 47) were randomly assigned to six telephone sessions of ACT or six telephone sessions of education/support. Patients completed measures of symptom interference and measures assessing the severity of pain, fatigue, sleep disturbance, depressive symptoms, and anxiety. RESULTS: The eligibility screening rate (64%) and high retention (83% at 8 weeks post-baseline) demonstrated feasibility. When examining within-group change, ACT participants showed decreases in symptom interference (i.e., fatigue interference and sleep-related impairment; Cohen's d range = - 0.23 to - 0.31) at 8 and 12 weeks post-baseline, whereas education/support participants showed minimal change in these outcomes (d range = - 0.03 to 0.07). Additionally, at 12 weeks post-baseline, ACT participants showed moderate decreases in fatigue and sleep disturbance (both ds = - 0.43), whereas education/support participants showed small decreases in these outcomes (ds = - 0.24 and - 0.18 for fatigue and sleep disturbance, respectively). Both the ACT and education/support groups showed reductions in depressive symptoms (ds = - 0.27 and - 0.28) at 12 weeks post-baseline. Group differences in all outcomes were not statistically significant. CONCLUSIONS: ACT shows feasibility and promise in improving fatigue and sleep-related outcomes in MBC patients and warrants further investigation

Three Different Types of Galaxy Alignment within Dark Matter Halos

Using a large galaxy group catalogue based on the Sloan Digital Sky Survey Data Release 4 we measure three different types of intrinsic galaxy alignment within groups: halo alignment between the orientation of the brightest group galaxies (BGG) and the distribution of its satellite galaxies, radial alignment between the orientation of a satellite galaxy and the direction towards its BGG, and direct alignment between the orientation of the BGG and that of its satellites. In agreement with previous studies we find that satellite galaxies are preferentially located along the major axis. In addition, on scales r < 0.7 Rvir we find that red satellites are preferentially aligned radially with the direction to the BGG. The orientations of blue satellites, however, are perfectly consistent with being isotropic. Finally, on scales r < 0.1 \Rvir, we find a weak but significant indication for direct alignment between satellites and BGGs. We briefly discuss the implications for weak lensing measurements.Comment: 4 pages, 4 figures, ApJL accepte

Two hundred years of land-use change in the South Swedish Uplands : comparison of historical map-based estimates with a pollen-based reconstruction using the landscape reconstruction algorithm

International audienceLong-term records of environmental history at decadal to millennial timescales enable an assessment of ecosystem variability and responses to past anthropogenic disturbances and are fundamental for the development of environmental management strategies. This study examines the local variability of land-use history in the South Swedish Uplands over the last 200 years based on pollen records from three lake-sediment successions. Temporal changes in the proportional cover of 14 plant taxa were quantified as percentages using the landscape reconstruction algorithm (LRA). The LRA-based estimates of the extent of four land-use categories (cropland, meadows/grassland, wetland, outland/woodland) were compared to corresponding estimates based on historical maps and aerial photographs from AD 1769–1823, 1837–1895, 1946 and 2005. Although the LRA approach tends to overestimate grassland cover by 10–30 % for the two earliest time periods, the reconstructed vegetation composition is generally in good agreement with estimates based on the historical records. Subsequently, the LRA approach was used to reconstruct the 200-year history of local land-use dynamics at 20-year intervals around two small lakes. The qualitative assessment of difference approach , which requires fewer assumptions and parameters than LRA for objective evaluation of between-site differences in plant abundances, provides consistent results in general. Significant differences exist in the land-use history between the sites. Local catchment characteristics, such as soil conditions and wetland cover, appear important for the development of human impact on the landscape. Quantifi-cations of past vegetation dynamics provide information on the amplitude, frequency and duration of the land-use changes and their effects on terrestrial and aquatic ecosystems , and should be taken into account when nature conservation strategies are developed