Chromosome-Level Genome Assembly of Chinese Sucker (Myxocyprinus asiaticus) Reveals Strongly Conserved Synteny Following a Catostomid-Specific Whole-Genome Duplication

publishedVersio

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Theoretical and experimental research on designer surface plasmons in a metamaterial with double sets of circular holes

The designer surface plasmons (DSPs) are studied by the use of a kind of metamaterial with a structure of double sets of circular holes: subwavelength apertures, and indentations. The diameter and spacing of the indentations are smaller at least one order of magnitude than those of the apertures. A theoretical model is built to analyze the DSPs sustained by the indentations by using effective dipoles method. The influence of the DSPs on the transmission property is revealed for electromagnetic waves passing through the apertures. In order to verify the theoretical predication, a set of the metamaterial samples is made and the transmission spectra are measured in microwave regime. Our results provide a new proof for the existence of DSPs and are promising for proposing some techniques for optoelectronic devices in terahertz and microwave regime

Adequacy of CPF health schemes.

Our project studies the impact of CPF by comparing projected Medisave savings of various income groups with projected healthcare costs. Different combinations of CPF health schemes are also taken into consideration In addition, we also aim to investigate which variables the various health CPF schemes are most sensitive to

Spatial Distribution of Groundwater Level Changes Induced by the 2006 Hengchun Earthquake Doublet

Water-level changes were ob served in 107 wells at 67 monitoring stations in the southern coastal plain of Tai wan during the 2006 Mw 7.1 Hengchun earthquake doublet. Two consecutive coseismic changes induced by the earth quake doublet can be observed from high-frequency data. Obervations from multiple-well stations indicate that the magnitude and direction of coseismic change may vary in wells of different depths. Coseismic rises were dominant on the south east side of the costal plain; whereas, coseismic falls prevailed on the north west side. In the transition zone, rises appeared in shallow wells whilst falls were evident in deep wells. As coseismic ground water level changes can reflect the tectonic strain field, tectonic extension likely dominates the deep subsurface in the transition area, and possibly in the en tire southern coastal plain. The coseismic rises in water level showed a tendency to de crease with distance from the hypocenter, but no clear trend was found for the coseismic falls

Chromosome-Level Genome Assembly of Chinese Sucker (Myxocyprinus asiaticus) Reveals Strongly Conserved Synteny Following a Catostomid-Specific Whole-Genome Duplication

publishedVersio

Yeast PI31 inhibits the proteasome by a direct multisite mechanism

Proteasome inhibitors are widely used as therapeutics and research tools, and typically target one of the three active sites, each present twice in the proteasome complex. An endogeneous proteasome inhibitor, PI31, was identified 30 years ago, but its inhibitory mechanism has remained unclear. Here, we identify the mechanism of Saccharomyces cerevisiae PI31, also known as Fub1. Using cryo-electron microscopy (cryo-EM), we show that the conserved carboxy-terminal domain of Fub1 is present inside the proteasome's barrel-shaped core particle (CP), where it simultaneously interacts with all six active sites. Targeted mutations of Fub1 disrupt proteasome inhibition at one active site, while leaving the other sites unaffected. Fub1 itself evades degradation through distinct mechanisms at each active site. The gate that allows substrates to access the CP is constitutively closed, and Fub1 is enriched in mutant CPs with an abnormally open gate, suggesting that Fub1 may function to neutralize aberrant proteasomes, thereby ensuring the fidelity of proteasome-mediated protein degradation

Automatic detection, localization, and volume estimation of ischemic infarcts in noncontrast computed tomographic scans : method and preliminary results

Sensitivity of noncontrast computed tomography (NCCT) in detecting hyperacute ( 8 hours), whereas the expert detection accuracy for these cases is 100\%. Moreover, the method detected all 21 early infarcts, of which 15 were missed by the stroke experts and 14 of 15 were missed by a general radiologist. The method performs automatic analysis in approximately 7 seconds.The results demonstrate potential benefits of our method for enhancing expert's performance because it quickly localizes the infarct and detects cases missed by experts, and it is to be considered as an aid in the emergency department because it substantially outperforms novice readers (100\% vs 27\%) in infarct detection on NCCT