Astrobites as a Community-led Model for Education, Science Communication, and Accessibility in Astrophysics

Support for early career astronomers who are just beginning to explore astronomy research is imperative to increase retention of diverse practitioners in the field. Since 2010, Astrobites has played an instrumental role in engaging members of the community -- particularly undergraduate and graduate students -- in research. In this white paper, the Astrobites collaboration outlines our multi-faceted online education platform that both eases the transition into astronomy research and promotes inclusive professional development opportunities. We additionally offer recommendations for how the astronomy community can reduce barriers to entry to astronomy research in the coming decade

Widespread Transcriptional Autosomal Dosage Compensation in Drosophila Correlates with Gene Expression Level

Little is known about dosage compensation in autosomal genes. Transcription-level compensation of deletions and other loss-of-function mutations may be a mechanism of dominance of wild-type alleles, a ubiquitous phenomenon whose nature has been a subject of a long debate. We measured gene expression in two isogenic Drosophila lines heterozygous for long deletions and compared our results with previously published gene expression data in a line heterozygous for a long duplication. We find that a majority of genes are at least partially compensated at transcription, both for ½-fold dosage (in heterozygotes for deletions) and for 1.5-fold dosage (in heterozygotes for a duplication). The degree of compensation does not vary among functional classes of genes. Compensation for deletions is stronger for highly expressed genes. In contrast, the degree of compensation for duplications is stronger for weakly expressed genes. Thus, partial transcriptional compensation appears to be based on regulatory mechanisms that insure high transcription levels of some genes and low transcription levels of other genes, instead of precise maintenance of a particular homeostatic expression level. Given the ubiquity of transcriptional compensation, dominance of wild-type alleles may be at least partially caused by of the regulation at transcription level

Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer

The aim of this study was to ascertain if oestrogen receptor ( ER) status predicts for pathological complete response (pCR) to neoadjuvant chemotherapy in operable breast cancer, and the effects of pCR on survival. Using a single-institution database, 435 patients were identified, who received neoadjuvant chemotherapy for operable breast cancer and were eligible for the analysis. Patients whose tumours were ER negative were more likely to achieve a pCR than patients who were ER positive (21.6 vs 8.1%,

Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma

Patients who have no residual invasive cancer following neoadjuvant chemotherapy for breast carcinoma have a better overall survival than those with residual disease. Many classification systems assessing pathological response to neoadjuvant chemotherapy include residual ductal carcinoma in situ (DCIS) only in the definition of pathological complete response. The purpose of this study was to investigate whether patients with residual DCIS only have the same prognosis as those with no residual invasive or in situ disease. A retrospective analysis of a prospectively maintained database identified 435 patients, who received neoadjuvant chemotherapy for operable breast cancer between February 1985 and February 2003. Of these, 30 (7%; 95% CI 5–9%) had no residual invasive disease or DCIS and 20 (5%; CI 3–7%) had residual DCIS only. With a median follow-up of 61 months, there was no statistical difference in disease-free survival, 80% (95% CI 60–90%) in those with no residual invasive or in situ disease and 61% (95% CI 35–80%) in those with DCIS only (P=0.4). No significant difference in 5-year overall survival was observed, 93% (95% CI 75–98%) in those with no residual invasive or in situ disease and 82% (95% CI 52–94%) in those with DCIS only (P=0.3). Due to the small number of patients and limited number of events in each group, it is not possible to draw definitive conclusions from this study. Further analyses of other databases are required to confirm our finding of no difference in disease-free and overall survival between patients with residual DCIS and those with no invasive or in situ disease following neoadjuvant chemotherapy for breast cancer

Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey: measurements of the growth of structure and expansion rate at z=0.57 from anisotropic clustering

We analyze the anisotropic clustering of massive galaxies from the Sloan Digital Sky Survey III Baryon Oscillation Spectroscopic Survey (BOSS) Data Release 9 (DR9) sample, which consists of 264,283 galaxies in the redshift range 0.43 < z < 0.7 spanning 3,275 square degrees. Both peculiar velocities and errors in the assumed redshift-distance relation ("Alcock-Paczynski effect") generate correlations between clustering amplitude and orientation with respect to the line-of-sight. Together with the sharp baryon acoustic oscillation (BAO) standard ruler, our measurements of the broadband shape of the monopole and quadrupole correlation functions simultaneously constrain the comoving angular diameter distance (2190 +/- 61 Mpc) to z=0.57, the Hubble expansion rate at z=0.57 (92.4 +/- 4.5 km/s/Mpc), and the growth rate of structure at that same redshift (d sigma8/d ln a = 0.43 +/- 0.069). Our analysis provides the best current direct determination of both DA and H in galaxy clustering data using this technique. If we further assume a LCDM expansion history, our growth constraint tightens to d sigma8/d ln a = 0.415 +/- 0.034. In combination with the cosmic microwave background, our measurements of DA, H, and growth all separately require dark energy at z > 0.57, and when combined imply \Omega_{\Lambda} = 0.74 +/- 0.016, independent of the Universe's evolution at z<0.57. In our companion paper (Samushia et al. prep), we explore further cosmological implications of these observations.Comment: 19 pages, 11 figures, submitted to MNRAS, comments welcom

Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria

Discussions and Reviews : Toward an ethology of human conflict: a review

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67149/2/10.1177_002200276701100310.pd

Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress