University of Wisconsin-Madison

About: University of Wisconsin-Madison is a education organization based out in Madison, Wisconsin, United States. It is known for research contribution in the topics: Population & Gene. The organization has 108707 authors who have published 237594 publications receiving 11883575 citations.

How Taxol/paclitaxel kills cancer cells

Abstract: Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ∼50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action.

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

Abstract: The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.

Enhancing The Reliability of Out-of-distribution Image Detection in Neural Networks

Abstract: We consider the problem of detecting out-of-distribution images in neural networks. We propose ODIN, a simple and effective method that does not require any change to a pre-trained neural network. Our method is based on the observation that using temperature scaling and adding small perturbations to the input can separate the softmax score distributions between in- and out-of-distribution images, allowing for more effective detection. We show in a series of experiments that ODIN is compatible with diverse network architectures and datasets. It consistently outperforms the baseline approach by a large margin, establishing a new state-of-the-art performance on this task. For example, ODIN reduces the false positive rate from the baseline 34.7% to 4.3% on the DenseNet (applied to CIFAR-10) when the true positive rate is 95%.

Erythromycin resistance by ribosome modification.

Abstract: Erythromycin inhibits protein synthesis by its effect on ribosome function (14, 118, 119) The metabolic modifications that enable cells to cope with the inhibitory action of erythromycin fall under major headings that include (i) target site alteration, (ii) antibiotic modification, and (iii) altered antibiotic transport This minireview concentrates on target site alteration, which for erythromycin is the 50S subunit of the ribosome The first clinical isolates of macrolide-resistant staphylococci were described in reports from France, England, Japan, and the United States shortly after the introduction of erythromycin into clinical practice in 1953 On the basis of current understanding of the biochemistry of erythromycin’s action, resistance in most of the strains that were described in early reports can be ascribed to a posttranscriptional modification of the 23S rRNA by an adenine-specific N-methyltransferase (methylase) specified by a class of genes bearing the name erm (erythromycin ribosome methylation) The last decade has seen the isolation and characterization of approximately 30 erm genes from diverse sources, ranging from clinical pathogens to actinomycetes that produce antibiotics; for many of these genes, both the respective nucleotide sequences that encode the methylases as well as the flanking sequences that control their expression have been determined A tabulation of the erm genes that have been described is presented in Table 1 Any discussion of mechanisms of resistance to macrolide antibiotics must include the chemically distinct, but functionally overlapping, lincosamide and streptogramin B families as well This type of resistance has therefore also been referred to as MLS resistance Members of the MLS antibiotic superfamily include, among the macrolides, carbomycin, clarithromycin, erythromycin, josamycin, midecamycin, mycinamicin, niddamycin, rosaramicin, roxithromycin, spiramycin, and tylosin; among the lincosamides, celesticetin, clindamycin, and lincomycin; and among the streptogramins, staphylomycin S, streptogramin B, and vernamycin B The streptogramin family is subdivided into A and B groups or alternatively into M and S groups, respectively Methylation of A2058 confers resistance to the Band S-group streptogramins but not to the Aand M-group streptogramins The reason for this grouping was originally based on empirical observations from clinical bacteriology that resistance to one class often involved resistance to the other two classes (11, 16, 35, 39, 41, 135); however, (i) the three classes of antibiotics interact competitively when binding to the 50S subunit, and only one antibiotic molecule can bind per 50S subunit (129, 130); this suggests that the binding sites for these antibiotics overlap or at least functionally interact (ii) Nucleotide alterations in 23S rRNA, both mutational and posttranscriptional, that confer coresistance to MLS antibiotics appear to cluster in the peptidyltransferase region in 23S rRNA domain V, providing a physical basis and a common location for their sites of action (50, 101–104, 109, 110, 128) (Fig 1 and Table 2), and (iii) footprinting experiments show that the nucleotides in 23S rRNA domain V are protected by bound MLS antibiotics against modification by agents such as dimethyl sulfate (DMS) and kethoxal that can derivatize purine and pyrimidine bases in single-stranded DNA or RNA (26, 76) (Table 3) The erm family of genes is not alone in conferring clinical resistance to macrolide antibiotics A notable early exception to the established MLS resistance pattern was the MS pattern reported by Janosy and coworkers (58, 59), who described clinical isolates that were coresistant to erythromycin and streptogramin B but that remained susceptible to lincosamide antibiotics The molecular basis for resistance in these strains was subsequently shown by Ross et al (94) to involve the active efflux of erythromycin and streptogramin B but not clindamycin Additional mechanisms of macrolide resistance, all associated with the acquisition of new genetic information, including structural modification of erythromycin by phosphorylation (82), glycosylation (60), and lactone ring cleavage by erythromycin esterase (2, 83), have been added to the list Mechanisms involving mutational alteration of genes that normally reside in the host and that encode either ribosomal protein or rRNA have also been described and will be discussed below in detail Reviews of erythromycin resistance that relate to material covered in the present work have been presented previously (4, 18, 20, 21, 28, 29, 133) Recent developments in the synthetic chemistry of semisynthetic macrolides, including the biological and clinical aspects of their actions, have been reviewed by Kirst (65, 66) A forthcoming review covers the inducible nature of MLS resistance and its implications for the mechanism of action of erythromycin (134)