Preparation of Novel Hydroxyethyl Amine Isosteres as Potential Cathepsin D Inhibitors

Cathepsin D is a lysosomal aspartic protease found in all mammalian cells and is considered to be one of the main catabolic proteinases. Cathepsin D has been suggested to play a role in the metastatic potential of several types of cancer. A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer, and ovarian cancer. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D inactivity, such as the HIV-1 aspartyl protease. We have undertaken the design, via computer molecular modeling, and the synthesis of (hydroxyethyl) amine isostere inhibitors, which are similar to potent inhibitors of the aspartyl HIV-1 protease. We now report the preparation of six compounds that contain novel hydroxyethyl isosteres with cyclic tertiary amines

The Molonglo Galactic Plane Survey: I. Overview and Images

The first epoch Molonglo Galactic Plane Survey (MGPS1) is a radio continuum survey made using the Molonglo Observatory Synthesis Telescope (MOST) at 843 MHz with a resolution of 43" X 43" cosec |delta|. The region surveyed is 245 deg < l < 355 deg, |b| < 1.5 deg. The thirteen 9 deg X 3 deg mosaic images presented here are the superposition of over 450 complete synthesis observations, each taking 12 h and covering 70' X 70' cosec |delta|. The root-mean-square sensitivity over much of the mosaiced survey is 1-2 mJy/beam (1 sigma), and the positional accuracy is approximately 1" X 1" cosec |delta| for sources brighter than 20 mJy. The dynamic range is no better than 250:1, and this also constrains the sensitivity in some parts of the images. The survey area of 330 sq deg contains well over 12,000 unresolved or barely resolved objects, almost all of which are extra-galactic sources lying in the Zone of Avoidance. In addition a significant fraction of this area is covered by extended, diffuse emission associated with thermal complexes, discrete H II regions, supernova remnants, and other structures in the Galactic interstellar medium.Comment: Paper with 3 figures and 1 table + Table 2 + 7 jpg grayscales for Fig 4. Astrophysical Journal Supplement (in press) see also http://www.astrop.physics.usyd.edu.au/MGP

Higher carbohydrate intake is associated with increased risk of allâ cause and diseaseâ specific mortality in head and neck cancer patients: results from a prospective cohort study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145268/1/ijc31413.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145268/2/ijc31413-sup-0001-suppinfo01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145268/3/ijc31413_am.pd

Emerging Massive Star Clusters Revealed: High Resolution Imaging of NGC 4449 from the Radio to the Ultraviolet

We present a multi-wavelength study of embedded massive clusters in the nearby (3.9 Mpc) starburst galaxy NGC 4449 in an effort to uncover the earliest phases of massive cluster evolution. By combining high resolution imaging from the radio to the ultraviolet, we reveal these clusters in the process of emerging from their gaseous and dusty birth cocoons. We use Very Large Array (VLA) observations at centimeter wavelengths to identify young clusters surrounded by ultra-dense HII regions, detectable via their production of thermal free-free radio continuum. Ultraviolet, optical and infrared observations are obtained from the Hubble and Spitzer Space Telescope archives for comparison. We detect 39 compact radio sources towards NGC 4449 at 3.6 cm using the highest resolution (1.3") and sensitivity (RMS ~ 12 uJy) VLA image of the galaxy to date. We reliably identify 13 thermal radio sources and their physical properties are derived using both nebular emission from the HII regions and SED fitting to the stellar continuum. These radio detected clusters have ages < 5 Myr and stellar masses of order 10^4 Msun. The measured extinctions are quite low: 12 of the 13 thermal radio sources have Av < 1.5, while the most obscured source has Av ~ 4.3. By combining results from the nebular and stellar emission, we find an I-band excess that is anti-correlated with cluster age and an apparent mass-age correlation. Additionally, we find evidence that local processes such as supernovae and stellar winds are likely playing an important role in triggering the current bursts of star formation within NGC 4449.Comment: Accepted for publication in the Astronomical Journal. 20 pages, 14 figure

Radio emission from Supernova Remnants

The explosion of a supernova releases almost instantaneously about 10^51 ergs of mechanic energy, changing irreversibly the physical and chemical properties of large regions in the galaxies. The stellar ejecta, the nebula resulting from the powerful shock waves, and sometimes a compact stellar remnant, constitute a supernova remnant (SNR). They can radiate their energy across the whole electromagnetic spectrum, but the great majority are radio sources. Almost 70 years after the first detection of radio emission coming from a SNR, great progress has been achieved in the comprehension of their physical characteristics and evolution. We review the present knowledge of different aspects of radio remnants, focusing on sources of the Milky Way and the Magellanic Clouds, where the SNRs can be spatially resolved. We present a brief overview of theoretical background, analyze morphology and polarization properties, and review and critical discuss different methods applied to determine the radio spectrum and distances. The consequences of the interaction between the SNR shocks and the surrounding medium are examined, including the question of whether SNRs can trigger the formation of new stars. Cases of multispectral comparison are presented. A section is devoted to reviewing recent results of radio SNRs in the Magellanic Clouds, with particular emphasis on the radio properties of SN 1987A, an ideal laboratory to investigate dynamical evolution of an SNR in near real time. The review concludes with a summary of issues on radio SNRs that deserve further study, and analyzing the prospects for future research with the latest generation radio telescopes.Comment: Revised version. 48 pages, 15 figure

A Novel Method for Evaluating Loading Rate During Running Regardless of Impact Peak

Recently there has been a focus on the relationship between the characteristics of the vertical ground reaction force (vGRF) and running injury occurrence. [1,2] AVLR is defined as the slope of the vGRF-time curve following initial contact. There are several methods for computing AVLR in the literature, however, the 20-80% method can only be calculated in the presence of an impact peak, [3] typically only associated with a rearfoot strike pattern. Additionally, the 3-12% method is unreliable when the impact peak occurs earlier than 12% of stance phase. This presents a problem when computing, interpreting and comparing research findings amongst runners with different foot strike patterns. To our knowledge, no study has described a method that can evaluate AVLR regardless of time or occurrence of the impact peak. The purpose of this study was to introduce the 3-12% auto method for calculating AVLR and compare it to the 3-12% and 20-80% methods

Cancer susceptibility and reproductive trade-offs: a model of the evolution of cancer defences

The factors influencing cancer susceptibility and why it varies across species are major open questions in the field of cancer biology. One underexplored source of variation in cancer susceptibility may arise from trade-offs between reproductive competitiveness (e.g. sexually selected traits, earlier reproduction and higher fertility) and cancer defence. We build a model that contrasts the probabilistic onset of cancer with other, extrinsic causes of mortality and use it to predict that intense reproductive competition will lower cancer defences and increase cancer incidence. We explore the trade-off between cancer defences and intraspecific competition across different extrinsic mortality conditions and different levels of trade-off intensity, and find the largest effect of competition on cancer in species where low extrinsic mortality combines with strong trade-offs. In such species, selection to delay cancer and selection to outcompete conspecifics are both strong, and the latter conflicts with the former. We discuss evidence for the assumed trade-off between reproductive competitiveness and cancer susceptibility. Sexually selected traits such as ornaments or large body size require high levels of cell proliferation and appear to be associated with greater cancer susceptibility. Similar associations exist for female traits such as continuous egg-laying in domestic hens and earlier reproductive maturity. Tradeoffs between reproduction and cancer defences may be instantiated by a variety of mechanisms, including higher levels of growth factors and hormones, less efficient cell-cycle control and less DNA repair, or simply a larger number of cell divisions (relevant when reproductive success requires large body size or rapid reproductive cycles). These mechanisms can affect intra- and interspecific variation in cancer susceptibility arising from rapid cell proliferation during reproductive maturation, intrasexual competition and reproduction

Validity of the optogait portable photoelectric cell system for quantification of spatial-temporal parameters of running gait

Gait analysis on a treadmill can be used to identify spatial-temporal parameters of gait in both healthy [1] and injured [2] individuals. Instrumented treadmills have been considered the gold standard for assessing certain running parameters; however, these treadmills are costly, require trained personnel to operate, and use custom code to calculate variables of interest from the raw data. The OPTOGait system is portable and can be used on any flat surface or treadmill to collect data. OPTOGait uses high-density photoelectric cells between transmitting and receiving bars which detect interruption in light signals due to a subject’s foot and automatically calculates spatial and temporal parameters [3]. While convenient, the reliability of the OPTOGait system for the assessment of gait parameters during running has not been studied. The purpose of this study was to examine the validity of spatial and temporal gait parameters calculated by the OPTOGait compared to an instrumented treadmill system during running