A Systematic Protocol for the Characterization of Hsp90 Modulators

This is the author's accepted manuscript. Made available by the permission of the publisher.Several Hsp90 modulators have been identified including the N-terminal ligand geldanamycin (GDA), the C-terminal ligand novobiocin (NB), and the co-chaperone disruptor celastrol. Other Hsp90 modulators elicit a mechanism of action that remains unknown. For example, the natural product gedunin and the synthetic anti-spermatogenic agent H2-gamendazole, recently identified Hsp90 modulators, manifest biological activity through undefined mechanisms. Herein, we report a series of biochemical techniques used to classify such modulators into identifiable categories. Such studies provided evidence that gedunin and H2-gamendazole both modulate Hsp90 via a mechanism similar to celastrol, and unlike NB or GDA

Berkeley Supernova Ia Program I: Observations, Data Reduction, and Spectroscopic Sample of 582 Low-Redshift Type Ia Supernovae

In this first paper in a series we present 1298 low-redshift (z\leq0.2) optical spectra of 582 Type Ia supernovae (SNe Ia) observed from 1989 through 2008 as part of the Berkeley SN Ia Program (BSNIP). 584 spectra of 199 SNe Ia have well-calibrated light curves with measured distance moduli, and many of the spectra have been corrected for host-galaxy contamination. Most of the data were obtained using the Kast double spectrograph mounted on the Shane 3 m telescope at Lick Observatory and have a typical wavelength range of 3300-10,400 Ang., roughly twice as wide as spectra from most previously published datasets. We present our observing and reduction procedures, and we describe the resulting SN Database (SNDB), which will be an online, public, searchable database containing all of our fully reduced spectra and companion photometry. In addition, we discuss our spectral classification scheme (using the SuperNova IDentification code, SNID; Blondin & Tonry 2007), utilising our newly constructed set of SNID spectral templates. These templates allow us to accurately classify our entire dataset, and by doing so we are able to reclassify a handful of objects as bona fide SNe Ia and a few other objects as members of some of the peculiar SN Ia subtypes. In fact, our dataset includes spectra of nearly 90 spectroscopically peculiar SNe Ia. We also present spectroscopic host-galaxy redshifts of some SNe Ia where these values were previously unknown. [Abridged]Comment: 34 pages, 11 figures, 11 tables, revised version, re-submitted to MNRAS. Spectra will be released in January 2013. The SN Database homepage (http://hercules.berkeley.edu/database/index_public.html) contains the full tables, plots of all spectra, and our new SNID template

The Distance to SN 1999em in NGC 1637 from the Expanding Photosphere Method

We present 30 optical spectra and 49 photometric epochs sampling the first 517 days after discovery of supernova (SN) 1999em, and derive its distance through the expanding photosphere method (EPM). SN 1999em is shown to be a Type II-plateau (II-P) event, with a photometric plateau lasting until about 100 days after explosion. We identify the dominant ions responsible for most of the absorption features seen in the optical portion of the spectrum during the plateau phase. We find the distance to SN 1999em to be D = 8.2 +/- 0.6 Mpc, with an explosion date of 5.3 +/- 1.4 days before discovery. We examine potential sources of systematic error in EPM-derived distances, and find the most significant to result from uncertainty in the theoretical modeling of the flux distribution emitted by the SN photosphere (i.e., the ``flux dilution factor''). We compare previously derived EPM distances to 5 SNe II in galaxies for which a recently revised Cepheid distance exists from the HST Key Project and find D(Cepheids) / D(EPM) = 0.96 +/- 0.09. Finally, we investigate the possible use of SNe II-P as standard candles and find that for 8 photometrically confirmed SNe II-P with previously derived EPM distances and SN 1999em, the mean plateau absolute brightness is M_V(plateau) = -16.4 +/- 0.6 mag, implying that distances good to ~30% (1-sigma) may be possible without the need for a complete EPM analysis. At M_V(plateau) = -15.9 +/- 0.2 mag, SN 1999em is somewhat fainter than the average SN II-P. The general consistency of absolute SNe II-P brightness during the plateau suggests that the standard candle assumption may allow SNe II-P to be viable cosmological beacons at z > 2.Comment: 79 pages, 26 figures, accepted for publication in the Publications of the Astronomical Society of the Pacifi

Unsafe care in residential settings for older adults. A content analysis of accreditation reports.

Background Residents of aged care services can experience safety incidents resulting in preventable serious harm. Accreditation is a commonly used strategy to improve the quality of care; however, narrative information within accreditation reports is not generally analysed as a source of safety information to inform learning. In Australia, the Aged Care Quality and Safety Commission (ACQSC), the sector regulator, undertakes over 500 accreditation assessments of residential aged care services against national standards every year. From these assessments, the ACQSC generates detailed Site Audit Reports. In over one-third (37%) of Site Audit Reports, standards relating to Personal and Clinical Care (Standard 3) are not being met. The aim of this study was to identify the types of resident Safety Risks that relate to Personal and Clinical Care Standards not being met during accreditation or re-accreditation. These data could inform priority setting at policy, regulatory and service levels. Methods An analytical framework was developed based on the World Health Organization’s International Classification for Patient Safety (ICPS) and other fields including Clinical Issue (the issue related to the incident impacting on the resident e.g., wound/skin or pain). Information relating to safety incidents in the Site Audit Reports was extracted and a content analysis undertaken using the analytical framework. Clinical Issue and the ICPS-based classification were combined to describe a clinically intuitive category (“Safety Risks”) to describe ways in which residents could experience unsafe care e.g., diagnosis/assessment of pain. The resulting data were descriptively analysed. Results The analysis included 65 Site Audit Reports that were undertaken between September 2020 – March 2021. There were 2,267 incidents classified into 274 types of resident Safety Risks. The twelve most frequently occurring Safety Risks account for only 32.3% of all incidents. Relatively frequently occurring Safety Risks were organisation management of infection control; diagnosis/assessment of pain, restraint, resident behaviours, falls; and multiple stages of wounds/skin management e.g., diagnosis/assessment, documentation, treatment, and deterioration. Conclusion The analysis has shown that accreditation reports contain valuable data that may inform prioritisation of resident Safety Risks in the Australian residential aged care sector. A large number of low frequency resident Safety Risks were detected in the accreditation reports. To address these, organisations may use implementation science approaches to facilitate evidence-based strategies to improve the quality of care delivered to residents. Improving the aged care workforces’ clinical skills base may address some of the Safety Risks associated with diagnosis/assessment and wound management

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

Advancing national animal health and welfare policy

The University College Dublin (UCD) School of Veterinary Medicine has a broad research agenda covering areas such as veterinary public health, epidemiology and national disease control, herd health management, drug delivery, pharmacology, parasitology, and One Health research. We work with national and international collaborators and, with the support of Zoetis, have a longstanding “UCD Squared” partnership with the University of California-Davis, which has established an ambitious program of research, drawing on expertise from a diverse community of veterinary and medical scientists and clinicians.Unusual, not sure if it can be called Journal Article or should be under another type perhap

Optical Spectra of Type Ia Supernovae at z=0.46 and z=1.2

We present optical spectra, obtained with the Keck 10-m telescope, of two high-redshift type Ia supernovae (SNe Ia) discovered by the High-z Supernova Search Team: SN 1999ff at z=0.455 and SN 1999fv at z~1.2, the highest-redshift published SN Ia spectrum. Both SNe were at maximum light when the spectra were taken. We compare our high-z spectra with low-z normal and peculiar SNe Ia as well as with SNe Ic, Ib, and II. There are no significant differences between SN 1999ff and normal SNe Ia at low redshift. SN 1999fv appears to be a SN Ia and does not resemble the most peculiar nearby SNe Ia.Comment: 6 pages including 2 figures; to appear in The Astrophysical Journal Letter

The October 2012 magnitude (Mw) 7.8 earthquake offshore Haida Gwaii, Canada

Alison L. Bird et al. report on the Mw 7.8 earthquake offshore Haida Gwaii, Canada, from 2012 for the Summary of the Bulletin of the International Seismological Centre

One-shot identification of SARS-CoV-2 S RBD escape mutants using yeast screening

The potential emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) escape mutants is a threat to the efficacy of existing vaccines and neutralizing antibody (nAb) therapies. An understanding of the antibody/S escape mutation landscape is urgently needed to preemptively address this threat. Here we describe a rapid method to identify escape mutants for nAbs targeting the S receptor binding site. We identified escape mutants for five nAbs, including three from the public germline class VH3-53 elicited by natural coronavirus disease 2019 (COVID-19) infection. Escape mutations predominantly mapped to the periphery of the angiotensin-converting enzyme 2 (ACE2) recognition site on the RBD with K417, D420, Y421, F486, and Q493 as notable hotspots. We provide libraries, methods, and software as an openly available community resource to accelerate new therapeutic strategies against SARS-CoV-2. &nbsp;</p

The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.

BACKGROUND: Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. RESULTS: To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAF(V600E) or NRAS(Q61K) driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAF(V600E) and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway. CONCLUSION: This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation