Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation.

Exposure to high levels of ionizing radiation (IR) leads to debilitating and dose-limiting gastrointestinal (GI) toxicity. Using three-dimensional mouse crypt culture, we demonstrated that p53 target PUMA mediates radiation-induced apoptosis via a cell-intrinsic mechanism, and identified the GSK-3 inhibitor CHIR99021 as a potent radioprotector. CHIR99021 treatment improved Lgr5+ cell survival and crypt regeneration after radiation in culture and mice. CHIR99021 treatment specifically blocked apoptosis and PUMA induction and K120 acetylation of p53 mediated by acetyl-transferase Tip60, while it had no effect on p53 stabilization, phosphorylation or p21 induction. CHIR99021 also protected human intestinal cultures from radiation by PUMA but not p21 suppression. These results demonstrate that p53 posttranslational modifications play a key role in the pathological and apoptotic response of the intestinal stem cells to radiation and can be targeted pharmacologically

Prevalence of qacA/B genes and mupirocin resistance among methicillin-resistant Staphylococcus aureus (MRSA) isolates in the setting of chlorhexidine bathing without mupirocin

OBJECTIVE: We aimed to determine the frequency of qacA/B chlorhexidine tolerance genes and high-level mupirocin resistance among MRSA isolates before and after the introduction of a chlorhexidine (CHG) daily bathing intervention in a surgical intensive care unit (SICU). DESIGN: Retrospective cohort study (2005–2012) SETTING: A large tertiary-care center PATIENTS: Patients admitted to SICU who had MRSA surveillance cultures of the anterior nares METHODS: A random sample of banked MRSA anterior nares isolates recovered during (2005) and after (2006–2012) implementation of a daily CHG bathing protocol was examined for qacA/B genes and high-level mupirocin resistance. Staphylococcal cassette chromosome mec (SCCmec) typing was also performed. RESULTS: Of the 504 randomly selected isolates (63 per year), 36 (7.1%) were qacA/B positive ( + ) and 35 (6.9%) were mupirocin resistant. Of these, 184 (36.5%) isolates were SCCmec type IV. There was a significant trend for increasing qacA/B (P= .02; highest prevalence, 16.9% in 2009 and 2010) and SCCmec type IV (P< .001; highest prevalence, 52.4% in 2012) during the study period. qacA/B( + ) MRSA isolates were more likely to be mupirocin resistant (9 of 36 [25%] qacA/B( + ) vs 26 of 468 [5.6%] qacA/B(−); P= .003). CONCLUSIONS: A long-term, daily CHG bathing protocol was associated with a change in the frequency of qacA/B genes in MRSA isolates recovered from the anterior nares over an 8-year period. This change in the frequency of qacA/B genes is most likely due to patients in those years being exposed in prior admissions. Future studies need to further evaluate the implications of universal CHG daily bathing on MRSA qacA/B genes among hospitalized patients

Calibration of the GLAST Burst Monitor detectors

The GLAST Burst Monitor (GBM) will augment the capabilities of GLAST for the detection of cosmic gamma-ray bursts by extending the energy range (20 MeV to > 300 GeV) of the Large Area Telescope (LAT) towards lower energies by 2 BGO-detectors (150 keV to 30 MeV) and 12 NaI(Tl) detectors (10 keV to 1 MeV). The physical detector response of the GBM instrument for GRBs is determined with the help of Monte Carlo simulations, which are supported and verified by on-ground calibration measurements, performed extensively with the individual detectors at the MPE in 2005. All flight and spare detectors were irradiated with calibrated radioactive sources in the laboratory (from 14 keV to 4.43 MeV). The energy/channel-relations, the dependences of energy resolution and effective areas on the energy and the angular responses were measured. Due to the low number of emission lines of radioactive sources below 100 keV, calibration measurements in the energy range from 10 keV to 60 keV were performed with the X-ray radiometry working group of the Physikalisch-Technische Bundesanstalt (PTB) at the BESSY synchrotron radiation facility, Berlin.Comment: 2 pages, 1 figure; to appear in the Proc. of the First Int. GLAST Symp. (Stanford, Feb. 5-8, 2007), eds. S.Ritz, P.F.Michelson, and C.Meegan, AIP Conf. Pro

Should Cities Offer Remote Work?

In December 2019, the SARS-CoV-2 virus was discovered in Wuhan, China. This highly contagious virus soon spread rapidly throughout the world and brought many countries and cities to a standstill through lockdowns, travel bans, and fear of illness and death. Many employers abandoned in-person work to prevent the spread of what became known as COVID-19, or COVID. Plans were made instead for employees to work from home as employers created modified work environments and moved meetings to online platforms. In 2022, once the virus was considered to be under control and fear began to subside, employers began to reopen for business and demanded employees return to in-person work. However, the known workplace had been changed forever as it had been proven that employees could successfully work remotely, meaning the flexible and modified workplaces became not only the norm, but the preference, for many employees. This paper will outline the pros and cons for remote workers, and why cities should consider a remote workplace

RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients

Background: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). Methods: Eligible patients with T-scores of the hip ( −2.5 vs. > −1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. Results: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. −5%, p<0.0001), left total hip (1% vs. −8%, p=0.0002), and left femoral neck (3% vs. −8%, p=0.0007). Conclusions: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL

Physiology, behavior, and conservation

Many animal populations are in decline as a result of human activity. Conservation practitioners are attempting to prevent further declines and loss of biodiversity as well as to facilitate recovery of endangered species, and they often rely on interdisciplinary approaches to generate conservation solutions. Two recent interfaces in conservation science involve animal behavior (i.e., conservation behavior) and physiology (i.e., conservation physiology). To date, these interfaces have been considered separate entities, but from both pragmatic and biological perspectives, there is merit in better integrating behavior and physiology to address applied conservation problems and to inform resource management. Although there are some institutional, conceptual, methodological, and communication-oriented challenges to integrating behavior and physiology to inform conservation actions, most of these barriers can be overcome. Through outlining several successful examples that integrate these disciplines, we conclude that physiology and behavior can together generate meaningful data to support animal conservation and management actions. Tangentially, applied conservation and management problems can, in turn, also help advance and reinvigorate the fundamental disciplines of animal physiology and behavior by providing advanced natural experiments that challenge traditional frameworks

An Account and Analysis of the Implementation of Various E‐Book Business Models at Queensland University of Technology, Australia

Queensland University of Technology (QUT) is a leading university based in the city of Brisbane, Queensland, Australia and is a selectively research intensive university with 2,500 higher degree research students and an overall student population of 45,000 students. The transition from print to online resources is largely completed and the library now provides access to 450,000 print books, 1,000 print journals, 600,000 e‐books, 120,000 e‐journals and 100,000 online videos. The e‐book collection is now used three times as much as the print book collection. This paper focuses on QUT Library’s e‐book strategy and the challenges of building and managing a rapidly growing collection of e‐books using a range of publishers, platforms, and business and financial models. The paper provides an account of QUT Library’s experiences in using patron‐driven acquisition (PDA) using e‐Book Library (EBL); the strategic procurement of publisher and subject collections by lease and outright purchase models, the more recent transition to evidence‐based selection (EBS) options provided by some publishers, and its piloting of e‐textbook models. The paper provides an in‐depth analysis of each of these business models at QUT, focusing on access verses collection development, usage, cost per use, and value for money

Ross River virus antibody prevalence in the Fiji Islands, 2013-2015

A unique outbreak of Ross River virus (RRV) infection was reported in Fiji in 1979. In 2013, 29 RRV seroprevalence among residents was 46.5%. Of those born after 1982, 37.4% had anti-RRV 30 antibodies. Between 2013-2015, 10.9% of residents had seroconverted to RRV suggesting 31 ongoing endemic circulation of RRV in Fiji

Myosin folding boosts solubility in cardiac muscle sarcomeres.

The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates that the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM. Myosin molecules were labeled in vivo with a green fluorescent protein (GFP) and imaged in intact hearts using multiphoton microscopy. Treatment of the intact hearts with mavacamten resulted in an unexpected &gt; 5-fold enhancement in GFP-myosin mobility within the sarcomere. In vitro biochemical assays suggested that mavacamten enhanced the mobility of GFP-myosin by increasing the solubility of myosin molecules, through the stabilization of a compact/folded conformation of the molecules, once disassociated from the thick filaments. These findings provide alternative insight into the mechanisms by which molecules exchange into and out of thick filaments and have implications for how mavacamten may affect cardiac contractility

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology