Type Ia Supernovae and the Hubble Constant

The focus of this review is the work that has been done during the 1990s on using Type Ia supernovae (SNe Ia) to measure the Hubble constant ($H_0$). SNe Ia are well suited for measuring $H_0$. A straightforward maximum-light color criterion can weed out the minority of observed events that are either intrinsically subluminous or substantially extinguished by dust, leaving a majority subsample that has observational absolute-magnitude dispersions of less than $\sigma_{obs}(M_B) \simeq \sigma_{obs}(M_V) \simeq 0.3$ mag. Correlations between absolute magnitude and one or more distance-independent SN Ia or parent-galaxy observables can be used to further standardize the absolute magnitudes to better than 0.2 mag. The absolute magnitudes can be calibrated in two independent ways --- empirically, using Cepheid-based distances to parent galaxies of SNe Ia, and physically, by light curve and spectrum fitting. At present the empirical and physical calibrations are in agreement at $M_B \simeq M_V \simeq -19.4$ or -19.5. Various ways that have been used to match Cepheid-calibrated SNe Ia or physical models to SNe Ia that have been observed out in the Hubble flow have given values of $H_0$ distributed throughout the range 54 to 67 km/s Mpc$^{-1}$. Astronomers who want a consensus value of $H_0$ from SNe Ia with conservative errors could, for now, use $60 \pm 10$ km/s Mpc^{-1}$.Comment: 46 pages. Hard copies of figures, all from the published literature, can be obtained from the author. With permission, from the Annual Review of Astronomy and Astrophysics, Volume 36, copyright 1998, by Annual Review

DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies.

Glioblastoma is the most frequently diagnosed type of primary brain tumour in adults. These aggressive tumours are characterised by inherent treatment resistance and disease progression, contributing to ~190,000 brain-tumour related deaths globally each year. Current therapeutic interventions consist of surgical resection followed by radiotherapy and temozolomide chemotherapy, but average survival is typically around 1 year, with less than 10% of patients surviving more than 5 years. Recently, a fourth treatment modality of intermediate-frequency low-intensity electric fields [called tumour-treating fields ( TTFields)] was clinically approved for glioblastoma in some countries after it was found to increase median overall survival rates by ~5 months in a phase III randomised clinical trial. However, beyond these treatments, attempts to establish more effective therapies have yielded little improvement in survival for patients over the last 50 years. This is in contrast to many other types of cancer and highlights glioblastoma as a recognised tumour of unmet clinical need. Previous work has revealed that glioblastomas contain stem-cell-like subpopulations that exhibit heightened expression of DNA damage response (DDR) factors, contributing to therapy resistance and disease relapse. Given that radiotherapy, chemotherapy and TTFields-based therapies all impact DDR mechanisms, this Review will focus on our current knowledge of the role of the DDR in glioblastoma biology and treatment. We also discuss the potential of effective multi-modal targeting of the DDR combined with standard-of-care therapies, as well as emerging therapeutic targets, in providing much-needed improvements in survival rates for patients

PolyQ Repeat Expansions in ATXN2 Associated with ALS Are CAA Interrupted Repeats

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive disease leading to paralysis and death. Recently, intermediate length polyglutamine (polyQ) repeats of 27–33 in ATAXIN-2 (ATXN2), encoding the ATXN2 protein, were found to increase risk for ALS. In ATXN2, polyQ expansions of ≥34, which are pure CAG repeat expansions, cause spinocerebellar ataxia type 2. However, similar length expansions that are interrupted with other codons, can present atypically with parkinsonism, suggesting that configuration of the repeat sequence plays an important role in disease manifestation in ATXN2 polyQ expansion diseases. Here we determined whether the expansions in ATXN2 associated with ALS were pure or interrupted CAG repeats, and defined single nucleotide polymorphisms (SNPs) rs695871 and rs695872 in exon 1 of the gene, to assess haplotype association. We found that the expanded repeat alleles of 40 ALS patients and 9 long-repeat length controls were all interrupted, bearing 1–3 CAA codons within the CAG repeat. 21/21 expanded ALS chromosomes with 3CAA interruptions arose from one haplotype (GT), while 18/19 expanded ALS chromosomes with <3CAA interruptions arose from a different haplotype (CC). Moreover, age of disease onset was significantly earlier in patients bearing 3 interruptions vs fewer, and was distinct between haplotypes. These results indicate that CAG repeat expansions in ATXN2 associated with ALS are uniformly interrupted repeats and that the nature of the repeat sequence and haplotype, as well as length of polyQ repeat, may play a role in the neurological effect conferred by expansions in ATXN2

Strategies to prevent intraoperative lung injury during cardiopulmonary bypass

During open heart surgery the influence of a series of factors such as cardiopulmonary bypass (CPB), hypothermia, operation and anaesthesia, as well as medication and transfusion can cause a diffuse trauma in the lungs. This injury leads mostly to a postoperative interstitial pulmonary oedema and abnormal gas exchange. Substantial improvements in all of the above mentioned factors may lead to a better lung function postoperatively. By avoiding CPB, reducing its time, or by minimizing the extracorporeal surface area with the use of miniaturized circuits of CPB, beneficial effects on lung function are reported. In addition, replacement of circuit surface with biocompatible surfaces like heparin-coated, and material-independent sources of blood activation, a better postoperative lung function is observed. Meticulous myocardial protection by using hypothermia and cardioplegia methods during ischemia and reperfusion remain one of the cornerstones of postoperative lung function. The partial restoration of pulmonary artery perfusion during CPB possibly contributes to prevent pulmonary ischemia and lung dysfunction. Using medication such as corticosteroids and aprotinin, which protect the lungs during CPB, and leukocyte depletion filters for operations expected to exceed 90 minutes in CPB-time appear to be protective against the toxic impact of CPB in the lungs. The newer methods of ultrafiltration used to scavenge pro-inflammatory factors seem to be protective for the lung function. In a similar way, reducing the use of cardiotomy suction device, as well as the contact-time between free blood and pericardium, it is expected that the postoperative lung function will be improved

Stochastic backgrounds of relic gravitons: a theoretical appraisal

Stochastic backgrounds or relic gravitons, if ever detected, will constitute a prima facie evidence of physical processes taking place during the earliest stages of the evolution of the plasma. The essentials of the stochastic backgrounds of relic gravitons are hereby introduced and reviewed. The pivotal observables customarily employed to infer the properties of the relic gravitons are discussed both in the framework of the $\Lambda$CDM paradigm as well as in neighboring contexts. The complementarity between experiments measuring the polarization of the Cosmic Microwave Background (such as, for instance, WMAP, Capmap, Quad, Cbi, just to mention a few) and wide band interferometers (e.g. Virgo, Ligo, Geo, Tama) is emphasized. While the analysis of the microwave sky strongly constrains the low-frequency tail of the relic graviton spectrum, wide-band detectors are sensitive to much higher frequencies where the spectral energy density depends chiefly upon the (poorly known) rate of post-inflationary expansion.Comment: 94 pages, 32 figure

Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards

Formaldehyde is a well-studied chemical and effects from inhalation exposures have been extensively characterized in numerous controlled studies with human volunteers, including asthmatics and other sensitive individuals, which provide a rich database on exposure concentrations that can reliably produce the symptoms of sensory irritation. Although individuals can differ in their sensitivity to odor and eye irritation, the majority of authoritative reviews of the formaldehyde literature have concluded that an air concentration of 0.3 ppm will provide protection from eye irritation for virtually everyone. A weight of evidence-based formaldehyde exposure limit of 0.1 ppm (100 ppb) is recommended as an indoor air level for all individuals for odor detection and sensory irritation. It has recently been suggested by the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and the US Environmental Protection Agency (US EPA) that formaldehyde is causally associated with nasopharyngeal cancer (NPC) and leukemia. This has led US EPA to conclude that irritation is not the most sensitive toxic endpoint and that carcinogenicity should dictate how to establish exposure limits for formaldehyde. In this review, a number of lines of reasoning and substantial scientific evidence are described and discussed, which leads to a conclusion that neither point of contact nor systemic effects of any type, including NPC or leukemia, are causally associated with exposure to formaldehyde. This conclusion supports the view that the equivocal epidemiology studies that suggest otherwise are almost certainly flawed by identified or yet to be unidentified confounding variables. Thus, this assessment concludes that a formaldehyde indoor air limit of 0.1 ppm should protect even particularly susceptible individuals from both irritation effects and any potential cancer hazard

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis