Local and global instabilities of flow in a flexible-walled channel

We consider laminar high-Reynolds-number flow through a long finite-length planar channel, where a segment of one wall is replaced by a massless membrane held under longitudinal tension. The flow is driven by a fixed pressure difference across the channel and is described using an integral form of the unsteady boundary-layer equations. The basic flow state, for which the channel has uniform width, exhibits static and oscillatory global instabilities, having distinct modal forms. In contrast, the corresponding local problem (neglecting boundary conditions associated with the rigid parts of the system) is found to be convectively, but not absolutely, unstable to small-amplitude disturbances in the absence of wall damping. We show how amplification of the primary global oscillatory instability can arise entirely from wave reflections with the rigid parts of the system, involving interacting travelling wave flutter and static-divergence modes that are convectively stable; alteration of the mean flow by oscillations makes the onset of this primary instability subcritical. We also show how distinct mechanisms of energy transfer differentiate the primary global mode from other modes of oscillatory instability

The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function

Poly (ADP-ribose) is synthesized at DNA single-strand breaks and can promote the recruitment of the scaffold protein, XRCC1. However, the mechanism and importance of this process has been challenged. To address this issue, we have characterized the mechanism of poly (ADP-ribose) binding by XRCC1 and examined its importance for XRCC1 function. We show that the phosphate-binding pocket in the central BRCT1 domain of XRCC1 is required for selective binding to poly (ADP-ribose) at low levels of ADP-ribosylation, and promotes interaction with cellular PARP1. We also show that the phosphate-binding pocket is required for EGFP-XRCC1 accumulation at DNA damage induced by UVA laser, H2O2, and at sites of sub-nuclear PCNA foci, suggesting that poly (ADP-ribose) promotes XRCC1 recruitment both at single-strand breaks globally across the genome and at sites of DNA replication stress. Finally, we show that the phosphate-binding pocket is required following DNA damage for XRCC1-dependent acceleration of DNA single-strand break repair, DNA base excision repair, and cell survival. These data support the hypothesis that poly (ADP-ribose) synthesis promotes XRCC1 recruitment at DNA damage sites and is important for XRCC1 function

International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate : A meta-analysis of 1446 patients

OBJECTIVE: To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment. METHODS: Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed. RESULTS: Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome. CONCLUSIONS: The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy.Peer reviewe

Habitability constraints by nutrient availability in atmospheres of rocky exoplanets

Life as we know it requires the presence of liquid water and the availability of nutrients, which are mainly based on the elements C, H, N, O, P, and S (CHNOPS) and trace metal micronutrients. We aim to understand the presence of these nutrients within atmospheres that show the presence of water cloud condensates, potentially allowing the existence of aerial biospheres. In this paper we introduce a framework of nutrient availability levels based on the presence of water condensates and the chemical state of the CHNOPS elements. These nutrient availability levels are applied to a set of atmospheric models based on different planetary surface compositions resulting in a range of atmospheric compositions. The atmospheric model is a bottom-to-top equilibrium chemistry atmospheric model which includes the atmosphere-crust interaction and the element depletion due to the formation of clouds. While the reduced forms of CNS are present at the water cloud base for most atmospheric compositions, P and metals are lacking. This indicates the potential bio-availability of CNS, while P and metals are limiting factors for aerial biospheres.Comment: accepted for publication in International Journal of Astrobiology, 12 pages + 11 pages appendi

TLDc proteins: new players in the oxidative stress response and neurological disease

Oxidative stress (OS) arises from an imbalance in the cellular redox state, which can lead to intracellular damage and ultimately cell death. OS occurs as a result of normal ageing, but it is also implicated as a common etiological factor in neurological disease; thus identifying novel proteins that modulate the OS response may facilitate the design of new therapeutic approaches applicable to many disorders. In this review, we describe the recent progress that has been made using a range of genetic approaches to understand a family of proteins that share the highly conserved TLDc domain. We highlight their shared ability to prevent OS-related cell death and their unique functional characteristics, as well as discussing their potential application as new neuroprotective factors. Furthermore, with an increasing number of pathogenic mutations leading to epilepsy and hearing loss being discovered in the TLDc protein TBC1D24, understanding the function of this family has important implications for a range of inherited neurological diseases