Trypanosoma brucei BRCA2 acts in a life cycle-specific genome stability process and dictates BRC repeat number-dependent RAD51 subnuclear dynamics

Trypanosoma brucei survives in mammals through antigenic variation, which is driven by RAD51-directed homologous recombination of Variant Surface Glycoproteins (VSG) genes, most of which reside in a subtelomeric repository of >1000 silent genes. A key regulator of RAD51 is BRCA2, which in T. brucei contains a dramatic expansion of a motif that mediates interaction with RAD51, termed the BRC repeats. BRCA2 mutants were made in both tsetse fly-derived and mammal-derived T. brucei, and we show that BRCA2 loss has less impact on the health of the former. In addition, we find that genome instability, a hallmark of BRCA2 loss in other organisms, is only seen in mammal-derived T. brucei. By generating cells expressing BRCA2 variants with altered BRC repeat numbers, we show that the BRC repeat expansion is crucial for RAD51 subnuclear dynamics after DNA damage. Finally, we document surprisingly limited co-localization of BRCA2 and RAD51 in the T. brucei nucleus, and we show that BRCA2 mutants display aberrant cell division, revealing a function distinct from BRC-mediated RAD51 interaction. We propose that BRCA2 acts to maintain the huge VSG repository of T. brucei, and this function has necessitated the evolution of extensive RAD51 interaction via the BRC repeats, allowing re-localization of the recombinase to general genome damage when needed

An ensemble of structures of Burkholderia pseudomallei 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase

An ensemble of crystal structures are reported for 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase from B. pseudomallei. The structures include two vanadate complexes, revealing the structure of a close analogue of the transition state for phosphate transfer

Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m−2, followed by a fixed dose of 5.0 g m−2 treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m−2 gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m−2 gemcitabine combined with 5.0 g m−2 treosulfan

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

Background: Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy. Methods: A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears. Results: Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL. Conclusions: Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here

Self-similar scaling and evolution in the galaxy cluster X-ray Luminosity-Temperature relation

We investigate the form and evolution of the X-ray luminosity-temperature (LT) relation of a sample of 114 galaxy clusters observed with Chandra at 0.1<z<1.3. The clusters were divided into subsamples based on their X-ray morphology or whether they host strong cool cores. We find that when the core regions are excluded, the most relaxed clusters (or those with the strongest cool cores) follow an LT relation with a slope that agrees well with simple self-similar expectations. This is supported by an analysis of the gas density profiles of the systems, which shows self-similar behaviour of the gas profiles of the relaxed clusters outside the core regions. By comparing our data with clusters in the REXCESS sample, which extends to lower masses, we find evidence that the self-similar behaviour of even the most relaxed clusters breaks at around 3.5keV. By contrast, the LT slopes of the subsamples of unrelaxed systems (or those without strong cool cores) are significantly steeper than the self-similar model, with lower mass systems appearing less luminous and higher mass systems appearing more luminous than the self-similar relation. We argue that these results are consistent with a model of non-gravitational energy input in clusters that combines central heating with entropy enhancements from merger shocks. Such enhancements could extend the impact of central energy input to larger radii in unrelaxed clusters, as suggested by our data. We also examine the evolution of the LT relation, and find that while the data appear inconsistent with simple self-similar evolution, the differences can be plausibly explained by selection bias, and thus we find no reason to rule out self-similar evolution. We show that the fraction of cool core clusters in our (non-representative) sample decreases at z>0.5 and discuss the effect of this on measurements of the evolution in the LT relation.Comment: 21 pages, 15 figures. Submitted to MNRAS. Comments welcom

Elevated <scp>CO₂</scp> interacts with nutrient inputs to restructure plant communities in phosphorus‐limited grasslands

AbstractGlobally pervasive increases in atmospheric CO2 and nitrogen (N) deposition could have substantial effects on plant communities, either directly or mediated by their interactions with soil nutrient limitation. While the direct consequences of N enrichment on plant communities are well documented, potential interactions with rising CO2 and globally widespread phosphorus (P) limitation remain poorly understood. We investigated the consequences of simultaneous elevated CO2 (eCO2) and N and P additions on grassland biodiversity, community and functional composition in P‐limited grasslands. We exposed soil‐turf monoliths from limestone and acidic grasslands that have received &gt;25 years of N additions (3.5 and 14 g m−2 year−1) and 11 (limestone) or 25 (acidic) years of P additions (3.5 g m−2 year−1) to eCO2 (600 ppm) for 3 years. Across both grasslands, eCO2, N and P additions significantly changed community composition. Limestone communities were more responsive to eCO2 and saw significant functional shifts resulting from eCO2–nutrient interactions. Here, legume cover tripled in response to combined eCO2 and P additions, and combined eCO2 and N treatments shifted functional dominance from grasses to sedges. We suggest that eCO2 may disproportionately benefit P acquisition by sedges by subsidising the carbon cost of locally intense root exudation at the expense of co‐occurring grasses. In contrast, the functional composition of the acidic grassland was insensitive to eCO2 and its interactions with nutrient additions. Greater diversity of P‐acquisition strategies in the limestone grassland, combined with a more functionally even and diverse community, may contribute to the stronger responses compared to the acidic grassland. Our work suggests we may see large changes in the composition and biodiversity of P‐limited grasslands in response to eCO2 and its interactions with nutrient loading, particularly where these contain a high diversity of P‐acquisition strategies or developmentally young soils with sufficient bioavailable mineral P.</jats:p

Improved constraints on the expansion rate of the Universe up to z~1.1 from the spectroscopic evolution of cosmic chronometers

We present new improved constraints on the Hubble parameter H(z) in the redshift range 0.15 < z < 1.1, obtained from the differential spectroscopic evolution of early-type galaxies as a function of redshift. We extract a large sample of early-type galaxies (\sim11000) from several spectroscopic surveys, spanning almost 8 billion years of cosmic lookback time (0.15 < z < 1.42). We select the most massive, red elliptical galaxies, passively evolving and without signature of ongoing star formation. Those galaxies can be used as standard cosmic chronometers, as firstly proposed by Jimenez & Loeb (2002), whose differential age evolution as a function of cosmic time directly probes H(z). We analyze the 4000 {\AA} break (D4000) as a function of redshift, use stellar population synthesis models to theoretically calibrate the dependence of the differential age evolution on the differential D4000, and estimate the Hubble parameter taking into account both statistical and systematical errors. We provide 8 new measurements of H(z) (see Tab. 4), and determine its change in H(z) to a precision of 5-12% mapping homogeneously the redshift range up to z \sim 1.1; for the first time, we place a constraint on H(z) at z \neq 0 with a precision comparable with the one achieved for the Hubble constant (about 5-6% at z \sim 0.2), and covered a redshift range (0.5 < z < 0.8) which is crucial to distinguish many different quintessence cosmologies. These measurements have been tested to best match a \Lambda CDM model, clearly providing a statistically robust indication that the Universe is undergoing an accelerated expansion. This method shows the potentiality to open a new avenue in constrain a variety of alternative cosmologies, especially when future surveys (e.g. Euclid) will open the possibility to extend it up to z \sim 2.Comment: 34 pages, 15 figures, 6 tables, published in JCAP. It is a companion to Moresco et al. (2012b, http://arxiv.org/abs/1201.6658) and Jimenez et al. (2012, http://arxiv.org/abs/1201.3608). The H(z) data can be downloaded at http://www.physics-astronomy.unibo.it/en/research/areas/astrophysics/cosmology-with-cosmic-chronometer

The XMM Cluster Survey: The interplay between the brightest cluster galaxy and the intra-cluster medium via AGN feedback

Using a sample of 123 X-ray clusters and groups drawn from the XMM-Cluster Survey first data release, we investigate the interplay between the brightest cluster galaxy (BCG), its black hole, and the intra-cluster/group medium (ICM). It appears that for groups and clusters with a BCG likely to host significant AGN feedback, gas cooling dominates in those with Tx > 2 keV while AGN feedback dominates below. This may be understood through the sub-unity exponent found in the scaling relation we derive between the BCG mass and cluster mass over the halo mass range 10^13 < M500 < 10^15Msol and the lack of correlation between radio luminosity and cluster mass, such that BCG AGN in groups can have relatively more energetic influence on the ICM. The Lx - Tx relation for systems with the most massive BCGs, or those with BCGs co-located with the peak of the ICM emission, is steeper than that for those with the least massive and most offset, which instead follows self-similarity. This is evidence that a combination of central gas cooling and powerful, well fuelled AGN causes the departure of the ICM from pure gravitational heating, with the steepened relation crossing self-similarity at Tx = 2 keV. Importantly, regardless of their black hole mass, BCGs are more likely to host radio-loud AGN if they are in a massive cluster (Tx > 2 keV) and again co-located with an effective fuel supply of dense, cooling gas. This demonstrates that the most massive black holes appear to know more about their host cluster than they do about their host galaxy. The results lead us to propose a physically motivated, empirical definition of 'cluster' and 'group', delineated at 2 keV.Comment: Accepted for publication in MNRAS - replaced to match corrected proo

Meandering rivers in modern desert basins: Implications for channel planform controls and prevegetation rivers

The influence of biotic processes in controlling the development of meandering channels in fluvial systems is controversial. The majority of the depositional history of the Earth's continents was devoid of significant biogeomorphic interactions, particularly those between vegetation and sedimentation processes. The prevailing perspective has been that prevegetation meandering channels rarely developed and that rivers with braided planforms dominated. However, recently acquired data demonstrate that meandering channel planforms are more widely preserved in prevegetation fluvial successions than previously thought. Understanding the role of prevailing fluvial dynamics in non- and poorly vegetated environments must rely on actualistic models derived from presently active rivers developed in sedimentary basins subject to desert-climate settings, the sparsest vegetated regions experiencing active sedimentation on Earth. These systems have fluvial depositional settings that most closely resemble those present in prevegetation (and extra-terrestrial) environments. Here, we present an analysis based on satellite imagery which reveals that rivers with meandering channel planforms are common in modern sedimentary basins in desert settings. Morphometric analysis of meandering fluvial channel behaviour, where vegetation is absent or highly restricted, shows that modern sparsely and non-vegetated meandering rivers occur across a range of slope gradients and basin settings, and possess a broad range of channel and meander-belt dimensions. The importance of meandering rivers in modern desert settings suggests that their abundance is likely underestimated in the prevegetation rock record, and models for recognition of their deposits need to be improved

Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates

Objectives: pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.Methods: DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.Results: increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.Conclusions: PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidate