Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria

A nuclear encoded mitochondrial heat-shock protein hsp60 is required for the assembly into oligomeric complexes of proteins imported into the mitochondrial matrix. hsp60 is a member of the 'chaperonin' class of protein factors, which include the Escherichia coli groEL protein and the Rubisco subunit-binding protein of chloroplast

Direct angiotensin AT2 receptor stimulation using a novel AT2 receptor agonist, compound 21, evokes neuroprotection in conscious hypertensive rats

Background: In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents. Methods and Results: Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury. Conclusion: These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development

Sensitivity of the ocean state to the vertical distribution of internal-tide-driven mixing

Author Posting. © American Meteorological Society, 2013. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 43 (2013): 602–615, doi:10.1175/JPO-D-12-055.1.The ocean interior stratification and meridional overturning circulation are largely sustained by diapycnal mixing. The breaking of internal tides is a major source of diapycnal mixing. Many recent climate models parameterize internal-tide breaking using the scheme of St. Laurent et al. While this parameterization dynamically accounts for internal-tide generation, the vertical distribution of the resultant mixing is ad hoc, prescribing energy dissipation to decay exponentially above the ocean bottom with a fixed-length scale. Recently, Polzin formulated a dynamically based parameterization, in which the vertical profile of dissipation decays algebraically with a varying decay scale, accounting for variable stratification using Wentzel–Kramers–Brillouin (WKB) stretching. This study compares two simulations using the St. Laurent and Polzin formulations in the Climate Model, version 2G (CM2G), ocean–ice–atmosphere coupled model, with the same formulation for internal-tide energy input. Focusing mainly on the Pacific Ocean, where the deep low-frequency variability is relatively small, the authors show that the ocean state shows modest but robust and significant sensitivity to the vertical profile of internal-tide-driven mixing. Therefore, not only the energy input to the internal tides matters, but also where in the vertical it is dissipated.This work is a component of the Internal- Wave Driven Mixing Climate Process Team funded by the National Science Foundation Grant OCE-0968721 and the National Oceanic and Atmospheric Administration, U.S. Department of Commerce, Award NA08OAR4320752.2013-09-0

Improving oceanic overflow representation in climate models : the Gravity Current Entrainment Climate Process Team

Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 90 (2009): 657-670, doi:10.1175/2008BAMS2667.1.Oceanic overflows are bottom-trapped density currents originating in semienclosed basins, such as the Nordic seas, or on continental shelves, such as the Antarctic shelf. Overflows are the source of most of the abyssal waters, and therefore play an important role in the large-scale ocean circulation, forming a component of the sinking branch of the thermohaline circulation. As they descend the continental slope, overflows mix vigorously with the surrounding oceanic waters, changing their density and transport significantly. These mixing processes occur on spatial scales well below the resolution of ocean climate models, with the result that deep waters and deep western boundary currents are simulated poorly. The Gravity Current Entrainment Climate Process Team was established by the U.S. Climate Variability and Prediction (CLIVAR) Program to accelerate the development and implementation of improved representations of overflows within large-scale climate models, bringing together climate model developers with those conducting observational, numerical, and laboratory process studies of overflows. Here, the organization of the Climate Process Team is described, and a few of the successes and lessons learned during this collaboration are highlighted, with some emphasis on the well-observed Mediterranean overflow. The Climate Process Team has developed several different overflow parameterizations, which are examined in a hierarchy of ocean models, from comparatively well-resolved regional models to the largest-scale global climate models.The Gravity Current Entrainment Climate Process Team was funded by NSF grants OCE-0336850 and OCE-0611572 and NOAA as a contribution to U.S.CLIVAR

Comparing ocean surface boundary vertical mixing schemes including langmuir turbulence

Six recent Langmuir turbulence parameterization schemes and five traditional schemes are implemented in a common single‐column modeling framework and consistently compared. These schemes are tested in scenarios versus matched large eddy simulations, across the globe with realistic forcing (JRA55‐do, WAVEWATCH‐III simulated waves) and initial conditions (Argo), and under realistic conditions as observed at ocean moorings. Traditional non‐Langmuir schemes systematically underpredict large eddy simulation vertical mixing under weak convective forcing, while Langmuir schemes vary in accuracy. Under global, realistic forcing Langmuir schemes produce 6% (−1% to 14% for 90% confidence) or 5.2 m (−0.2 m to 17.4 m for 90% confidence) deeper monthly mean mixed layer depths than their non‐Langmuir counterparts, with the greatest differences in extratropical regions, especially the Southern Ocean in austral summer. Discrepancies among Langmuir schemes are large (15% in mixed layer depth standard deviation over the mean): largest under wave‐driven turbulence with stabilizing buoyancy forcing, next largest under strongly wave‐driven conditions with weak buoyancy forcing, and agreeing during strong convective forcing. Non‐Langmuir schemes disagree with each other to a lesser extent, with a similar ordering. Langmuir discrepancies obscure a cross‐scheme estimate of the Langmuir effect magnitude under realistic forcing, highlighting limited understanding and numerical deficiencies. Maps of the regions and seasons where the greatest discrepancies occur are provided to guide further studies and observations

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Climate Process Team on internal wave–driven ocean mixing

Author Posting. © American Meteorological Society, 2017. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 98 (2017): 2429-2454, doi:10.1175/BAMS-D-16-0030.1.Diapycnal mixing plays a primary role in the thermodynamic balance of the ocean and, consequently, in oceanic heat and carbon uptake and storage. Though observed mixing rates are on average consistent with values required by inverse models, recent attention has focused on the dramatic spatial variability, spanning several orders of magnitude, of mixing rates in both the upper and deep ocean. Away from ocean boundaries, the spatiotemporal patterns of mixing are largely driven by the geography of generation, propagation, and dissipation of internal waves, which supply much of the power for turbulent mixing. Over the last 5 years and under the auspices of U.S. Climate Variability and Predictability Program (CLIVAR), a National Science Foundation (NSF)- and National Oceanic and Atmospheric Administration (NOAA)-supported Climate Process Team has been engaged in developing, implementing, and testing dynamics-based parameterizations for internal wave–driven turbulent mixing in global ocean models. The work has primarily focused on turbulence 1) near sites of internal tide generation, 2) in the upper ocean related to wind-generated near inertial motions, 3) due to internal lee waves generated by low-frequency mesoscale flows over topography, and 4) at ocean margins. Here, we review recent progress, describe the tools developed, and discuss future directions.We are grateful to U.S. CLIVAR for their leadership in instigating and facilitating the Climate Process Team program. We are indebted to NSF and NOAA for sponsoring the CPT series.2018-06-0

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations