Visions of a Martian Future

As we look beyond our terrestrial boundary to a multi-planetary future for humankind, it becomes paramount to anticipate the challenges of various human factors on the most likely scenario for this future: permanent human settlement of Mars. Even if technical hurdles are circumvented to provide adequate resources for basic physiological and psychological needs, Homo sapiens will not survive on an alien planet if a dysfunctional psyche prohibits the utilization of these resources. No matter how far we soar into the stars, our psychologies for future generations will be forever tethered to the totality of our surroundings. By shaping our environment toward survival and welfare during the voyage to Mars and in a Martian colony, we indirectly shape our psyches and prepare them for a mission of unprecedented alienation and duration. Once on Mars, human factors such as leadership structure, social organization and code of conduct, group size, gender balance, developmental cycle, mobility, length of stay and the ecological settings and type and manner of subsistence, will create a novel Martian culture. The degree that settlers are severed from the Earth will affect how radically foreign this culture will be when compared with cultures on Earth

Ergonomic constraints for astronauts : challenges and opportunities today and for the future

Manned spaceflight is ergonomically constrained by living and working in a confined space in microgravity where astronauts on both short and long duration missions are exposed to daily radiation levels well above those received on Earth. Living in microgravity, especially on long duration missions aboard the International Space Station has deleterious physiological and psychological effects on astronaut health and astronauts may receive on one mission exposure to a cumulative radiation dose normally received in a lifetime on Earth. It is unrealistic at present to contemplate continuous missions of greater than 1 yr and to mitigate against current ergonomic constraints, space agencies have outlined roadmaps to introduce artificial gravity and develop strategies for conferring human resistance to radiation. In parallel, the concept of whole brain emulation (WBE) and ‘uploading’ of human consciousness on to a platform within the rapidly growing field of artificial intelligence is one scenario which may remove the future requirement for a physical crew. This paper highlights incidents and accidents which have resulted in astronaut injury because of ergonomics in space, considers the timing of deployment of technology roadmaps and draws together multi-disciplinary fields to project a future whereby deep space travel may be manned by an e-crew, devoid of many of the established ergonomic boundaries that apply to human astronauts

Molecular basis of FIR-mediated c-myc transcriptional control

The far upstream element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR), which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment, showing that the tandem RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system precisely regulates c-myc transcription and suggest that a small change in FBP-FIR affinity leads to a substantial effect on c-Myc concentration.MRC Grant-in-aid U11757455

Photochemical dihydrogen production using an analogue of the active site of [NiFe] hydrogenase

The photoproduction of dihydrogen (H2) by a low molecular weight analogue of the active site of [NiFe] hydrogenase has been investigated by the reduction of the [NiFe2] cluster, 1, by a photosensitier PS (PS = [ReCl(CO)3(bpy)] or [Ru(bpy)3][PF6]2). Reductive quenching of the 3MLCT excited state of the photosensitiser by NEt3 or N(CH2CH2OH)3 (TEOA) generates PS•−, and subsequent intermolecular electron transfer to 1 produces the reduced anionic form of 1. Time-resolved infrared spectroscopy (TRIR) has been used to probe the intermediates throughout the reduction of 1 and subsequent photocatalytic H2 production from [HTEOA][BF4], which was monitored by gas chromatography. Two structural isomers of the reduced form of 1 (1a•− and 1b•−) were detected by Fourier transform infrared spectroscopy (FTIR) in both CH3CN and DMF (dimethylformamide), while only 1a•− was detected in CH2Cl2. Structures for these intermediates are proposed from the results of density functional theory calculations and FTIR spectroscopy. 1a•− is assigned to a similar structure to 1 with six terminal carbonyl ligands, while calculations suggest that in 1b•− two of the carbonyl groups bridge the Fe centres, consistent with the peak observed at 1714 cm−1 in the FTIR spectrum for 1b•− in CH3CN, assigned to a ν(CO) stretching vibration. The formation of 1a•− and 1b•− and the production of H2 was studied in CH3CN, DMF and CH2Cl2. Although the more catalytically active species (1a•− or 1b•−) could not be determined, photocatalysis was observed only in CH3CN and DMF

Interlaboratory study for coral Sr/Ca and other element/Ca ratio measurements

The Sr/Ca ratio of coral aragonite is used to reconstruct past sea surface temperature (SST). Twentyone laboratories took part in an interlaboratory study of coral Sr/Ca measurements. Results show interlaboratory bias can be significant, and in the extreme case could result in a range in SST estimates of 7°C. However, most of the data fall within a narrower range and the Porites coral reference material JCp- 1 is now characterized well enough to have a certified Sr/Ca value of 8.838 mmol/mol with an expanded uncertainty of 0.089 mmol/mol following International Association of Geoanalysts (IAG) guidelines. This uncertainty, at the 95% confidence level, equates to 1.5°C for SST estimates using Porites, so is approaching fitness for purpose. The comparable median within laboratory error is <0.5°C. This difference in uncertainties illustrates the interlaboratory bias component that should be reduced through the use of reference materials like the JCp-1. There are many potential sources contributing to biases in comparative methods but traces of Sr in Ca standards and uncertainties in reference solution composition can account for half of the combined uncertainty. Consensus values that fulfil the requirements to be certified values were also obtained for Mg/Ca in JCp-1 and for Sr/Ca and Mg/Ca ratios in the JCt-1 giant clam reference material. Reference values with variable fitness for purpose have also been obtained for Li/Ca, B/Ca, Ba/Ca, and U/Ca in both reference materials. In future, studies reporting coral element/Ca data should also report the average value obtained for a reference material such as the JCp-1

Temperature and carbonate ion effects on Mg/Ca and Sr/Ca ratios in benthic foraminifera : aragonitic species Hoeglundina elegans

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 21 (2006): PA1007, doi:10.1029/2005PA001158.Core top samples from Atlantic (Little Bahama Banks (LBB)) and Pacific (Hawaii and Indonesia) depth transects have been analyzed in order to assess the influence of bottom water temperature (BWT) and aragonite saturation levels on Mg/Ca and Sr/Ca ratios in the aragonitic benthic foraminifer Hoeglundina elegans. Both the Mg/Ca and Sr/Ca ratios in H. elegans tests show a general decrease with increasing water depth. Although at each site the decreasing trends are consistent with the in situ temperature profile, Mg/Ca and Sr/Ca ratios in LBB are substantially higher than in Indonesia and Hawaii at comparable water depths with a greater difference observed with increasing water depth. Because we find no significant difference between results obtained on “live” and “dead” specimens, we propose that these differences are due to primary effects on the metal uptake during test formation. Evaluation of the water column properties at each site suggests that in situ CO3 ion concentrations play an important role in determining the H. elegans Mg/Ca and Sr/Ca ratios. The CO3 ion effect is limited, however, only to aragonite saturation levels ([ΔCO3]aragonite) below 15 μmol kg−1. Above this level, temperature exerts a dominant effect. Accordingly, we propose that Mg/Ca and Sr/Ca in H. elegans tests can be used to reconstruct thermocline temperatures only in waters oversaturated with respect to the mineral aragonite using the following relationships: Mg/Ca = (0.034 ± 0.002)BWT + (0.96 ± 0.03) and Sr/Ca = (0.060 ± 0.002)BWT + (1.53 ± 0.03) (for [ΔCO3]aragonite > 15 μmol kg−1). The standard error associated with these equations is about ±1.1°C. Reconstruction of deeper water temperatures is complicated because in undersaturated waters, changes in Mg/Ca and Sr/Ca ratios reflect a combination of changes in [CO3] and BWT. Overall, we find that Sr/Ca, rather than Mg/Ca, in H. elegans may be a more accurate proxy for reconstructing paleotemperatures.Yair Rosenthal acknowledges the support of Amtzia Genin and the Hebrew University, Forchheimer Fellowship, during his sabbatical in the Inter-University Institute in Eilat, Israel. This project has been funded by NSF Awards OCE 0220922 to Y.R. and OCE 0220776 to D.W.O. and B.K.L

Orientation of the central domains of KSRP and its implications for the interaction with the RNA targets

KSRP is a multi-domain RNA-binding protein that recruits the exosome-containing mRNA degradation complex to mRNAs coding for cellular proliferation and inflammatory response factors. The selectivity of this mRNA degradation mechanism relies on KSRP recognition of AU-rich elements in the mRNA 3′UTR, that is mediated by KSRP’s KH domains. Our structural analysis shows that the inter-domain linker orients the two central KH domains of KSRP—and their RNA-binding surfaces—creating a two-domain unit. We also show that this inter-domain arrangement is important to the interaction with KSRP’s RNA targets

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targetedpanel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations

Measurement Challenges in Shared Decision Making: Putting the ‘Patient’ in Patient‐Reported Measures

Measuring clinicians\u27 shared decision-making (SDM) performance is a key requirement given the intensity of policy interest in many developed countries - yet it remains one of the most difficult methodological challenges, which is a concern for many stakeholders. In this Viewpoint Article, we investigate the development of existing patient-reported measures (PRMs) of SDM identified in a recent review. We find that patients were involved in the development of only four of the 13 measures. This lack of patient involvement in PRM development is associated with two major threats to content validity, common to all 13 PRMs of SDM: (i) an assumption of patient awareness of \u27decision points\u27 and (ii) an assumption that there is only one decision point in each healthcare consultation. We provide detailed examples of these threats and their impact on accurate assessment of SDM processes and outcomes, which may hamper efforts to introduce incentives for SDM implementation. We propose cognitive interviewing as a recommended method of involving patients in the design of PRMs in the field of SDM and provide a practical example of this approach