Keeping the dream alive: Managing the Space Station Program, 1982 to 1986

The management is described and analyzed of the formative years of the NASA Space Station Program (1982 to 1986), beginning with the successful initiative for program approval by Administrator James M. Beggs through to the decision to bring program management to Reston, Virginia. Emphasis is on internal management issues related to the implementation of the various phases of the program. Themes examined are the problem of bringing programmatic and institutional interests together and focusing them to forward the program; centralized versus decentralized control of the program; how the history of NASA and of the individual installations affected the decisions made; and the pressure from those outside NASA. The four sections are: (1) the decision to build the space station, (2) the design of the management experiment, (3) the experiment comes to life, and (4) the decision reversal

Comprehensive Approach to Analyzing Rare Genetic Variants

Recent findings suggest that rare variants play an important role in both monogenic and common diseases. Due to their rarity, however, it remains unclear how to appropriately analyze the association between such variants and disease. A common approach entails combining rare variants together based on a priori information and analyzing them as a single group. Here one must make some assumptions about what to aggregate. Instead, we propose two approaches to empirically determine the most efficient grouping of rare variants. The first considers multiple possible groupings using existing information. The second is an agnostic “step-up” approach that determines an optimal grouping of rare variants analytically and does not rely on prior information. To evaluate these approaches, we undertook a simulation study using sequence data from genes in the one-carbon folate metabolic pathway. Our results show that using prior information to group rare variants is advantageous only when information is quite accurate, but the step-up approach works well across a broad range of plausible scenarios. This agnostic approach allows one to efficiently analyze the association between rare variants and disease while avoiding assumptions required by other approaches for grouping such variants

Detailed Analysis of the Pulsations During and After Bursts from the Bursting Pulsar (GRO J1744-28)

The hard X-ray bursts observed during both major outbursts of the Bursting Pulsar (GRO J1744-28) show pulsations near the neutron star spin frequency with an enhanced amplitude relative to that of the persistent emission. Consistent with previous work, we find that the pulsations within bursts lag behind their expected arrival times based upon the persistent pulsar ephemeris. For an ensemble of 1293 bursts recorded with the Burst and Transient Source Experiment, the average burst pulse time delay is 61.0 +/- 0.8 ms in the 25 - 50 keV energy range and 72 +/- 5 ms in the 50 - 100 keV band. The residual time delay from 10 to 240 s following the start of the burst is 18.1 +/- 0.7 ms (25 - 50 keV). A significant correlation of the average burst time delay with burst peak flux is found. Our results are consistent with the model of the pulse time lags presented by Miller (1996).Comment: 11 pages, accepted for publication in Ap

Rapid, widespread transduction of the murine myocardium using self-complementary Adeno-associated virus

Adeno-associated virus (AAV) has shown great promise as a gene transfer vector. However, the incubation time needed to attain significant levels of gene expression is often too long for some clinical applications. Self-complementary AAV (scAAV) enters the cell as double stranded DNA, eliminating the step of second-strand synthesis, proven to be the rate-limiting step for gene expression of single-stranded AAV (ssAAV). The aim of this study was to compare the efficiency of these two types of AAV vectors in the murine myocardium. Four day old CD-1 mice were injected with either of the two AAV constructs, both expressing GFP and packaged into the AAV1 capsid. The animals were held for 4, 6, 11 or 21 days, after which they were euthanized and their hearts were excised. Serial sections of the myocardial tissue were used for real-time PCR quantification of AAV genome copies and for confocal microscopy. Although we observed similar numbers of AAV genomes at each of the different time points present in both the scAAV and the ssAAV infected hearts, microscopic analysis showed expression of GFP as early as 4 days in animals injected with the scAAV, while little or no expression was observed with the ssAAV constructs until day 11. AAV transduction of murine myocardium is therefore significantly enhanced using scAAV constructs

An Approximation for the rp-Process

Hot (explosive) hydrogen burning or the Rapid Proton Capture Process (rp-process) occurs in a number of astrophysical environments. Novae and X-ray bursts are the most prominent ones, but accretion disks around black holes and other sites are candidates as well. The expensive and often multidimensional hydro calculations for such events require an accurate prediction of the thermonuclear energy generation, while avoiding full nucleosynthesis network calculations. In the present investigation we present an approximation scheme applicable in a temperature range which covers the whole range of all presently known astrophysical sites. It is based on the concept of slowly varying hydrogen and helium abundances and assumes a kind of local steady flow by requiring that all reactions entering and leaving a nucleus add up to a zero flux. This scheme can adapt itself automatically and covers situations at low temperatures, characterized by a steady flow of reactions, as well as high temperature regimes where a $(p,\gamma)-(\gamma,p)$-equilibrium is established. In addition to a gain of a factor of 15 in computational speed over a full network calculation, and an energy generation accurate to more than 15 %, this scheme also allows to predict correctly individual isotopic abundances. Thus, it delivers all features of a full network at a highly reduced cost and can easily be implemented in hydro calculations.Comment: 18 pages, LaTeX using astrobib and aas2pp4, includes PostScript figures; Astrophysical Journal, in press. PostScript source also available at http://quasar.physik.unibas.ch/preps.htm

Independent evolution of pain insensitivity in African mole-rats: origins and mechanisms

Abstract: The naked mole-rat (Heterocephalus glaber) is famous for its longevity and unusual physiology. This eusocial species that lives in highly ordered and hierarchical colonies with a single breeding queen, also discovered secrets enabling somewhat pain-free living around 20 million years ago. Unlike most mammals, naked mole-rats do not feel the burn of chili pepper’s active ingredient, capsaicin, nor the sting of acid. Indeed, by accumulating mutations in genes encoding proteins that are only now being exploited as targets for new pain therapies (the nerve growth factor receptor TrkA and voltage-gated sodium channel, NaV1.7), this species mastered the art of analgesia before humans evolved. Recently, we have identified pain insensitivity as a trait shared by several closely related African mole-rat species. One of these African mole-rats, the Highveld mole-rat (Cryptomys hottentotus pretoriae), is uniquely completely impervious and pain free when confronted with electrophilic compounds that activate the TRPA1 ion channel. The Highveld mole-rat has evolved a biophysical mechanism to shut down the activation of sensory neurons that drive pain. In this review, we will show how mole-rats have evolved pain insensitivity as well as discussing what the proximate factors may have been that led to the evolution of pain-free traits

Independent evolution of pain insensitivity in African mole-rats: origins and mechanisms

Abstract: The naked mole-rat (Heterocephalus glaber) is famous for its longevity and unusual physiology. This eusocial species that lives in highly ordered and hierarchical colonies with a single breeding queen, also discovered secrets enabling somewhat pain-free living around 20 million years ago. Unlike most mammals, naked mole-rats do not feel the burn of chili pepper’s active ingredient, capsaicin, nor the sting of acid. Indeed, by accumulating mutations in genes encoding proteins that are only now being exploited as targets for new pain therapies (the nerve growth factor receptor TrkA and voltage-gated sodium channel, NaV1.7), this species mastered the art of analgesia before humans evolved. Recently, we have identified pain insensitivity as a trait shared by several closely related African mole-rat species. One of these African mole-rats, the Highveld mole-rat (Cryptomys hottentotus pretoriae), is uniquely completely impervious and pain free when confronted with electrophilic compounds that activate the TRPA1 ion channel. The Highveld mole-rat has evolved a biophysical mechanism to shut down the activation of sensory neurons that drive pain. In this review, we will show how mole-rats have evolved pain insensitivity as well as discussing what the proximate factors may have been that led to the evolution of pain-free traits

Maximising the impact of qualitative research in feasibility studies for randomised controlled trials: guidance for researchers

Feasibility studies are increasingly undertaken in preparation for randomised controlled trials in order to explore uncertainties and enable trialists to optimise the intervention or the conduct of the trial. Qualitative research can be used to examine and address key uncertainties prior to a full trial. We present guidance that researchers, research funders and reviewers may wish to consider when assessing or undertaking qualitative research within feasibility studies for randomised controlled trials. The guidance consists of 16 items within five domains: research questions, data collection, analysis, teamwork and reporting. Appropriate and well conducted qualitative research can make an important contribution to feasibility studies for randomised controlled trials. This guidance may help researchers to consider the full range of contributions that qualitative research can make in relation to their particular trial. The guidance may also help researchers and others to reflect on the utility of such qualitative research in practice, so that trial teams can decide when and how best to use these approaches in future studies

Functional neurokinin and NMDA receptor activity in an animal naturally lacking substance P: the naked mole-rat.

Naked mole-rats are extremely unusual among mammals in that their cutaneous C-fibers lack the neuropeptide Substance P (SP). In other mammals, SP plays an important role in nociception: it is released from C-fibers onto spinal neurons where it facilitates NMDA receptor activity and causes sensitization that can last for minutes, hours or days. In the present study, we tested the effects of intrathecal application of: 1) SP, 2) an SP antagonist (GR-82334), and 3) an NMDA antagonist (APV) on heat-evoked foot withdrawal. In the naked mole-rat, at a high enough concentration, application of SP caused a large, immediate, and long-lasting sensitization of foot withdrawal latency that was transiently reversed by application of either antagonist. However, neither SP nor NMDA antagonists had an effect when administered alone to naïve animals. In contrast, both antagonists induced an increase in basal withdrawal latency in mice. These results indicate that spinal neurons in naked mole-rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced. We propose that the natural lack of SP in naked mole-rat C-fibers may have resulted during adaptation to living in a chronically high carbon dioxide, high ammonia environment that, in other mammals, would stimulate C-fibers and evoke nocifensive behavior.This work was supported by National Science Foundation grant 0744979, Sonderforschungsbereich 665, and the Alexander von Humboldt Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Sources of Community Health Worker Motivation: A Qualitative Study in Morogoro Region, Tanzania.

There is a renewed interest in community health workers (CHWs) in Tanzania, but also a concern that low motivation of CHWs may decrease the benefits of investments in CHW programs. This study aimed to explore sources of CHW motivation to inform programs in Tanzania and similar contexts. We conducted semi-structured interviews with 20 CHWs in Morogoro Region, Tanzania. Interviews were digitally recorded, transcribed, and coded prior to translation and thematic analysis. The authors then conducted a literature review on CHW motivation and a framework that aligned with our findings was modified to guide the presentation of results. Sources of CHW motivation were identified at the individual, family, community, and organizational levels. At the individual level, CHWs are predisposed to volunteer work and apply knowledge gained to their own problems and those of their families and communities. Families and communities supplement other sources of motivation by providing moral, financial, and material support, including service fees, supplies, money for transportation, and help with farm work and CHW tasks. Resistance to CHW work exhibited by families and community members is limited. The organizational level (the government and its development partners) provides motivation in the form of stipends, potential employment, materials, training, and supervision, but inadequate remuneration and supplies discourage CHWs. Supervision can also be dis-incentivizing if perceived as a sign of poor performance. Tanzanian CHWs who work despite not receiving a salary have an intrinsic desire to volunteer, and their motivation often derives from support received from their families when other sources of motivation are insufficient. Policy-makers and program managers should consider the burden that a lack of remuneration imposes on the families of CHWs. In addition, CHWs' intrinsic desire to volunteer does not preclude a desire for external rewards. Rather, adequate and formal financial incentives and in-kind alternatives would allow already-motivated CHWs to increase their commitment to their work