Life Science on the International Space Station Using the Next Generation of Cargo Vehicles

With the retirement of the Space Shuttle and the transition of the International Space Station (ISS) from assembly to full laboratory capabilities, the opportunity to perform life science research in space has increased dramatically, while the operational considerations associated with transportation of the experiments has changed dramatically. US researchers have allocations on the European Automated Transfer Vehicle (ATV) and Japanese H-II Transfer Vehicle (HTV). In addition, the International Space Station (ISS) Cargo Resupply Services (CRS) contract will provide consumables and payloads to and from the ISS via the unmanned SpaceX (offers launch and return capabilities) and Orbital (offers only launch capabilities) resupply vehicles. Early requirements drove the capabilities of the vehicle providers; however, many other engineering considerations affect the actual design and operations plans. To better enable the use of the International Space Station as a National Laboratory, ground and on-orbit facility development can augment the vehicle capabilities to better support needs for cell biology, animal research, and conditioned sample return. NASA Life scientists with experience launching research on the space shuttle can find the trades between the capabilities of the many different vehicles to be confusing. In this presentation we will summarize vehicle and associated ground processing capabilities as well as key concepts of operations for different types of life sciences research being launched in the cargo vehicles. We will provide the latest status of vehicle capabilities and support hardware and facilities development being made to enable the broadest implementation of life sciences research on the ISS

Patients with aortic stenosis exhibit early improved endothelial function following transcatheter aortic valve replacement: The eFAST study

BACKGROUND: Patients with severe aortic stenosis (AS) exhibit systemic endothelial dysfunction, which can be associated with myocardial ischaemia in absence of obstructive coronary disease. Transcatheter aortic valve replacement (TAVR) is used to treat severe AS in patients with high or prohibitive surgical risk. However, it remains unknown whether endothelial function recovers post-TAVR. We therefore sought to assess the early and late changes in flow-mediated dilation (FMD), a measure of endothelial function, following TAVR. METHODS: Patients undergoing TAVR for severe AS had ultrasound assessment of brachial endothelial-independent and -dependent FMD. Measurements were performed pre-TAVR, at early follow-up (<48 h post-TAVR) and late follow-up (4-6 weeks post-TAVR). RESULTS: 27 patients (mean age 82.0 ± 7.0; 33.3% female) were recruited; 37.0% had diabetes mellitus and 59.3% had hypertension. Brachial artery FMD increased from 4.2 ± 1.6% (pre-TAVR) to 9.7 ± 3.5% at early follow-up (p < 0.0001). At late follow-up, improvement compared with early follow-up was sustained (8.7 ± 1.9%, p = 0.27). Resting brachial arterial flow velocities decreased significantly at late follow-up (11.24 ± 5.16 vs. 7.73 ± 2.79 cm/s, p = 0.003). Concordantly, at late follow-up, there was decrease in resting wall shear stress (WSS; 14.8 ± 7.8 vs. 10.6 ± 4.8dyne/cm2, p = 0.01), peak WSS (73.1 ± 34.1 vs. 58.8 ± 27.8dyne/cm2, p = 0.03) and cumulative WSS (3543 ± 1852 vs. 2504 ± 1089dyne·s/cm2, p = 0.002). Additionally, a favourable inverse correlation between cumulative WSS and FMD was restored at late follow-up (r = -0.21 vs. r = 0.49). CONCLUSION: Endothelial function in patients with AS improves early post-TAVR and this improvement is sustained. This likely occurs as a result of improved arterial haemodynamics, leading to lower localised WSS and release of vasoactive mediators that may also alleviate myocardial ischaemia

Neuronal survival induced by neurotrophins requires calmodulin

It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its downstream target, protein kinase B (PKB), play a central role in the signaling of cell survival triggered by neurotrophins (NTs). In this report, we have analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs. We have found that reduction of intracellular Ca2+ concentration or functional blockade of CaM abolished NGF-induced activation of PKB in PC12 cells. Similar results were obtained in cultures of chicken spinal cord motoneurons treated with brain-derived neurotrophic factor (BDNF). Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF. This effect was counteracted by the transient expression of constitutive active forms of the PKB, indicating that CaM regulates NT-induced cell survival through the activation of the PKB. We have investigated the mechanisms whereby CaM regulates the activation of the PKB, and we have found that CaM was necessary for the proper generation and/or accumulation of the products of the PI 3-kinase in intact cells

Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients

The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg m−2 (2 h i.v. infusion) and raltitrexed 3.0 mg m−2 (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg m−2 (2 h i.v. infusion) and 5-fluorouracil 1050 mg m−2 i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43–79) years; ECOG performance status was 0 in 26 patients, ⩾1 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1–12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13–38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10–30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was ⩾1.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients

Cervical dystonia incidence and diagnostic delay in a multiethnic population.

BackgroundCurrent cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized.ObjectivesTo determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization.MethodsWe identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration.ResultsCD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68).ConclusionsCD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society

Building better Sex Robots: Lessons from Feminist Pornography

How should we react to the development of sexbot technology? Taking their cue from anti-porn feminism, several academic critics lament the development of sexbot technology, arguing that it objectifies and subordinates women, is likely to promote misogynistic attitudes toward sex, and may need to be banned or restricted. In this chapter I argue for an alternative response. Taking my cue from the sex positive ‘feminist porn’ movement, I argue that the best response to the development of ‘bad’ sexbots is to make better ones. This will require changes to the content, process and context of sexbot development. Doing so will acknowledge the valuable role that technology can play in human sexuality, and allow us to challenge gendered norms and assumptions about male and female sexual desire. This will not be a panacea to the social problems that could arise from sexbot development, but it offers a more realistic and hopeful vision for the future of this technology in a pluralistic and progressive society

Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe

Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis

Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Accumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 201