Some inconvenient truths about biosignatures involving two chemical species on Earth-like exoplanets

The detection of strong thermochemical disequilibrium in the atmosphere of an extrasolar planet is thought to be a potential biosignature. In this article we present a previously unidentified kind of false positive that can mimic a disequilibrium or any other biosignature that involves two chemical species. We consider a scenario where the exoplanet hosts a moon that has its own atmosphere and neither of the atmospheres is in chemical disequilibrium. Our results show that the integrated spectrum of the planet and the moon closely resembles that of a single object in strong chemical disequilibrium. We derive a firm limit on the maximum spectral resolution that can be obtained for both directly imaged and transiting planets. The spectral resolution of even idealized space-based spectrographs that might be achievable in the next several decades is in general insufficient to break the degeneracy. Both chemical species can only be definitively confirmed in the same object if absorption features of both chemicals can be unambiguously identified and their combined depth exceeds 100%.With almost a thousand confirmed exoplanets [Open Exoplanet Catalogue (1)], the prospects of detecting signs of a biosphere on a body outside our own solar system are more promising than ever before. However, there are still huge technological and theoretical challenges to overcome before one can hope to make a clear detection of life on an exoplanet. In this article, we discuss one of these complications, the possibility of false positives due to the presence of an exomoon orbiting the exoplanet.There are many ways that life on an exoplanet might affect the planet’s appearance, ranging from deliberate signals from intelligent civilizations (2) to subtler signs of simple life. To characterize an extrasolar world as fully as possible, we ideally would measure its spectrum as a function of time in both the optical and the infrared parts of the spectrum (e.g., refs. 3–6). For example, spectral evidence of water could suggest that a planet might be habitable. It has also been suggested that an intriguing indication of life might be an increase in the planet’s albedo toward the infrared part of the spectrum, which on Earth can be associated with vegetation (7). However, these features alone would not be smoking-gun proof of the presence of life. The terms “biomarker” and “biosignature” generally refer to chemicals or combinations of chemicals that could be produced by life and that could not be (or are unlikely to be) produced abiotically; hereafter, we use these terms interchangeably. If biosignature gases are detected in the spectrum of an exoplanet, the probability that they actually indicate life depends both on the prior probability of life (8) and on the probability that the observed spectroscopic feature could be produced abiotically. The latter possibility is the subject of this paper.Byproducts of metabolism are often thought of as the most promising biomarker (9–15). More specifically, an extreme thermodynamic disequilibrium of two molecules in the atmosphere is considered a biosignature (16–18). An example of two such species is the simultaneous presence of O₂ and a reduced gas such as CH₄. It is important to point out that a disequilibrium in a planet’s atmosphere should not be considered as clear evidence for life. [Also note that the Earth might have never had a phase of strong, observable O₂/CH₄ disequilibrium (19).] There is a long list of abiotic sources that could also create a disequilibrium such as impacts (20), photochemistry (21), and geochemistry (14).In this article, we describe a previously unidentified scenario for a possible false positive biosignature. If the exoplanet hosts a moon that has an atmosphere itself, the simultaneous observation of the planet and moon modifies the observed spectrum (see also refs. 22 and 23) and can produce a signal that looks like a disequilibrium in one atmosphere but is in fact created by two atmospheres blended together. It might be extremely difficult to discern that an exoplanet even has a moon, let alone that one component of a two-chemical biosignature comes from the moon instead of the planet.The outline of this article is as follows. We first describe our model atmospheres and present simulated spectra. Using those synthetic spectra, we show that the combined spectrum from an oxygen-rich atmosphere such as that of the Earth and a methane-rich atmosphere such as that of Titan indeed looks like it could have come from a single atmosphere with a strong disequilibrium. We then calculate a strong upper limit on the spectral resolution of such a system as observed from Earth under ideal conditions with a plausibly sized space telescope. Our estimate shows that the spectral resolution for such a system is unlikely to exceed ∼1,600 with foreseeable technology. Given this maximum possible resolution, discriminating between a single planet and a planet–moon system is in general unlikely to be possible.^† Nevertheless, we conclude with a summary and a positive outlook with two possibilities that can provide genuine biosignatures. The first possibility is to find a single chemical species that is sufficient to indicate life. The second one requires the unambiguous identification of both species’ absorption features and the combined depth of the features needs to exceed 100%.     

A perivascular niche in the bone marrow hosts quiescent and proliferating tumorigenic colorectal cancer cells

Disseminated tumor cells (dTCs) can frequently be detected in the bone marrow (BM) of colorectal cancer (CRC) patients, raising the possibility that the BM serves as a reservoir for metastatic tumor cells. Identification of dTCs in BM aspirates harbors the potential of assessing therapeutic outcome and directing therapy intensity with limited risk and effort. Still, the functional and prognostic relevance of dTCs is not fully established. We have previously shown that CRC cell clones can be traced to the BM of mice carrying patient-derived xenografts. However, cellular interactions, proliferative state and tumorigenicity of dTCs remain largely unknown. Here, we applied a coculture system modeling the microvascular niche and used immunofluorescence imaging of the murine BM to show that primary CRC cells migrate toward endothelial tubes. dTCs in the BM were rare, but detectable in mice with xenografts from most patient samples (8/10) predominantly at perivascular sites. Comparable to primary tumors, a substantial fraction of proliferating dTCs was detected in the BM. However, most dTCs were found as isolated cells, indicating that dividing dTCs rather separate than aggregate to metastatic clones—a phenomenon frequently observed in the microvascular niche model. Clonal tracking identified subsets of self-renewing tumor-initiating cells in the BM that formed tumors out of BM transplants, including one subset that did not drive primary tumor growth. Our results indicate an important role of the perivascular BM niche for CRC cell dissemination and show that dTCs can be a potential source for tumor relapse and tumor heterogeneity.     

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.     

Acute alcohol decreases gangliosides in mouse brain

We have reported that single doses of alcohol diminish total sialic acid in rat brain. Recent results indicate that this effect seems to be largely accounted for by alcohol-induced reduction in gangliosides. In these experiments, five replicate groups of mice were injected IP with a single dose of 20% alcohol and saline as control. At 1 hour postinjection, alcohol decreased total brain gangliosides (p less than 0.03) at 1 and 2 g/kg, but not at 3, 4, and 6 g/kg. Free whole-brain sialic acid was increased by 2 g/kg alcohol, which is consistent with the observed decrement in gangliosides at this dose. However, activity of sialidase on the endogenous substrates was not greatly affected by 2 g/kg of alcohol, indicating that ganglioside decrement is probably not attributable to activation of the catabolic enzyme. These results confirm and extend our earlier reports that incriminated gangliosides in the acute action of alcohol. The data also raise the possibility that the effect is due to the "excitatory," rather than the depressive actions of alcohol. Moreover, the action may involve an increased hydrolysis of membrane gangliosides by sialidase.     

The faster the better: anastomosis time influences patient survival after deceased donor kidney transplantation

Despite a continuously growing knowledge of the impact of factors on kidney graft function, such as donor age, body mass index, and cold ischemia time, few data are available regarding anastomosis time (AT) and its impact on long‐term results. We investigated whether surgical AT correlates with patient and graft survival after kidney transplantation performing a retrospective analysis of 1245 consecutive deceased donor kidney transplantations between 01/2000 and 12/2010 at Innsbruck Medical University. Kaplan–Meier and log‐rank analyses were carried out for 1‐ and 5‐year patient and graft survival. AT was defined as time from anastomosis start until reperfusion. Median AT was 30 min. Five‐year survival of allografts with an AT >30 min was 76.6% compared with 80.6% in the group with AT <30 min (P = 0.027). Patient survival in the group with higher AT similarly was inferior with 85.7% after 5 years compared with 89.6% (P < 0.0001) [Correction added on February 18, 2015, after first online publication: the percentage value for patient survival was previously incorrect and have now been changed to 89.6%]. Cox regression analysis revealed AT as an independent significant factor for patient survival (HR 1.021 per minute; 95% CI 1.006–1.037; P = 0.006). As longer AT closely correlates with inferior long‐term patient survival, it has to be considered as a major risk factor for inferior long‐term results after deceased donor kidney transplantation.     

Rocaglates as Antivirals: Comparing the Effects on Viral Resistance,Anti-Coronaviral Activity,RNA-Clamping on eIF4A and Immune Cell Toxicity

Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5′-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.     

Methylene blue-assisted lymph node dissection in combination with ex vivo sentinel lymph node mapping in gastric cancer

Aims:  Lymph node (LN) stage is still the strongest prognostic marker in potentially curable gastric cancer. Accuracy of histopathological lymph node assessment depends on the number of investigated LNs and detection rate of metastases and micrometastases. The aim was to perform a feasibility study employing intra-arterial methylene blue injection – a novel method to improve LN harvest – and ex vivo sentinel LN mapping.
Methods and results:  A total of 33 cases were enrolled, including 14 retrospective cases that served as a control group. The methylene group showed a highly significant improved mean LN harvest compared with unstained cases, with 38 ± 14 versus 21 ± 10 LNs ( P  < 0.001), respectively. The detection rate of ex vivo sentinel mapping was 88%. No skip metastases occurred.
Conclusion:  Both techniques have the potential to improve the accuracy of histopathological LN staging and can be combined successfully.