Mars Extant Life: What's Next? Conference Report.

On November 5-8, 2019, the "Mars Extant Life: What's Next?" conference was convened in Carlsbad, New Mexico. The conference gathered a community of actively publishing experts in disciplines related to habitability and astrobiology. Primary conclusions are as follows: A significant subset of conference attendees concluded that there is a realistic possibility that Mars hosts indigenous microbial life. A powerful theme that permeated the conference is that the key to the search for martian extant life lies in identifying and exploring refugia ("oases"), where conditions are either permanently or episodically significantly more hospitable than average. Based on our existing knowledge of Mars, conference participants highlighted four potential martian refugium (not listed in priority order): Caves, Deep Subsurface, Ices, and Salts. The conference group did not attempt to reach a consensus prioritization of these candidate environments, but instead felt that a defensible prioritization would require a future competitive process. Within the context of these candidate environments, we identified a variety of geological search strategies that could narrow the search space. Additionally, we summarized a number of measurement techniques that could be used to detect evidence of extant life (if present). Again, it was not within the scope of the conference to prioritize these measurement techniques-that is best left for the competitive process. We specifically note that the number and sensitivity of detection methods that could be implemented if samples were returned to Earth greatly exceed the methodologies that could be used at Mars. Finally, important lessons to guide extant life search processes can be derived both from experiments carried out in terrestrial laboratories and analog field sites and from theoretical modeling.

MasterOnline Periodontology and Implant Therapy-revisited after seven years: A case study of the structures and outcomes in a blended learning CPD.

INTRODUCTION: There is a great need for postgraduate training and continuing professional development (CPD), specifically in the field of periodontology. Despite the plenty of periodontal CPDs, there is a lack of information about the performance of CPDs in a blended learning setting. This study is a case study of the structures and outcomes in a blended learning CPD programme in periodontology, the MasterOnline Periodontology and Implant Therapy hosted by the University of Freiburg's Dental School. MATERIAL AND METHODS: The structures of the blended learning CPD were analysed with the aims to (i) make explicit how various innovative educational methods and ICT tools can be successfully applied to a Web-supported postgraduate periodontology training programme, (ii) identify the programme's impact on learning transfer in students' dental practices and (iii) identify other outcomes, synergies and any changes required during the existence. Using qualitative interviewing, the various types of learning transfer and elements of the study programme that foster transfer could be exemplified. RESULTS: A period of 7 years was analysed. In this duration, 50 students successfully graduated to a master of science. Qualitative interviews were performed with six students and four teachers affirming the learning transfer in a blended learning setting. CONCLUSIONS: This case study shows that blended learning can be a successful approach for CPD in dentistry.

[Concentration of Emergency Departments: the wrong way to economize]. / Concentratie van de spoedeisende hulp.

In this paper we investigate whether it is economically beneficial to concentrate Emergency Departments (EDs) in large hospitals. We recognise economies of scale and economies of chain. The latter reflect the effects on costs of patients receiving further treatments in hospital, be it admissions or out-patient appointments, after visiting the ED. We conclude that there are product-specific economies of scale. On the one hand, hospitals benefit by increasing ED services. However, this is not in line with the diseconomies of scale observed for larger hospitals as a whole. This contradiction is called the economies of scale paradox. There are internal incentives to upscale services, such as EDs, in order to benefit from the product-specific economies of scale. However, a price is to be paid by the hospital for the upscaling of its ED. Based on these results, the resulting recommendation for policy development is that, in spite of the fact that concentrating EDs seems to be advantageous, upscaling of EDs must be rejected.

Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression.

Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared with wild-type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells. Analysis of the primary tumors showed significant increase in vimentin protein expression in the MKR mice compared with WT. We hypothesized that vimentin was an important mediator in the effect of hyperinsulinemia on breast cancer metastasis. Lentiviral short hairpin RNA knockdown of vimentin led to a significant decrease in invasion of the MVT-1 cells and abrogated the increase in cell invasion in response to insulin. In the pre-diabetic MKR mouse, vimentin knockdown led to a decrease in pulmonary metastases. In vitro, we found that insulin increased pAKT, prevented caspase 3 activation, and increased vimentin. Inhibiting the phosphatidylinositol 3 kinase/AKT pathway, using NVP-BKM120, increased active caspase 3 and decreased vimentin levels. This study is the first to show that vimentin has an important role in tumor metastasis in vivo in the setting of pre-diabetes and endogenous hyperinsulinemia. Vimentin targeting may be an important therapeutic strategy to reduce metastases in patients with obesity, pre-diabetes or T2D.

Soil diversity and hydration as observed by ChemCam at Gale crater, Mars.

The ChemCam instrument, which provides insight into martian soil chemistry at the submillimeter scale, identified two principal soil types along the Curiosity rover traverse: a fine-grained mafic type and a locally derived, coarse-grained felsic type. The mafic soil component is representative of widespread martian soils and is similar in composition to the martian dust. It possesses a ubiquitous hydrogen signature in ChemCam spectra, corresponding to the hydration of the amorphous phases found in the soil by the CheMin instrument. This hydration likely accounts for an important fraction of the global hydration of the surface seen by previous orbital measurements. ChemCam analyses did not reveal any significant exchange of water vapor between the regolith and the atmosphere. These observations provide constraints on the nature of the amorphous phases and their hydration.

[Implementing in-patient smoking cessation interventions. Basic characteristics of smoking patients in a lung health department]. / Implementierung von Maßnahmen zur Tabakentwöhnung im Krankenhaus. Basisdaten eines pneumologischen Patientenkollektivs.

BACKGROUND: Hospitals have a unique key role in promoting smoking cessation. However, cessation interventions are uncommon in clinical routine despite their proven effectiveness. For planning a tailored intervention for hospitalised patients we examined the characteristics of smokers in our department for lung diseases. METHODS AND PATIENTS: From July to September 2009 we evaluated the smoking status of all admitted patients. The smoking status was validated by measuring the CO-Hb. Smokers admitted for the first time on one of our regular wards received a comprehensive questionnaire. Patients with a duration of stay of 2 days or less and patients with substantial cognitive or linguistic limitations were excluded. Clinical data was collected from the participating smokers. RESULTS: 25% of all admitted patients were smokers. The participation rate was almost 90% of the eligible smokers. Our questionnaire was very well accepted und provided multitude helpful information for a following cessation counselling. Up to 3 or 4 smokers per day should be anticipated for a cessation intervention at an 80-bed-hospital. At least one counselling contact could be enabled. Although 75% of participants had experienced at least one unsuccessful quit attempt, only a minority used any support or help for cessation so far. CONCLUSIONS: Specific questionnaires to evaluate the smoking history of patients in hospitals are very suitable and facilitate a subsequent bedside-counseling. To come up with their key role in promoting smoking cessation more hospitals as yet should implement cessation interventions.

High resolution stereoscopic volume visualization of the mouse arginine vasopressin system.

New imaging technologies have increased our capabilities to resolve three-dimensional structures from microscopic samples. Laser-scanning confocal microscopy is particularly amenable to this task because it allows the researcher to optically section biological samples, creating three-dimensional image volumes. However, a number of problems arise when studying neural tissue samples. These include data set size, physical scanning restrictions, volume registration and display. To deal with these issues, we undertook large-scale confocal scanning microscopy in order to visualize neural networks spanning multiple tissue sections. We demonstrate a technique to create and visualize a three-dimensional digital reconstruction of the hypothalamic arginine vasopressin neuroendocrine system in the male mouse. The generated three-dimensional data included a volume of tissue that measures 4.35 mm x 2.6 mm x 1.4mm with a voxel resolution of 1.2 microm. The dataset matrix included 3508 x 2072 x 700 pixels and was a composite of 19,600 optical sections. Once reconstructed into a single volume, the data is suitable for interactive stereoscopic projection. Stereoscopic imaging provides greater insight and understanding of spatial relationships in neural tissues' inherently three-dimensional structure. This technique provides a model approach for the development of data sets that can provide new and informative volume rendered views of brain structures. This study affirms the value of stereoscopic volume-based visualization in neuroscience research and education, and the feasibility of creating large-scale high resolution interactive three-dimensional reconstructions of neural tissue from microscopic imagery.

Measurement of the absorption of concentrated dyes and their use for quantitative imaging of surface topography.

We propose a method to image the surface topography of transparent objects. The space between the object and the opposite closely positioned surface (such as a cover glass or a slide) is filled with a strongly absorbing dye. The contrast is generated by recording a transmission image at a wavelength where the dye absorbs. Since the transmitted intensity depends on the depth of the dye layer, it carries information about the relief of the tested surface. With sufficiently concentrated dyes, nanometre unevenness of a surface can be detected. By using less-concentrated solutions, it is possible to image and measure larger objects, such as biological cells. At the present stage, biological applications of the method are only semi-quantitative, but the method still provides detailed information about cell shapes that is not readily obtainable with other imaging techniques. Conversion of the image grey scale into the units of vertical distance requires knowledge of the absorption coefficient of the dye. The same method that is used for imaging can be adapted to measure the absorption coefficient of concentrated dyes. The solution to be analyzed is placed between a glass slide and a spherical lens of known radius. The absorption coefficient is determined from attenuation of transmitted intensity as a function of the distance to the centre. At the same time, the interference pattern in the reflected image allows measurement of the refractive index of the dye.

Concentrated dyes as a source of two-dimensional fluorescent field for characterization of a confocal microscope.

The axial spread function is a useful tool for evaluation of a confocal microscope. It can be obtained experimentally by scanning a uniform fluorescent layer whose thickness is significantly below the resolution limit. Previous researchers have created thin fluorescent films by chemical synthesis. We show here that concentrated fluorescent dyes with a strong absorption at the excitation wavelength can serve as a good approximation of thin fluorescent films. The vertical intensity profiles of such dyes are symmetrical and represent the true axial resolution of a microscope. Solutions of dyes sufficiently opaque to test confocal microscopes with high-NA objectives can be prepared from sodium fluorescein, acid fuchsin and acid blue 9 for excitation at 488 nm, 543 nm and 633 nm, respectively.

Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network.

BACKGROUND: There is no standard first line treatment for mantle cell lymphoma. PATIENTS AND METHODS: This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide, vincristine doxorubicin, dexamethasone (modified R-hyperCVAD) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years. Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. RESULTS: Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. CONCLUSION: In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity.

Piezosurgery--a new safe technique in cranial osteoplasty?

All surgical interventions on the neurocranium bear the risk of injury of the dura mater and development of a cerebrospinal fluid fistula. Therefore, despite careful preparation, damage to the dura mater cannot always be omitted. Especially after surgery and in patients with increased intracranial pressure (craniosynostoses) there is a high risk of perforating the dura. In this article a new surgical technique for osteotomy (Piezosurgery) that avoids perforation of the dura is presented. Ultrasonic microvibrations allow a selective cut of only mineralized structures without damage to the soft tissue. Even in case of accidental contact the dura remains undamaged. This advantage is also useful for bone splitting, to separate the tabula externa from the tabula interna in situ, without any risk of dura perforation even in case of the very thin bones in an infantile skull. The present work shows the applicability of piezoelectric surgery in high-risk patients after osteotomy, avoiding perforation of the dura mater.

Empirical assessment of the economic behaviour of Dutch general hospitals.

We study the cost structure and efficiency of Dutch general hospitals over the period 1985-1995. Several studies on the efficiency of hospitals now exist. Most of them start from the assumption that hospital management attempts to minimize cost. We went beyond this assumption by trying to collect empirical evidence on management behaviour with respect to patient selection. We did so by estimating both the direct cost function and the indirect cost function as proposed by Färe and Primont and compared the results. We found that acknowledging the possibility of output reallocation increases the validity of optimizing models in the hospital sector but a complete indirect optimizing model ignores that some output categories are less flexible especially in the short run. Endogenous shifts in the allocation of patients appear to be realized through time by increased specialization of hospitals. We suggest that a mixed direct-indirect cost model is probably preferable.

Electrophysiological properties of the L-type Ca(2+) current in cardiomyocytes from bluefin tuna and Pacific mackerel.

Tunas are capable of exceptionally high maximum metabolic rates; such capability requires rapid delivery of oxygen and metabolic substrate to the tissues. This requirement is met, in part, by exceptionally high maximum cardiac outputs, opening the possibility that myocardial Ca(2+) delivery is enhanced in myocytes from tuna compared with those from other fish. In this study, we investigated the electrophysiological properties of the cardiac L-type Ca(2+) channel current (I(Ca)) to test the hypothesis that Ca(2+) influx would be large and have faster kinetics in cardiomyocytes from Pacific bluefin tuna (Thunnus orientalis) than in those from its sister taxon, the Pacific mackerel (Scombe japonicus). In accordance with this hypothesis, I(Ca) in atrial myocytes from bluefin tuna had significantly greater peak current amplitudes and faster fast inactivation kinetics (-4.4 +/- 0.2 pA/pF and 25.9 +/- 1.6 ms, respectively) than those from mackerel (-2.7 +/- 0.5 pA/pF and 32.3 +/- 3.8 ms, respectively). Steady-state activation, inactivation, and recovery from inactivation were also faster in atrial myocytes from tuna than from mackerel. In ventricular myocytes, current amplitude and activation and inactivation rates were similar in both species but elevated compared with those of other teleosts. These results indicate enhanced I(Ca) in atrial myocytes from bluefin tuna compared with Pacific mackerel; this enhanced I(Ca) may be associated with elevated cardiac performance, because I(Ca) delivers the majority of Ca(2+) involved in excitation-contraction coupling in most fish hearts. Similarly, I(Ca) is enhanced in the ventricle of both species compared with other teleosts and may play a role in the robust cardiac performance of fishes of the family Scombridae.

The influence of His94 and Pro149 in modulating the activity of V. cholerae DsbA.

DsbA is the primary catalyst of disulfide bond formation in the periplasm of gram-negative bacteria. Numerous theoretical and experimental studies have been undertaken to determine the molecular mechanisms by which DsbA acts as a potent oxidant, whereas the homologous cytoplasmic protein, thioredoxin, acts as a reductant. Many of these studies have focused on the nature of the two residues that lie between the active-site cysteines. Although these are clearly important, they are not solely responsible for the differences in activity between these thiol-disulfide oxidoreductases. Q97 in the helical domain of E. coli DsbA has been implicated in influencing the redox potential of E. coli DsbA. In V. cholerae DsbA, the analogous residue is H94. In this study, the effect of H94 on the oxidase activity of DsbA is examined, along with the role of the conserved cis-proline residue P149. The DsbA mutant H94L shows a nearly fourfold increase in activity over the wild-type enzyme. To our knowledge, this is the first time an increase in the normal activity of a thiol-disulfide oxidoreductase has been reported. Potential reasons for this increase in activity are discussed.

The ups and downs of MEK kinase interactions.

MEK kinases (MEKKs) comprise a family of related serine-threonine protein kinases that regulate mitogen-activated protein kinase (MAPK) signalling pathways leading to c-Jun NH2-terminal kinase (JNK) and p38 activation, induced by cellular stress (e.g., UV and gamma irradiation, osmotic stress, heat shock, protein synthesis inhibitors), inflammatory cytokines (e.g., tumour necrosis factor alpha, TNFalpha, and interleukin-1, IL1) and G protein-coupled receptor agonists (e.g., thrombin). These stress-activated kinases have been implicated in apoptosis, oncogenic transformation, and inflammatory responses in various cell types. At present, the signalling events involving MEKKs are not well understood. This review summarises our current knowledge concerning the regulation and function of MEKK family members, with particular emphasis on those factors capable of directly interacting with distinct MEKK isoforms.

Enantioselective synthesis of a mitosane core assisted by diversity-based catalyst discovery.

[reaction: see text]. Synthesis of mitosane 1 in optically pure form is reported. A retrosynthetic plan that proceeds through racemic allylic alcohol 3 was carried out. This intermediate served as a test substrate for a rapid screen of a small library (152 members) of peptide-based kinetic resolution catalysts. Peptide 9 was found to effect kinetic resolution with k(rel) = 27. Alcohol (-)-3 was then converted to optically pure (-)-1 in eight steps.

A quality-adjusted cost function in a regulated industry: the case of Dutch nursing homes.

The primary objective of this paper is to examine the cost structure of the Dutch nursing home industry, using econometric techniques. In this paper we present a model that combines economic behaviour and quality of services measured by a latent variable. We propose a simple method for identifying and estimating cost functions in the presence of endogenous, unobserved quality. Estimating this quality-adjusted cost function and the corresponding cost share equations indicates that quality is negatively related to the input prices of nurses and other personnel, indicating that nursing homes have a preference for labour. We also show that the quality-adjusted model is superior to a model with exogenous quality.

A novel mechanism of body mass regulation.

While significant attention has been devoted to the identification of hormonal factors that control body mass, little attention has been paid to the role of mechanical loading on animal mass. Here, we provide evidence that intraperitoneal implantation of metabolically inert mass results in a compensatory reduction in tissue mass. Deer mice (Peromyscus maniculatus) were surgically implanted with weights of 1, 2 or 3 g. There was a resulting loss of tissue mass (total body mass minus implant mass) that was proportional to the mass of the implant. This reduction in tissue mass followed a reduction in food intake in animals with 3 g implants. Evaluation of body composition failed to identify any single component that contributed to the loss of tissue mass. Removal of implants led to a transient restoration of body mass to levels similar to the total body mass of those control animals in which the implant had not been removed. However, within 12 days of implant removal, body mass again declined to the level seen before implant removal. These results suggest the existence of a set point that is sensitive to changes in the perception of mass and that is transduced via neural pathways.

Experimental shock chemistry of aqueous amino acid solutions and the cometary delivery of prebiotic compounds.

A series of shock experiments were conducted to assess the feasibility of the delivery of organic compounds to the Earth via cometary impacts. Aqueous solutions containing near-saturation levels of amino acids (lysine, norvaline, aminobutyric acid, proline, and phenylalanine) were sealed inside stainless steel capsules and shocked by ballistic impact with a steel projectile plate accelerated along a 12-m-long gun barrel to velocities of 0.5-1.9 km sec-1. Pressure-temperature-time histories of the shocked fluids were calculated using 1D hydrodynamical simulations. Maximum conditions experienced by the solutions lasted 0.85-2.7 microseconds and ranged from 5.1-21 GPa and 412-870 K. Recovered sample capsules were milled open and liquid was extracted. Samples were analyzed using high performance liquid chromatography (HPLC) and mass spectrometry (MS). In all experiments, a large fraction of the amino acids survived. We observed differences in kinetic behavior and the degree of survivability among the amino acids. Aminobutyric acid appeared to be the least reactive, and phenylalanine appeared to be the most reactive of the amino acids. The impact process resulted in the formation of peptide bonds; new compounds included amino acid dimers and cyclic diketopiperazines. In our experiments, and in certain naturally occurring impacts, pressure has a greater influence than temperature in determining reaction pathways. Our results support the hypothesis that significant concentrations of organic material could survive a natural impact process.

Longitudinal variation in muscle protein expression and contraction kinetics of largemouth bass axial muscle.

The present study investigates muscle protein expression in largemouth bass Micropterus salmoides through intra- and intermyomeric comparisons of white muscle. Using denaturing SDS-polyacrylamide gel electrophoresis, muscle protein expression in the arm and cone regions of sequential myomeres was compared for three bass. Low percentage (4.75 %) polyacrylamide-SDS gels and cyanogen bromide (CNBr) peptide mapping revealed no obvious intramyomeric differences between the myosin heavy chains of the arm and cone regions. Electrophoresis of myofibrils and muscle homogenates on higher percentage gels also failed to demonstrate any significant differences between arm and cone regions in either the myosin light chains or any of the major insoluble and soluble contractile proteins. Two differences were discovered intermyomerically: (i) the ratio of two troponin T isoforms changed from head to tail and (ii) caudal muscle had a lower total parvalbumin content than rostral muscle. Since troponin T and parvalbumin have been implicated in the regulation of skeletal muscle kinetics, longitudinal variation in muscle contraction kinetics was predicted. Subsequent experiments revealed that bass rostral white muscle showed faster rates of activation and relaxation than more caudal muscle, as has been observed in white muscle of other fish species. Rostral-caudal variations in white muscle protein composition and contractile properties are predicted to affect patterns of power production during fast, unsteady swimming.