Single Mars Research Articles

314: EXTRACORPOREAL LIVER ASSIST DEVICE FOR ACUTE LIVER INJURY DUE TO LIKELY PARTIAL UREA CYCLE DISORDER

Introduction: Extracorporeal liver assist device (ELAD) is used to bridge patients in acute liver failure to transplant or in severe acute liver injury until spontaneous recovery. ELAD employs an albumin circuit to dialyze albumin-bound toxins from the blood stream. Urea is an albumin bound molecule formed in the liver as a result of nitrogen breakdown. Urea Cycle Disorders (UCDs) are a rare group of genetic enzymatic deficiencies that typically manifest early in life but partial enzymatic deficiencies can present later in life in times of metabolic stress. Description: A 38-year-old female presented with progressive encephalopathy 2 months after being diagnosed with alcoholic hepatitis at which time she had stopped drinking alcohol. She had no prior liver disease. Initial labs showed an elevated ammonia level of 87 mcmol/L, despite decrease in total bilirubin from 33 mg/dL to 3.5mg/dL, and INR of 1.9 to 1.4 since the peak of her alcoholic hepatitis. She had no imaging evidence of cirrhosis and had normal aminotransferases, platelets, and renal function. Initial head CT, infectious evaluation, and work-up for alternate etiologies of acute liver injury were unremarkable. She was intubated for progressive hepatic encephalopathy on hospital day 9. Her ammonia level significantly rose to 203 mcmol/L and a repeat head CT showed diffuse cerebral edema. Due to a rising ammonia level to 247 mcmol/L and CT evidence of progressive cerebral edema despite mannitol, therapeutic hyperventilation, and sedation. She was started on MARS (TM) therapy on hospital day 11. After one 7-hour session, her ammonia level decreased to 101 mcmol/L, mental status improved and head CT showed improved cerebral edema. A urinary orotic acid level was elevated at 1.8 mmol per mol of creatinine. Discussion: A partial UCD was suspected due to atypical time course of encephalopathy and hyperammonemia in the context of improving liver synthetic function and absence of cirrhosis. Genetic testing is pending however, a partial UCD is likely given the elevated urinary orotic acid. A single case report exists of confirmed acquired glutamine synthetase deficiency after orthotopic liver transplant that also improved after a single MARS session. Our report adds to the scarce literature on this topic.

High Capacity Immunomagnetic Isolation of Apheresis Samples in an Automated Closed System

Abstract Cell therapy development, including Chimeric antigen receptor (CAR)-T cells, involves many steps and requires processing on average 3 billion white blood cells or more. Automated large scale immunomagnetic cell isolation with high efficiency and throughput in a closed system is desired to enrich T cells from apheresis products. Current automated, high capacity methods are time consuming, high cost, low yield and can potentially influence the physiology of the target cells. We have developed an automated closed magnetic separation platform, MARS® Bar to address these problems. This platform uses three uniquely designed magnetic separation modules and each magnetic module can perform positive or negative selection of target cells in a fluidic chamber at high flow rate (1mL/min per module). On this platform we have developed cell isolation reagents and program with minimal cell preparation. In the pilot study, we isolated 116 million CD3+ T cells from 267million CD45+ cells in a single LSR chamber on a single MARS® module. The entire automated process took less than 15 minutes to complete and resulted in > 95% purity and > 96% recovery of CD3+ T cells. The isolated cells were then activated and expanded, with results showing high proliferation and the dominant population being central memory T cells. The unique MARS® Bar matrix-free design has unlimited capacity because of the automated release of positively captured cells and very low carry-over. This was validated by processing greater than 3 billion leukocytes at 20 million cells per mL within the three modules in parallel and intermittent release of captured cells for collection. The MARS® Bar can be easily integrated into standard T cell production workflow.

Coupling wavelet transform with multivariate adaptive regression spline for simulating suspended sediment load: Independent testing approach

ABSTRACT Accurate prediction of suspended sediment load (SSL) of a river is very important as it directly affects the performance of the corresponding hydraulic structures. SSL can give valuable information on the catchment erodibility and deposition of the sediment being produced through scouring phenomenon. Despite the hydraulic approaches for studying the scouring/sedimentation processes in streams, hydrologic approaches may provide valuable information about SSL deposition magnitudes as well as its temporal distribution in relation with the streamflow power. A hydrologic-based approach through coupling the wavelet-based processed signals and multi adaptive regression spline (WMARS) methodology is suggested in the present paper for the first time to predict SSL values of rivers using the simultaneous streamflow and SSL records. The developed models were assessed through the most powerful k-fold testing data scanning procedure. The obtained results showed the superiority of the proposed hybrid WMARS models over the single MARS and traditional sediment rating curve techniques. Due to the presence of hysteresis effects during the study periods, adaptation of k-fold testing assessment approach is very necessary to get better insight about the models performances.

Two billion years of magmatism recorded from a single Mars meteorite ejection site.

The timing and nature of igneous activity recorded at a single Mars ejection site can be determined from the isotope analyses of Martian meteorites. Northwest Africa (NWA) 7635 has an Sm-Nd crystallization age of 2.403 ± 0.140 billion years, and isotope data indicate that it is derived from an incompatible trace element-depleted mantle source similar to that which produced a geochemically distinct group of 327- to 574-million-year-old "depleted" shergottites. Cosmogenic nuclide data demonstrate that NWA 7635 was ejected from Mars 1.1 million years ago (Ma), as were at least 10 other depleted shergottites. The shared ejection age is consistent with a common ejection site for these meteorites. The spatial association of 327- to 2403-Ma depleted shergottites indicates >2 billion years of magmatism from a long-lived and geochemically distinct volcanic center near the ejection site.

Sporadic formation of slope streaks on Mars

Slope streaks are a form of gravity-driven mass-movements that frequently occur on Mars today. The cause of slope streak formation remains unclear; both, dry and wet processes have been suggested. Here, we observationally constrain the time of the year during which slope streaks form. Imagery from four Mars-orbiting cameras is mined to identify locations that have been imaged repeatedly, and the overlapping images are surveyed for streak activity. A search algorithm automatically finds the locations on the surface that have been imaged most often based on a graph representation. Dark slope streaks are found to form sporadically throughout the Mars year. At one study site in the Olympus Mons Aureole, observations constrain slope streak formation to at least five distinct time intervals within a single Mars year. New slope streaks form spatially isolated or in small groups within a few kilometers of one another. The observations suggest that slope streak triggering is unrelated to season and not caused by any large regional events. Most slope streaks are caused by sporadic events of small spatial extent.

MOC observations of the 2001 Mars planet-encircling dust storm

From 15 September 1997 through 21 January 2006, only a single planet-encircling martian dust storm was observed by MGS-MOC. The onset of the storm occurred on 26 June 2001 ( L s = 184.7 ° ), earliest recorded to date. It was initiated in the southern mid-to-low latitudes by a series of local dust storm pulses that developed along the seasonal cap edge in Malea and in Hellas basin ( L s = 176.2 ° – 184.4 ° ) . The initial expansion of the storm, though asymmetric, was very rapid in all directions (3–32 m s −1). The main direction of propagation, however, was to the east, with the storm becoming planet encircling in the southern hemisphere on L s = 192.3 ° . Several distinct centers of active dust lifting were associated with the storm, with the longest persisting for 86 sols (Syria–Claritas). These regional storms helped generate and sustain a dust cloud (“haze”), which reached an altitude of about 60 km and a peak opacity of τ dust ∼ 5.0 . By L s = 197.0 ° , the cloud had encircled the entire planet between 59.0° S and 60.0° N, obscuring all but the largest volcanoes. The decay phase began around L s ∼ 200.4 ° with atmospheric dust concentrations returning to nominal seasonal low-levels at L s ∼ 304.0 ° . Exponential decay time constants ranged from 30–117 sols. The storm caused substantial regional albedo changes (darkening and brightening) as a result of the redistribution (removal and deposition) of a thin veneer of surface dust at least 0.1–11.1 μm thick. It also caused changes in meteorological phenomena (i.e., dust storms, dust devils, clouds, recession of the polar caps, and possibly surface temperatures) that persisted for just a few weeks to more than a single Mars year. The redistribution of dust by large annual regional storms might help explain the long period (∼30 years) between the largest planet-encircling dust storms events.

Survival of endospores of Bacillus subtilis on spacecraft surfaces under simulated martian environments: : implications for the forward contamination of Mars

Experiments were conducted in a Mars simulation chamber (MSC) to characterize the survival of endospores of Bacillus subtilis under high UV irradiation and simulated martian conditions. The MSC was used to create Mars surface environments in which pressure (8.5 mb), temperature (−80, −40, −10, or +23 °C), gas composition (Earth-normal N 2/O 2 mix, pure N 2, pure CO 2, or a Mars gas mix), and UV-VIS-NIR fluence rates (200–1200 nm) were maintained within tight limits. The Mars gas mix was composed of CO 2 (95.3%), N 2 (2.7%), Ar (1.7%), O 2 (0.2%), and water vapor (0.03%). Experiments were conducted to measure the effects of pressure, gas composition, and temperature alone or in combination with Mars-normal UV-VIS-NIR light environments. Endospores of B. subtilis, were deposited on aluminum coupons as monolayers in which the average density applied to coupons was 2.47×10 6 bacteria per sample. Populations of B. subtilis placed on aluminum coupons and subjected to an Earth-normal temperature (23 °C), pressure (1013 mb), and gas mix (normal N 2/O 2 ratio) but illuminated with a Mars-normal UV-VIS-NIR spectrum were reduced by over 99.9% after 30 sec exposure to Mars-normal UV fluence rates. However, it required at least 15 min of Mars-normal UV exposure to reduce bacterial populations on aluminum coupons to non-recoverable levels. These results were duplicated when bacteria were exposed to Mars-normal environments of temperature (−10 °C), pressure (8.5 mb), gas composition (pure CO 2), and UV fluence rates. In other experiments, results indicated that the gas composition of the atmosphere and the temperature of the bacterial monolayers at the time of Mars UV exposure had no effects on the survival of bacterial endospores. But Mars-normal pressures (8.5 mb) were found to reduce survival by approximately 20–35% compared to Earth-normal pressures (1013 mb). The primary implications of these results are (a) that greater than 99.9% of bacterial populations on sun-exposed surfaces of spacecraft are likely to be inactivated within a few tens of seconds to a few minutes on the surface of Mars, and (b) that within a single Mars day under clear-sky conditions bacterial populations on sun-exposed surfaces of spacecraft will be sterilized. Furthermore, these results suggest that the high UV fluence rates on the martian surface can be an important resource in minimizing the forward contamination of Mars.

Extracorporeal liver support by recirculating albumin dialysis: analysing the effect of the first clinically used generation of the MARSystem.

Albumin dialysis with the MARSystem is used in many hospitals to support excretory hepatic function in acute or acute on chronic liver failure. Potential pathogenic albumin bound substances accumulated in excretory liver insufficiency can be removed from patients blood by dialysis against albumin solution. A specific membrane enables the selective transport of albumin bound metabolites to the albumin containing dialysate compartment, where the loaded transport albumin is cleared and regenerated at the same time by adsorption columns and a second dialyser. Between 1993 and 1995 different membranes, set-ups and components in albumin dialysis were tested and led finally to the recirculating MARSystem with a modified polysulphone based membrane (P3/5S Gambro, Hechingen) and two adsorption columns (N350 and BR 350, ASAHI Medical Ltd.), which showed the best performance at this time. This first generation of MARSystems was used clinically between 1995 and 1998 with only minor changes in 15 patients with acute (n = 1) or acute deterioration of chronic liver disease in our department until the improved next generation of MARSystems has been available (MARS set and monitor, Teraklin AG, Rostock, Germany). Changes in blood tests pre/post during 95 single MARS treatments and in clinical status over treatment period were evaluated retrospectively. A significant decrease of albumin bound substances (average reduction during single MARS treatments: bilirubin -18%, bile acids -43.7%) as well as of water soluble metabolites (creatinine -32%, urea -31%) was observed. During extracorporeal therapy also a significant drop in platelets (- 15.4%) and a prolongation of activated prothrombin time (- 21%) was documented, whereas haemoglobin, WBC, electrolytes as well as transaminases and albumin were not affected significantly. Albumin dialysis with the first generation of MARS enables the removal of albumin bound and water soluble toxins. Unwanted side-effects and changes in laboratory tests are comparable to conventional haemodialysis (drop of platelets and prolongation of coagulation tests). The elimination of albumin bound and water soluble substances was accompanied by an improvement of clinical status.

Protein:DNA interactions at chromosomal loop attachment sites

We have recently identified an evolutionarily conserved class of sequences that organize chromosomal loops in the interphase nucleus, which we have termed "matrix association regions" (MARs). MARs are about 200 bp long, AT-rich, contain topoisomerase II consensus sequences and other AT-rich sequence motifs, often reside near cis-acting regulatory sequences, and their binding sites are abundant (greater than 10,000 per mammalian nucleus). Here we demonstrate that the interactions between the mouse kappa immunoglobulin gene MAR and topoisomerase II or the "nuclear matrix" occur between multiple and sometimes overlapping binding sites. Interestingly, the sites most susceptible to topoisomerase II cleavage are localized near the breakpoints of a previously described illegitimate recombination event. The presence of multiple binding sites within single MARs may allow DNA and RNA polymerase passage without disrupting primary loop organization.