Exercise training reduces arterial stiffness in women with high blood pressure: a systematic review and meta-analysis.

The acute and long-term benefits of exercise on cardiovascular health are well established, yet the optimal mode of exercise training that improves arterial stiffness in women with high blood pressure remains unclear. The aim of this systematic review and meta-analysis was to assess the influence of aerobic and resistance training on arterial stiffness in women with high blood pressure. After an extensive search of four online databases, six randomized controlled trials met the inclusion criteria and were included in meta-analyses. Data were extracted from six studies examining the influence of exercise on arterial stiffness assessed by pulse wave velocity (PWV) and were expressed as standardized mean difference (SMD). Whereas aerobic exercise significantly reduced arterial PWV in women with high blood pressure after long-term training [SMD -1.87, 95% confidence interval (CI) -2.34 to -1.40], resistance training had a more modest effect that was borderline statistically significant (SMD -0.31, 95% CI -0.65 to 0.03). These findings suggest regular long-term aerobic exercise training (i.e. 12-20 week interventions) reduces arterial stiffness in women with high blood pressure. Although not statistically significant, the modest number of included trials and lack of publication bias encourages further assessments on the efficacy of resistance exercise for improving arterial stiffness in women with high blood pressure. Given the unique benefits of aerobic and resistance training, particularly for postmenopausal women (e.g. bone health and muscular strength), both modes of training should be encouraged for women with high blood pressure to enhance arterial function and support favorable cardiovascular outcomes.

Moderate to Vigorous-intensity Continuous Training versus Highintensity Interval Training for Improving VO2max in Women: A Systematic Review and Meta-analysis.

Traditional continuous training and high-intensity interval training (HIIT) can increase maximal oxygen uptake (V̇O2max). However, there is conflicting evidence regarding which form of training demonstrates the greatest improvements to V̇O2max, and data in women is sparse. We conducted a systematic review and meta-analyses to assess whether moderate to vigorous-intensity continuous training (MVICT) or HIIT was superior at improving V̇O2max in women. Randomised controlled and parallel studies examined the influence of MVICT and/or HIIT on V̇O2max in women. There was no statistical difference in V̇O2max improvements after training between women in the MVICT and HIIT cohorts (mean difference [MD]: -0.42, 95%CI: -1.43 to 0.60, p>0.05). Both MVICT and HIIT increased V̇O2max from baseline (MD: 3.20, 95% CI: 2.73 to 3.67 and MD: 3.16, 95% CI 2.09 to 4.24, respectively, p<0.001). Greater improvements in V̇O2max were observed in women who participated in more training sessions in both training formats. Long-HIIT was superior to short-HIIT protocols at increasing V̇O2max. Although MVICT and long-HIIT sessions elicited greater increases in V̇O2max in younger women compared to short-HIIT protocols, these differences were negligible in older women. Our findings suggest MVICT and HIIT are equally effective strategies for improving V̇O2max and indicate an effect of age on its response to training in women.

Biomechanical Comparison of Cannulated Screw Osteosynthesis With Tension-Band Wiring for Proximal Fractures of the Fifth Metatarsal (Jones Fracture).

Jones fractures, which lie at the junction of the diaphysis to the metaphysis of the fifth metatarsal, are a well-described clinical issue. There are various surgical approaches, including the commonly performed cannulated screw osteosyntheses, and the less frequently used tension-band approach. The aim is to compare the biomechanical stability of these osteosyntheses. We performed an osteotomy on 16 fresh frozen fifth metatarsal bones from body donors representing a Jones fracture. The fractures were treated pairwise with screw osteosynthesis or tension-band wiring. This was followed by cyclic axial bending until osteosynthesis failure. Stability under axial bending force was higher in the screw osteosynthesis (mean: 70.0 ± 66.5 N) compared to the tension-band wiring (mean: 35.7 ± 23.3 N) group although not reaching statistical significance (p = .116). The study shows no statistically significant difference in biomechanical stability under axial loading between screw osteosynthesis and tension band wiring. Based on the data obtained, no differences can be observed from a biomechanical point of view. The study supports the established method of treating Jones fractures primarily with screw osteosynthesis. In addition, the data suggest that tension band wiring may be a good alternative osteosynthesis, for example, after failed casting treatment or failure of primary osteosynthesis.

Prevalence of Patients with Uncontrolled Asthma Despite NVL/GINA Step 4/5 Treatment in Germany.

Purpose: Asthma is one of the most prevalent chronic diseases in Germany affecting 4-5% of all adults and 10% of children. Despite the availability of biologicals in recent years, studies show patients with inadequately controlled severe asthma in real life. The aim of the current study was to characterize and estimate the number of patients with NVL/GINA level 4 or 5 asthma and signs of poor control in Germany. Patients and Methods: In 2021, we retrospectively analyzed data collected during 2019 using the IQVIA™ LRx and IQVIA™ Disease Analyzer databases which contain anonymized longitudinal data covering approximately 80% of statutory health insurance (GKV) prescriptions in Germany with most relevant information about prescriptions, basic patient demographics or location of the prescriber; the IQVIA™ Disease Analyzer anonymized electronic medical records from a representative sample of office-based GPs and specialists. An expert committee of pulmonologists from different hospitals and expert practices supported the study. Asthma patients treated according to NVL/GINA 4/5 who used SABAs frequently (≥3 on days with no ICS-containing prescriptions/year) and/or received prescriptions for oral corticosteroids (OCS) (score of ≥2/year, a pulmonologist prescription scored 1.0, GP 0.75) were classified as severe, uncontrolled asthma. Results: In 2019, 3.4 million patients received at least two prescriptions of respiratory medications and 2.4 million patients on maintenance respiratory treatment have asthma. A total of 625,000 asthma patients were treated according to NVL/GINA step 4 or 5. Among these, 54,000 were uncontrolled according to the pre-defined OCS and/or SABA use, which corresponds to approximately 15% of patients in certain regions. Conclusion: In 2019, approximately 54,000 patients in Germany treated according to NVL/GINA step 4/5 had evidence suggestive for poor asthma control, up to 15% of patients in certain regions. Yet, only 12,000 patients overall were being treated with biologicals suggesting a possible treatment gap that requires further investigation.

German regional variation of acute and high oral corticosteroid use for asthma.

OBJECTIVE: To improve understanding of real-world asthma treatment and inform physician education, we evaluated regional variation in asthma prevalence and oral corticosteroid (OCS) use across Germany. METHODS: We developed a machine learning gradient-boosted tree model with IMS® Disease Analyzer electronic medical records, which cover 3% of German patients. This model had a 91% accuracy in predicting the presence of asthma and chronic obstructive pulmonary disease. We applied the model to the IMS® Longitudinal Prescription database, with 82% national coverage, to classify patients receiving treatment for airflow obstruction from October 2017-September 2018 in 63 regions in Germany. RESULTS: Of 2.4 million individuals under statutory health insurance predicted to have asthma, 13.7%, 18.7%, 36.5%, 29.4%, and 1.7% received treatment classified as Global Initiative for Asthma (GINA) Steps 1, 2, 3, 4, and 5, respectively. Approximately 7-15% of those at GINA Steps 1-4 and 35% at Step 5 treatment received ≥1 acute OCS prescription (duration <10 days). Of patients receiving GINA Steps 1-4 and Step 5 treatments, 1-3% and 86%, respectively, received ≥1 high-dosage OCS prescription. Cumulative OCS dosage and percentages of patients receiving OCS differed substantially across regions, and regions with lower OCS use had greater use of biologic therapies. CONCLUSIONS: Both acute and high OCS use varied regionally across Germany, with overall use suggesting patients are considerable risk of adverse effects and long-term health consequences.Supplemental data for this article can be accessed at publisher's website.

Low Density Lipoprotein Receptor-Related Protein-1 (LRP1) Is Involved in the Uptake of Clostridioides difficile Toxin A and Serves as an Internalizing Receptor.

Toxin producing Clostridioides difficile strains cause gastrointestinal infections with the large glucosylating protein toxins A (TcdA) and B (TcdB) being major virulence factors responsible for the onset of symptoms. TcdA and TcdB enter their target cells via receptor-mediated endocytosis. Inside the cell, the toxins glucosylate and thereby inactivate small GTPases of the Rho-/Ras subfamilies resulting in actin reorganization and cell death. The receptors of TcdA are still elusive, glycoprotein 96 (gp96), the low density lipoprotein receptor family (LDLR) and sulfated glycosaminoglycans (sGAGs) have most recently been suggested as receptors for TcdA. In this study, we provide evidence on rapid endocytosis of Low density lipoprotein Receptor-related Protein-1 (LRP1) into fibroblasts and Caco-2 cells by exploiting biotinylation of cell surface proteins. In contrast, gp96 was not endocytosed either in the presence or absence of TcdA. The kinetics of internalization of TfR and LRP1 were comparable in the presence and the absence of TcdA, excluding that TcdA facilitates its internalization by triggering internalization of its receptors. Exploiting fibroblasts with a genetic deletion of LRP1, TcdA was about one order of magnitude less potent in LRP1-deficient cells as compared to the corresponding control cells. In contrast, TcdB exhibited a comparable potency in LRP1-proficient and -deficient fibroblasts. These findings suggested a role of LRP1 in the cellular uptake of TcdA but not of TcdB. Correspondingly, binding of TcdA to the cell surface of LRP1-deficient fibroblasts was reduced as compared with LRP1-proficient fibroblasts. Finally, TcdA bound to LRP1 ligand binding type repeat cluster II (amino acid 786-1,165) and cluster IV (amino acid 3332-3779). In conclusion, LRP1 appears to serve as an endocytic receptor and gp96 as a non-endocytic receptor for TcdA.

A Single Amino Acid Residue Regulates PTEN-Binding and Stability of the Spinal Muscular Atrophy Protein SMN.

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA.

ORIGIN: a novel and compact Laser Desorption - Mass Spectrometry system for sensitive in situ detection of amino acids on extraterrestrial surfaces.

For the last four decades space exploration missions have searched for molecular life on planetary surfaces beyond Earth. Often pyrolysis gas chromatography mass spectrometry has been used as payload on such space exploration missions. These instruments have relatively low detection sensitivity and their measurements are often undermined by the presence of chloride salts and minerals. Currently, ocean worlds in the outer Solar System, such as the icy moons Europa and Enceladus, represent potentially habitable environments and are therefore prime targets for the search for biosignatures. For future space exploration missions, novel measurement concepts, capable of detecting low concentrations of biomolecules with significantly improved sensitivity and specificity are required. Here we report on a novel analytical technique for the detection of extremely low concentrations of amino acids using ORIGIN, a compact and lightweight laser desorption ionization - mass spectrometer designed and developed for in situ space exploration missions. The identified unique mass fragmentation patterns of amino acids coupled to a multi-position laser scan, allows for a robust identification and quantification of amino acids. With a detection limit of a few fmol mm-2, and the possibility for sub-fmol detection sensitivity, this measurement technique excels current space exploration systems by three orders of magnitude. Moreover, our detection method is not affected by chemical alterations through surface minerals and/or salts, such as NaCl that is expected to be present at the percent level on ocean worlds. Our results demonstrate that ORIGIN is a promising instrument for the detection of signatures of life and ready for upcoming space missions, such as the Europa Lander.

Biosignature Analysis of Mars Soil Analogs from the Atacama Desert: Challenges and Implications for Future Missions to Mars.

The detection of biosignatures on Mars is of outstanding interest in the current field of astrobiology and drives various fields of research, ranging from new sample collection strategies to the development of more sensitive detection techniques. Detailed analysis of the organic content in Mars analog materials collected from extreme environments on Earth improves the current understanding of biosignature preservation and detection under conditions similar to those of Mars. In this article, we examined the biological fingerprint of several locations in the Atacama Desert (Chile), which include different wet and dry, and intermediate to high elevation salt flats (also named salars). Liquid chromatography and multidimensional gas chromatography mass spectrometry measurement techniques were used for the detection and analysis of amino acids extracted from the salt crusts and sediments by using sophisticated extraction procedures. Illumina 16S amplicon sequencing was used for the identification of microbial communities associated with the different sample locations. Although amino acid load and organic carbon and nitrogen quantities were generally low, it was found that most of the samples harbored complex and versatile microbial communities, which were dominated by (extremely) halophilic microorganisms (most notably by species of the Archaeal family Halobacteriaceae). The dominance of salts (i.e., halites and sulfates) in the investigated samples leaves its mark on the composition of the microbial communities but does not appear to hinder the potential of life to flourish since it can clearly adapt to the higher concentrations. Although the Atacama Desert is one of the driest and harshest environments on Earth, it is shown that there are still sub-locations where life is able to maintain a foothold, and, as such, salt flats could be considered as interesting targets for future life exploration missions on Mars.

Profilin2a-phosphorylation as a regulatory mechanism for actin dynamics.

Profilin is a major regulator of actin dynamics in multiple specific processes localized in different cellular compartments. This specificity is not only meditated by its binding to actin but also its interaction with phospholipids such as phosphatidylinositol (4,5)-bisphosphate (PIP2 ) at the membrane and a plethora of proteins containing poly-L-proline (PLP) stretches. These interactions are fine-tuned by posttranslational modifications such as phosphorylation. Several phospho-sites have already been identified for profilin1, the ubiquitously expressed isoform. However, little is known about the phosphorylation of profilin2a. Profilin2a is a neuronal isoform important for synapse function. Here, we identified several putative profilin2a phospho-sites in silico and tested recombinant phospho-mimetics with regard to their actin-, PLP-, and PIP2 -binding properties. Moreover, we assessed their impact on actin dynamics employing a pyrene-actin polymerization assay. Results indicate that distinct phospho-sites modulate specific profilin2a functions. We could identify a molecular switch site at serine residue 71 which completely abrogated actin binding-as well as other sites important for fine-tuning of different functions, for example, tyrosine 29 for PLP binding. Our findings suggest that differential profilin2a phosphorylation is a sensitive mechanism for regulating its neuronal functions. Moreover, the dysregulation of profilin2a phosphorylation may contribute to neurodegeneration.

Deviations in positioning variable pitch screws- scaphoid waist fractures.

INTRODUCTION: Operative therapy using a headless cannulated variable pitch compression screw is the gold standard for the treatment of instable scaphoid fractures. HYPOTHESIS: Deviation from the central placement is associated with a loss of stability and stiffness. MATERIAL AND METHODS: An artificial bone model was manufactured and different screw positions (central, 10° and 20° to the long axis) were assessed. A shearing test with axial force on the 45° flexed scaphoid was applied. RESULTS: The inserted variable pitch screw showed the highest stiffness and failure force in a position in the long axis. At 10 degrees, a slight decrease in stiffness (32.7N/mm±9.3N/mm) and failure force (41.6N±13.2N) was observed, while a significant reduction in stiffness (29.3N/mm±4.6N/mm) and failure force (50.3N±19.5N) was measured at 20 degrees. DISCUSSION: Deviations in the angle of insertion of the compression screw cause loss in failure force, thus deviations from the central placement is associated with less stability and stiffness. LEVEL OF PROOF: Controlled laboratory study (basic science study, biomechanical testing).

Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo.

Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients.

Expression and (Lacking) Internalization of the Cell Surface Receptors of Clostridioides difficile Toxin B.

Toxin-producing strains of Clostridioides difficile and Clostridium perfringens cause infections of the gastrointestinal tract in humans and ruminants, with the toxins being major virulence factors, essential for the infection, and responsible for the onset of severe symptoms. C. difficile toxin A (TcdA) and toxin B (TcdB), and the large cytotoxin (TpeL) from C. perfringens are single chain bacterial protein toxins with an AB-like toxin structure. The C-terminal delivery domain mediates cell entry of the N-terminal glycosyltransferase domain by receptor-mediated endocytosis. Several cell surface proteins have been proposed to serve as toxin receptors, including chondroitin-sulfate proteoglycan 4 (CSPG4), poliovirus receptor-like 3 (PVRL3), and frizzled-1/2/7 (FZD1/2/7) for TcdB and LDL-receptor-related protein-1 (LRP1) for TpeL. The expression of the TcdB receptors was investigated in human intestinal organoids (HIOs) and in cultured cell lines. HIOs from four human donors exhibited a comparable profile of receptor expression, with PVRL3, LRP1, and FZD7 being expressed and CSPG4 and FZD2 not being expressed. In human epithelial Caco-2 cells and HT29 cells as well as in immortalized murine fibroblasts, either receptor FZD2/7, CSPG4, PVRL3, and LRP1 was expressed. The question whether the toxins take advantage of the normal turnover of their receptors (i.e., constitutive endocytosis and recycling) from the cell surface or whether the toxins activity induce the internalization of their receptors has not yet been addressed. For the analysis of receptor internalization, temperature-induced uptake of biotinylated toxin receptors into immortalized mouse embryonic fibroblasts (MEFs) and Caco-2 cells was exploited. Solely LRP1 exhibited constitutive endocytosis from the plasma membrane to the endosome, which might be abused by TpeL (and possibly TcdB as well) for cell entry. Furthermore, internalization of CSPG4, PVRL3, FZD2, and FZD7 was observed neither in MEFs nor in Caco-2 cells. FZD2/7, CSPG4, and PVRL3 did thus exhibit no constitutive recycling. The presence of TcdB and the p38 activation induced by anisomycin were not able to induce or enhance CSPG4 or PVRL3 uptake in MEFs. In conclusion, FZD2/7, CSPG4, and PVRL3 seem to serve as cell surface binding receptors rather than internalizing receptors of TcdB.

Structure-guided design and functional characterization of an artificial red light-regulated guanylate/adenylate cyclase for optogenetic applications.

Genetically targeting biological systems to control cellular processes with light is the concept of optogenetics. Despite impressive developments in this field, underlying molecular mechanisms of signal transduction of the employed photoreceptor modules are frequently not sufficiently understood to rationally design new optogenetic tools. Here, we investigate the requirements for functional coupling of red light-sensing phytochromes with non-natural enzymatic effectors by creating a series of constructs featuring the Deinococcus radiodurans bacteriophytochrome linked to a Synechocystis guanylate/adenylate cyclase. Incorporating characteristic structural elements important for cyclase regulation in our designs, we identified several red light-regulated fusions with promising properties. We provide details of one light-activated construct with low dark-state activity and high dynamic range that outperforms previous optogenetic tools in vitro and expands our in vivo toolkit, as demonstrated by manipulation of Caenorhabditis elegans locomotor activity. The full-length crystal structure of this phytochrome-linked cyclase revealed molecular details of photoreceptor-effector coupling, highlighting the importance of the regulatory cyclase element. Analysis of conformational dynamics by hydrogen-deuterium exchange in different functional states enriched our understanding of phytochrome signaling and signal integration by effectors. We found that light-induced conformational changes in the phytochrome destabilize the coiled-coil sensor-effector linker, which releases the cyclase regulatory element from an inhibited conformation, increasing cyclase activity of this artificial system. Future designs of optogenetic functionalities may benefit from our work, indicating that rational considerations for the effector improve the rate of success of initial designs to obtain optogenetic tools with superior properties.

Reversible and Efficient Light-Induced Molecular Switching on an Insulator Surface.

Prototypical molecular switches such as azobenzenes exhibit two states, i.e., trans and cis, with different characteristic physical properties. In recent years various derivatives were investigated on metallic surfaces. However, bulk insulators as supporting substrate reveal important advantages since they allow electronic decoupling from the environment, which is key to control the switching properties. Here, we report on the light-induced isomerization of an azobenzene derivative on a bulk insulator surface, in this case calcite (101̅4), studied by atomic force microscopy with submolecular resolution. Surprisingly, cis isomers appear on the surface already directly after preparation, indicating kinetic trapping. The photoisomerization process is reversible, as the use of different light sources results in specific molecular assemblies of each isomer. The process turns out to be very efficient and even comparable to molecules in solution, which we assign to the rather weak molecular interaction with the insulator surface, in contrast to metals.

Differing long term trends for two common amphibian species (Bufo bufo and Rana temporaria) in alpine landscapes of Salzburg, Austria.

This study focuses on the population trends of two widespread European anuran species: the common toad (Bufo bufo) and the common frog (Rana temporaria). The basis of this study is data gathered over two decades of amphibian fencing alongside roads in the Austrian state of Salzburg. Different statistical approaches were used to analyse the data. Overall average increase or decrease of each species was estimated by calculating a simple average locality index. In addition the statistical software TRIM was used to verify these trends as well as to categorize the data based on the geographic location of each migration site. The results show differing overall trends for the two species: the common toad being stable and the common frog showing a substantial decline over the last two decades. Further analyses based on geographic categorization reveal the strongest decrease in the alpine range of the species. Drainage and agricultural intensification are still ongoing problems within alpine areas, not only in Salzburg. Particularly in respect to micro-climate and the availability of spawning places these changes appear to have a greater impact on the habitats of the common frog than the common toad. Therefore we consider habitat destruction to be the main potential reason behind this dramatic decline. We also conclude that the substantial loss of biomass of a widespread species such as the common frog must have a severe, and often overlooked, ecological impact.

Photoactivation Mechanism of a Bacterial Light-Regulated Adenylyl Cyclase.

Light-regulated enzymes enable organisms to quickly respond to changing light conditions. We characterize a photoactivatable adenylyl cyclase (AC) from Beggiatoa sp. (bPAC) that translates a blue light signal into the production of the second messenger cyclic AMP. bPAC contains a BLUF photoreceptor domain that senses blue light using a flavin chromophore, linked to an AC domain. We present a dark state crystal structure of bPAC that closely resembles the recently published structure of the homologous OaPAC from Oscillatoria acuminata. To elucidate the structural mechanism of light-dependent AC activation by the BLUF domain, we determined the crystal structures of illuminated bPAC and of a pseudo-lit state variant. We use hydrogen-deuterium exchange measurements of secondary structure dynamics and hypothesis-driven point mutations to trace the activation pathway from the chromophore in the BLUF domain to the active site of the cyclase. The structural changes are relayed from the residues interacting with the excited chromophore through a conserved kink of the BLUF ß-sheet to a tongue-like extrusion of the AC domain that regulates active site opening and repositions catalytic residues. Our findings not only show the specific molecular pathway of photoactivation in BLUF-regulated ACs but also have implications for the general understanding of signaling in BLUF domains and of the activation of ACs.

Invariant Chain Complexes and Clusters as Platforms for MIF Signaling.

Invariant chain (Ii/CD74) has been identified as a surface receptor for migration inhibitory factor (MIF). Most cells that express Ii also synthesize major histocompatibility complex class II (MHC II) molecules, which depend on Ii as a chaperone and a targeting factor. The assembly of nonameric complexes consisting of one Ii trimer and three MHC II molecules (each of which is a heterodimer) has been regarded as a prerequisite for efficient delivery to the cell surface. Due to rapid endocytosis, however, only low levels of Ii-MHC II complexes are displayed on the cell surface of professional antigen presenting cells and very little free Ii trimers. The association of Ii and MHC II has been reported to block the interaction with MIF, thus questioning the role of surface Ii as a receptor for MIF on MHC II-expressing cells. Recent work offers a potential solution to this conundrum: Many Ii-complexes at the cell surface appear to be under-saturated with MHC II, leaving unoccupied Ii subunits as potential binding sites for MIF. Some of this work also sheds light on novel aspects of signal transduction by Ii-bound MIF in B-lymphocytes: membrane raft association of Ii-MHC II complexes enables MIF to target Ii-MHC II to antigen-clustered B-cell-receptors (BCR) and to foster BCR-driven signaling and intracellular trafficking.

The Mars Organic Molecule Analyzer (MOMA) Instrument: Characterization of Organic Material in Martian Sediments.

The Mars Organic Molecule Analyzer (MOMA) instrument onboard the ESA/Roscosmos ExoMars rover (to launch in July, 2020) will analyze volatile and refractory organic compounds in martian surface and subsurface sediments. In this study, we describe the design, current status of development, and analytical capabilities of the instrument. Data acquired on preliminary MOMA flight-like hardware and experimental setups are also presented, illustrating their contribution to the overall science return of the mission. Key Words: Mars-Mass spectrometry-Life detection-Planetary instrumentation. Astrobiology 17, 655-685.