The WISDOM Radar: Unveiling the Subsurface Beneath the ExoMars Rover and Identifying the Best Locations for Drilling

The search for evidence of past or present life on Mars is the principal objective of the 2020 ESA-Roscosmos ExoMars Rover mission. If such evidence is to be found anywhere, it will most likely be in the subsurface, where organic molecules are shielded from the destructive effects of ionizing radiation and atmospheric oxidants. For this reason, the ExoMars Rover mission has been optimized to investigate the subsurface to identify, understand, and sample those locations where conditions for the preservation of evidence of past life are most likely to be found. The Water Ice Subsurface Deposit Observation on Mars (WISDOM) ground-penetrating radar has been designed to provide information about the nature of the shallow subsurface over depth ranging from 3 to 10 m (with a vertical resolution of up to 3 cm), depending on the dielectric properties of the regolith. This depth range is critical to understanding the geologic evolution stratigraphy and distribution and state of subsurface H2O, which provide important clues in the search for life and the identification of optimal drilling sites for investigation and sampling by the Rover's 2-m drill. WISDOM will help ensure the safety and success of drilling operations by identification of potential hazards that might interfere with retrieval of subsurface samples

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Fatigue Is Not Associated with Impaired Function of Regulatory T Cells in Untreated Patients with Multiple Sclerosis

Background: The pathophysiology of multiple sclerosis (MS)-associated fatigue is poorly understood. Immunological mechanisms may play a role. Alterations in immunological profile indicate a chronic immune activation in MS patients with fatigue. T-regulatory (Treg) cells seem to play a key role in coordinating autoimmune mechanisms in MS. This is the first study investigating the relationship between Treg cell function and fatigue in MS patients. Methods: In this cross-sectional in vitro, ex vivo study, we isolated peripheral blood mononuclear cells (PBMCs) from 20 MS patients with fatigue, determined lymphocyte subsets by flow cytometry and suppressive function of Treg cells in PBMC cultures with antigen stimulation. Forkhead box protein 3 expression was evaluated by PCR. Results were compared with 20 MS patients without fatigue and with 19 healthy controls. Results: Leukocytes and lymphocyte subsets including Treg cell frequency did not differ in patients with and without fatigue. Co-culturing of Treg cells with CD4+CD25– cells did not lead to a significant suppression of myelin basic protein- and pokeweed mitogen-induced proliferation in MS patients in contrast to healthy controls. There were no statistical differences between MS patients with and without fatigue regarding this suppression activity. Conclusions: Fatigue seems not to be associated with impaired function of Treg cells in untreated MS patients

Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantation—Immune signature correlates with response

SummaryAcute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (allo‐HCT) is often driven by immune‐related mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graft‐versus‐leukaemia effect. Still, data about using this combination regimen after allo‐HCT are limited. We conducted a prospective, phase II, open‐label, single‐arm study in which we treated patients with haematological AML relapse after allo‐HCT with HMA plus the anti‐PD‐1 antibody nivolumab. The response was correlated with DNA‐, RNA‐ and protein‐based single‐cell technology assessments to identify biomarkers associated with therapeutic efficacy. Sixteen patients received a median number of 2 (range 1–7) nivolumab applications. The overall response rate (CR/PR) at day 42 was 25%, and another 25% of the patients achieved stable disease. The median overall survival was 15.6 months. High‐parametric cytometry documented a higher frequency of activated (ICOS$^{+}$, HLA‐DR$^{+}$), low senescence (KLRG1$^{−}$, CD57$^{−}$) CD8$^{+}$ effector T cells in responders. We confirmed these findings in a preclinical model. Single‐cell transcriptomics revealed a pro‐inflammatory rewiring of the expression profile of T and myeloid cells in responders. In summary, the study indicates that the post‐allo‐HCT HMA/nivolumab combination induces anti‐AML immune responses in selected patients and could be considered as a bridging approach to a second allo‐HCT. Trial‐registration: EudraCT‐No. 2017‐002194‐18

A phonetically-based approach to the phonology of [v] in Hungarian

We propose a unified, surface-based functionalist analysis of the phonology of Hungarian v, which is shown to fare better than past generative formalist/representational models. The model introduced can account for the two-fold patterning of v with respect to voicing assimilation without evoking exceptional means. Furthermore, it can also explain certain asymmetries as well as graduality displayed by v's phonotactic distribution, namely, that some clusters are more frequent in the lexicon, whereas others are marginal. The analysis is grounded in the aerodynamics of v's articulation (which involves inherently contradictory targets) as well as in the relative perceptibility of its contrast in various contexts. It is shown with the help of quantitative experiments that v's phonological patterning is directly derivable from these phonetic factors