HLA-F*01:01 presents peptides with N-terminal flexibility and a preferred length of 16 residues.

HLA-F belongs to the non-classical HLA-Ib molecules with a marginal polymorphic nature and tissue-restricted distribution. HLA-F is a ligand of the NK cell receptor KIR3DS1, whose activation initiates an antiviral downstream immune response and lead to delayed disease progression of HIV-1. During the time course of HIV infection, the expression of HLA-F is upregulated while its interaction with KIR3DS1 is diminished. Understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response and the molecules function. In this study, we were able to recover stable pHLA-F*01:01 complexes and analyze the characteristics of peptides naturally presented by HLA-F. These HLA-F-restricted peptides exhibit a non-canonical length without a defined N-terminal anchor. The peptide characteristics lead to a unique presentation profile and influence the stability of the protein. Furthermore, we demonstrate that almost all source proteins of HLA-F-restricted peptides are described to interact with HIV proteins. Understanding the balance switch between HLA-Ia and HLA-F expression and peptide selection will support to understand the role of HLA-F in viral pathogenesis

Barrier-properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length

Nup98 FG repeat domains comprise hydrophobic FG motifs linked through uncharged spacers. FG motifs capture nuclear transport receptors (NTRs) during nuclear pore complex (NPC) passage, confer inter-repeat cohesion, and condense the domains into a selective phase with NPC-typical barrier properties. We found that shortening inter-FG spacers enhances cohesion, increases phase density, and tightens such barrier – consistent with a sieve-like phase. Phase separation tolerated mutations of Nup98-typical GLFG motifs, provided the domain-hydrophobicity remained preserved. NTR-entry, however, was sensitive to (certain) deviations from canonical FG motifs, suggesting a co-evolutionary adaptation. Unexpectedly, we found that arginines promote efficient FG-phase entry also by means other than cation-π interactions. Although incompatible with NTR·cargo complexes, a YG phase displayed remarkable transport selectivity, particularly for evolved GFPNTR-variants. GLFG to FSFG mutations made the FG phase hypercohesive, precluding NTR-entry. Longer spacers relieved this hypercohesive phenotype. The antagonism between cohesion and NTR·FG interactions appears thus key to transport selectivity

Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP

Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk.We thank Miguel Sánchez for text editing. We thank Erika R. Geisbrecht, Kenneth Irvine, and Ariberto Fassati for kindly providing reagents. This study was supported by grants from the Spanish Ministry of Science and Innovation (MICIIN)/Agencia Estatal de Investigación (AEI)/European Regional Development Fund (ARDF/FEDER) “A way to make Europe” (PID2020-118658RB-I00, SAF2017-83130-R, IGP-SO grant MINSEV1512-07-2016, CSD2009-0016 and BFU2016-81912-REDC), Comunidad Autónoma de Madrid (Tec4Bio-CM, S2018/NMT¬4443), Fundació La Marató de TV3 (201936-30-31), “La Caixa” Foundation (HR20-00075) and AECC (PROYE20089DELP) all to M.A.d.P. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 641639. M.G.G. and L.S. are sponsored by FPU fellowships (FPU15/03776 and FPU18/05394, respectively). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MICIIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence CEX2020-001041-S

Managing student mental health: The challenges faced by academics on professional health care courses

To explore how academics on nursing and healthcare programmes are managing their roles and responsibility in relation to student mental health. There is growing concern about the mental health of university students in general and healthcare students in particular. Shifts in Higher Education policy, encouraging a ‘whole university approach,’ may place greater responsibility for student mental health on academics. However, little is known about the challenges that poor student mental health creates for academics on healthcare programmes. A qualitative approach, using semi‐structured interviews and focus groups, provided the opportunity for in‐depth analysis. Fourteen academics on healthcare programmes, including seven lecturers from nursing programmes, were interviewed between May and June 2017. Constant comparison analysis was followed to support grounded theory. Four key themes emerged. Academics had difficulty identifying and maintaining boundaries due to competing academic and professional identities. Student disclosures are accompanied by challenges arising due to professional responsibilities. Supporting student mental health on placement is difficult. Academics are aware and concerned about the potential negative impact of course content and practice on student mental health. This is the first study to explore in‐depth the challenges faced by academics on healthcare programmes by the rising prevalence of and concern for, student mental health. The findings indicate that leaders of nursing education programmes and their managers, need to be aware that academics face complex challenges in managing and responding student mental health and may struggle to maintain boundaries due, in part, to competing professional identities.Part funded by University of Derby VC Ideas Foru

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways

A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N^2,N^4-dibenzylquinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy

Attitude control for satellites flying in VLEO using aerodynamic surfaces

This paper analyses the use of aerodynamic control surfaces, whether passive or active, in order to carry out very low Earth orbit (VLEO) attitude maneuver operations. Flying a satellite in a very low Earth orbit with an altitude of less than 450 km, namely VLEO, is a technological challenge. It leads to several advantages, such as increasing the resolution of optical payloads or increase signal to noise ratio, among others. The atmospheric density in VLEO is much higher than in typical low earth orbit altitudes, but still free molecular flow. This has serious consequences for the maneuverability of a satellite because significant aerodynamic torques and forces are produced. In order to guarantee the controllability of the spacecraft they have to be analyzed in depth. Moreover, at VLEO the density of atomic oxygen increases, which enables the use of air-breathing electric propulsion (ABEP). Scientists are researching in this field to use ABEP as a drag compensation system, and consequently an attitude control based on aerodynamic control could make sense. This combination of technologies may represent an opportunity to open new markets. In this work, several satellite geometric configurations were considered to analyze aerodynamic control: 3-axis control with feather configuration and 2-axis control with shuttlecock configuration. The analysis was performed by simulating the attitude of the satellite as well as the disturbances affecting the spacecraft. The models implemented to simulate the disturbances were the following: Gravitational gradient torque disturbance, magnetic dipole torque disturbance (magnetic field model IGRF12), and aerodynamic torque disturbances (aerodynamic model DTM2013 and wind model HWM14).The maneuvers analyzed were the following: detumbling or attitude stabilization, pointing and demisability. Different VLEO parameters were analyzed for every geometric configuration and spacecraft maneuver. The results determined which of the analyzed geometric configurations suits better for every maneuver

Inductive Plasma Thruster (IPT) design for an Atmosphere-Breathing Electric Propulsion System (ABEP)

Challenging space missions include those at very low altitudes, where the atmosphere is source of aerodynamic drag on the spacecraft, therefore an efficient propulsion system is required to extend the mission lifetime. One solution is Atmosphere-Breathing Electric Propulsion (ABEP). It collects atmospheric particles to use as propellant for an electric thruster. This would minimize the requirement of limited propellant availability. The system could be applied to any planet with atmosphere, enabling new mission at these altitude ranges for continuous orbiting. Challenging is also the presence of reactive chemical species, such as atomic oxygen in Earth orbit. Such components are erosion source of (not only) propulsion system components, i.e. acceleration grids, electrodes, and discharge channels of conventional EP systems (RIT and HET). IRS is developing within the DISCOVERER project an intake and a thruster for an ABEP system. This paper deals with the design and first operation of the inductive plasma thruster (IPT) developed at IRS. The paper describes its design aided by numerical tools such as HELIC and ADAMANT. Such a device is based on RF electrodeless discharge aided by externally applied static magnetic field. The IPT is composed by a movable injector, to variate the discharge channel length, and a movable electromagnet to variate position and intensity of the magnetic field. By changing these parameters along with a novel antenna design for electric propulsion, the aim is to achieve the highest efficiency for the ionization stage by enabling the formation of helicon-based discharge. Finally, the designed IPT is presented and the feature of the birdcage antenna highlighted

The N-terminus of CD14 acts to bind apoptotic cells and confers rapid-tethering capabilities on non-myeloid cells:CD14 and rapid tethering of apoptotic cells

Cell death and removal of cell corpses in a timely manner is a key event in both physiological and pathological situations including tissue homeostasis and the resolution of inflammation. Phagocytic clearance of cells dying by apoptosis is a complex sequential process comprising attraction, recognition, tethering, signalling and ultimately phagocytosis and degradation of cell corpses. A wide range of molecules acting as apoptotic cell-associated ligands, phagocyte-associated receptors or soluble bridging molecules have been implicated within this process. The role of myeloid cell CD14 in mediating apoptotic cell interactions with macrophages has long been known though key molecules and residues involved have not been defined. Here we sought to further dissect the function of CD14 in apoptotic cell clearance. A novel panel of THP-1 cell-derived phagocytes was employed to demonstrate that CD14 mediates effective apoptotic cell interactions with macrophages in the absence of detectable TLR4 whilst binding and responsiveness to LPS requires TLR4. Using a targeted series of CD14 point mutants expressed in non-myeloid cells we reveal CD14 residue 11 as key in the binding of apoptotic cells whilst other residues are reported as key for LPS binding. Importantly we note that expression of CD14 in non-myeloid cells confers the ability to bind rapidly to apoptotic cells. Analysis of a panel of epithelial cells reveals that a number naturally express CD14 and that this is competent to mediate apoptotic cell clearance. Taken together these data suggest that CD14 relies on residue 11 for apoptotic cell tethering and it may be an important tethering molecule on so called 'non-professional' phagocytes thus contributing to apoptotic cell clearance in a non-myeloid setting. Furthermore these data establish CD14 as a rapid-acting tethering molecule, expressed in monocytes, which may thus confer responsiveness of circulating monocytes to apoptotic cell derived material. © 2013 Thomas et al