Rcf1 and Rcf2, Members of the Hypoxia-induced Gene 1 Protein Family, Are Critical Components of the Mitochondrial Cytochrome bc1-cytochrome Oxidase Supercomplex

We report that Rcf1 (formerly Aim31), a member of the conserved hypoxia-induced gene 1 (Hig1) protein family, represents a novel component of the yeast cytochrome bc1-cytochrome c oxidase (COX) supercomplex. Rcf1 (respiratory supercomplex factor 1) partitions with the COX complex, and evidence that it may act as a bridge to the cytochrome bc1 complex is presented. Rcf1 interacts with the Cox3 subunit and can do so prior to their assembly into the COX complex. A close proximity of Rcf1 and members of the ADP/ATP carrier (AAC) family was also established. Rcf1 displays overlapping function with another Hig1-related protein, Rcf2 (formerly Aim38), and their joint presence is required for optimal COX enzyme activity and the correct assembly of the cytochrome bc1-COX supercomplex. Rcf1 and Rcf2 can independently associate with the cytochrome bc1-COX supercomplex, indicating that at least two forms of this supercomplex exist within mitochondria. We provide evidence that the association with the cytochrome bc1-COX supercomplex and regulation of the COX complex are a conserved feature of Hig1 family members. Based on our findings, we propose a model where the Hig1 proteins regulate the COX enzyme activity through Cox3 and associated Cox12 protein, in a manner that may be influenced by the neighboring AAC proteins

T cell reactivity and regulation in human cancer

Modulation of co-inhibitory and co-stimulatory immune checkpoint molecules with antibody-based therapies has emerged as a promising anti-cancer strategy, however response rates to such agents are modest. The discrepancy in activity observed between mouse models and human cancers is rarely acknowledged, but deciphering this might provide valuable insights into underlying mechanisms of response and resistance. Through parallel analysis of mouse models and human cancers, this study demonstrates the importance of the local microenvironment in determining the activity of immune modulatory antibodies (mAb), providing novel insights into the mechanism of anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) and anti-interleukin-2 receptor alpha chain (IL-2Rα, CD25) antibodies. A limitation of such approaches is the requirement for a pre-existing T cell infiltrate. In human tumours, paucity of immune infiltrate is well recognised, highlighting the need to identify relevant drivers of T cell infiltration. Complementary analysis of genomic and immunological landscapes in human tumours demonstrates that beyond total neoantigen burden, clonal architecture influences anti-tumour immunity, with prognostic implication and predictive value in the context of immune checkpoint modulation. Targeting clonal neoantigens, present on every tumour cell, might hold promise in overcoming the significant therapeutic challenge posed by tumour evolution and consequent intra-tumour heterogeneity

Maternal obesity management using mobile technology : a feasibility study to evaluate a text messaging based complex intervention during pregnancy.

Background. Maternal obesity and excessive gestational weight gain (GWG) are on the rise with negative impact on pregnancy and birth outcomes. Research into managing GWG using accessible technology is limited. The maternal obesity management using mobile technology (MOMTech) study aimed at evaluating the feasibility of text messaging based complex intervention designed to support obese women (BMI ≥ 30) with healthier lifestyles and limit GWG. Methods. Participants received two daily text messages, supported by four appointments with healthy lifestyle midwife, diet and activity goal setting, and self-monitoring diaries. The comparison group were obese mothers who declined to participate but consented for their routinely collected data to be used for comparison. Postnatal interviews and focus groups with participants and the comparison group explored the intervention’s acceptability and suggested improvements. Results. Fourteen women completed the study which did not allow statistical analyses. However, participants had lower mean GWG than the comparison group (6.65 kg versus 9.74 kg) and few (28% versus 50%) exceeded the Institute of Medicine’s upper limit of 9 kg GWG for obese women. Conclusions. MOMTech was feasible within clinical setting and acceptable intervention to support women to limit GWG. Before further trials, slight modifications are planned to recruitment, text messages, and the logistics of consultation visits

Electron localisation function in current-density-functional theory

We present a generalisation of the electron localisation function (ELF) to current-density-functional theory as a descriptor for the properties of molecules in the presence of magnetic fields. The resulting current ELF (cELF) is examined for a range of small molecular systems in field strengths up to B0 = 235 kT (one atomic unit). The cELF clearly depicts the compression of the molecular electronic structure in the directions perpendicular to the applied field and exhibits a structure similar to that of the physical current densities. A topological analysis is performed to examine the changes in chemical bonding upon application of a magnetic field

Reducing pain during wound dressings in burn care using virtual reality: a study of perceived impact and usability with patients and nurses.

Burns patients often suffer severe pain during interventions such as dressing changes, even with analgesia. Virtual Reality (VR) can be used to distract patients and reduce pain. However, more evidence is needed from the patients and staff using the technology about its use in clinical practice and the impact of different VR strategies. This small-scale qualitative study explored patient and staff perceptions of the impact and usability of active and passive VR during painful dressing changes. Five patients took part in three observed dressing changes - one with an active VR scenario developed for the study, one with passive VR and one with no VR - following which they were interviewed about their experiences. Three nurses who performed the dressing changes participated in a focus group. Thematic analysis of the resulting data generated four themes: 'Caution replaced by contentment', 'Distraction and implications for pain and wound care', 'Anxiety, control and enjoyment' and 'Preparation and communication concerns'. Results suggested that user-informed active VR was acceptable to burn patients, helped manage their perceived pain, and was both usable and desirable within the clinical environment. Further testing with larger samples is now required

A mixed-methods investigation into the acceptability, usability and perceived effectiveness of active and passive virtual reality scenarios in managing pain under experimental conditions

Burns patients often suffer excruciating pain during clinical procedures, even with analgesia. Virtual Reality as an adjunct to pharmacological therapy has proved promising in the management of burn pain. More evidence is needed regarding specific forms of Virtual Reality. This mixed-method study examined the impact of active and passive Virtual Reality scenarios in experimental conditions, gathering data relating to user experience, acceptability and effectiveness in managing pain. Four scenarios were developed or selected following a consultative workshop with burns survivors and clinicians. Each was trialled using a cold pressor test with 15 University students. Data were gathered regarding pain threshold and tolerance at baseline and during each exposure. Short interviews were conducted afterwards. The two active scenarios were ranked highest and significantly extended participants pain threshold and tolerance times compared to passive and baseline conditions. Passive scenarios offered little distraction and relief from pain. Active scenarios were perceived to be engaging, challenging, distracting and immersive. They reduced subjective awareness of pain, though suggestions were made for further improvements. Results suggested that active Virtual Reality was acceptable and enjoyable as a means of helping to control experimental pain. Following suggested improvements, scenarios should now be tested in the clinical environment

Non-perturbative calculation of molecular magnetic properties within current-density functional theory

We present a novel implementation of Kohn-Sham density-functional theory utilizing London atomic orbitals as basis functions. External magnetic elds are treated non-perturbatively, which enables the study of both magnetic response properties and the effects of strong fields, using either standard density functionals or current-density functionals - the implementation is the first fully self-consistent implementation of the latter for molecules. Pilot applications are presented for the finite-field calculation of molecular magnetizabilities, hypermagnetizabilities and nuclear magnetic resonance shielding constants, focusing on the impact of current-density functionals on the accuracy of the results. Existing current-density functionals based on the gauge-invariant vorticity are tested and found to be sensitive to numerical details of their implementation. Furthermore, when appropriately regularized, the resulting magnetic properties show no improvement over standard density-functional results. An advantage of the present implementation is the ability to apply density-functional theory to molecules in very strong magnetic fields, where the perturbative approach breaks down. Comparison with high accuracy full-conguration-interaction results shows that the inadequacies of current-density approximations are exacerbated with increasing magnetic field strength. Standard density-functionals remain well behaved but fail to deliver high accuracy. The need for improved current-dependent density-functionals, and how they may be tested using the presented implementation, is discussed in light of our findings