Mutational Analysis of the QRRQ Motif in the Yeast Hig1 Type 2 Protein Rcf1 Reveals a Regulatory Role for the Cytochrome \u3cem\u3ec\u3c/em\u3e Oxidase Complex

The yeast Rcf1 protein is a member of the conserved family of proteins termed the hypoxia-induced gene (domain) 1 (Hig1 or HIGD1) family. Rcf1 interacts with components of the mitochondrial oxidative phosphorylation system, in particular the cytochrome bc1(complex III)-cytochrome c oxidase (complex IV) supercomplex (termed III-IV) and the ADP/ATP carrier proteins. Rcf1 plays a role in the assembly and modulation of the activity of complex IV; however, the molecular basis for how Rcf1 influences the activity of complex IV is currently unknown. Hig1 type 2 isoforms, which include the Rcf1 protein, are characterized in part by the presence of a conserved motif, (Q/I)X3(R/H)XRX3Q, termed here the QRRQ motif. We show that mutation of conserved residues within the Rcf1 QRRQ motif alters the interactions between Rcf1 and partner proteins and results in the destabilization of complex IV and alteration of its enzymatic properties. Our findings indicate that Rcf1 does not serve as a stoichiometric component, i.e. as a subunit of complex IV, to support its activity. Rather, we propose that Rcf1 serves to dynamically interact with complex IV during its assembly process and, in doing so, regulates a late maturation step of complex IV. We speculate that the Rcf1/Hig1 proteins play a role in the incorporation and/or remodeling of lipids, in particular cardiolipin, into complex IV and. possibly, other mitochondrial proteins such as ADP/ATP carrier proteins

Understanding 19th century ‘baby-farming’ women who killed: aberration or ‘rational’ act?

Writing for Frontier, PhD student Joshua Stuart-Bennett explains his research into the child killing activity associated with Victorian ‘baby-farming’. In contrast to understandings that have been based upon cases of individual women and their nature, he hopes to place the phenomenon within the wider social, cultural and historical context to reframe our perception of these women and their crimes

Lung transplantation in cystic fibrosis: Trends and controversies

This article is not an overview of all facets of lung transplantation in cystic fibrosis (CF), but rather it is intended as a review of current allocation controversies, as well as of trends in diagnostics and management in lung transplant recipients and in patients with end-stage lung disease. Despite changes in donor and recipient selection, long-term survival in pediatric lung transplant has continued to be limited by chronic lung allograft dysfunction (CLAD). Due to, in part, this short survival benefit, transplant continues to be an appropriate option for only a subset of pediatric patients with CF. The feasibility of transplant as a therapeutic option is also affected by the limited pediatric organ supply, which has moreover contributed to controversy over lung allocation. Debates over the allocation of this scarce resource, however, may also help to drive innovation in the field of lung transplant. Longer pretransplant survival—as aided by new lung bypass technologies, for example—could help to alleviate organ shortages, as well as facilitate the transport of organs to suitable pediatric recipients. Improved diagnosis and treatment for CLAD and for antibody-mediated rejection have the potential to extend survival in pediatric lung transplant. Regardless, the relative rarity of transplant could pose future challenges for pediatric lung transplant programs, which require adequate numbers of patients to maintain proper expertise

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

Sensory attenuation in sport and rehabilitation:perspective from research in Parkinson's disease

People with Parkinson’s disease (PD) experience motor symptoms that are affected by sensory information in the environment. Sensory attenuation describes the modulation of sensory input caused by motor intent. This appears to be altered in PD and may index important sensorimotor processes underpinning PD symptoms. We review recent findings investigating sensory attenuation and reconcile seemingly disparate results with an emphasis on task-relevance in the modulation of sensory input. Sensory attenuation paradigms, across different sensory modalities, capture how two identical stimuli can elicit markedly different perceptual experiences depending on our predictions of the event, but also the context in which the event occurs. In particular, it appears as though contextual information may be used to suppress or facilitate a response to a stimulus on the basis of task-relevance. We support this viewpoint by considering the role of the basal ganglia in task-relevant sensory filtering and the use of contextual signals in complex environments to shape action and perception. This perspective highlights the dual effect of basal ganglia dysfunction in PD, whereby a reduced capacity to filter task-relevant signals harms the ability to integrate contextual cues, just when such cues are required to effectively navigate and interact with our environment. Finally, we suggest how this framework might be used to establish principles for effective rehabilitation in the treatment of PD

Pathway-Based Genomics Prediction using Generalized Elastic Net.

We present a novel regularization scheme called The Generalized Elastic Net (GELnet) that incorporates gene pathway information into feature selection. The proposed formulation is applicable to a wide variety of problems in which the interpretation of predictive features using known molecular interactions is desired. The method naturally steers solutions toward sets of mechanistically interlinked genes. Using experiments on synthetic data, we demonstrate that pathway-guided results maintain, and often improve, the accuracy of predictors even in cases where the full gene network is unknown. We apply the method to predict the drug response of breast cancer cell lines. GELnet is able to reveal genetic determinants of sensitivity and resistance for several compounds. In particular, for an EGFR/HER2 inhibitor, it finds a possible trans-differentiation resistance mechanism missed by the corresponding pathway agnostic approach

Don’t mention this around the Christmas table: Brexit, inequality and the demographic divide

A great deal of research has already been conducted on why the UK voted to leave the EU and which groups of voters were most likely to back leave and remain. Danny Dorling, Ben Stuart and Joshua Stubbs present a comprehensive analysis of the vote, writing that although there is generally a stark age divide amongst voters concerning the European Union, the same can also potentially be said for divides in the spread and centralisation of wealth across the UK