Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend the lifespan of model organisms. The Caenorhabditis elegans isp-1 gene encodes the Rieske iron-sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain). The partial loss of function allele, isp-1(qm150), leads to several pleiotropic phenotypes. To better understand the molecular mechanisms of ISP-1 function, we sought to identify genetic suppressors of the delayed development of isp-1(qm150) animals. Here we report a series of intragenic suppressors, all located within a highly conserved six amino acid tether region of ISP-1. These intragenic mutations suppress all of the evaluated isp-1(qm150) phenotypes, including developmental rate, pharyngeal pumping rate, brood size, body movement, activation of the mitochondrial unfolded protein response reporter, CO 2 production, mitochondrial oxidative phosphorylation, and lifespan extension. Furthermore, analogous mutations show a similar effect when engineered into the budding yeast Rieske iron-sulfur protein Rip1, revealing remarkable conservation of the structure-function relationship of these residues across highly divergent species. The focus on a single subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes points to a common underlying molecular mechanism, for which we propose a "spring-loaded" model. These observations provide insights into how gating and control processes influence the function of ISP-1 in mediating pleiotropic phenotypes including developmental rate, movement, sensitivity to stress, and longevity.itochondria are sites for adenosine 5′-triphosphate (ATP) production by oxidative phosphorylation, cellular calcium buffering, iron-sulfur cluster biogenesis, reactive oxygen species (ROS) formation, and regulation of apoptosis. Although inherited defects in mitochondrial function are most often associated with severe childhood disorders, a large number of age-related diseases such as heart disease, cancer, diabetes, obesity, and neurodegeneration have also been linked to mitochondrial dysfunction (1, 2).In Caenorhabditis elegans, multiple studies have demonstrated that reduced electron transport chain activity (ETC) can lead to increased lifespan. These include mutations in the coenzyme Q biosynthetic gene clk-1, the pyrophosphokinase gene tpk-1, and the Rieske iron-sulfur protein isp-1 (3-7). Following RNAi knockdown of ETC components, several other proteins have been implicated in lifespan extension, including HIF-1, GCN-2, CEP-1, CEH-23, TAF-4, AHA-1, CEH-18, JUN-1, NHR-27, and NHR-49 (8-12). In addition, it was proposed that the mitochondrial unfolded protein response (mtUPR) directly mediated lifespan extension from ETC inhibition (13); however, more recent work has suggested that induction of the mtUPR is neither necessary nor sufficient to extend li...

Human papillomavirus (HPV)-associated cervical cancer is a leading cause of cancer deaths in women. Here we present an integrated multi-omic analysis of 643 cervical squamous cell carcinomas (CSCC, the most common histological variant of cervical cancer), representing patient populations from the USA, Europe and Sub-Saharan Africa and identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 and C2 tumours can be driven by either of the two most common HPV types in cervical cancer (16 and 18) and while HPV16 and HPV18 are overrepresented among C1 and C2 tumours respectively, the prognostic difference between groups is not due to HPV type. C2 tumours, which comprise approximately 20% of CSCCs across these cohorts, display distinct genomic alterations, including loss or mutation of the STK11 tumour suppressor gene, increased expression of several immune checkpoint genes and differences in the tumour immune microenvironment that may explain the shorter survival associated with this group. In conclusion, we identify two therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.

The data delivered by a new reservoir mapping while drilling (RMWD) tool provides more geological information than that from any other logging-while-drilling (LWD) technology previously available in the oil field. Its answer product images the surrounding formation structure, and the resulting maps can be used by the geoscientists to improve their understanding of the subsurface, the well placement and the reservoir.To take advantage of the richness of the measurements and deep depth of investigation across multiple formation boundaries, an automatic stochastic inversion has been developed that combines approximately a hundred phase and attenuation measurements at various frequencies and transmitter-to-receiver distances. This efficient Bayesian model-based stochastic inversion runs in parallel with multiple independent search instances that randomly sample hundreds of thousands of formation models using a Markov chain Monte Carlo method. All samples above a quality threshold over the solution space are used to generate the distribution of formation models that intrinsically contain the information for model uncertainties.RMWD is a highly nonlinear problem; inverting for a unique solution is analytically difficult due to the well-known local minima issue. The stochastic method addresses that by sampling thousands of possible formation models and outputting a distribution of layered models that are consistent with the measurements. Statistical distributions are displayed for formation resistivity, anisotropy and dip at each logging point. Additionally, the median formation models for resistivity are shown along the well trajectory as a curtain section plot. This provides an intuitive interpretation for the entire reservoir formation around the tool. The inversion curtain section plot can be overlaid with the seismic formation model for combined interpretation. Furthermore, the curtain plot provides graphical information for dip and distance to boundary, which are critical for field applications such as landing, geosteering, remote fluid contact identification, etc. The stochastic-sampling-based answer product has been intensively field tested and has proven to provide reliable estimation of the formation geometries and fluid distributions in many locations and geological environments worldwide.Field applications and simulated examples of the stochastic inversion include remote detection of the reservoir to enable accurate landing, navigating multilayered reservoirs, remote identification of fluid contacts and reservoir characterization in the presence of faults. The stochastic inversion samples the formation properties randomly and provides the distribution of formation properties based on a large number of samples, instead of providing only the most likely solution as is typical for deterministic inversions. A statistical method of presenting inversion results in formation space provides an instant and intuitive understanding of the formation surrounding the tool. Quantifying the non-uniqueness of the inverted fo...

1 2 Cervical cancer is caused by carcinogenic human papillomavirus infection and represents one of the 3 leading causes of cancer death worldwide. Effective means of tumour classification are required for 4 better disease understanding. We performed an integrated multi-omic analysis of 655 cervical 5 cancers, using epigenomic and transcriptomic signatures to discover two distinct cervical cancer 6 subtypes we named "typical" and "atypical". Typical tumours were largely HPV16-driven and 7 frequently displayed an 'immune-hot' tumour microenvironment. Atypical tumours were associated 8 with poor prognosis; they were more likely to be driven by HPVs from the HPV18-containing a7 clade, 9 displayed distinct genomic aberrations, greater evidence of past immunoediting and a 10

Introduction: Tafazzin acylates immature monolysocardiolipin to form mature cardiolipin. Cardiolipin is the signature phospholipid of the mitochondrial inner membrane required for respiratory efficiency and regulation of apoptosis. Mitochondrial respiration is reduced in atherosclerosis. However, whether tafazzin regulates vascular smooth mucle cell (VSMC) mitochondrial function and contributes to atherosclerosis is unclear. Hypothesis: Tafazzin regulates VSMC mitochondrial function and atherosclerosis development. Methods: We examined tafazzin expression and regulation in human plaques and VSMCs. We determined the in vitro effects of tafazzin using siRNA mediated cell silencing or lentiviral infection to express either tafazzin (Taz) or tafazzin with a transacylase defective mutation (Taz H69Q ). We also generated mice expressing VSMC restricted Taz or Taz H69Q and crossed them with apolipoprotein E deficient mice (SM22α-Taz/ApoE -/- or SM22α-Taz H69Q /ApoE -/- ) to study tafazzin in vivo Results: Tafazzin mRNA and protein is decreased in plaque and plaque VSMCs. MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low density lipoprotein. Tafazzin silencing and expression of Taz H69Q reduces mitochondrial respiration, decreases ATP content (0.13±0.01nmoles vs 0.21±0.01nmole, n=4), and promotes apoptosis. SM22α-Taz H69Q /ApoE -/- mice showed increased plaque burden (28±2.3% vs 17±2.1%, n=17), increased necrotic core and reduced fibrous cap areas. In contrast, over-expression of tafazzin increases VSMC mitochondrial respiration and protects against apoptosis. SM22α-Taz/ApoE -/- mice showed no change in plaque burden but increased features of plaque stability. SS-31, which binds and stabilises cardiolipin, improves mitochondrial respiration and decreases apoptosis in SM22α-Taz H69Q /ApoE -/- VSMCs. Conclusions: Tafazzin expression is decreased in plaque VSMCs and is negatively regulated by microRNA 125a-5p. Defective tafazzin decreases mitochondrial respiration, increases apoptosis and promotes atherosclerosis. Tafazzin is therefore an important and unrecognised regulator of VSMC mitochondrial function and atherosclerosis.