CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma

Metabolic adjustments are necessary for the initiation, proliferation, and spread of cancer cells. Although mitochondria have been shown to move to cancer cells from their microenvironment, the metabolic consequences of this phenomenon have yet to be fully elucidated. Here we report that multiple myeloma (MM) cells use mitochondrial-based metabolism as well as glycolysis when located within the bone marrow microenvironment (BMM). The reliance of MM cells on oxidative phosphorylation was caused by intercellular mitochondrial transfer to MM cells from neighboring non-malignant bone marrow stromal cells (BMSC). This mitochondrial transfer occurred through tumor-derived tunneling nanotubes (TNT). Moreover, shRNA mediated knockdown of CD38 inhibits mitochondrial transfer and TNT formation in-vitro and blocks mitochondrial transfer and improves animal survival in vivo. This study describes a potential treatment strategy to inhibit mitochondrial transfer for clinical benefit and scientifically expands the understanding of the functional effects of mitochondrial transfer on tumor metabolism

A Comparative Analysis of Gene Expression Patterns and Cell Phenotypes between Cervical and Peripheral Blood Mononuclear Cells

Studies of the immunological environment in the female genital tract (FGT) are critical for the development of vaccines or microbicides to halt the spread of sexually transmitted infections. Challenges arise due to the difficulties of sampling from this site, and the majority of studies have been conducted utilising peripheral blood mononuclear cells. Identifying functional differences between immune cells of the FGT and peripheral blood would aid in our understanding of mucosal immunology. We compared the gene expression profile of mononuclear cells at these two sites. Messenger RNA expression analysis was performed using gene expression arrays on matched cervical mononuclear cells and peripheral blood mononuclear cells. Further cellular phenotyping was done by 10 colour flow cytometry. Of the 22,185 genes expressed by these samples, 5345 genes were significantly differentially expressed between the cell populations. Most differences can be explained by significantly lower levels of T and B cells and higher levels of macrophages and dendritic cells in the FGT compared with peripheral blood. Several immunologically relevant pathways such as apoptosis and innate immune signalling, and a variety of cytokines and cytokine receptors were differentially expressed. This study highlights the importance of the unique immunological environment of the FGT and identifies important differences between systemic and mucosal immune compartments

Enduring science: Three decades of observing the Northeast Atlantic from the Porcupine Abyssal Plain Sustained Observatory (PAP-SO)

Until the 1980s, the deep sea was generally considered to be a particularly stable environment, free from major temporal variations (Sanders, 1968). Studies in the abyssal northeast Atlantic by Billett et al. (1983), and subsequently Lampitt (1985) discovered seasonal pulses of surface primary production-derived particulate organic matter (phytodetritus), and hence carbon, at abyssal depths. These early observations were subsequently extended to the central oceanic region of the NE Atlantic (Pfannkuche, 1993; Thiel et al., 1989), and prompted the establishment of more concerted time series studies in the Porcupine Abyssal Plain area. Today, the Porcupine Abyssal Plain Sustained Observatory (PAP–SO) is a multidisciplinary open-ocean time series site in the NE Atlantic (48°50′N 16°30′W, 4850 m water depth; Fig. 1), focused on the study of connections between the surface and deep ocean. In situ measurements of climatically and environmentally relevant variables have been made for more than 30 years. This represents an exceptionally long time series - a recent compilation of biological time series data, across terrestrial, freshwater, and marine realms, indicates an average duration of only 13-years (Dornelas et al., 2018). Long-term time series in the deep sea are rare, particularly those collecting data from surface to seabed. The PAP-SO is one of two abyssal long-term time series sites globally (Smith et al. 2015), the other being a thirty-year time series at Station M in the northeastern Pacific Ocean (34°50′N, 123°00′W, ~4000 m water depth), maintained by the Monterey Bay Aquarium Research Institute (Smith et al., 2020). This ‘sibling’ abyssal time series site also aims to understand the connections between the surface ocean and the seabed, using many similar techniques (Smith et al., 2017), facilitating comparisons between the two sites (e.g. Durden et al., 2019; Durden et al., 2020a; Laguionie-Marchais et al., 2013; Smith et al., 2009). Another source of extended comparison is the 21 year time series Long-Term Ecological Research Observatory HAUSGARTEN, Frontiers in Arctic Marine Monitoring (FRAM) in the Fram Strait between the North Atlantic and the central Arctic Ocean (78.5°N–80°N, 05°W–11°E, 250–5500 m water depth), maintained by the Alfred Wegener Institute for Polar and Marine Research (Soltwedel et al., 2016; Soltwedel et al., 2005). Much of our understanding of temporal variation in the deep sea, and connections between the surface ocean and the seabed have been derived from research conducted at these observatories

sFDvent: A global trait database for deep‐sea hydrothermal‐vent fauna

Motivation: Traits are increasingly being used to quantify global biodiversity patterns, with trait databases growing in size and number, across diverse taxa. Despite grow‐ ing interest in a trait‐based approach to the biodiversity of the deep sea, where the impacts of human activities (including seabed mining) accelerate, there is no single re‐ pository for species traits for deep‐sea chemosynthesis‐based ecosystems, including hydrothermal vents. Using an international, collaborative approach, we have compiled the first global‐scale trait database for deep‐sea hydrothermal‐vent fauna – sFD‐ vent (sDiv‐funded trait database for the Functional Diversity of vents). We formed a funded working group to select traits appropriate to: (a) capture the performance of vent species and their influence on ecosystem processes, and (b) compare trait‐based diversity in different ecosystems. Forty contributors, representing expertise across most known hydrothermal‐vent systems and taxa, scored species traits using online collaborative tools and shared workspaces. Here, we characterise the sFDvent da‐ tabase, describe our approach, and evaluate its scope. Finally, we compare the sFD‐ vent database to similar databases from shallow‐marine and terrestrial ecosystems to highlight how the sFDvent database can inform cross‐ecosystem comparisons. We also make the sFDvent database publicly available online by assigning a persistent, unique DOI. Main types of variable contained: Six hundred and forty‐six vent species names, associated location information (33 regions), and scores for 13 traits (in categories: community structure, generalist/specialist, geographic distribution, habitat use, life history, mobility, species associations, symbiont, and trophic structure). Contributor IDs, certainty scores, and references are also provided. Spatial location and grain: Global coverage (grain size: ocean basin), spanning eight ocean basins, including vents on 12 mid‐ocean ridges and 6 back‐arc spreading centres. Time period and grain: sFDvent includes information on deep‐sea vent species, and associated taxonomic updates, since they were first discovered in 1977. Time is not recorded. The database will be updated every 5 years. Major taxa and level of measurement: Deep‐sea hydrothermal‐vent fauna with spe‐ cies‐level identification present or in progress. Software format: .csv and MS Excel (.xlsx).This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Modelling distributions of Aedes aegypti and Aedes albopictus using climate, host density and interspecies competition.

Florida faces the challenge of repeated introduction and autochthonous transmission of arboviruses transmitted by Aedes aegypti and Aedes albopictus. Empirically-based predictive models of the spatial distribution of these species would aid surveillance and vector control efforts. To predict the occurrence and abundance of these species, we fit a mixed-effects zero-inflated negative binomial regression to a mosquito surveillance dataset with records from more than 200,000 trap days, representative of 53% of the land area and ranging from 2004 to 2018 in Florida. We found an asymmetrical competitive interaction between adult populations of Aedes aegypti and Aedes albopictus for the sampled sites. Wind speed was negatively associated with the occurrence and abundance of both vectors. Our model predictions show high accuracy (72.9% to 94.5%) in validation tests leaving out a random 10% subset of sites and data since 2017, suggesting a potential for predicting the distribution of the two Aedes vectors

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Towards building equitable health systems in Sub-Saharan Africa: lessons from case studies on operational research

<p>Abstract</p> <p>Background</p> <p>Published practical examples of how to bridge gaps between research, policy and practice in health systems research in Sub Saharan Africa are scarce. The aim of our study was to use a case study approach to analyse how and why different operational health research projects in Africa have contributed to health systems strengthening and promoted equity in health service provision.</p> <p>Methods</p> <p>Using case studies we have collated and analysed practical examples of operational research projects on health in Sub-Saharan Africa which demonstrate how the links between research, policy and action can be strengthened to build effective and pro-poor health systems. To ensure rigour, we selected the case studies using pre-defined criteria, mapped their characteristics systematically using a case study development framework, and analysed the research impact process of each case study using the RAPID framework for research-policy links. This process enabled analysis of common themes, successes and weaknesses.</p> <p>Results</p> <p>3 operational research projects met our case study criteria: HIV counselling and testing services in Kenya; provision of TB services in grocery stores in Malawi; and community diagnostics for anaemia, TB and malaria in Nigeria. <b>Political context and external influences: </b>in each case study context there was a need for new knowledge and approaches to meet policy requirements for equitable service delivery. Collaboration between researchers and key policy players began at the inception of operational research cycles. <b>Links</b>: critical in these operational research projects was the development of partnerships for capacity building to support new services or new players in service delivery. <b>Evidence: </b>evidence was used to promote policy dialogue around equity in different ways throughout the research cycle, such as in determining the topic area and in development of indicators.</p> <p>Conclusion</p> <p>Building equitable health systems means considering equity at different stages of the research cycle. Partnerships for capacity building promotes demand, delivery and uptake of research. Links with those who use and benefit from research, such as communities, service providers and policy makers, contribute to the timeliness and relevance of the research agenda and a receptive research-policy-practice interface. Our study highlights the need to advocate for a global research culture that values and funds these multiple levels of engagement.</p

Burkholderia Type VI Secretion Systems Have Distinct Roles in Eukaryotic and Bacterial Cell Interactions

Bacteria that live in the environment have evolved pathways specialized to defend against eukaryotic organisms or other bacteria. In this manuscript, we systematically examined the role of the five type VI secretion systems (T6SSs) of Burkholderia thailandensis (B. thai) in eukaryotic and bacterial cell interactions. Consistent with phylogenetic analyses comparing the distribution of the B. thai T6SSs with well-characterized bacterial and eukaryotic cell-targeting T6SSs, we found that T6SS-5 plays a critical role in the virulence of the organism in a murine melioidosis model, while a strain lacking the other four T6SSs remained as virulent as the wild-type. The function of T6SS-5 appeared to be specialized to the host and not related to an in vivo growth defect, as ΔT6SS-5 was fully virulent in mice lacking MyD88. Next we probed the role of the five systems in interbacterial interactions. From a group of 31 diverse bacteria, we identified several organisms that competed less effectively against wild-type B. thai than a strain lacking T6SS-1 function. Inactivation of T6SS-1 renders B. thai greatly more susceptible to cell contact-induced stasis by Pseudomonas putida, Pseudomonas fluorescens and Serratia proteamaculans—leaving it 100- to 1000-fold less fit than the wild-type in competition experiments with these organisms. Flow cell biofilm assays showed that T6S-dependent interbacterial interactions are likely relevant in the environment. B. thai cells lacking T6SS-1 were rapidly displaced in mixed biofilms with P. putida, whereas wild-type cells persisted and overran the competitor. Our data show that T6SSs within a single organism can have distinct functions in eukaryotic versus bacterial cell interactions. These systems are likely to be a decisive factor in the survival of bacterial cells of one species in intimate association with those of another, such as in polymicrobial communities present both in the environment and in many infections

Spatial Distribution of the Pathways of Cholesterol Homeostasis in Human Retina

The retina is a light-sensitive tissue lining the inner surface of the eye and one of the few human organs whose cholesterol maintenance is still poorly understood. Challenges in studies of the retina include its complex multicellular and multilayered structure; unique cell types and functions; and specific physico-chemical environment.We isolated specimens of the neural retina (NR) and underlying retinal pigment epithelium (RPE)/choroid from six deceased human donors and evaluated them for expression of genes and proteins representing the major pathways of cholesterol input, output and regulation. Eighty-four genes were studied by PCR array, 16 genes were assessed by quantitative real time PCR, and 13 proteins were characterized by immunohistochemistry. Cholesterol distribution among different retinal layers was analyzed as well by histochemical staining with filipin. Our major findings pertain to two adjacent retinal layers: the photoreceptor outer segments of NR and the RPE. We demonstrate that in the photoreceptor outer segments, cholesterol biosynthesis, catabolism and regulation via LXR and SREBP are weak or absent and cholesterol content is the lowest of all retinal layers. Cholesterol maintenance in the RPE is different, yet the gene expression also does not appear to be regulated by the SREBPs and varies significantly among different individuals.This comprehensive investigation provides important insights into the relationship and spatial distribution of different pathways of cholesterol input, output and regulation in the NR-RPE region. The data obtained are important for deciphering the putative link between cholesterol and age-related macular degeneration, a major cause of irreversible vision loss in the elderly