Progranulin is expressed within motor neurons and promotes neuronal cell survival

<p>Abstract</p> <p>Background</p> <p>Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U) associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival.</p> <p>Results</p> <p><it>In situ </it>hybridisation and immunohistochemical techniques revealed that the <it>progranulin </it>gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human <it>progranulin </it>gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months). This is mediated at least in part through an anti-apoptotic mechanism. Control cells, while expressing basal levels of progranulin do not survive in serum free conditions. Knockdown of progranulin expression using shRNA technology further reduced cell survival.</p> <p>Conclusion</p> <p>Neurons are among the most long-lived cells in the body and are subject to low levels of toxic challenges throughout life. We have demonstrated that progranulin is abundantly expressed in motor neurons and is cytoprotective over prolonged periods when over-expressed in a neuronal cell line. This work highlights the importance of progranulin as neuroprotective growth factor and may represent a therapeutic target for neurodegenerative diseases including motor neuron disease.</p

Axial Involvement in Psoriatic Arthritis cohort (AXIS): the protocol of a joint project of the Assessment of SpondyloArthritis international Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

BACKGROUND: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research. DESIGN: Prospective, multicenter, multinational, cross-sectional study. METHODS AND ANALYSES: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of ⩽10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information. ETHICS: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Registration: ClinicalTrials.gov ID: NCT04434885

Axial Involvement in Psoriatic Arthritis cohort (AXIS): the protocol of a joint project of the Assessment of SpondyloArthritis international Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

BACKGROUND: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research. DESIGN: Prospective, multicenter, multinational, cross-sectional study. METHODS AND ANALYSES: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of ⩽10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information. ETHICS: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Registration: ClinicalTrials.gov ID: NCT04434885

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Redirecting research efforts on the diversification-performance linkage: The search for synergy

We review the literature on the diversification-performance (D-P) relationship to a) propose that the time is ripe for a renewed attack on understanding the relationship between diversification and firm performance, and b) outline a new approach to attacking the question. Our paper makes four main contributions. First, through a review of the literature we establish the inherent complexities in the D-P relationship and the methodological challenges confronted by the literature in reaching its current conclusion of a non-linear relationship between diversification and performance. Second, we argue that to better guide managers the literature needs to develop along a complementary path – whereas past research has often focused on answering the big question of does diversification affect firm performance, this second path would focus more on identifying the precise micro-mechanisms through which diversification adds or subtracts value. Third, we outline a new approach to the investigation of this topic, based on (a) identifying the precise underlying mechanisms through which diversification affects performance; (b) identifying performance outcomes that are “proximate” to the mechanism that the researcher is studying, and (c) identifying an appropriate research design that can enable a causal claim. Finally, we outline a set of directions for future research

The Marine Microbial Eukaryote Transcriptome Sequencing Project (MMETSP): illuminating the functional diversity of eukaryotic life in the oceans through transcriptome sequencing

International audienceCurrent sampling of genomic sequence data from eukaryotes is relatively poor, biased, and inadequate to address important questions about their biology, evolution, and ecology; this Community Page describes a resource of 700 transcriptomes from marine microbial eukaryotes to help understand their role in the world's oceans

Airborne Signals from a Wounded Leaf Facilitate Viral Spreading and Induce Antibacterial Resistance in Neighboring Plants

Many plants release airborne volatile compounds in response to wounding due to pathogenic assault. These compounds serve as plant defenses and are involved in plant signaling. Here, we study the effects of pectin methylesterase (PME)-generated methanol release from wounded plants (“emitters”) on the defensive reactions of neighboring “receiver” plants. Plant leaf wounding resulted in the synthesis of PME and a spike in methanol released into the air. Gaseous methanol or vapors from wounded PME-transgenic plants induced resistance to the bacterial pathogen Ralstonia solanacearum in the leaves of non-wounded neighboring “receiver” plants. In experiments with different volatile organic compounds, gaseous methanol was the only airborne factor that could induce antibacterial resistance in neighboring plants. In an effort to understand the mechanisms by which methanol stimulates the antibacterial resistance of “receiver” plants, we constructed forward and reverse suppression subtractive hybridization cDNA libraries from Nicotiana benthamiana plants exposed to methanol. We identified multiple methanol-inducible genes (MIGs), most of which are involved in defense or cell-to-cell trafficking. We then isolated the most affected genes for further analysis: β-1,3-glucanase (BG), a previously unidentified gene (MIG-21), and non-cell-autonomous pathway protein (NCAPP). Experiments with Tobacco mosaic virus (TMV) and a vector encoding two tandem copies of green fluorescent protein as a tracer of cell-to-cell movement showed the increased gating capacity of plasmodesmata in the presence of BG, MIG-21, and NCAPP. The increased gating capacity is accompanied by enhanced TMV reproduction in the “receivers”. Overall, our data indicate that methanol emitted by a wounded plant acts as a signal that enhances antibacterial resistance and facilitates viral spread in neighboring plants

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown