A Greedy Algorithm for Building Compact Binary Activated Neural Networks

We study binary activated neural networks in the context of regression tasks, provide guarantees on the expressiveness of these particular networks and propose a greedy algorithm for building such networks. Aiming for predictors having small resources needs, the greedy approach does not need to fix in advance an architecture for the network: this one is built one layer at a time, one neuron at a time, leading to predictors that aren't needlessly wide and deep for a given task. Similarly to boosting algorithms, our approach guarantees a training loss reduction every time a neuron is added to a layer. This greatly differs from most binary activated neural networks training schemes that rely on stochastic gradient descent (circumventing the 0-almost-everywhere derivative problem of the binary activation function by surrogates such as the straight through estimator or continuous binarization). We show that our method provides compact and sparse predictors while obtaining similar performances to state-of-the-art methods for training binary activated networks

PAC-Bayesian Learning of Aggregated Binary Activated Neural Networks with Probabilities over Representations

Considering a probability distribution over parameters is known as an efficient strategy to learn a neural network with non-differentiable activation functions. We study the expectation of a probabilistic neural network as a predictor by itself, focusing on the aggregation of binary activated neural networks with normal distributions over real-valued weights. Our work leverages a recent analysis derived from the PAC-Bayesian framework that derives tight generalization bounds and learning procedures for the expected output value of such an aggregation, which is given by an analytical expression. While the combinatorial nature of the latter has been circumvented by approximations in previous works, we show that the exact computation remains tractable for deep but narrow neural networks, thanks to a dynamic programming approach. This leads us to a peculiar bound minimization learning algorithm for binary activated neural networks, where the forward pass propagates probabilities over representations instead of activation values. A stochastic counterpart that scales to wide architectures is proposed

Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells

BACKGROUND: Endometrial cancer is the fourth most prominent cancer among all feminine cancers in the Western world. Resveratrol, a natural anti-oxidant found in red wine emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on uterine cancer cells is poorly understood. At the molecular level, resveratrol has been reported to inhibit cyclooxygenase (COX) expression and/or activity; in endometrial cancer cells, COX-2 is overexpressed and confers cellular resistance to apoptosis. The aim of the present study was to determine if resveratrol could exert anti-proliferative and pro-apoptotic activity over uterine cancer cells upon inhibition of COX-2 expression and/or activity. Six different human uterine cancer cell lines were used as a model (HeLa, Hec-1A, KLE, RL95-2, Ishikawa and EN-1078D). RESULTS AND DISCUSSION: High-dose of resveratrol triggered apoptosis in five out of six uterine cancer cell lines, as judged from Hoechst nuclear staining and effector caspase cleavage. In accordance, uterine cancer cell proliferation was decreased. Resveratrol also reduced cellular levels of the phosphorylated/active form of anti-apoptotic kinase AKT. Endogenous COX-2 protein levels were decreased, concomitant with a decrease in production of COX metabolites PGE2 and PGF2α, in each uterine cancer cell line expressing detectable levels of COX-1 and/or COX-2 in presence of resveratrol. Although COX expression was identified as a target of resveratrol in uterine cancer cells, inhibition of COX activity or exogenously added PGE2 did not modulate the effect of resveratrol on cellular proliferation. CONCLUSION: High-dose of resveratrol exerts tumoricidal activity over uterine cancer cells and regulates COX expression. In these cells, resveratrol would not directly target COX activity, but possibly other enzymes involved in prostaglandin synthesis that act downstream of the COXs

Waterborne Signaling Primes the Expression of Elicitor-Induced Genes and Buffers the Oxidative Responses in the Brown Alga Laminaria digitata

As marine sessile organisms, seaweeds must respond efficiently to biotic and abiotic challenges in their natural environment to reduce the fitness consequences of wounds and oxidative stress. This study explores the early steps of the defense responses of a large marine brown alga (the tangle kelp Laminaria digitata) and investigates its ability to transmit a warning message to neighboring conspecifics. We compared the early responses to elicitation with oligoguluronates in laboratory-grown and harvested wild individuals of L. digitata. We followed the release of H2O2 and the concomitant production of volatile organic compounds. We also monitored the kinetics of expression of defense-related genes following the oxidative burst. Laboratory-grown algae were transplanted in kelp habitats to further evaluate their responses to elicitation after a transient immersion in natural seawater. In addition, a novel conditioning procedure was established to mimic field conditions in the laboratory. Our experiments showed that L. digitata integrates waterborne cues present in the kelp bed and/or released from elicited neighboring plants. Indeed, the exposure to elicited conspecifics changes the patterns of oxidative burst and volatile emissions and potentiates this kelp for faster induction of genes specifically regulated in response to oligoguluronates. Thus, waterborne signals shape the elicitor-induced responses of kelps through a yet unknown mechanism reminiscent of priming in land plants

Co-Infection with the Friend Retrovirus and Mouse Scrapie Does Not Alter Prion Disease Pathogenesis in Susceptible Mice

Prion diseases are fatal, transmissible neurodegenerative diseases of the central nervous system. An abnormally protease-resistant and insoluble form (PrPSc) of the normally soluble protease-sensitive host prion protein (PrPC) is the major component of the infectious prion. During the course of prion disease, PrPSc accumulates primarily in the lymphoreticular and central nervous systems. Recent studies have shown that co-infection of prion-infected fibroblast cells with the Moloney murine leukemia virus (Mo-MuLV) strongly enhanced the release and spread of scrapie infectivity in cell culture, suggesting that retroviral coinfection might significantly influence prion spread and disease incubation times in vivo. We now show that another retrovirus, the murine leukemia virus Friend (F-MuLV), also enhanced the release and spread of scrapie infectivity in cell culture. However, peripheral co-infection of mice with both Friend virus and the mouse scrapie strain 22L did not alter scrapie disease incubation times, the levels of PrPSc in the brain or spleen, or the distribution of pathological lesions in the brain. Thus, retroviral co-infection does not necessarily alter prion disease pathogenesis in vivo, most likely because of different cell-specific sites of replication for scrapie and F-MuLV

The Prion Protein Has RNA Binding and Chaperoning Properties Characteristic of Nucleocapsid Protein NCp7 of HIV-1

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Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles

Background: The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology. Methods: Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged-matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT-qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls. Results: An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti-CD63 immuno-blocking of vesicle uptake. Conclusions: ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS

The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis

TAR DNA binding protein of 43 kDa (TDP-43)-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS.Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their fifth to seventh decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies.The G376V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro, and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue.The identification of individuals with TDP-43-related myopathy, but not ALS, implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype. Zibold et al. identify a new TDP-43 missense variant (G376V) in two French families affected by late-onset distal myopathy but not ALS. The findings support a primary role for TDP-43 in skeletal muscle pathophysiology and suggest that TARDBP screening should be included in the genetic work-up of patients with distal myopathy

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Seismic structure of an oceanic core complex at the Mid-Atlantic Ridge, 22°19′N

We present results from a seismic refraction and wide-angle experiment surveying an oceanic core complex on the Mid-Atlantic Ridge at 22°19′N. Oceanic core complexes are settings where petrological sampling found exposed lower crustal and upper mantle rocks, exhumed by asymmetric crustal accretion involving detachment faulting at magmatically starved ridge sections. Tomographic inversion of our seismic data yielded lateral variations of P wave velocity within the upper 3 to 4 km of the lithosphere across the median valley. A joint modeling procedure of seismic P wave travel times and marine gravity field data was used to constrain crustal thickness variations and the structure of the uppermost mantle. A gradual increase of seismic velocities from the median valley to the east is connected to aging of the oceanic crust, while a rapid change of seismic velocities at the western ridge flank indicates profound differences in lithology between conjugated ridge flanks, caused by un-roofing lower crust rocks. Under the core complex crust is approximately 40% thinner than in the median valley and under the conjugated eastern flank. Clear PmP reflections turning under the western ridge flank suggest the creation of a Moho boundary and hence continuous magmatic accretion during core complex formation