Therapeutic Approaches to Delay the Onset of Alzheimer's Disease

The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of small aggregates of amyloid-β (Aβ) peptides. Thus, targeting these two abnormalities of the AD brain may hold promising therapeutic value for delaying the onset of AD. In his paper, we discuss two potential approaches to delay the onset of AD. The first is the use of low dose of diaminophenothiazins (redox active agents) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. Diaminophenothiazines enhance mitochondrial metabolic activity and heme synthesis, both key factors in intermediary metabolism of the AD brain.The second is to use the naturally occurring osmolytes to prevent the formation of toxic forms of Aβ and prevent oxidative stress. Scientific evidence suggests that both approaches may change course of the basic mechanism of neurodegeneration in AD. Osmolytes are brain metabolites which accumulate in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation without perturbing other cellular processes. Osmolytes may inhibit the formation of Aβ oligomers in vivo, thus preventing the formation of soluble oligomers. The potential significance of combining diaminophenothiazins and osmolytes to treat AD is discussed

Strategic management in a national oil corporation: the case of Libya

YesThis empirical study investigated senior managers’ perceptions and application of strategic management in the Libyan National Oil Corporation (NOC). Key factors influencing the processes of strategic management were identified and overall findings have been compared with a model of strategic management. A case study approach was adopted, based on a two-stage research design. The first stage comprised of a survey involving seventy senior managers and was followed by twelve semi-structured interviews to deepen the questionnaire findings with qualitative data. Findings suggest that the Libyan NOC may have relied too heavily in the past on strategy formulation and strategic management as the preserve of a very few individuals at the top of the organization. Whilst political directives set the strategy for the whole organisation, a gap in knowledge and understanding existed between the senior business managers and the political appointments to the Board. The case study does not necessarily reflect the situation in other NOCs. Furthermore, it excludes the impact of the revolution in Libya. Recommendations have been made for improving practice concerned steps in the strategic management process and senior managers’ effectiveness within the Board team. In the context of an example of a state-owned enterprise, the inclusion of three elements was suggested: Board effectiveness, medium-term objectives and social responsibility as an aspect of environmental scanning. This is a first time empirical study of senior managers’ perceptions of strategic management in a National Oil Company

SPI-GCN: A Simple Permutation-Invariant Graph Convolutional Network

A wide range of machine learning problems involve handling graph-structured data. Existing machine learning approaches for graphs, however, often imply computing expensive graph similarity measures, preprocessing input graphs, or explicitly ordering graph nodes. In this work, we present a novel and simple convolutional neural network architecture for supervised learning on graphs that is provably invariant to node permutation. The proposed architecture operates directly on arbitrary graphs and performs no node sorting. It also uses a simple multi-layer perceptron for prediction as opposed to conventional convolution layers commonly used in other deep learning approaches for graphs. Despite its simplicity, our architecture is competitive with state-of-the-art graph kernels and existing graph neural networks on benchmark graph classification data sets. Our approach clearly outperforms other deep learning algorithms for graphs on multiple multiclass classification tasks. We also evaluate our approach on a real-world original application in materials science, on which we achieve extremely reasonable results

ContainerGym: A Real-World Reinforcement Learning Benchmark for Resource Allocation

We present ContainerGym, a benchmark for reinforcement learning inspired by a real-world industrial resource allocation task. The proposed benchmark encodes a range of challenges commonly encountered in real-world sequential decision making problems, such as uncertainty. It can be configured to instantiate problems of varying degrees of difficulty, e.g., in terms of variable dimensionality. Our benchmark differs from other reinforcement learning benchmarks, including the ones aiming to encode real-world difficulties, in that it is directly derived from a real-world industrial problem, which underwent minimal simplification and streamlining. It is sufficiently versatile to evaluate reinforcement learning algorithms on any real-world problem that fits our resource allocation framework. We provide results of standard baseline methods. Going beyond the usual training reward curves, our results and the statistical tools used to interpret them allow to highlight interesting limitations of well-known deep reinforcement learning algorithms, namely PPO, TRPO and DQN

A Switch from Canonical to Noncanonical Wnt Signaling Mediates Drug Resistance in Colon Cancer Cells

Butyrate, a fermentation product of fiber in the colon, acts as a histone deacetylase inhibitor (HDACi) and induces apoptosis in colon cancer (CC) cells in vitro. We have reported that the apoptotic effects of butyrate are dependent upon the hyperactivation of the Wnt/beta-catenin pathway. However, prolonged exposure of CC cells to increasing concentrations of butyrate results in the acquisition of resistance to the Wnt/beta-catenin- and apoptosis-inducing effects of this agent, as well as cross-resistance to structurally different HDACis. Here we report that one mechanism whereby HDACi resistance arises is through the increase of beta-catenin-independent (noncanonical) Wnt signaling. Compared to HDACi-sensitive HCT-116 CC cells, HDACi-resistant HCT-R cells exhibit higher levels of AKT/PKB cell survival signaling, which is in part induced by WNT5A and its receptor ROR2. The induction of AKT signaling by HDACis is also detected in other CC cell lines, albeit to a lesser extent than in the drug-resistant HCT-R cells. The observations suggested that the apoptotic effect of butyrate and other HDACis in CC cells can be augmented by inhibitors of pAKT. In agreement with the hypothesis, the combination of MK2206, a pAKT inhibitor, and a HDACi (butyrate or LBH589) induced higher apoptosis in CC cells compared to each agent alone. The exposure to both agents also re-sensitized the HCT-R cells to apoptosis. Finally, the concept of simultaneously inducing canonical Wnt activity and suppressing AKT signaling was translated into a combination of diet-derived agents. Diet-derived pAKT inhibitors (caffeic acid phethyl ester, sulforaphane, dilallyl trisulfide) suppressed the butyrate-induced levels of pAKT, and increased the apoptotic effects of butyrate in both drug-sensitive and drug-resistant CC cells

Data mining of small RNA-Seq suggests an association between prostate cancer and altered abundance of 5' transfer RNA halves in seminal fluid and prostatic tissues

Extracellular RNAs are gaining clinical interest as biofluid-based noninvasive markers for diseases, especially cancer. In particular, derivatives of transfer RNA (tRNA) are emerging as a new class of small-noncoding RNAs with high biomarker potential. We and others previously reported alterations in serum levels of specific tRNA halves in disease states including cancer. Here, we explored seminal fluid for tRNA halves as potential markers of prostate cancer. We found that 5' tRNA halves are abundant in seminal fluid and are elevated in prostate cancer relative to noncancer patients. Importantly, most of these tRNA halves are also detectable in prostatic tissues, and a subset were increased in malignant relative to adjacent normal tissue. These findings emphasize the potential of 5' tRNA halves as noninvasive markers for prostate cancer screening and diagnosis and provide leads for future work to elucidate a putative role of the 5' tRNA halves in carcinogenesis.Joseph M Dhahbi, Hani Atamna and Luke A Selt

Augmented Lagrangian Constraint Handling for CMA-ES---Case of a Single Linear Constraint

International audienceWe consider the problem of minimizing a function f subject to a single inequality constraint g(x) <= 0, in a black-box scenario. We present a co-variance matrix adaptation evolution strategy using an adaptive augmented La-grangian method to handle the constraint. We show that our algorithm is an instance of a general framework that allows to build an adaptive constraint handling algorithm from a general randomized adaptive algorithm for unconstrained optimization. We assess the performance of our algorithm on a set of linearly constrained functions, including convex quadratic and ill-conditioned functions, and observe linear convergence to the optimum

Cell surface enzyme attachment is mediated by family 37 carbohydrate-binding modules, unique to Ruminococcus albus

The rumen bacterium Ruminococcus albus binds to and degrades crystalline cellulosic substrates via a unique cellulose degradation system. A unique family of carbohydrate-binding modules (CBM37), located at the C terminus of different glycoside hydrolases, appears to be responsible both for anchoring these enzymes to the bacterial cell surface and for substrate binding

Enhanced hydrogen peroxide generation accompanies the beneficial bioenergetic effects of methylene blue in isolated brain mitochondria

The redox dye methylene blue (MB) is proven to have beneficial effects in various models of neurodegenerative diseases. Here we investigated the effects of MB (100 nM, 300 nM, and 1 μM) on key bioenergetic parameters and on H2O2 production/elimination in isolated guinea pig brain mitochondria under normal as well as respiration-impaired conditions. As measured by high-resolution Oxygraph the rate of resting oxygen consumption was increased, but the ADP-stimulated respiration was unaffected by MB with any of the substrates (glutamate malate, succinate, or α-glycerophosphate) used for supporting mitochondrial respiration. In mitochondria treated with inhibitors of complex I or complex III MB moderately but significantly increased the rate of ATP production, restored ΔΨm, and increased the rate of Ca2+ uptake. The effects of MB are consistent with transferring electrons from upstream components of the electron transport chain to cytochrome c, which is energetically favorable when the flow of electrons in the respiratory chain is compromised. On the other hand, MB significantly increased the production of H2O2 measured by Amplex UltraRed fluorimetry under all conditions, in resting, ATP-synthesizing, and respiration-impaired mitochondria, with each substrate combination supporting respiration. Furthermore, it also decreased the elimination of H2O2. Generation of H2O2 without superoxide formation, observed in the presence of MB, is interpreted as a result of reduction of molecular oxygen to H2O2 by the reduced MB. The elevated generation and impaired elimination of H2O2 should be considered for the overall oxidative state of mitochondria treated with MB

Impaired Iron Status in Aging Research

Aging is associated with disturbances in iron metabolism and storage. During the last decade, remarkable progress has been made toward understanding their cellular and molecular mechanisms in aging and age-associated diseases using both cultured cells and animal models. The field has moved beyond descriptive studies to potential intervention studies focusing on iron chelation and removal. However, some findings remain controversial and inconsistent. This review summarizes important features of iron dyshomeostasis in aging research with a particular emphasis on current knowledge of the mechanisms underlying age-associated disorders in rodent models