The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes ...of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate.
Depression predisposes to medical illnesses and advances biological aging indicated by shorter telomere length, accelerated brain aging and advanced epigenetic aging. Medical illnesses also increase ...the risk of late-life depression. The reciprocal relationships of depression with aging-related and disease-related processes have generated pathogenetic hypotheses and provided treatment targets. Targeting risk factors of vascular disease in mid-life is a logical approach in prevention of vascular depression. The depression-executive dysfunction and the vascular depression syndromes have clinical presentations and neuroimaging findings consistent with frontostriatal abnormalities. Dopamine D
agonists are effective in depression of Parkinson's disease and their efficacy needs to be assessed in these two syndromes. Computerized cognitive remediation targeting functions of the cognitive control network may improve both executive functions and depressive symptoms of late-life major depression. Significant progress has been made in neurostimulation treatments in depressed younger adults. TMS targeting deep structures responsible for mood regulation is well tolerated by older adults and its efficacy in syndromes of late-life depression needs to be studied. Efficacious psychotherapies for late-life depression exist, but are underutilized in part because of their complexity. Streamlined, stepped psychotherapies targeting behaviors assumed to result from dysfunction of brain networks implicated in late-life depression can be easy to learn and have potential for dissemination. However, their effectiveness needs further investigation. Depression increases the risk of dementing disorders. Antidepressants are rather ineffective in treating depression of demented patients, but long-term use of antidepressants may reduce the risk of dementia. However, confirmation studies are needed.
Marketers are being challenged by a deluge of data that is well beyond the capacity of their organizations to comprehend and use. Their strategies are not keeping up with the disruptive effects of ...technology-empowered customers; the proliferation of media, channel, and customer contact points; or the possibilities for microsegmentation. Closing the widening gap between the accelerating complexity of their markets and the limited ability of their organizations to respond demands new thinking about marketing capabilities. Three adaptive capabilities are needed: (1) Vigilant market learning that enhances deep market insights with an advance warning system to anticipate market changes and unmet needs, (2) adaptive market experimentation that continuously learns from experiments, and (3) open marketing that forges relationships with those at the forefront of new media and social networking technologies and mobilizes the skills of current partners. The benefits of these adaptive capabilities will only be realized in organizations that are more resilient and free-flowing, with vigilant leadership and more adaptive business models.
•Research studies on the performance of structural aluminium alloys are discussed.•Research on material and structural members are tabulated.•Applicability of the international design specifications ...is reviewed.•Recommendations for future research in this field are stated.
Over the last few decades aluminium alloys have been increasingly used in the construction sector due to their favourable properties. Thereafter, many research projects have been carried out with the aim to obtain a more comprehensive understanding of their structural performance and develop accurate and reliable design formulae. The scope of this paper is to provide a comprehensive review of research by discussing the reported experimental, numerical and analytical work on structural aluminium alloys. The paper presents an overview of research studies on the mechanical properties of aluminium alloys under monotonic, cyclic and thermal loading conditions. Moreover, a considerable amount of experimental and numerical investigations focussing on the structural performance and design of aluminium columns, beams and beam-columns is reviewed. The performance of connections and composite aluminium-concrete members is also discussed. Comments on the suitability of the international design specifications to structural aluminium alloys are included. Within the review, knowledge gaps are identified and the corresponding research work to fill these gaps is recommended.
Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like zinc (Zn). The pleiotropic cytokine granulocyte macrophage-colony ...stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF-activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription-factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7; the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H+ channel function and triggered reactive oxygen species generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function.
Display omitted
•Metallothioneins, or Zn-sequestering proteins, drive GM-CSF effector function•Zn sequestration augments production of reactive oxygen species via HV1•GM-CSF triggers Zn deprivation and enhances ROS to kill fungi in macrophages•GM-CSF drives Zn sequestration in vivo and in human macrophages
Organizing for Marketing Excellence Moorman, Christine; Day, George S.
Journal of marketing,
11/2016, Letnik:
80, Številka:
6
Journal Article
Recenzirano
Marketing organization is the interface of the firm with its markets and where the work of marketing gets done. This review of the past 25 years of scholarship on marketing organization examines the ...individual and integrative roles of four elements of marketing organization—capabilities, configuration (including structure, metrics, and incentives), culture, and the human capital of marketing leadership and talent. The authors indicate that these four elements are mobilized through seven marketing activities (7As) that occur during the marketing strategy process. These activities enable the firm to anticipate market changes, adapt the strategy to stay ahead of competition, align the organization to the strategy and market, activate effective implementation, ensure accountability for results, attract resources, and manage marketing assets. How well the firm manages these seven activities throughout the marketing strategy process determines the performance payoffs from marketing organization. Future research priorities outlined for the elements of marketing organization, their integration, and their impact on the 7As offer directions for the study of organizing for marketing excellence.
The Amazon rainforest is the Earth’s largest reservoir of plant and animal diversity, and it has been subjected to especially high rates of land use change, primarily to cattle pasture. This ...conversion has had a strongly negative effect on biological diversity, reducing the number of plant and animal species and homogenizing communities. We report here that microbial biodiversity also responds strongly to conversion of the Amazon rainforest, but in a manner different from plants and animals. Local taxonomic and phylogenetic diversity of soil bacteria increases after conversion, but communities become more similar across space. This homogenization is driven by the loss of forest soil bacteria with restricted ranges (endemics) and results in a net loss of diversity. This study shows homogenization of microbial communities in response to human activities. Given that soil microbes represent the majority of biodiversity in terrestrial ecosystems and are intimately involved in ecosystem functions, we argue that microbial biodiversity loss should be taken into account when assessing the impact of land use change in tropical forests.
This monograph treats the usefulness of flavor physics as probes of the TeV scale, with the aim of providing a timely introduction to the emerging LHC era. By concentrating only with the TeV scale ...connection, a large part of the B factory output can be bypassed. The emphasis here is on loop-induced processes, which enables the probing of virtual TeV scale physics through quantum processes. Two-thirds of the book is concerned with b s or bs bs transitions. It takes an experimental perspective resulting in selecting processes, rather than the theories or models, as the basis to explore flavor physics as probe of the TeV scale. The guiding principle has been, unless it can be identified as the smoking gun, it is better to stick to the simplest (rather than elaborate) explanation of an effect that requires New Physics. Luckily, focusing on heavy flavor as a probe of TeV scale physics, these technicalities can be engaged, thus acknowledging their beauty, but avoiding getting ensnared by them, while aiming for the deeper, higher scale physics that such probes afford. This tracts orinated as a plenary talk at the SUSY 2007 conference in Karlsruhe, Germany.
This paper proposes a multi-layer neural network structure for few-shot image recognition of novel categories. The proposed multi-layer neural network architecture encodes transferable knowledge ...extracted from a large annotated dataset of base categories. This architecture is then applied to novel categories containing only a few samples. The transfer of knowledge is carried out at the feature-extraction and the classification levels distributed across the two training stages. In the first-training stage, we introduce the relative feature to capture the structure of the data as well as obtain a low-dimensional discriminative space. Secondly, we account for the variable variance of different categories by using a network to predict the variance of each class. Classification is then performed by computing the Mahalanobis distance to the mean-class representation in contrast to previous approaches that used the Euclidean distance. In the second-training stage, a category-agnostic mapping is learned from the mean-sample representation to its corresponding class-prototype representation. This is because the mean-sample representation may not accurately represent the novel category prototype. Finally, we evaluate the proposed network structure on four standard few-shot image recognition datasets, where our proposed few-shot learning system produces competitive performance compared to previous work. We also extensively studied and analyzed the contribution of each component of our proposed framework.
PDF
