Brain accumulation of the amyloid-β (Aβ) peptide is believed to be the initial event in the Alzheimer disease (AD) process. Aβ accumulation begins 15-20 years before clinical symptoms occur, mainly ...owing to defective brain clearance of the peptide. Over the past 20 years, we have seen intensive efforts to decrease the levels of Aβ monomers, oligomers, aggregates and plaques using compounds that decrease production, antagonize aggregation or increase brain clearance of Aβ. Unfortunately, these approaches have failed to show clinical benefit in large clinical trials involving patients with mild to moderate AD. Clinical trials in patients at earlier stages of the disease are ongoing, but the initial results have not been clinically impressive. Efforts are now being directed against Aβ oligomers, the most neurotoxic molecular species, and monoclonal antibodies directed against these oligomers are producing encouraging results. However, Aβ oligomers are in equilibrium with both monomeric and aggregated species; thus, previous drugs that efficiently removed monomeric Aβ or Aβ plaques should have produced clinical benefits. In patients with sporadic AD, Aβ accumulation could be a reactive compensatory response to neuronal damage of unknown cause, and alternative strategies, including interference with modifiable risk factors, might be needed to defeat this devastating disease.
The Plant Peptidome Tavormina, Patrizia; De Coninck, Barbara; Nikonorova, Natalia ...
The Plant cell,
08/2015, Volume:
27, Issue:
8
Journal Article
Peer reviewed
Open access
Peptides fulfill a plethora of functions in plant growth, development, and stress responses. They act as key components of cell-to-cell communication, interfere with signaling and response pathways, ...or display antimicrobial activity. Strikingly, both the diversity and amount of plant peptides have been largely underestimated. Most characterized plant peptides to date acting as small signaling peptides or antimicrobial peptides are derived from nonfunctional precursor proteins. However, evidence is emerging on peptides derived from a functional protein, directly translated from small open reading frames (without the involvement of a precursor) or even encoded by primary transcripts of microRNAs. These novel types of peptides further add to the complexity of the plant peptidome, even though their number is still limited and functional characterization as well as translational evidence are often controversial. Here, we provide a comprehensive overview of the reported types of plant peptides, including their described functional and structural properties. We propose a novel, unifying peptide classification system to emphasize the enormous diversity in peptide synthesis and consequent complexity of the still expanding knowledge on the plant peptidome.
Plant defensins are small, cysteine-rich peptides that possess biological activity towards a broad range of organisms. Their activity is primarily directed against fungi, but bactericidal and ...insecticidal actions have also been reported. The mode of action of various antifungal plant defensins has been studied extensively during the last decades and several of their fungal targets have been identified to date. This review summarizes the mechanism of action of well-characterized antifungal plant defensins, including RsAFP2, MsDef1, MtDef4, NaD1 and Psd1, and points out the variety by which antifungal plant defensins affect microbial cell viability. Furthermore, this review summarizes production routes for plant defensins, either via heterologous expression or chemical synthesis. As plant defensins are generally considered non-toxic for plant and mammalian cells, they are regarded as attractive candidates for further development into novel antimicrobial agents.
The fungal pathogen Botrytis cinerea establishes a necrotrophic interaction with its host plants, including lettuce (Lactuca sativa), causing it to wilt, collapse and eventually dry up and die, which ...results in serious economic losses. Global expression profiling using RNAseq and the newly sequenced lettuce genome identified a complex network of genes involved in the lettuce–B. cinerea interaction. The observed high number of differentially expressed genes allowed us to classify them according to the biological pathways in which they are implicated, generating a holistic picture. Most pronounced were the induction of the phenylpropanoid pathway and terpenoid biosynthesis, whereas photosynthesis was globally down‐regulated at 48 h post‐inoculation. Large‐scale comparison with data available on the interaction of B. cinerea with the model plant Arabidopsis thaliana revealed both general and species‐specific responses to infection with this pathogen. Surprisingly, expression analysis of selected genes could not detect significant systemic transcriptional alterations in lettuce leaves distant from the inoculation site. Additionally, we assessed the response of these lettuce genes to a biotrophic pathogen, Bremia lactucae, revealing that similar pathways are induced during compatible interactions of lettuce with necrotrophic and biotrophic pathogens.
This study includes an extended RNAseq analysis of the locally induced defence responses in leaves of lettuce after inoculation with Botrytis cinerea, an economically important pathogen affecting many dicot plant species. To our knowledge, this is the first reported quantitative transcriptomic study of lettuce, which was possible after the recent unravelling of the lettuce genome. The observed high number of differentially expressed genes allowed us to classify them according to the biological pathways indicating the induction of secondary metabolism, with the phenylpropanoid pathway and terpenoid biosynthesis among the most pronounced responses. Subsequent qRT‐PCR‐based gene expression analysis on a limited set of genes resulting from our RNAseq‐study revealed a high similarity in (i) the response in locally infected versus systemic leaves and (ii) in the induction of similar pathways during compatible interactions of lettuce with necrotrophic versus biotrophic pathogens.
Alzheimer's disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat the disease by ...reducing brain accumulation of amyloid-β in patients with Alzheimer's disease, with no success. While anti-amyloid-β therapies continue to be tested in prodromal patients with Alzheimer's disease and in subjects at risk of developing Alzheimer's disease, there is an urgent need to provide therapeutic support to patients with established Alzheimer's disease for whom current symptomatic treatment (acetylcholinesterase inhibitors and N-methyl d-aspartate antagonist) provide limited help. The possibility of an infectious aetiology for Alzheimer's disease has been repeatedly postulated over the past three decades. Infiltration of the brain by pathogens may act as a trigger or co-factor for Alzheimer's disease, with Herpes simplex virus type 1, Chlamydia pneumoniae, and Porphyromonas gingivalis being most frequently implicated. These pathogens may directly cross a weakened blood-brain barrier, reach the CNS and cause neurological damage by eliciting neuroinflammation. Alternatively, pathogens may cross a weakened intestinal barrier, reach vascular circulation and then cross blood-brain barrier or cause low grade chronic inflammation and subsequent neuroinflammation from the periphery. The gut microbiota comprises a complex community of microorganisms. Increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may impact Alzheimer's disease pathogenesis. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation and brain amyloid-β deposition in subjects with cognitive impairment. Oral microbiota may also influence Alzheimer's disease risk through circulatory or neural access to the brain. At least two possibilities can be envisaged to explain the association of suspected pathogens and Alzheimer's disease. One is that patients with Alzheimer's disease are particularly prone to microbial infections. The other is that microbial infection is a contributing cause of Alzheimer's disease. Therapeutic trials with antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents are being tested in patients with Alzheimer's disease in double-blind placebo-controlled studies. Although combined antibiotic therapy was found to be effective in animal models of Alzheimer's disease, antibacterial drugs are not being widely investigated in patients with Alzheimer's disease. This is because it is not clear which bacterial populations in the gut of patients with Alzheimer's disease are overexpressed and if safe, selective antibacterials are available for them. On the other hand, a bacterial protease inhibitor targeting P. gingivalis toxins is now being tested in patients with Alzheimer's disease. Clinical studies are needed to test if countering bacterial infection may be beneficial in patients with established Alzheimer's disease.
The amyloid‐β (Aβ) cascade hypothesis of Alzheimer disease (AD) holds that brain accumulation of Aβ initiates the disease process. Accordingly, drug research has targeted Aβ production, clearance, ...and deposition as therapeutic strategies. Unfortunately, candidate drugs have failed to show clinical benefit in established, early, or prodromal disease, or in those with high AD risk. Currently, monoclonal antibodies specifically directed against the most neurotoxic Aβ forms are undergoing large‐scale trials to confirm initially encouraging results. However, recent findings on the normal physiology of Aβ suggest that accumulation may be compensatory rather than the pathological initiator. If this is true, alternative strategies will be needed to defeat this devastating disease. ANN NEUROL 2019;85:303–315.
Semiconductor nanowires have potential applications in photovoltaics, batteries, and thermoelectrics. We report a top-down fabrication method that involves the combination of ...superionic-solid-state-stamping (S4) patterning with metal-assisted-chemical-etching (MacEtch), to produce silicon nanowire arrays with defined geometry and optical properties in a manufacturable fashion. Strong light emission in the entire visible and near infrared wavelength range at room temperature, tunable by etching condition, attributed to surface features, and enhanced by silver surface plasmon, is demonstrated.
In structural biology, deriving and refining atomic models into maps obtained from X‐ray crystallography or cryo electron microscopy (cryo‐EM) is essential for the detailed interpretation of a ...structure and its functional implications through interactions so that for example hydrogen bonds, drug specificity and associated molecular mechanisms can be analysed. This commentary summarizes the latest features of the Phenix software and also highlights the fact that cryo‐EM increasingly contributes to data depositions in the PDB and EMDB.
In structural biology, deriving and refining atomic models into maps obtained from X‐ray crystallography or cryo electron microscopy (cryo‐EM) is essential for the detailed interpretation of a structure and its functional implications through interactions so that for example hydrogen bonds, drug specificity and associated molecular mechanisms can be analysed. This commentary summarizes the latest features of the Phenix software and also highlights the fact that cryo‐EM increasingly contributes to data depositions in the PDB and EMDB.
Recent advances in the field of electron cryomicroscopy (cryo‐EM) have resulted in a rapidly increasing number of atomic models of biomacromolecules that have been solved using this technique and ...deposited in the Protein Data Bank and the Electron Microscopy Data Bank. Similar to macromolecular crystallography, validation tools for these models and maps are required. While some of these validation tools may be borrowed from crystallography, new methods specifically designed for cryo‐EM validation are required. Here, new computational methods and tools implemented in PHENIX are discussed, including d99 to estimate resolution, phenix.auto_sharpen to improve maps and phenix.mtriage to analyze cryo‐EM maps. It is suggested that cryo‐EM half‐maps and masks should be deposited to facilitate the evaluation and validation of cryo‐EM‐derived atomic models and maps. The application of these tools to deposited cryo‐EM atomic models and maps is also presented.
New methods and PHENIX tools for quality assessment of cryo‐EM maps, atomic models and model‐to‐map fitting are presented. Results of systematic application of these tools to high‐resolution cryo‐EM maps and corresponding atomic models are analyzed and discussed.
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