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Plant NLRs are modular immune receptors that trigger rapid cell death in response to attempted infection by pathogens. A highly conserved nucleotide-binding domain shared with APAF-1, various R-proteins and CED-4 (NB-ARC domain) is proposed to act as a molecular switch, cycling between ADP (repressed) and ATP (active) bound forms. Studies of plant NLR NB-ARC domains have revealed functional similarities to mammalian homologues, and provided insight into potential mechanisms of regulation. However, further advances have been limited by difficulties in obtaining sufficient yields of protein suitable for structural and biochemical techniques. From protein expression screens in Escherichia coli and Sf9 insect cells, we defined suitable conditions to produce the NB-ARC domain from the tomato NLR NRC1. Biophysical analyses of this domain showed it is a folded, soluble protein. Structural studies revealed the NRC1 NB-ARC domain had co-purified with ADP, and confirmed predicted structural similarities between plant NLR NB-ARC domains and their mammalian homologues.

John Steele and Stephen Wallace discuss recent advances in the chemical and biotechnological synthesis of the prolific platform chemical adipic acid.

The term ‘endemic parkinsonism’ refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.Endemic parkinsonism occurs only in specific locations or populations. Here, Menšíková et al. describe clusters of endemic parkinsonism and highlight that those linked to neurotoxic environmental factors seem to be disappearing, while genetically determined clusters persist.

The production of plant helical virus-like particles (VLPs) via plant-based expression has been problematic with previous studies suggesting that an RNA scaffold may be necessary for their efficient production. To examine this, we compared the accumulation of VLPs from two potexviruses, papaya mosaic virus and alternanthera mosaic virus (AltMV), when the coat proteins were expressed from a replicating potato virus X- based vector (pEff) and a non-replicating vector (pEAQ-HT). Significantly greater quantities of VLPs could be purified when pEff was used. The pEff system was also very efficient at producing VLPs of helical viruses from different virus families. Examination of the RNA content of AltMV and tobacco mosaic virus VLPs produced from pEff revealed the presence of vector-derived RNA sequences, suggesting that the replicating RNA acts as a scaffold for VLP assembly. Cryo-EM analysis of the AltMV VLPs showed they had a structure very similar to that of authentic potexvirus particles. Thus, we conclude that vectors generating replicating forms of RNA, such as pEff, are very efficient for producing helical VLPs.

The past 30 years have seen the growth of plant molecular farming as an approach to the production of recombinant proteins for pharmaceutical and biotechnological uses. Much of this effort has focused on producing vaccine candidates against viral diseases, including those caused by enveloped viruses. These represent a particular challenge given the difficulties associated with expressing and purifying membrane-bound proteins and achieving correct assembly. Despite this, there have been notable successes both from a biochemical and a clinical perspective, with a number of clinical trials showing great promise. This review will explore the history and current status of plant-produced vaccine candidates against enveloped viruses to date, with a particular focus on virus-like particles (VLPs), which mimic authentic virus structures but do not contain infectious genetic material.

Increases in intracellular calcium concentration ([Ca²⁺] c ) mediate plant responses to stress by regulating the expression of genes encoding proteins that confer tolerance. Several plant stress genes have previously been shown to be calciumregulated, and in one case, a specific promoter motif Abscisic Acid Responsive-Element (ABRE) has been found to be regulated by calcium. A comprehensive survey of the Arabidopsis thaiiana transcriptome for calcium-regulated promoter motifs was performed by measuring the expression of genes in Arabidopsis seedlings responding to three calcium elevations of different characteristics, using full genome microarray analysis. This work revealed a total of 269 genes upregulated by [Ca²⁺] c in Arabidopsis. Bioinformatic analysis strongly indicated that at least four promoter motifs were [Ca²⁺] c -regulated in planta. We confirmed this finding by expressing in plants chimeric gene constructs controlled exclusively by these cis-elements and by testing the necessity and sufficiency of calcium for their expression. Our data reveal that the C-Repeat/Drought-Responsive Element, Site II, and CAM box (along with the previously identified ABRE) promoter motifs are calcium-regulated. The identification of these promoter elements targeted by the second messenger intracellular calcium has implications for plant signaling in response to a variety of stimuli, including cold, drought, and biotic stress.

Guam ALS/PDC is a severe tangle forming disorder endemic to Guam with features overlapping such neurodegenerative disorders as Alzheimer disease (AD), Parkinson disease (PD), progressive supranuclear palsy (PSP), ALS, corticobasal degeneration (CBD) and pallido-ponto-nigral degeneration (PPND). Since the prevalence is declining, we examined brain tissue from 35 clinically diagnosed Chamorro patients with ALS/PDC and two Chamorro controls autopsied between 1946 and 2006, to determine if distinct variations in the pathology could be identified up to this time. Although the age at autopsy increased by 4.5–5 years per decade, we identified no qualitative differences in pathological deposits with antibodies against tau, ubiquitin, Aβ, α-synuclein and TDP-43, indicating that these more recently identified proteins have been involved in the neuropathogenesis over the past 6 decades. Tau and TDP-43 positive neuronal, oligodendroglial and astrocytic inclusions involving multiple nerve fiber tracts occurred in both the ALS and PDC types, reinforcing the concept that these forms are part of the same disorder. The results obtained may help to define the commonality of the Guam disease with other tangle forming disorders and may help in monitoring the epidemiological changes that are taking place.

Parkinsonism-Dementia Complex (PDC) is one phenotype of a disappearing neurodegenerative disease (Guam ALS-PDC) that shows clinical and neuropathological relationships with amyotrophic lateral sclerosis (ALS), atypical parkinsonism and Alzheimer's disease. ALS-PDC has been linked with exposure to environmental factors (notably cycad plant neurotoxins), but evidence from human and animal studies is inconclusive. Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful in vitro system to explore the underlying cause of PDC. iPSC lines were derived from lymphocytes of a PDC-affected Guamanian Chamorro female patient and an age- and gender-matched healthy Chamorro resident of PDC-unaffected Saipan using non-integrating episomal plasmids. iPSCs derived from both patients expressed pluripotency markers (Oct4, SSEA-4, TRA-1-60, Sox2) prior to the generation of neuroprogenitor cells (hNPCs), neurons and astrocytes. An embryoid body protocol was used to derive hNPCs from both iPSC lines while a differentiation media was used to generate neurons from hNPCs. hNPCs derived from both iPSC patients' lines displayed established neuroprogenitor markers (nestin, Sox2), while the differentiated hNPCs exhibited both neuronal (beta-tubulin III, Map2, doublecortin) and synaptic (synaptophysin, PSD-95) markers. Expression of these protein markers in hNPCs and neurons by dot blotting was also observed for both lines. Astrocyte progenitor cells and mature astrocytes with appropriate markers were also developed from the hNPCs of both lines using commercial kits. Development of these patient-derived iPSCs provides a human model for evaluating the role of environmental (e.g., cycad toxins) and genetic factors in ALS-PDC and possibly other related neurodegenerative diseases.

The parkinsonism dementia complex of Guam (bodig disease) is characterized by severe neurofibrillary tangle (NFT) development without the senile plaques which characterize Alzheimer's disease. Here we analyze eight cases of bodig and three control cases from Guam, for the numbers of unaffected pyramidal neurons, intracellular NFTs (iNFTs), and extracellular NFTs (eNFTs) in hippocampal sectors CA1 and CA4. We utilized Alz50 immunostaining to identify iNFTs, amyloid P immunostaining to identify eNFTs, and cresyl violet staining to identify the surviving pyramidal neurons. We developed a modification of the Bielschowsky silver staining method which distinguished iNFTs from eNFTs and found the numbers of iNFTs and eNFTs identified by this method to be comparable to those obtained by immunohistochemical staining. In CA4, the combined total of unaffected pyramidal neurons, iNFTs and eNFTs was found to be remarkably constant in all the cases studied. The density of eNFTs correlated significantly and negatively with the density of surviving neurons, which included unaffected neurons and iNFTs. CA1 was more intensely affected than CA4. The combined total of unaffected pyramidal neurons, iNFTs and eNFTs was still relatively constant, although greater variability was recorded. Our results suggest that loss of pyramidal neurons is proportional to the appearance of eNFTs. The eNFTs accumulate, without evidence of disappearance through phagocytosis.