Fungal secretomes—nature’s toolbox for white biotechnology

Adapting their metabolism to varying carbon and nitrogen sources, saprophytic fungi produce an arsenal of extracellular enzymes, the secretome, which allows for an efficient degradation of lignocelluloses and further biopolymers. Based on fundamental advances in electrophoretic, chromatographic, and mass spectrometric techniques on the one hand and the availability of annotated fungal genomes and sophisticated bioinformatic software tools on the other hand, a detailed analysis of fungal secretomes has become feasible. While a number of reports on ascomycetous secretomes of, e.g., Aspergillus, Trichoderma, and Fusarium species are already available, studies on basidiomycetes have been mainly focused on the two model organisms Phanerochaete chrysosporium and Coprinopsis cinerea so far. Though an impressive number and diversity of fungal biocatalysts has been revealed by secretome analyses, the identity and function of many extracellular proteins still remains to be elucidated. A comprehensive understanding of the qualitative and quantitative composition of fungal secretomes, together with their synergistic actions and kinetic expression profiles, will allow for the development of optimized enzyme cocktails for white biotechnology.     

Multifaceted Alzheimer’s Disease: Building a Roadmap for Advancement of Novel Therapies

Neurochemical Research - Alzheimer's disease (AD) is one of the most prevailing neurodegenerative disorders of elderly humans associated with cognitive damage. Biochemical, epigenetic, and...     

A life cycle method for assessment of a colliery’s eco-indicator

Global Scope and Background  The study was aimed at presenting the methodology of the process eco-indicator, in relation to hard coal mines, and thereby making evaluation of the impact of the mine’s coal extraction process on the environment. The life cycle of a mine is made up of three phases: opening and developing the mine’s deposit, extraction of the mine’s deposit, closing the mine. Methods  The assessment of environmental influence of mining operation of a colliery was executed on a basis of the life cycle analysis, in accordance with the standard series PN-EN 14040. The environmental loads caused by individual unit processes were calculated by means of the aforementioned methodology with division into the basic influence categories: human health, ecosystem quality and natural resources. The obtained values of eco-indicators for the individual unit processes made it possible to compare the unit-process-caused environmental loads. Mean values of the eco-indicators of the individual unit processes were calculated by means of the inventory analysis covering 38 collieries. Next, these indicators were used to compare environmental load values by each similar process in a colliery. A total eco-indicator was calculated for colliery by summing up the eco-indicators of the individual unit processes. The eco-indicators, structured as above, were calculated for the phase of opening out a deposit and for the phase of extraction. Results and Discussion  The model mine in the phase of extraction of a deposit causes a total environmental load which expressed in points of the eco-indicator 99 amounts to 23.9 [MEw]. In the ‘human health’ category losses amount to 8.4 per cent, in the ‘quality of ecosystem’ 0.6 per cent and in the ‘resourses’ category 91 per cent. The greatest losses in all categories are caused by the process of getting body of coal and the next greatest ones are:

Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer’s Disease

Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer’s disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.     

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT_2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT_2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT_2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT_2A receptor inverse agonist, selectivity for 5-HT_2A over 5-HT_2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.     

Centiloid scale analysis for 18F-THK5351 PET imaging in Alzheimer’s disease

PurposeA standardized method for quantification is required for analyzing PET data, but such standards have not been established for tau PET imaging. The Centiloid scale has recently been proposed as a standard method for quantifying amyloid deposition on PET imaging. Therefore, the present study aimed to apply the Centiloid scale to ¹⁸F-THK5351 PET imaging in Alzheimer’s disease (AD).MethodsWe acquired ¹⁸F-THK5351 PET, ¹¹C-PiB PET, and MR images from 47 cognitively normal (CN) individuals and 28 patients with AD with mild to moderate dementia. PET images were spatially normalized to Montreal Neurological Institute space. The PET signals were then normalized using the signal in the reference volume of interest (VOI). Target VOI for specific ¹⁸F-THK5351 retention in AD was extracted by voxel-wise comparison of PET images between the 47 CN individuals and 16 AD patients with moderate dementia. Scale anchor points were defined by the CN individuals as 0-anchor points and by that of the average of the typical AD patients as 100-anchor points.ResultsSpecific retention of ¹⁸F-THK5351 was predominant in the angular gyrus, inferior temporal cortex, and parieto-occipital regions in patients with AD. Standardized uptake value ratio (SUVR) of 1.227 and 1.797 were defined as 0- and 100-anchor points, respectively. ¹⁸F-THK5351 PET data could be expressed using the Centiloid scale, with the SUVR of the ¹⁸F-THK5351 PET images converted to Centiloid using our VOI, the standard Centiloid reference VOI, and the following equation: Centiloid = 169.0 × SUVR–204.6.ConclusionCentiloid methods can be applied to tau PET imaging using ¹⁸F-THK5351.     

Michael Parker Banton: an appreciation of his life’s work

This article is an appreciation of the contributions to ethnic and racial studies and to British sociology in general of Michael Parker Banton. It reviews his career and also his major publications, including also arguments against him made by his principal critics and his responses to these. It points out the specificity of his contributions and argues for his unique importance in defining and developing the field of ethnic and race relations in British sociology during the second half of the twentieth century and into the present century. It also mentions his many contributions to public life.     

Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer’s disease

A summary of the recently published efforts on tacrine derivatives as a renewed potential therapeutic approach for the treatment of Alzheimer’s disease is presented.     

Eye-tracking women’s preferences for men’s somatotypes

Judging physical attractiveness involves sight, touch, sound and smells. Where visual judgments are concerned, attentional processes may have evolved to prioritize sex-typical traits that reflect cues signaling direct or indirect (i.e. genetic) benefits. Behavioral techniques that measure response times or eye movements provide a powerful test of this assumption by directly assessing how attractiveness influences the deployment of attention. We used eye-tracking to characterize women’s visual attention to men’s back-posed bodies, which varied in overall fat and muscle distribution, while they judged the potential of each model for a short- or long-term relationship. We hypothesized that when judging male bodily attractiveness women would focus more on the upper body musculature of all somatotypes, as it is a signal of metabolic health, immunocompetence and underlying endocrine function. Results showed that mesomorphs (muscular men) received the highest attractiveness ratings, followed by ectomorphs (lean men) and endomorphs (heavily-set men). For eye movements, attention was evenly distributed to the upper and lower back of both ectomorphs and mesomorphs. In contrast, for endomorphs the lower back, including the waist, captured more attention over the viewing period. These patterns in visual attention were evident in the first second of viewing, suggesting that body composition is identified early in viewing and guides attention to body regions that provide salient biological information during judgments of men’s bodily attractiveness.     

Multimodal retinal imaging to detect and understand Alzheimer’s and Parkinson’s disease

Retinal neurodegeneration and visual dysfunctions have been reported in a majority of Alzheimer’s and Parkinson’s patients, and, in light of the quest for novel biomarkers for these neurodegenerative proteinopathies, the retina has been receiving increasing attention as an organ for diagnosing, monitoring, and understanding disease. Thinning of retinal layers, abnormalities in vasculature, and protein deposition can be imaged at unprecedented resolution, which offers a unique systems biology view on the cellular and molecular changes underlying these pathologies. It makes the retina not only a promising target for biomarker development, but it also suggests that novel fundamental insights into the pathophysiology of Alzheimer’s and Parkinson’s disease can be obtained by studying the retina–brain axis.     

18F-labeled benzimidazopyridine derivatives for PET imaging of tau pathology in Alzheimer’s disease

Hyperphosphorylated tau proteins are one of the neuropathological hallmarks in the Alzheimer’s disease (AD) brain. The in vivo imaging of tau aggregates with nuclear medical imaging probes is helpful for the further comprehension of and medical intervention in the AD pathology. For tau-selective PET imaging, we newly designed and synthesized ¹⁸F-labeled benzimidazopyridine (BIP) derivatives with fluoroalkylamino groups, [¹⁸F]IBIPF1 and [¹⁸F]IBIPF2, and evaluated their utilities as tau imaging probes. They both bound selectively to tau against amyloid β (Aβ) aggregates in AD brain sections in vitro, and showed good pharmacokinetics in mouse brains in vivo. Notably, [¹⁸F]IBIPF1 exhibited high tau-selectivity (Tau/Aβ ratio = 34.8), high brain uptake (6.22% ID/g at 2 min postinjection), and subsequent washout (2.77% ID/g at 30 min postinjection). In vivo analysis of radiometabolites indicated that [¹⁸F]IBIPF1 was stable against metabolism in the mouse brain. These encouraging preclinical results suggest that further structural optimization based on the BIP scaffold may lead to the development of more useful tau imaging probes.     

Novel imaging agents for β-amyloid plaque based on the N-benzoylindole core

We report the synthesis and evaluation of a series of N-benzoylindole derivatives as novel potential imaging agents for β-amyloid plaques. In vitro binding studies using Aβ(1-40) aggregates versus [(125)I]TZDM showed that all these derivatives demonstrated high binding affinities (K(i) values ranged from 8.4 to 121.6 nM). Moreover, two radioiodinated compounds [(125)I]7 and [(125)I]14 were prepared. Autoradiography for [(125)I]14 displayed intense and specific labeling of Aβ plaques in the brain sections of AD model mice (C57, APP/PS1) with low background. In vivo biodistribution in normal mice exhibited sufficient initial brain uptake for imaging (2.19% and 2.00%ID/g at 2 min postinjection for [(125)I]7 and [(125)I]14, respectively). Although additional modifications are necessary to improve brain uptake and clearance from the brain, the N-benzoylindole may be served as a backbone structure to develop novel β-amyloid imaging probes.     

Clathrin’s life beyond 40: Connecting biochemistry with physiology and disease

Understanding of the range and mechanisms of clathrin functions has developed exponentially since clathrin's discovery in 1975. Here, newly established molecular mechanisms that regulate clathrin activity and connect clathrin pathways to differentiation, disease and physiological processes such as glucose metabolism are reviewed. Diversity and commonalities of clathrin pathways across the tree of life reveal species-specific differences enabling functional plasticity in both membrane traffic and cytokinesis. New structural information on clathrin coat formation and cargo interactions emphasises the interplay between clathrin, adaptor proteins, lipids and cargo, and how this interplay regulates quality control of clathrin’s function and is compromised in infection and neurological disease. Roles for balancing clathrin-mediated cargo transport are defined in stem cell development and additional disease states.