The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Proteostasis, or protein homeostasis, encompasses the maintenance of the conformational and functional integrity of the proteome and involves an integrated network of cellular pathways. Molecular chaperones, such as the small heat shock proteins (sHsps), are key elements of the proteostasis network that have crucial roles in inhibiting the aggregation of misfolded proteins. Failure of the proteostasis network can lead to the accumulation of misfolded proteins into intracellular and extracellular deposits. Deposits containing fibrillar forms of α-sy-nuclein (α-syn) are characteristic of neurodegenerative disorders including Parkinson\u27s disease and dementia with Lewy bodies. Here we show that the sHsp Hsp27 (HSPB1) binds to α-syn fibrils, inhibiting fibril growth by preventing elongation. Using total internal reflection fluorescence (TIRF)- based imaging methods, we show that Hsp27 binds along the surface of α-syn fibrils, decreasing their hydrophobicity. Binding of Hsp27 also inhibits cytotoxicity of α-syn fibrils. Our results demonstrate that the ability of sHsps, such as Hsp27, to bind fibrils represents an important mechanism through which they May mitigate cellular toxicity associated with aberrant protein aggregation. Fibril binding May represent a generic mechanism by which chaperone-active sHsps interact with aggregation-prone proteins, highlighting the potential to target sHsp activity to prevent or disrupt the onset and progression of α-syn aggregation associated with α-synucleinopathies

Comparative analysis of the responses to water stress in eggplant (Solanum melongena) cultivars

[EN] Little information is available on the physiological and biochemical responses to water stress in eggplant (Solanum melongena). We valuated four genetically diverse eggplant varieties (MEL3-MEL6) under control and water stress conditions. Measurements were taken for plant growth, tissue water content, levels of chlorophylls a and b, carotenoids, roline, malondialdehyde, total phenolics, total flavonoids, superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase APX), and glutathione reductase (GR) activities. For most traits, the water stress treatment had a greater contribution than the variety effect to the total sums of squares in an ANOVA analysis, except for total flavonoids, SOD, APX, and GR. The water stress treatment had a strong effect on plant growth and tissue water content. In general, water tress reduced the three photosynthetic pigments, increased proline, malondialdehyde, total phenolics, and total flavonoids, although some varietal differences were ob- served. Different patterns were also detected in the activities of the four enzymes evaluated, but few differences were observed for individual varieties between the control and water stress treatments. Many significant phe- notypic orrelations were observed among the traits studied, but only eight environmental correlations were detected. A PCA analysis distinctly separated individuals according to the treatment, and revealed a clearer separation of varieties under water stress than under control conditions, pointing to varietal differences in the responses to stress. Our results suggest that proline could be used as a marker for drought stress tolerance in this species. The information obtained provides new insight on the physiological and biochemical responses of eggplant to drought stressAuthors are grateful to the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No 677379 (G2P-SOL project: Linking genetic resources, genomes and phenotypes of Solanaceous crops), to Ministerio de Economfa, Industria y Competitividad and Fondo Europeo de Desarrollo Regional (grant AGL2015-64755-R from MINECO/FEDER), to Ministerio de Ciencia, Innovation y Universidades, Agencia Estatal de Investigation and Fondo Europeo de Desarrollo Regional (grant RTI-2018-094592-B-100 from MCIU/AEI/FEDER, UE), to the Generalitat Valenciana and Fondo Social Europeo (Ayuda a Grupos Emergentes; GV/2019/033), to the Vicerrectorado de Investigacien, Innovation y Transferencia de la Universitat Politecnica de Valencia (Ayuda a Primeros Proyectos de Investigation; PAID-06-18), and to the initiative "Adapting Agriculture to Climate Change: Collecting, Protecting and Preparing Crop Wild Relatives", which is supported by the Government of Norway. This latter project is managed by the Global Crop Diversity Trust with the Millennium Seed Bank of the Royal Botanic Gardens, Kew and implemented in partnership with national and international gene banks and plant breeding institutes around the world. For further information see the project website: http://www.cwrdiversity.org/. Mariola Plazas is grateful to Generalitat Valenciana and Fondo Social Europeo for a post-doctoral contract (APOSTD/2018/014). The contribution of Huu Trong Nguyen to this paper has been developed as a result of a mobility stay funded by Erasmus + KA1 Erasmus Mundus Joint Master Degrees Programme of the European Commission under the PLANT HEALTH project.Plazas, M.; Nguyen, HT.; González-Orenga, S.; Fita, A.; Vicente, O.; Prohens Tomás, J.; Boscaiu, M. (2019). Comparative analysis of the responses to water stress in eggplant (Solanum melongena) cultivars. Plant Physiology and Biochemistry. 143:72-82. https://doi.org/10.1016/j.plaphy.2019.08.031S728214

State pension funds and corporate social responsibility: do beneficiaries’ political values influence funds’ investment decisions?

This study explores the underlying drivers of US public pension funds’ tendency to tilt their portfolios towards companies with stronger corporate social responsibility (CSR). Studying the equity holdings of large, internally-managed US state pension funds, we find evidence that the political leaning of their beneficiaries and political pressures by state politicians affect funds’ investment decisions. State pension funds from states with Democratic-leaning beneficiaries tilt their portfolios more strongly towards companies that perform well on CSR issues, and this tendency is intensified when the state government is dominated by Democratic state politicians. Moreover, we find that funds which tilt their portfolios towards companies with superior CSR scores generate a slightly higher return compared with their counterparts. Overall, our findings indicate that funds align their investment choices with the financial and non-financial interests of their beneficiaries when deciding whether to incorporate CSR into their equity allocations

Biomaterial-Based Implantable Devices for Cancer Therapy

This review article focuses on the current local therapies mediated by implanted macroscaled biomaterials available or proposed for fighting cancer and also highlights the upcoming research in this field. Several authoritative review articles have collected and discussed the state-of-the-art as well as the advancements in using biomaterial-based micro- and nano-particle systems for drug delivery in cancer therapy. On the other hand, implantable biomaterial devices are emerging as highly versatile therapeutic platforms, which deserve an increased attention by the healthcare scientific community, as they are able to offer innovative, more effective and creative strategies against tumors. This review summarizes the current approaches which exploit biomaterial-based devices as implantable tools for locally administrating drugs and describes their specific medical applications, which mainly target resected brain tumors or brain metastases for the inaccessibility of conventional chemotherapies. Moreover, a special focus in this review is given to innovative approaches, such as combined delivery therapies, as well as to alternative approaches, such as scaffolds for gene therapy, cancer immunotherapy and metastatic cell capture, the later as promising future trends in implantable biomaterials for cancer applications

Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database.

BACKGROUND: Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by the expansion of the polyglutamine repeat region in the huntingtin gene. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. To obtain a systematic overview of these genes, which may serve as therapeutic targets, CHDI Foundation has recently established the HD Research Crossroads database. With currently over 800 cataloged genes, this web-based resource constitutes the most extensive curation of genes relevant to HD. It provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD in a holistic manner. METHODS: To gain a synoptic view of therapeutic targets for HD, we have carried out a variety of bioinformatical and statistical analyses to scrutinize the functional association of genes curated in the HD Research Crossroads database. In particular, enrichment analyses were performed with respect to Gene Ontology categories, KEGG signaling pathways, and Pfam protein families. For selected processes, we also analyzed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Research Crossroads database with previous genome-wide linkage studies. RESULTS: Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signaling), but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signaling). For follow-up studies, we provide a regularly updated compendium of molecular mechanism, that are associated with HD, at http://hdtt.sysbiolab.eu Additionally, we derived a candidate set of 24 novel genetic modifiers, including histone deacetylase 3 (HDAC3), metabotropic glutamate receptor 1 (GRM1), CDK5 regulatory subunit 2 (CDK5R2), and coactivator 1ß of the peroxisome proliferator-activated receptor gamma (PPARGC1B). CONCLUSIONS: The results of our study give us an intriguing picture of the molecular complexity of HD. Our analyses can be seen as a first step towards a comprehensive list of biological processes, molecular functions, and pathways involved in HD, and may provide a basis for the development of more holistic disease models and new therapeutics

Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis

Background: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort.// Methods: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2.// Findings: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9–59·8; I2=77%), 60% (56–64; I2=35%) were women, and 80% (72–89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid β in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75–87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56–75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90–97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93–100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90–97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54–88; I2=89%), Lewy body disease (44%, 25–62; I2=77%), and cerebrovascular injury (42%, 24–60; I2=88%).// Interpretation: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity