A calcium-sensitive antibody isolates soluble amyloid-ß aggregates and fibrils from Alzheimer's disease brain.

Aqueously soluble oligomers of amyloid-ß peptide may be the principal neurotoxic forms of amyloid-ß in Alzheimer's disease, initiating downstream events that include tau hyperphosphorylation, neuritic/synaptic injury, microgliosis and neuron loss. Synthetic oligomeric amyloid-ß has been studied extensively, but little is known about the biochemistry of natural oligomeric amyloid-ß in human brain, even though it is more potent than simple synthetic peptides and comprises truncated and modified amyloid-ß monomers. We hypothesized that monoclonal antibodies specific to neurotoxic oligomeric amyloid-ß could be used to isolate it for further study. Here we report a unique human monoclonal antibody (B24) raised against synthetic oligomeric amyloid-ß that potently prevents Alzheimer's disease brain oligomeric amyloid-ß-induced impairment of hippocampal long-term potentiation. B24 binds natural and synthetic oligomeric amyloid-ß and a subset of amyloid plaques, but only in the presence of Ca2+. The amyloid-ß N terminus is required for B24 binding. Hydroxyapatite chromatography revealed that natural oligomeric amyloid-ß is highly avid for Ca2+. We took advantage of the reversible Ca2+-dependence of B24 binding to perform non-denaturing immunoaffinity isolation of oligomeric amyloid-ß from Alzheimer's disease brain-soluble extracts. Unexpectedly, the immunopurified material contained amyloid fibrils visualized by electron microscopy and amenable to further structural characterization. B24-purified human oligomeric amyloid-ß inhibited mouse hippocampal long-term potentiation. These findings identify a calcium-dependent method for purifying bioactive brain oligomeric amyloid-ß, at least some of which appears fibrillar.

Variations on a theme in fruit development: the PLE lineage of MADS-box genes in tomato (TAGL1) and other species.

MAIN CONCLUSION: This article focuses on the role of TOMATO AGAMOUS-LIKE 1 (TAGL1) on a wide range of ripening functions in tomato. We also examine orthologs of this gene in related species that produce different fruit types and discuss some evolutionary implications. TOMATO AGAMOUS-LIKE 1 (TAGL1) is a MADS-box transcription factor gene that belongs to the PLENA (PLE) lineage within the AGAMOUS (AG) clade. The most well-studied genes in this lineage are the SHATTERPROOF (SHP) genes in Arabidopsis, known to be involved in dehiscence zone formation during silique development. In tomato, TAGL1 has been shown to control several aspects of tomato fruit ripening. Most notably, carotenoid synthesis seems to be controlled by TAGL1, likely via the ethylene synthesis and signaling pathway and in combination with RIPENING INHIBITOR (RIN). In addition, TAGL1 regulates genes involved in cell cycle regulation, flavonoid and lignin biosynthesis, and cuticle development. We discuss many of the genes in these different pathways that are likely controlled by TAGL1, directly or indirectly. We also examine the relationship of TAGL1 with known and putative interaction partners. PLE lineage genes have also been examined in other species such as Antirrhinum, Petunia, and Nicotiana and provide an interesting example of conservation and diversification of function in species that produce very different types of fleshy and dry fruits. The control of lignification may be a common mechanism for this group of genes. Lastly, we discuss future work needed to elucidate the TAGL1 regulatory pathway in tomato and to help better understand the functional diversification of genes in this lineage in related species.

Investigating the impact of financial concerns on symptoms of depression in UK healthcare workers: data from the UK-REACH nationwide cohort study.

BACKGROUND: Exploration of the association between financial concerns and depression in UK healthcare workers (HCWs) is paramount given the current 'cost of living crisis', ongoing strike action and recruitment/retention problems in the National Health Service. AIMS: To assess the impact of financial concerns on the risk of depression in HCWs, how these concerns have changed over time and what factors might predict financial concerns. METHOD: We used longitudinal survey data from a UK-wide cohort of HCWs to determine whether financial concerns at baseline (December 2020 to March 2021) were associated with depression (measured with the Public Health Questionnaire-2) at follow-up (June to October 2022). We used logistic regression to examine the association between financial concerns and depression, and ordinal logistic regression to establish predictors of developing financial concerns. RESULTS: A total of 3521 HCWs were included. Those concerned about their financial situation at baseline had higher odds of developing depressive symptoms at follow-up. Financial concerns increased in 43.8% of HCWs and decreased in 9%. Those in nursing, midwifery and other nursing roles had over twice the odds of developing financial concerns compared with those in medical roles. CONCLUSIONS: Financial concerns are increasing in prevalence and predict the later development of depressive symptoms in UK HCWs. Those in nursing, midwifery and other allied nursing roles may have been disproportionately affected. Our results are concerning given the potential effects on sickness absence and staff retention. Policy makers should act to alleviate financial concerns to reduce the impact this may have on a discontent workforce plagued by understaffing.