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Seeded propagation of amyloid-beta (Aβ) pathology is suggested to contribute to the progression of Alzheimer’s disease. Local overproduction of aggregation-prone Aβ variants could explain the focal initiation of a seeding cascade that subsequently triggers widespread pathology. Several animal models support this seeding concept by demonstrating accelerated Aβ deposition following inoculation with Aβ-containing homogenates, however its role in progressive neurodegeneration remains unclear. Here, we present a non-invasive approach to study Aβ seeding processes in vivo using Drosophila models. We show that small amounts of aggregation-competent Aβ 42 seeds, generated in selected neuronal clusters, can induce the deposition of the pan-neuronally expressed and otherwise soluble Aβ 40 . Moreover, our models visualize the accelerated formation and propagation of amyloid pathology throughout the brain, which correlates with severe neurotoxicity. Taken together, these in vivo models provide mechanistic insights into disease-related processes and represent versatile genetic tools to determine novel modifiers of the Aβ seeding cascade. Seeding of amyloid beta from one brain region to another is thought to contribute to the progression of Alzheimer’s disease, although to date most studies have depended on inoculation of animals with exogenous amyloid. Here the authors describe a genetic seed and target system in Drosophila which may be useful for the mechanistic study of seeding of amyloid in vivo.

The identification of protein binding residues helps to understand their biological processes as protein function is often defined through ligand binding, such as to other proteins, small molecules, ions, or nucleotides. Methods predicting binding residues often err for intrinsically disordered proteins or regions (IDPs/IDPRs), often also referred to as molecular recognition features (MoRFs). Here, we presented a novel machine learning (ML) model trained to specifically predict binding regions in IDPRs. The proposed model, IDBindT5, leveraged embeddings from the protein language model (pLM) ProtT5 to reach a balanced accuracy of 57.2 ± 3.6% (95% confidence interval). Assessed on the same data set, this did not differ at the 95% CI from the state-of-the-art (SOTA) methods ANCHOR2 and DeepDISOBind that rely on expert-crafted features and evolutionary information from multiple sequence alignments (MSAs). Assessed on other data, methods such as SPOT-MoRF reached higher MCCs. IDBindT5’s SOTA predictions are much faster than other methods, easily enabling full-proteome analyses. Our findings emphasize the potential of pLMs as a promising approach for exploring and predicting features of disordered proteins. The model and a comprehensive manual are publicly available at https://github.com/jahnl/binding_in_disorder .

BACKGROUND AND AIMS: Rice plants (Oryza sativa L.) contain large quantities of silicon (Si) in form of phytoliths, which increase their resistance to abiotic and biotic stresses. The Si cycle through rice fields is hardly studied. We tested how increasing Si availability affects rice growth and the decomposability of the straw. Secondly we tested the role of straw recycling for Si availability. METHODS: In a field experiment, we applied three levels of silica gel during one rice cropping season. In a follow-up laboratory experiment, we used straw produced in the field experiment, having different Si concentrations, and studied straw decomposition, straw Si release, and Si uptake by plants. RESULTS: Silicon fertilization increased Si contents, biomass production, and grain yield of rice plants. Increased Si uptake by rice decreased concentrations of C and some essential nutrients (N, P, K, Ca, and Mg) in the straw, and increased straw decomposability and Si release. CONCLUSIONS: Fertilization with silica gel is an option to improve Si supply to rice plants growing on weathered soils with low levels of plant-available Si. Phytoliths from fresh rice straw dissolve fast in soil, thus, recycling of rice straw is an important source of plant-available Si.

Bacteria can encode dozens of different immune systems that protect them from infection by mobile genetic elements (MGEs). MGEs themselves may also carry immune systems, such as CRISPR-Cas, to target competitor MGEs. It is unclear when this is favored by natural selection, and whether toxin–antitoxin (TA) systems—common competitive mechanisms carried by plasmids—can alter their efficacy. Here, we develop and test novel theory to analyze the outcome of competition between plasmids when one carries a CRISPR-Cas system that targets the other plasmid. Our mathematical model and experiments using Escherichia coli and competing IncP plasmids reveal that plasmid-borne CRISPR-Cas is beneficial to the plasmid carrying it when the plasmid has not recently transferred to a new host. However, CRISPR-Cas is selected against when the plasmid carrying it transfers horizontally, if a resident competitor plasmid encodes a TA system that elicits post-segregational killing. Consistent with a TA barrier to plasmid-borne CRISPR-Cas, a bioinformatic analysis reveals that naturally occurring CRISPR-Cas-bearing plasmids avoid targeting other plasmids with TA systems across bacterial genera. Our work shows how the benefit of plasmid-borne CRISPR-Cas is severely reduced against TA-encoding competitor plasmids, but only when plasmid-borne CRISPR-Cas is horizontally transferred. These findings have key implications for the distribution of prokaryotic defenses and our understanding of their role in competition between MGEs, and the utility of CRISPR-Cas as a tool to remove plasmids from pathogenic bacteria.

The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P 2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis -elements that are important for both unconventional secretion and trans-cellular propagation of tau.

We compare the performance of three most accepted reagents for organic matter removal: hydrogen peroxide (H2O2), sodium hypochlorite (NaOCl) and disodium peroxodisulfate (Na2S2O8). Removal of organic matter from soil is mostly incomplete with the efficiency of removal depending on reaction conditions and sample properties. Generally, NaOCl and Na2S2O8 are more effective in organic C removal than H2O2. Alkaline conditions and additives favoring dispersion and/or desorption of organic matter, such as sodium pyrophosphate, seem to be crucial for C removal. Pyrophosphate and additives for pH control (bicarbonate) may irreversibly adsorb to mineral surfaces. In soils with a large proportion of organic matter bound to the mineral matrix, for example subsoils, or rich in clay-sized minerals (Fe oxides, poorly crystalline Fe and Al phases, expandable phyllosilicates), C removal can be little irrespective of the reagents used. Residual organic C seems to seems to represent largely refractory organic matter, and comprises mainly pyrogenic materials and aliphatic compounds. If protected by close association with minerals, other organic constituents such as low-molecular weight carboxylic acids, lignin-derived and N-containing compounds may escape chemical destruction. For determination of mineral phase properties, treatment with H2O2 should be avoided since it may promote organic-assisted dissolution of poorly crystalline minerals at low pH, disintegration of expandable clay minerals, and transformation of vermiculite into mica-like products due to NH4(+) fixation. Sodium hypochlorite and Na2S2O8 are less harmful for minerals than H2O2. While the NaOCl procedure (pH 9.5) may dissolve Al hydroxides, alkaline conditions favor the precipitation of metals released upon destruction of organic matter. Prolonged heating to >40 degrees C during any treatment may transform poorly crystalline minerals into more crystalline ones. Sodium hypochlorite can be used at 25 degrees C, thus preventing heat-induced mineral alteration.

Accumulating evidence suggests beneficial effects of media stories featuring individuals mastering their suicidal crises, but effects have not been assessed for psychiatric patients. We randomized n = 172 adult psychiatric patients (n = 172, 97.1% inpatients) to read an educative article featuring a person mastering a suicidal crisis (n = 92) or an unrelated article (n = 80) in a single-blind randomized controlled trial. Questionnaire data were collected before (T1) and after exposure (T2) as well as 1 week later (study end-point, T3). The primary outcome was suicidal ideation as assessed with the Reasons for Living Inventory; secondary outcomes were help-seeking intentions, mood, hopelessness, and stigmatization. Differences between patients with affective versus other diagnoses were explored based on interaction tests. We found that patients with affective disorders (n = 99) experienced a small-sized reduction of suicidal ideation at 1-week follow up (mean difference to control group [MD] at T3 = -0.17 [95% CI -0.33, -0.03], d = -0.15), whereas patients with nonaffective diagnoses (n = 73) experienced a small-sized increase (T2: MD = 0.24 [95% CI 0.06, 0.42], d = 0.19). Intervention group participants further experienced a nonsustained increase of help-seeking intentions (T2: MD = 0.53 [95% CI 0.11, 0.95], d = 0.19) and a nonsustained deterioration of mood (T2: MD = -0.14 [95% CI -0.27, -0.02], d = -0.17). This study suggests that patients with affective disorders appear to benefit from media materials featuring mastery of suicidal crises. More research is needed to better understand which patient groups are at possible risk of unintended effects.

Although most proteins can assemble into amyloid-like fibrils in vitro under extreme conditions, how proteins form amyloid fibrils in vivo remains unresolved. Identifying rare aggregation-prone species under physiologically relevant conditions and defining their structural properties is therefore an important challenge. By solving the folding mechanism of the naturally amyloidogenic protein β-2-microglobulin at pH 7.0 and 37 °C and correlating the concentrations of different species with the rate of fibril elongation, we identify a specific folding intermediate, containing a non-native trans -proline isomer, as the direct precursor of fibril elongation. Structural analysis using NMR shows that this species is highly native-like but contains perturbation of the edge strands that normally protect β-sandwich proteins from self-association. The results demonstrate that aggregation pathways can involve self-assembly of highly native-like folding intermediates, and have implications for the prevention of this, and other, amyloid disorders.

Introduction: Suicide is a public health problem worldwide, and spiritual experiences may be important positive experiences or coping mechanisms for difficulties associated with surviving a suicide loss. Studies have found that continuing bonds through spiritual experiences are common among individuals bereaved by suicide. However, the literature lacks depth in understanding these experiences, such as sense of presence. Aims: The aim of this study was to qualitatively examine descriptions of continuing bonds through spiritual experiences after death by suicide. Method: A total of 1301 individuals bereaved by suicide provided 2443 free responses about their spiritual experiences based on four different prompts, which were analyzed using an inductive approach. Results: Nine common themes were identified, selected for interest, and reported: (1) a helpful sense of comfort; (2) a helpful sense of connection with the deceased; (3) intense sadness evoked by the spiritual experiences; (4) confusion regarding the spiritual experiences; (5) negative reminders of the deceased or negative meanings of spiritual experiences; (6) evidence of an afterlife; (7) general importance of the spiritual experiences’ meaning; (8) impact of and on religious beliefs; and (9) others’ responses to disclosure of suicide or spiritual experiences. Conclusion: For the overwhelming majority of participants, spiritual experiences such as a sense of presence have deep meaning and are often regarded as a positive source of healing and transformation after a suicide death.

Quantal neurotransmitter release at excitatory synapses depends on glutamate import into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Of the three known transporters, VGLUT1 and VGLUT2 are expressed prominently in the adult brain, but during the first two weeks of postnatal development, VGLUT2 expression predominates. Targeted deletion of VGLUT1 in mice causes lethality in the third postnatal week. Glutamatergic neurotransmission is drastically reduced in neurons from VGLUT1-deficient mice, with a specific reduction in quantal size. The remaining activity correlates with the expression of VGLUT2. This reduction in glutamatergic neurotransmission can be rescued and enhanced with overexpression of VGLUT1. These results show that the expression level of VGLUTs determines the amount of glutamate that is loaded into vesicles and released and thereby regulates the efficacy of neurotransmission.