The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, ...collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention.
Eosinophils play a homeostatic role in the body’s immune responses. These cells are involved in combating some parasitic, bacterial, and viral infections and certain cancers and have pathologic roles ...in diseases including asthma, chronic rhinosinusitis with nasal polyps, eosinophilic gastrointestinal disorders, and hypereosinophilic syndromes. Treatment of eosinophilic diseases has traditionally been through nonspecific eosinophil attenuation by use of glucocorticoids. However, several novel biologic therapies targeting eosinophil maturation factors, such as interleukin (IL)-5 and the IL-5 receptor or IL-4/IL-13, have recently been approved for clinical use. Despite the success of biologic therapies, some patients with eosinophilic inflammatory disease may not achieve adequate symptom control, underlining the need to further investigate the contribution of patient characteristics, such as comorbidities and other processes, in driving ongoing disease activity. New research has shown that eosinophils are also involved in several homeostatic processes, including metabolism, tissue remodeling and development, neuronal regulation, epithelial and microbiome regulation, and immunoregulation, indicating that these cells may play a crucial role in metabolic regulation and organ function in healthy humans. Consequently, further investigation is needed into the homeostatic roles of eosinophils and eosinophil-mediated processes across different tissues and their varied microenvironments. Such work may provide important insights into the role of eosinophils not only under disease conditions but also in health. This narrative review synthesizes relevant publications retrieved from PubMed informed by author expertise to provide new insights into the diverse roles of eosinophils in health and disease, with particular emphasis on the implications for current and future development of eosinophil-targeted therapies.
Tungsten-182 heterogeneity in modern ocean island basalts Mundl, Andrea; Touboul, Mathieu; Jackson, Matthew G. ...
Science (American Association for the Advancement of Science),
04/2017, Letnik:
356, Številka:
6333
Journal Article
Recenzirano
Odprti dostop
New tungsten isotope data for modern ocean island basalts (OIB) from Hawaii, Samoa, and Iceland reveal variable 182W/184W, ranging from that of the ambient upper mantle to ratios as much as 18 parts ...per million lower. The tungsten isotopic data negatively correlate with ³He/⁴He. These data indicate that each OIB system accesses domains within Earth that formed within the first 60 million years of solar system history. Combined isotopic and chemical characteristics projected for these ancient domains indicate that they contain metal and are repositories of noble gases. We suggest that the most likely source candidates are mega–ultralow-velocity zones, which lie beneath Hawaii, Samoa, and Iceland but not beneath hot spots whose OIB yield normal 182W and homogeneously low ³He/⁴He.
The noble gas isotope systematics of ocean island basalts suggest the existence of primordial mantle signatures in the deep mantle. Yet, the isotopic compositions of lithophile elements (Sr, Nd, Hf) ...in these lavas require derivation from a mantle source that is geochemically depleted by melt extraction rather than primitive. Here, this apparent contradiction is resolved by employing a compilation of the Sr, Nd, and Hf isotope composition of kimberlites-volcanic rocks that originate at great depth beneath continents. This compilation includes kimberlites as old as 2.06 billion years and shows that kimberlites do not derive from a primitive mantle source but sample the same geochemically depleted component (where geochemical depletion refers to ancient melt extraction) common to most oceanic island basalts, previously called PREMA (prevalent mantle) or FOZO (focal zone). Extrapolation of the Nd and Hf isotopic compositions of the kimberlite source to the age of Earth formation yields a
Nd/
Nd-
Hf/
Hf composition within error of chondrite meteorites, which include the likely parent bodies of Earth. This supports a hypothesis where the source of kimberlites and ocean island basalts contains a long-lived component that formed by melt extraction from a domain with chondritic
Nd/
Nd and
Hf/
Hf shortly after Earth accretion. The geographic distribution of kimberlites containing the PREMA component suggests that these remnants of early Earth differentiation are located in large seismically anomalous regions corresponding to thermochemical piles above the core-mantle boundary. PREMA could have been stored in these structures for most of Earth's history, partially shielded from convective homogenization.
How much of Earth's compositional variation dates to processes that occurred during planet formation remains an unanswered question. High-precision tungsten isotopic data from rocks from two large ...igneous provinces, the North Atlantic Igneous Province and the Ontong Java Plateau, reveal preservation to the Phanerozoic of tungsten isotopic heterogeneities in the mantle. These heterogeneities, caused by the decay of hafnium-182 in mantle domains with high hafnium/tungsten ratios, were created during the first ~50 million years of solar system history, indicating that portions of the mantle that formed during Earth's primary accretionary period have survived to the present.
Volcanic hotspots are thought to be fed by hot, active upwellings from the deep mantle, with excess temperatures (
) ~100° to 300°C higher than those of mid-ocean ridges. However,
estimates are ...limited in geographical coverage and often inconsistent for individual hotspots. We infer the temperature of oceanic hotspots and ridges simultaneously by converting seismic velocity to temperature. We show that while ~45% of plume-fed hotspots are hot (
≥ 155°C), ~15% are cold (
≤ 36°C) and ~40% are not hot enough to actively upwell (50°C ≤
≤ 136°C). Hot hotspots have an extremely high helium-3/helium-4 ratio and buoyancy flux, but cold hotspots do not. The latter may originate at upper mantle depths. Alternatively, the deep plumes that feed them may be entrained and cooled by small-scale convection.
Sr and Pb isotopes exhibit global trends with the concentrations of major elements (SiO
2, TiO
2, FeO, Al
2O
3 and K
2O) and major elements ratios (CaO/Al
2O
3 and K
2O/TiO
2) in the shield-stage ...lavas from 18 oceanic hotspots (including Hawaii, Iceland, Galapagos, Cook-Australs, St. Helena, Cape Verde, Cameroon, Canary, Madeira, Comoros, Azores, Samoa, Society, Marquesas, Mascarene, Kerguelen, Pitcairn, and Selvagen). Based on the relationships between major elements and isotopes in ocean island basalts (OIBs), we find that the lavas derived from the mantle end members, HIMU (or high ‘μ’
=
238U/
204Pb), EM1 (enriched mantle 1), EM2 (enriched mantle 2), and DMM (depleted MORB mid-ocean ridge basalt mantle) exhibit distinct major element characteristics: When compared to oceanic hotspots globally, the hotspots with a HIMU (radiogenic Pb-isotopes and low
87Sr/
86Sr) component, such as St. Helena and Cook-Australs, exhibit high CaO/Al
2O
3, FeO
T, and TiO
2 and low SiO
2 and Al
2O
3. EM1 (enriched mantle 1; intermediate
87Sr/
86Sr and low
206Pb/
204Pb; sampled by hotspots like Pitcairn and Kerguelen) and EM2 (enriched mantle 2; high
87Sr/
86Sr and intermediate
206Pb/
204Pb; sampled by hotspots like Samoa and Societies) exhibit higher K
2O concentrations and K
2O/TiO
2 weight ratios than HIMU lavas. EM1 lavas exhibit the lowest CaO/Al
2O
3 in the OIB dataset, and this sets EM1 apart from EM2. A plot of CaO/Al
2O
3 vs K
2O/TiO
2 perfectly resolves the four mantle end member lavas.
Melting processes (pressure, temperature and degree of melting) fail to provide an explanation for the full spectrum of major element concentrations in OIBs. Such processes also fail to explain the correlations between major elements and radiogenic isotopes. Instead, a long, time integrated history of various parent–daughter elements appears to be coupled to major element and/or volatile heterogeneity in the mantle source. End member lava compositions are compared with experimental partial melt compositions to place constraints on the lithological characteristics of the mantle end members.
Mantle plumes upwelling beneath moving tectonic plates generate age-progressive chains of volcanos (hotspot chains) used to reconstruct plate motion. However, these hotspots appear to move relative ...to each other, implying that plumes are not laterally fixed. The lack of age constraints on long-lived, coeval hotspot chains hinders attempts to reconstruct plate motion and quantify relative plume motions. Here we provide
Ar/
Ar ages for a newly identified long-lived mantle plume, which formed the Rurutu hotspot chain. By comparing the inter-hotspot distances between three Pacific hotspots, we show that Hawaii is unique in its strong, rapid southward motion from 60 to 50 Myrs ago, consistent with paleomagnetic observations. Conversely, the Rurutu and Louisville chains show little motion. Current geodynamic plume motion models can reproduce the first-order motions for these plumes, but only when each plume is rooted in the lowermost mantle.
At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and ...reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.
Quantum computation features known examples of hardware acceleration for certain problems, but is challenging to realize because of its susceptibility to small errors from noise or imperfect control. ...The principles of fault tolerance may enable computational acceleration with imperfect hardware, but they place strict requirements on the character and correlation of errors
. For many qubit technologies
, some challenges to achieving fault tolerance can be traced to correlated errors arising from the need to control qubits by injecting microwave energy matching qubit resonances. Here we demonstrate an alternative approach to quantum computation that uses energy-degenerate encoded qubit states controlled by nearest-neighbour contact interactions that partially swap the spin states of electrons with those of their neighbours. Calibrated sequences of such partial swaps, implemented using only voltage pulses, allow universal quantum control while bypassing microwave-associated correlated error sources
. We use an array of six
Si/SiGe quantum dots, built using a platform that is capable of extending in two dimensions following processes used in conventional microelectronics
. We quantify the operational fidelity of universal control of two encoded qubits using interleaved randomized benchmarking
, finding a fidelity of 96.3% ± 0.7% for encoded controlled NOT operations and 99.3% ± 0.5% for encoded SWAP. The quantum coherence offered by enriched silicon
, the all-electrical and low-crosstalk-control of partial swap operations
and the configurable insensitivity of our encoding to certain error sources
all combine to offer a strong pathway towards scalable fault tolerance and computational advantage.
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