Search

Amyloid fibrils of tau are increasingly accepted as a cause of neuronal death and brain atrophy in Alzheimer's disease (AD). Diminishing tau aggregation is a promising strategy in the search for efficacious AD therapeutics. Previously, our laboratory designed a six-residue, nonnatural amino acid inhibitor D-TLKIVW peptide (6-DP), which can prevent tau aggregation in vitro. However, it cannot block cell-to-cell transmission of tau aggregation. Here, we find D-TLKIVWC (7-DP), a d-cysteine extension of 6-DP, not only prevents tau aggregation but also fragments tau fibrils extracted from AD brains to neutralize their seeding ability and protect neuronal cells from tau-induced toxicity. To facilitate the transport of 7-DP across the blood-brain barrier, we conjugated it to magnetic nanoparticles (MNPs). The MNPs-DP complex retains the inhibition and fragmentation properties of 7-DP alone. Ten weeks of MNPs-DP treatment appear to reverse neurological deficits in the PS19 mouse model of AD. This work offers a direction for development of therapies to target tau fibrils.

Despite much effort, antibody therapies for Alzheimers disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.

The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP's propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

The nickel content of nickel-based high-temperature alloy is between 50% and 70%, and the alloy contents of chromium, iron, cobalt, molybdenum, aluminum, titanium and tungsten are within 20%. A method of high resolution plasma mass spectrometry was established to determine the trace elements in nickel-based high-temperature alloy. According to the principle of large isotope abundance, small interference and high sensitivity, the isotopes and resolution of the elements to be measured were optimized, the interferences of most of the multi-atom and double-charged ions were effectively eliminated. The mass spectral interferences of matrix, compositions of alloy and dissolving acid on the trace elements were investigated. The appropriate internal standard of caesium was selected to overcome the matrix effect and reduce the signal drift. Chromium was extracted by methylisobutylone, the extraction efficiency reached up to 99.7%, which eliminated the mass spectral interference of principal component molybdenum in the nickel-based high-temperature alloy. The linear correlation coefficient of the calibration curve was greater than 0.999, and the method detection limit was between 0.002 1 and 0.074 μg/g. The trace elements in the reference material was analyzed, the relative standard deviation (RSD, n=6) was between 2.9% and 7.8%, and the measured value was very consistent with the standard value. This method is simple, fast, accurate and reliable, which can meet the requirement of trace elements determination in nickel-based high-temperature alloy.

The dolomite reservoirs in the fourth member of Leikoupo formation of the western Sichuan gas field have good prospects for natural gas exploration and development. However, the conventional and one-dimensional nuclear magnetic resonance (1D NMR) logging data are not sufficient for a definitive classification of the reservoir fluid type, likely because of heterogeneity of the reservoirs. Through geological characteristics analysis, log response analysis and two-dimensional (2D) NMR experiment, the environmental factors and technical parameters leading to the differences between the laboratory results and actual logging data were determined. According to the analysis of T2-T1 and T1/T2 (R) differences, the distribution range of drilling fluid, bound fluid, movable water and natural gas signals in the 2D NMR spectra was delineated to build a gas-water 2D NMR identification chart. The results obtained using the identification chart were verified with the actual drilling test results. Complementary to conventional and 1D NMR logging, the 2D NMR identification method was proposed, and can be used to determine the fluid properties in the dolomite reservoirs effectively.

Formation porosity can be calculated from one-dimensional nuclear magnetic resonance (NMR) logging data with a fixed cutoff value and the volume model of conventional logging data. However, the porosity calculated with this method often appears to be overestimated in the enlarged hole section. In this work, the calculation methods for T2 and T1 nuclear magnetic porosity from NMR results of core samples and two-dimensional NMR logging data were investigated. Firstly, the characteristics of NMR relaxation spectra of fluids at different pore sizes were obtained and used to analyze the distribution range of pore diameter and affecting factors of the cutoff value of the drilling fluid peak. A model for estimating the cutoff value of the drilling fluid relaxation time was then established. A method for calculating the effective porosity was then proposed with variable cutoff value of clay bond water relaxation time, according to the deterministic principle about cutoff value of clay bond water relaxation time in un-enlarged and enlarged hole section. The method proposed was applied to the data from many wells, and demonstrated better accuracy than the traditional method using T1 distribution spectra. The method can effectively solve the problem of overestimated porosity in the enlarged hole section and meet the requirement for reservoir evaluation.

BACKGROUND Iron is the most abundant element on earth with variable valences. It is widely distributed in various minerals, rocks, fluids and organisms, and is involved in diagenesis, mineralization, hydrothermal activities and life activities. The study of iron isotope composition provides important information for geochemistry, astrochemistry and biochemistry. The accurate measurement of Fe isotopes is an important basis for the development of related research. OBJECTIVES To summarize the research progress of Fe isotope measurement technology. METHODS The current chemical separation and purification methods and main instrumental analysis techniques commonly used for iron isotopes, were compared and analyzed in this review, and the mechanism of different types of fractionations during mass spectrometry were discussed. These advances included:(1) Improvement of anion resin during determination of iron isotope by solution method; (2) Mass spectrometry development from traditional thermal ionization mass spectrometry to multi-collector inductively coupled plasma mass spectrometry; (3) Development of laser in situ analytical technology. On this basis, the steps and calibration methods that would cause iron isotope fractionation during the analysis were summarized, and the advantages and disadvantages of different analytical methods were reviewed. RESULTS The analysis process of solution method was long and complicated, but the precision was high (0.03‰, 2SD) and the method was stable. In situ iron isotope analysis method developed from nanosecond laser denudation to femtosecond laser denudation, with shorter pulse duration, higher pulse peak intensity (up to 1012W), and focusing intensity exceeding 1020W/cm2. In situ iron isotope analysis method was fast and had high spatial resolution, which can be used to discuss the geochemical process from the microscopic perspective. However, the presence of matrix effects limited the widespread use of iron isotopes. CONCLUSIONS Shortening solution analysis process and developing a series of matrix-matched standard samples are the research direction of iron isotope analysis.

In the era of big data, the rich data resources of the petroleum industry not only provide auxiliary decision-making support for the production and scientific research of petroleum enterprises, but also play a vital role in the digital transformation of enterprises. From the perspective of petroleum exploration data management technology, this paper divides its past development process into database technology stage, data warehouse technology stage, data lake technology stage, data integration platform stage, and special application of big data technology by combing the relevant literature. At present, it is in the initial stage of the construction of the data middle office. The core problem that needs to be solved is to match the calculation type with the most suitable computing framework, optimize the allocation of computing resources, and give full play to the processing capabilities of the data middle office.

Bitumen, which is widely used in various applications, is facing the challenge of being unsustainable. Many strategies are proposed to recycle or replace bitumen. However, most of them can not address the unsustainability of bitumen from the roots. On the other hand, sulfur exists widely on the earth as a kind of industrial waste despite its extensive applications. Herein, a series of bitumen‐like polymers from elemental sulfur is obtained through an inverse vulcanization reaction. The sulfur‐containing polymers exhibit self‐healing, non‐toxic, and adjustable properties depending on the working environment. Based on these features, the applications of sulfur‐containing polymers in self‐healing waterproof sealants, impact‐resistance or shock‐absorption devices, and non‐Newtonian speed bumps are demonstrated. With the method of synthesizing multifunctional bitumen‐like polymers from sulfur wastes, a feasible way is provided to solve simultaneously the challenging problem of bitumen's unsustainability as well as sulfur's utilization, with the advantages including easy massed‐fabrication, non‐toxicity, extremely low cost (≈2 cents per gram) and environment friendliness. [ABSTRACT FROM AUTHOR]

143Nd/144Nd isotope ratio is the key for Sm-Nd isotope method. The 143Nd/144Nd isotope ratio of geological samples varies within a small range, and thus the 143Nd/144Nd isotope ratio analysis must be precise. In order to obtain high precision and high accuracy of the analytical data, the analysis process involving Nd isotope reference material plays an important role. The previous Nd isotope reference material is neodymium oxide, which have been exhausted in recent three decades. A national reference material of 143Nd/144Nd isotope ratio was introduced in this paper, which shows sufficient homogeneity and stability. The certified value of this reference material was determined by eleven participating laboratories using MC-TIMS and MC-ICP-MS. The 143Nd/144Nd isotope ratio value for the reference material is 0.512438, with a combined expanded uncertainty (k=2) of 5×10-6. The standard solution gets certification in May, 2015 and the Serial number is GSB 04-3258—2015. The standard solution can be used for quality monitoring of the equipment calibration and analysis process during the 143Nd/144Nd ratio determination for geology, resources, ocean, environment, archaeological and other type samples.