Method Exploration of Self-adaptive Entity Matching in Map Fusion

AbstractEntity matching is a crucial and hard technology in map fusion. Current methods still exists some deficiencies, such as matching efficiency is not high, low degree of automation and poor universality, these methods can not meet the matching needs of large data integration, therefore, the urgent need to develop more effective and intelligent methods. This paper analyzed present research situation and existing problems of entity matching, illustrated the necessity of developing self-adaptive entity matching, pointed out urgent research contents and key issues that need to be resolved urgently in self-adaptive entity matching, provided preliminary research scheme of implementing self-adaptive entity matching, finally, introduced characteristics and advantages of self-adaptive entity matching method presented in this paper

Modellierung und hocheffiziente Berechnung der lastabhängigen Eisenverluste in permanentmagneterregten Synchronmaschinen

Diese Arbeit behandelt die Eisenverluste in permanentmagneterregten Synchronmaschinen und erarbeitet eine in der Ingenieurspraxis umsetzbare Simulationsmethodik, welche die praktische Charakterisierung weichmagnetischer Werkstoffe durch erweiterte Messmethoden mit Werkstoffmodellen zur numerischen Berechnung verknüpft. Des Weiteren stellt diese Arbeit eine neuartige Berechnungsmethode vor, um den Rechenaufwand der numerischen Berechnung zu reduzieren

The Association Between PM2.5 and Depression in China.

While China has been experiencing unprecedented economic growth, depression is becoming one of the most striking social and mental health problems in recent years. Such a paradox to progress may partially be due to the notoriously poor air quality of the country. To verify this argument, we constructed an index of the prevalence of depression (IPD) using internet search query volumes in Baidu to proxy the potential depression and examined how IPD is associated with PM2.5, the major air pollutant in China. Our results from 2-way fixed effects models reveal that a 100 μg·m-3 increase in previous week's PM2.5 in a city is significantly associated with 0.279 increase in its IPD, comparable to 7.34 hours decrease in weekly daylight, and such relationship is particularly pronounced in the spring and summer and in East and South areas. Our findings of large-scale pattern suggest that PM2.5 at current levels in China poses serious mental health risks

Chronic treatment with anesthetic propofol attenuates β-amyloid protein levels in brain tissues of aged mice

Alzheimer’s disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of β-amyloid protein (Aβ) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Aβ levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Aβ (Aβ40 and Aβ42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of β-site amyloid precursor protein cleaving enzyme (the enzyme for Aβ generation), and increased the levels of neprilysin (the enzyme for Aβ degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Aβ levels potentially via decreasing brain levels of β-site amyloid precursor protein cleaving enzyme, thus decreasing Aβ generation; and via increasing brain neprilysin levels, thus increasing Aβ degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research

High-throughput screening in larval zebrafish identifies novel potent sedative-hypnotics

BACKGROUND: Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. METHODS: The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. RESULTS: Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-D-aspartate and neuronal nicotinic receptors. CONCLUSIONS: Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.This work was supported by grants from Shanghai Jiaotong University School of Medicine, Shanghai, China, and the Chinese Medical Association, Beijing, China (both to Dr. Yang). The Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts, supported this work through a Research Scholars Award and an Innovation Grant (both to Dr. Forman). Contributions to this research from the Boston University Center for Molecular Discovery, Boston, Massachusetts (to Drs. Porco, Brown, Schaus, and Xu, and to Mr. Trilles), were supported by a grant from the National Institutes of Health, Bethesda, Maryland (grant No. R24 GM111625). (Shanghai Jiaotong University School of Medicine, Shanghai, China; Chinese Medical Association, Beijing, China; Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts; R24 GM111625 - National Institutes of Health, Bethesda, Maryland)Accepted manuscript2019-09-0

The association between PM2.5 exposure and suicidal ideation: a prefectural panel study.

BACKGROUND: Suicidal ideation is subject to serious underestimation among existing public health studies. While numerous factors have been recognized in affecting suicidal thoughts and behaviors (STB), the associated environmental risks have been poorly understood. Foremost among the various environment risks were air pollution, in particular, the PM2.5. The present study attempted to examine the relationship between PM2.5 level and local weekly index of suicidal ideation (ISI). METHODS: Using Internet search query volumes in Baidu (2017), the largest internet search engine in China, we constructed a prefectural panel data (278 prefectures, 52 weeks) and employed dynamic panel GMM system estimation to analyze the relationship between weekly concentration of PM2.5 (Mean = 87 μg·m- 3) and the index of suicidal ideation (Mean = 49.9). RESULTS: The results indicate that in the spring and winter, a 10 μg·m- 3 increase in the prior week's PM2.5 in a Chinese city is significantly associated with 0.020 increase in ISI in spring and a 0.007 increase in ISI in winter, after taking account other co-pollutants and meteorological conditions. CONCLUSION: We innovatively proposed the measure of suicidal ideation and provided suggestive evidence of a positive association between suicidal ideation and PM2.5 level

Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice

ARHGEF6 belongs to the family of guanine nucleotide exchange factors (GEFs) for Rho GTPases, and it specifically activates Rho GTPases CDC42 and RAC1. Arhgef6 is the X-linked intellectual disability gene also known as XLID46, and clinical features of patients carrying Arhgef6 mutations include intellectual disability and, in some cases, sensorineural hearing loss. Rho GTPases act as molecular switches in many cellular processes. Their activities are regulated by binding or hydrolysis of GTP, which is facilitated by GEFs and GTPase-activating proteins, respectively. RAC1 and CDC42 have been shown to play important roles in hair cell (HC) stereocilia development. However, the role of ARHGEF6 in inner ear development and hearing function has not yet been investigated. Here, we found that ARHGEF6 is expressed in mouse cochlear HCs, including the HC stereocilia. We established Arhgef6 knockdown mice using the clustered regularly interspaced short palindromic repeat-associated Cas9 nuclease (CRISPR-Cas9) genome editing technique. We showed that ARHGEF6 was indispensable for the maintenance of outer hair cell (OHC) stereocilia, and loss of ARHGEF6 in mice caused HC stereocilia deficits that eventually led to progressive HC loss and hearing loss. However, the loss of ARHGEF6 did not affect the synapse density and did not affect the mechanoelectrical transduction currents in OHCs at postnatal day 3. At the molecular level, the levels of active CDC42 and RAC1 were dramatically decreased in the Arhgef6 knockdown mice, suggesting that ARHGEF6 regulates stereocilia maintenance through RAC1/CDC42

HYBRID TUMOR PENETRATING FERRITIN NANOCAGES AS A HYPOXIA TARGETING NANOCARRIER FOR CANCER TREATMENT

Background: Tumor hypoxia plays a key role in promoting tumor progression and metastasis, and thus serves as a critical therapeutic target. However, hypoxic regions within solid tumors are hard to be reached by systemically administered therapeutics due to the poor vascularization and tumor extracellular matrix (ECM) barrier. In reality, hypoxia-tropic drug delivery platforms have been lacking. Human ferritin nanocage (FTn) possesses intrinsic affinity to human transferrin receptor 1 (TfR1) and rodent T-cell immunoglobulin mucin 2 (TIM-2) which are upregulated in hypoxic tumor cells, and thus FTn can be potentially used to deliver therapeutic payloads to tumor hypoxia. Methods: Protein disassembly and reassembly process was used to engineer hybrid FTn that possessed varying degrees of surface polyethylene glycol (PEG) coatings, while retaining the TfR1/TIM-2 target ability. The resulting hybrid PEG-FTn were characterized by transmission electron microscopy, size exclusion chromatography and dynamic light scattering. The tissue penetration and cellular uptake of hybrid PEG-FTn were evaluated and compared using 3D multicellular spheroids in vitro or flank tumor-bearing mice in vivo, both based on 3LL tumor cells. A hypoxia-inducible factor 1 inhibitor, acriflavine (AF), was loaded into the nanocages as a model drug and the pharmacokinetic profile was compared with free AF. Results: Hybrid PEG-FTn with varying PEGylation degrees were synthesized and extensively screened based on physicochemical properties and in vitro behaviors. We identified a lead hybrid PEG-FTn of which surface PEG modification promoted penetration of the nanocages through 3LL-based tumor tissues both in vitro and in vivo without compromising their ability to accumulate in tumor hypoxia via TfR1/TIM-2. The lead hybrid PEG-FTn, following systemic administration, provided prolonged circulation and enhanced accumulation of the payloads (i.e. AF) compared to the identically administered, dose-matched free AF. Conclusion: The hybrid PEG-FTn is an excellent drug delivery system for the delivery of therapeutics, particularly hypoxia-modulating agents, to hypoxic regions within solid tumors

HYBRID TUMOR PENETRATING FERRITIN NANOCAGES AS A HYPOXIA TARGETING NANOCARRIER FOR CANCER TREATMENT

Background: Tumor hypoxia plays a key role in promoting tumor progression and metastasis, and thus serves as a critical therapeutic target. However, hypoxic regions within solid tumors are hard to be reached by systemically administered therapeutics due to the poor vascularization and tumor extracellular matrix (ECM) barrier. In reality, hypoxia-tropic drug delivery platforms have been lacking. Human ferritin nanocage (FTn) possesses intrinsic affinity to human transferrin receptor 1 (TfR1) and rodent T-cell immunoglobulin mucin 2 (TIM-2) which are upregulated in hypoxic tumor cells, and thus FTn can be potentially used to deliver therapeutic payloads to tumor hypoxia. Methods: Protein disassembly and reassembly process was used to engineer hybrid FTn that possessed varying degrees of surface polyethylene glycol (PEG) coatings, while retaining the TfR1/TIM-2 target ability. The resulting hybrid PEG-FTn were characterized by transmission electron microscopy, size exclusion chromatography and dynamic light scattering. The tissue penetration and cellular uptake of hybrid PEG-FTn were evaluated and compared using 3D multicellular spheroids in vitro or flank tumor-bearing mice in vivo, both based on 3LL tumor cells. A hypoxia-inducible factor 1 inhibitor, acriflavine (AF), was loaded into the nanocages as a model drug and the pharmacokinetic profile was compared with free AF. Results: Hybrid PEG-FTn with varying PEGylation degrees were synthesized and extensively screened based on physicochemical properties and in vitro behaviors. We identified a lead hybrid PEG-FTn of which surface PEG modification promoted penetration of the nanocages through 3LL-based tumor tissues both in vitro and in vivo without compromising their ability to accumulate in tumor hypoxia via TfR1/TIM-2. The lead hybrid PEG-FTn, following systemic administration, provided prolonged circulation and enhanced accumulation of the payloads (i.e. AF) compared to the identically administered, dose-matched free AF. Conclusion: The hybrid PEG-FTn is an excellent drug delivery system for the delivery of therapeutics, particularly hypoxia-modulating agents, to hypoxic regions within solid tumors

De novo design of protein binders as functional therapeutics

Thesis (Ph.D.)--University of Washington, 2023De novo design of protein binding proteins (minibinders) with target structure information alone remains a grand challenge. A general computational design framework includes (1) generation of binder backbones, (2) sequence design and side-chain refinement, (3) resampling, and (4) prediction of binding and evaluation of the minibinders as a monomer. In Chapter 1, I review the improved computational minibinder design method I have contributed to develop. With these cutting-edge pipelines, I describe two strategies of applying designed minibinders as novel functional therapeutics: in Chapter 2, I report the design of minibinder antagonists as immune modulator for cytokine storm; in Chapter 3, I report the design of endocytosis ligands for target degradation and signaling amplification. Overall, the minibinder is a brand-new drug modality/platform with advantages of ultra-stability, high-specificity, robust production, and modularity. The work described indicate the great potential of the minibinder to bridge the gap of existing therapeutics and revolutionize the future of protein drug development