Search results for: Xiao Zhou

Authors: G. Cunningham, E. Cantor, X. Wu, F. Shen, G. Jiang, S. Philips, C. Bales, Y. Xiao, T. R. Cummins, J. C. Fehrenbacher, B. P. Schneider

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Background: Taxane-induced peripheral neuropathy (TIPN) is the most devastating survivorship issue for patients receiving therapy. Dose reductions due to TIPN in the curative setting lead to inferior outcomes for African American patients, as prior research has shown that this group is more susceptible to developing severe neuropathy. The mechanistic underpinnings of TIPN, however, have not been entirely elucidated. While it would be appealing to use primary tissue to study the development of TIPN, procuring nerves from patients is not realistically feasible, as nerve biopsies are painful and may result in permanent damage. Therefore, our laboratory has investigated paclitaxel-induced neuronal morphological and molecular changes using an ex vivo model of human-induced pluripotent stem cell (iPSC)-derived neurons. Methods: iPSCs are undifferentiated and endlessly dividing cells that can be generated from a patient’s somatic cells, such as peripheral blood mononuclear cells (PBMCs). We successfully reprogrammed PBMCs into iPSCs using the Erythroid Progenitor Reprograming Kit (STEMCell Technologiesᵀᴹ); pluripotency was verified by flow cytometry analysis. iPSCs were then induced into neurons using a differentiation protocol that bypasses the neural progenitor stage and uses selected small-molecule modulators of key signaling pathways (SMAD, Notch, FGFR1 inhibition, and Wnt activation). Results: Flow cytometry analysis revealed expression of core pluripotency transcription factors Nanog, Oct3/4 and Sox2 in iPSCs overlaps with commercially purchased pluripotent cell line UCSD064i-20-2. Trilineage differentiation of iPSCs was confirmed with immunofluorescent imaging with germ-layer-specific markers; Sox17 and ExoA2 for ectoderm, Nestin, and Pax6 for mesoderm, and Ncam and Brachyury for endoderm. Sensory neuron markers, β-III tubulin, and Peripherin were applied to stain the cells for the maturity of iPSC-derived neurons. Patch-clamp electrophysiology and calcitonin gene-related peptide (CGRP) release data supported the functionality of the induced neurons and provided insight into the timing for which downstream assays could be performed (week 4 post-induction). We have also performed a cell viability assay and fluorescence-activated cell sorting (FACS) using four cell-surface markers (CD184, CD44, CD15, and CD24) to select a neuronal population. At least 70% of the cells were viable in the isolated neuron population. Conclusion: We have found that these iPSC-derived neurons recapitulate mature neuronal phenotypes and demonstrate functionality. Thus, this represents a patient-derived ex vivo neuronal model to investigate the molecular mechanisms of clinical TIPN.

Keywords: chemotherapy, iPSC-derived neurons, peripheral neuropathy, taxane, paclitaxel

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Authors: Ying Li, Rui Hu, Shizhen Chen, Xin Zhou, Yunhuang Yang

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Prostate cancer is one of the leading causes of cancer-related death among men. Prostate-specific antigen (PSA), a specific product of prostatic epithelial cells, is an important indicator of prostate cancer. Though PSA is not a specific serum biomarker for the screening of prostate cancer, it is recognized as an indicator for prostate cancer recurrence and response to therapy for patient’s post-prostatectomy. Since radical prostatectomy eliminates the source of PSA production, serum PSA levels fall below 50 pg/mL, and may be below the detection limit of clinical immunoassays (current clinical immunoassay lower limit of detection is around 10 pg/mL). Many clinical studies have shown that intervention at low PSA levels was able to improve patient outcomes significantly. Therefore, ultra-sensitive and precise assays that can accurately quantify extremely low levels of PSA (below 1-10 pg/mL) will facilitate the assessment of patients for the possibility of early adjuvant or salvage treatment. Currently, the commercially available ultra-sensitive ELISA kit (not used clinically) can only reach a detection limit of 3-10 pg/mL. Other platforms developed by different research groups could achieve a detection limit as low as 0.33 pg/mL, but they relied on sophisticated instruments to get the final readout. Herein we report a microfluidic platform for point-of-care (POC) detection of PSA with a detection limit of 0.5 pg/mL and without the assistance of any equipment. This platform is based on a previously reported volumetric-bar-chart chip (V-Chip), which applies platinum nanoparticles (PtNPs) as the ELISA probe to convert the biomarker concentration to the volume of oxygen gas that further pushes the red ink to form a visualized bar-chart. The length of each bar is used to quantify the biomarker concentration of each sample. We devised a long reading channel V-Chip (LV-Chip) in this work to achieve a wide detection window. In addition, LV-Chip employed a unique enzyme-free ELISA probe that enriched PtNPs significantly and owned 500-fold enhanced catalytic ability over that of previous V-Chip, resulting in a significantly improved detection limit. LV-Chip is able to complete a PSA assay for five samples in 20 min. The device was applied to detect PSA in 50 patient serum samples, and the on-chip results demonstrated good correlation with conventional immunoassay. In addition, the PSA levels in finger-prick whole blood samples from healthy volunteers were successfully measured on the device. This completely stand-alone LV-Chip platform enables convenient POC testing for patient follow-up in the physician’s office and is also useful in resource-constrained settings.

Keywords: point-of-care detection, microfluidics, PSA, ultra-sensitive

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Authors: Haifeng Zhou, Tsungyang Liow, Xiaoguang Tu, Eujin Lim, Chao Li, Junfeng Song, Xianshu Luo, Ying Huang, Lianxi Jia, Lianwee Luo, Kim Dowon, Qing Fang, Mingbin Yu, Guoqiang Lo

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Several Germanium photodetectors (PD) built on silicon micro-disks are fabricated on the standard Si photonics multiple project wafers (MPW) and demonstrated to exhibit very low dark current, satisfactory operation bandwidth and moderate responsivity. Among them, a vertical p-i-n Ge PD based on a 2.0 µm-radius micro-disk has a dark current of as low as 35 nA, compared to a conventional PD current of 1 µA with an area of 100 µm2. The operation bandwidth is around 15 GHz at a reverse bias of 1V. The responsivity is about 0.6 A/W. Microdisk is a striking planar structure in integrated optics to enhance light-matter interaction and construct various photonics devices. The disk geometries feature in strongly and circularly confining light into an ultra-small volume in the form of whispering gallery modes. A laser may benefit from a microdisk in which a single mode overlaps the gain materials both spatially and spectrally. Compared to microrings, micro-disk removes the inner boundaries to enable even better compactness, which also makes it very suitable for some scenarios that electrical connections are needed. For example, an ultra-low power (≈ fJ) athermal Si modulator has been demonstrated with a bit rate of 25Gbit/s by confining both photons and electrically-driven carriers into a microscale volume.In this work, we study Si-based PDs with Ge selectively grown on a microdisk with the radius of a few microns. The unique feature of using microdisk for Ge photodetector is that mode selection is not important. In the applications of laser or other passive optical components, microdisk must be designed very carefully to excite the fundamental mode in a microdisk in that essentially the microdisk usually supports many higher order modes in the radial directions. However, for detector applications, this is not an issue because the local light absorption is mode insensitive. Light power carried by all modes are expected to be converted into photo-current. Another benefit of using microdisk is that the power circulation inside avoids any introduction of the reflector. A complete simulation model with all involved materials taken into account is established to study the promise of microdisk structures for photodetector by using finite difference time domain (FDTD) method. By viewing from the current preliminary data, the directions to further improve the device performance are also discussed.

Keywords: integrated optical devices, silicon photonics, micro-resonator, photodetectors

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Authors: Man-Yu Wong, Siyu Zhou, Zhiqiang Cao

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In quality of life, health service utilization is an important determinant of medical resource expenditures on Colorectal cancer (CRC) care, a better understanding of the increased utilization of health services is essential for optimizing the allocation of healthcare resources to services and thus for enhancing the service quality, especially for high expenditure on CRC care like Hong Kong region. In assessing the association between the health-related quality of life (HRQOL) and health service utilization in patients with colorectal neoplasm, count data models can be used, which account for over dispersion or extra zero counts. In our data, the HRQOL evaluation is a self-reported measure obtained from a questionnaire completed by the patients, misreports and variations in the data are inevitable. Besides, there are more zero counts from the observed number of clinical consultations (observed frequency of zero counts = 206) than those from a Poisson distribution with mean equal to 1.33 (expected frequency of zero counts = 156). This suggests that excess of zero counts may exist. Therefore, we study tests for detecting zero-inflation in models with measurement error in covariates. Method: Under classical measurement error model, the approximate likelihood function for zero-inflation Poisson regression model can be obtained, then Approximate Maximum Likelihood Estimation(AMLE) can be derived accordingly, which is consistent and asymptotically normally distributed. By calculating score function and Fisher information based on AMLE, a score test is proposed to detect zero-inflation effect in ZIP model with measurement error. The proposed test follows asymptotically standard normal distribution under H0, and it is consistent with the test proposed for zero-inflation effect when there is no measurement error. Results: Simulation results show that empirical power of our proposed test is the highest among existing tests for zero-inflation in ZIP model with measurement error. In real data analysis, with or without considering measurement error in covariates, existing tests, and our proposed test all imply H0 should be rejected with P-value less than 0.001, i.e., zero-inflation effect is very significant, ZIP model is superior to Poisson model for analyzing this data. However, if measurement error in covariates is not considered, only one covariate is significant; if measurement error in covariates is considered, only another covariate is significant. Moreover, the direction of coefficient estimations for these two covariates is different in ZIP regression model with or without considering measurement error. Conclusion: In our study, compared to Poisson model, ZIP model should be chosen when assessing the association between condition-specific HRQOL and health service utilization in patients with colorectal neoplasm. and models taking measurement error into account will result in statistically more reliable and precise information.

Keywords: count data, measurement error, score test, zero inflation

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Authors: Liang Zhou, Qinke Sun

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Taking the Yangtze River Economic Belt as an example, using long-term nighttime lighting data from DMSP/OLS from 1992 to 2012, support vector machine classification (SVM) was used to quantitatively extract urban built-up areas of economic belts, and spatial analysis of expansion intensity index, standard deviation ellipse, etc. was introduced. The model conducts detailed and in-depth discussions on the strength, direction, and type of the expansion of the middle and lower reaches of the economic belt and the key node cities. The results show that: (1) From 1992 to 2012, the built-up areas of the major cities in the Yangtze River Valley showed a rapid expansion trend. The built-up area expanded by 60,392 km², and the average annual expansion rate was 31%, that is, from 9615 km² in 1992 to 70007 km² in 2012. The spatial gradient analysis of the watershed shows that the expansion of urban built-up areas in the middle and lower reaches of the river basin takes Shanghai as the leading force, and the 'bottom-up' model shows an expanding pattern of 'upstream-downstream-middle-range' declines. The average annual rate of expansion is 36% and 35%, respectively. 17% of which the midstream expansion rate is about 50% of the upstream and downstream. (2) The analysis of expansion intensity shows that the urban expansion intensity in the Yangtze River Basin has generally shown an upward trend, the downstream region has continued to rise, and the upper and middle reaches have experienced different amplitude fluctuations. To further analyze the strength of urban expansion at key nodes, Chengdu, Chongqing, and Wuhan in the upper and middle reaches maintain a high degree of consistency with the intensity of regional expansion. Node cities with Shanghai as the core downstream continue to maintain a high level of expansion. (3) The standard deviation ellipse analysis shows that the overall center of gravity of the Yangtze River basin city is located in Anqing City, Anhui Province, and it showed a phenomenon of reciprocating movement from 1992 to 2012. The nighttime standard deviation ellipse distribution range increased from 61.96 km² to 76.52 km². The growth of the major axis of the ellipse was significantly larger than that of the minor axis. It had obvious east-west axiality, in which the nighttime lights in the downstream area occupied in the entire luminosity scale urban system leading position.

Keywords: urban space, support vector machine, spatial characteristics, night lights, Yangtze River Economic Belt

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Authors: Shi-Bo Feng, Sheng-Jie Zhang, Jin Zhou

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The relationship between microbial diversity and algal bloom has received considerable attention for decades. Microbes undoubtedly affect annual bloom events and impact the physiology of both partners, as well as shape ecosystem diversity. However, knowledge about interactions and network correlations among broader-spectrum microbes that lead to the dynamics in a complete bloom cycle are limited. In this study, pyrosequencing and network approaches simultaneously assessed the associate patterns among bacteria, archaea, and microeukaryotes in surface water and sediments in response to a natural dinoflagellate (Alexandrium sp.) bloom. In surface water, among the bacterial community, Gamma-Proteobacteria and Bacteroidetes dominated in the initial bloom stage, while Alpha-Proteobacteria, Cyanobacteria, and Actinobacteria become the most abundant taxa during the post-stage. In the archaea biosphere, it clustered predominantly with Methanogenic members in the early pre-bloom period while the majority of species identified in the later-bloom stage were ammonia-oxidizing archaea and Halobacteriales. In eukaryotes, dinoflagellate (Alexandrium sp.) was dominated in the onset stage, whereas multiply species (such as microzooplankton, diatom, green algae, and rotifera) coexistence in bloom collapse stag. In sediments, the microbial species biomass and richness are much higher than the water body. Only Flavobacteriales and Rhodobacterales showed a slight response to bloom stages. Unlike the bacteria, there are small fluctuations of archaeal and eukaryotic structure in the sediment. The network analyses among the inter-specific associations show that bacteria (Alteromonadaceae, Oceanospirillaceae, Cryomorphaceae, and Piscirickettsiaceae) and some zooplankton (Mediophyceae, Mamiellophyceae, Dictyochophyceae and Trebouxiophyceae) have a stronger impact on the structuring of phytoplankton communities than archaeal effects. The changes in population were also significantly shaped by water temperature and substrate availability (N & P resources). The results suggest that clades are specialized at different time-periods and that the pre-bloom succession was mainly a bottom-up controlled, and late-bloom period was controlled by top-down patterns. Additionally, phytoplankton and prokaryotic communities correlated better with each other, which indicate interactions among microorganisms are critical in controlling plankton dynamics and fates. Our results supplied a wider view (temporal and spatial scales) to understand the microbial ecological responses and their network association during algal blooming. It gives us a potential multidisciplinary explanation for algal-microbe interaction and helps us beyond the traditional view linked to patterns of algal bloom initiation, development, decline, and biogeochemistry.

Keywords: microbial community, harmful algal bloom, ecological process, network

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Authors: Ming Zhou, Taeho Park

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Early stage technologies have been particularly challenging to manage due to high degrees of their numerous uncertainties. Most research results directly out of a research lab tend to be at their early, if not the infant stage. A long while uncertain commercialization process awaits these lab results. The majority of such lab technologies go nowhere and never get commercialized due to various reasons. Any efforts or financial resources put into managing these technologies turn fruitless. High stake naturally calls for better results, which make a patenting decision harder to make. A good and well protected patent goes a long way for commercialization of the technology. Our preliminary research showed that there was not a simple yet productive procedure for such valuation. Most of the studies now have been theoretical and overly comprehensive where practical suggestions were non-existent. Hence, we attempted to develop a simple and highly implementable procedure for efficient and scalable valuation. We thoroughly reviewed existing research, interviewed practitioners in the Silicon Valley area, and surveyed university technology offices. Instead of presenting another theoretical and exhaustive research, we aimed at developing a practical guidance that a government agency and/or university office could easily deploy and get things moving to later steps of managing early stage technologies. We provided a procedure to thriftily value and make the patenting decision. A patenting index was developed using survey data and expert opinions. We identified the most important factors to be used in the patenting decision using survey ratings. The rating then assisted us in generating good relative weights for the later scoring and weighted averaging step. More importantly, we validated our procedure by testing it with our practitioner contacts. Their inputs produced a general yet highly practical cut schedule. Such schedule of realistic practices has yet to be witnessed our current research. Although a technology office may choose to deviate from our cuts, what we offered here at least provided a simple and meaningful starting point. This procedure was welcomed by practitioners in our expert panel and university officers in our interview group. This research contributed to our current understanding and practices of managing early stage technologies by instating a heuristically simple yet theoretical solid method for the patenting decision. Our findings generated top decision factors, decision processes and decision thresholds of key parameters. This research offered a more practical perspective which further completed our extant knowledge. Our results could be impacted by our sample size and even biased a bit by our focus on the Silicon Valley area. Future research, blessed with bigger data size and more insights, may want to further train and validate our parameter values in order to obtain more consistent results and analyze our decision factors for different industries.

Keywords: technology management, early stage technology, patent, decision

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Authors: Lei Zhou, Dan Li, Ruiqi Ren, Chao Li, Yali Wang, Daxin Ni, Zijian Feng, Timothy M. Uyeki, Qun Li

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Since the first human infections with avian influenza A(H7N9) virus were identified in early 2013, 1533 cases of laboratory-confirmed A(H7N9) virus infections were reported and confirmed as of September 13, 2017. The fifth epidemic was defined as starting from September 1, 2016, and the number of A(H7N9) cases has surged since the end of December in 2016. On February 18, 2017, the A(H7N9) cases who were infected with highly pathogenic avian influenza (HPAI) virus was reported from Southern China. The HPAI A(H7N9) cases were identified and then an investigation and analyses were conducted to assess whether disease severity in humans has changed with HPAI A(H7N9) compared with low pathogenic avian influenza (LPAI) A(H7N9) virus infection. Methods: All confirmed cases with A(H7N9) virus infections reported throughout mainland China from September 1, 2016, to September 13, 2017, were included. Cases' information was extracted from field investigation reports and the notifiable infectious surveillance system to describe the demographic, clinical, and epidemiologic characteristics. Descriptive statistics were used to compare HPAI A(H7N9) cases with all LPAI A(H7N9) cases reported during the fifth epidemic. Results: A total of 27 cases of HPAI A(H7N9) virus were identified infection from five provinces, including Guangxi (44%), Guangdong (33%), Hunan (15%), Hebei (4%) and Shangxi (4%). The median age of cases of HPAI A(H7N9) virus infection was 60 years (range, 15 to 80) and most of them were male (59%) and lived in rural areas (78%). All 27 cases had live poultry related exposures within 10 days before their illness onset. In comparison with LPAI A(H7N9) case-patients, HPAI A(H7N9) case-patients were significantly more likely to live in rural areas (78% vs. 51%; p = 0.006), have exposure to the sick or dead poultry (56% vs. 19%; p = 0.000), and be hospitalized earlier (median 3 vs. 4 days; p = 0.007). No significant differences were observed in median age, sex, prevalence of underlying chronic medical conditions, median time from illness onset to first medical service seeking, starting antiviral treatment, and diagnosis. Although the median time from illness onset to death (9 vs. 13 days) was shorter and the overall case-fatality proportion (48% vs. 38%) was higher for HPAI A(H7N9) case-patients than for LPAI A(H7N9) case-patients, these differences were not statistically significant. Conclusions: Our findings indicate that HPAI A(H7N9) virus infection was associated with exposure to sick and dead poultry in rural areas when visited live poultry market or in the backyard. In the fifth epidemic in mainland China, HPAI A (H7N9) case-patients were hospitalized earlier than LPAI A(H7N9) case-patients. Although the difference was not statistically significant, the mortality of HPAI A (H7N9) case-patients was obviously higher than that of LPAI A(H7N9) case-patients, indicating a potential severity change of HPAI A(H7N9) virus infection.

Keywords: Avian influenza A (H7N9) virus, highly pathogenic avian influenza (HPAI), case-patients, poultry

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Authors: Dechao Meng, Yongqi Dong, Qiyuan Feng, Zhangzhang Cui, Xiang Hu, Haoliang Huang, Genhao Liang, Huanhua Wang, Hua Zhou, Hawoong Hong, Jinghua Guo, Qingyou Lu, Xiaofang Zhai, Yalin Lu

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Great efforts have been taken to reveal the intrinsic origins of emerging ferromagnetism (FM) in strained LaCoO₃ (LCO) films. However, some macro magnetic performances of LCO are still not well understood and even controversial, such as magnetic anisotropy. Determining and understanding magnetic anisotropy might help to find the true causes of FM in turn. Perpendicular magnetic anisotropy (PMA) was the first time to be directly observed in high-quality LCO films with different thickness. The in-plane (IP) and out of plane (OOP) remnant magnetic moment ratio of 30 unit cell (u.c.) films is as large as 20. The easy axis lays in the OOP direction with an IP/OOP coercive field ratio of 10. What's more, the PMA could be simply tuned by changing the thickness. With the thickness increases, the IP/OOP magnetic moment ratio remarkably decrease with magnetic easy axis changing from OOP to IP. Such a huge and tunable PMA performance exhibit strong potentials in fundamental researches or applications. What causes PMA is the first concern. More OOP orbitals occupation may be one of the micro reasons of PMA. A cluster-like magnetic domain pattern was found in 30 u.c. with no obvious color contrasts, similar to that of LaAlO₃/SrTiO₃ films. And the nanosize domains could not be totally switched even at a large OOP magnetic field of 23 T. It indicates strong IP characters or none OOP magnetism of some clusters. The IP magnetic domains might influence the magnetic performance and help to form PMA. Meanwhile some possible nonmagnetic clusters might be the reason why the measured moments of LCO films are smaller than the calculated values 2 μB/Co, one of the biggest confusions in LCO films.What tunes PMA seems much more interesting. Totally different magnetic domain patterns were found in 180 u.c. films with cluster magnetic domains surrounded by < 110 > cross-hatch lines. These lines were regarded as structure domain walls (DWs) determined by 3D reciprocal space mapping (RSM). Two groups of in-plane features with fourfold symmetry were observed near the film diffraction peaks in (002) 3D-RSM. One is along < 110 > directions with a larger intensity, which is well match the lines on the surfaces. The other is much weaker and along < 100 > directions, which is from the normal lattice titling of films deposited on cubic substrates. The < 110 > domain features obtained from (103) and (113) 3D-RSMs exhibit similar evolution of the DWs percentages and magnetic behavior. Structure domains and domain walls are believed to tune PMA performances by transform more IP magnetic moments to OOP. Last but not the least, thick films with lots of structure domains exhibit different electrical transport behaviors. A metal-to-insulator transition (MIT) and an angular dependent negative magnetic resistivity were observed near 150 K, higher than FM transition temperature but similar to that of spin-orbital coupling related 1/4 order diffraction peaks.

Keywords: structure domain, magnetic anisotropy, magnetic domain, domain wall, 3D-RSM, strain

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Authors: Narin Ozturk, Xiao-Mei Li, Sylvie Giachetti, Francis Levi, Alper Okyar

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P-glycoprotein (P-gp, MDR1, ABCB1) is a transmembrane protein acting as an ATP-dependent efflux pump and functions as a biological barrier by extruding drugs and xenobiotics out of cells in healthy tissues especially in intestines, liver and brain as well as in tumor cells. The circadian timing system controls a variety of biological functions in mammals including xenobiotic metabolism and detoxification, proliferation and cell cycle events, and may affect pharmacokinetics, toxicity and efficacy of drugs. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is active against many cancers, and its pharmacokinetics depend on P-gp. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus with respect to the intestinal P-gp expression rhythms in mdr1a::Luc mice using Real Time-Biolumicorder (RT-BIO) System. Mdr1a::Luc male mice were synchronized with 12 h of Light and 12 h of Dark (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding Light onset). After 1-week baseline recordings, everolimus (5 mg/kg/day x 14 days) was administered orally at ZT1-resting period- and ZT13-activity period- to mdr1a::Luc mice singly housed in an innovative monitoring device, Real Time-Biolumicorder units which let us monitor real-time and long-term gene expression in freely moving mice. D-luciferin (1.5 mg/mL) was dissolved in drinking water. Mouse intestinal mdr1a::Luc oscillation profile reflecting P-gp gene expression and locomotor activity pattern were recorded every minute with the photomultiplier tube and infrared sensor respectively. General behavior and clinical signs were monitored, and body weight was measured every day as an index of toxicity. Drug-induced body weight change was expressed relative to body weight on the initial treatment day. Statistical significance of differences between groups was validated with ANOVA. Circadian rhythms were validated with Cosinor Analysis. Everolimus toxicity changed as a function of drug timing, which was least following dosing at ZT13, near the onset of the activity span in male mice. Mean body weight loss was nearly twice as large in mice treated with 5 mg/kg everolimus at ZT1 as compared to ZT13 (8.9% vs. 5.4%; ANOVA, p < 0.001). Based on the body weight loss and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13. Both rest-activity and mdr1a::Luc expression displayed stable 24-h periodic rhythms before everolimus and in both vehicle-treated controls. Real-time bioluminescence pattern of mdr1a revealed a circadian rhythm with a 24-h period with an acrophase at ZT16 (Cosinor, p < 0.001). Mdr1a expression remained rhythmic in everolimus-treated mice, whereas down-regulation was observed in P-gp expression in 2 of 4 mice. The study identified the circadian pattern of intestinal P-gp expression with an unprecedented precision. The circadian timing depending on the P-gp expression rhythms may play a crucial role in the tolerability/toxicity of everolimus. The circadian changes in mdr1a genes deserve further studies regarding their relevance for in vitro and in vivo chronotolerance of mdr1a-transported anticancer drugs. Chronotherapy with P-gp-effluxed anticancer drugs could then be applied according to their rhythmic patterns in host and tumor to jointly maximize treatment efficacy and minimize toxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, mdr1a::Luc mice, p-glycoprotein

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Authors: Rongrong Liu, Li Wang, Hui Xu, Jianpei Fang, Sixi Liu, Xiaolin Yin, Junbin Liang, Gaohui Yan, Yaoyun Li, Yali Zhou, Xinyu Li, Yue Li, Lei Shi, Yongrong Lai, Junjiu Huang, Xinhua Zhang

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Background: Beta-Thalassemia is caused by reduced (β+) or absent (β0) synthesis of the β-globin chains of hemoglobin. Transfusions and oral iron chelation therapy have improved the quality of life for patients with Transfusion-Dependent thalassemia (TDT). Recent advances in genome editing platforms of CRISPR-Cas9 have paved the way for induction of HbF by reactivating expression of γ-chain.Aims: We performed CRISPR-Cas9-mediated genome editing of hematopoietic stem cells to mutate HBG1/HBG2 promoter sequence, thereby representing a naturally occurring HPFH-liked mutation, producing RM-001. Here, we present an initial assessment of safety and efficacy of RM-001 in patients with TDT. Methods: Patients (6–35 y of age) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/y or ≥10 units/y in the previous 2 y were eligible. CD34+ cells were edited with CRISPR-Cas9 using a guide RNA specific for the binding site of BCL11A on the HBG1/2 promoter. Prior to RM-001 product infusion (day 0), patients received myeloablative conditioning with Busulfan from day-7 to day-4. Patients were monitored for AEs Hb expression.Results: Data cut as of 28 Feb 2024, 16 TDT patients have been treated with RM-001 and followed ≥3 months. 5 of these 16 patients had finished their 24 months follow up. Eleven patients have β0/β0 genotype and five patients have β0/β+ genotype. In addition to β-thalassemia, two patients had α- deletion with the genotype of --/αα. Efficacy:All patients received a single dose intravenous infusion of RM-001 cells. 5 of them had been followed 24 months or longer. All patients achieved transfusion-independent (TI, total Hb continued ≥ 9g/dL) (Figure1). Patients demonstrated sustained and clinically meaningful increases in HbF levels since 4 month post-RM-001 infusion (Figure.2). Total hemoglobin in all patients was stable at 10-12g/dL during the follow-up period. Safety:The adverse events observed after RM-001 infusion were consistent with those that are typical of Busulfan-based myeloablation. The allelic editing analysis at 6-month visit showed that the on-target allelic editing frequency in bone marrow cells was 73.44% (64.65% to 84.6%, n=13).Summary/Conclusion: This interim analysis, in which all the 19 patients age from 7.9 to 25yo met the success criteria for the trial with respect to transfusion independence, showed that autologous HBG1/2 promoter-modified CD34+ HSPCs gene therapy resulted in an adequate amount of HbF as early as 2 months after infusion led to near-normal hemoglobin levels, remained transfusion-free through the reported period without product related SAE. After RM-001 infusion, high levels of HbF proportion and on-target editing in bone marrow cells were maintained. Submitted on behalf of the RM-001 Investigators.

Keywords: thalassemian, genetherapy, CRISPR/Cas9, HbF

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Authors: Weijing Zhou, Yuting Lei, Francis Nolan

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In the domain of second language acquisition, whenever pronunciation errors or acquisition difficulties are found, researchers habitually attribute them to the negative transfer of the native language or local dialect. To what extent do Mandarin and local dialects affect English phonological acquisition for Chinese learners of English as a foreign language (EFL)? Little evidence, however, has been found via empirical research in China. To address this core issue, the present study conducted phonetic experiments to explore the roles of local dialects and Mandarin in Chinese EFL learners’ acquisition of L2 English consonants. Besides Mandarin, the sole national language in China, Suzhou dialect was selected as the target local dialect because of its distinct phonology from Mandarin. The experimental group consisted of 30 junior English majors at Yangzhou University, who were born and lived in Suzhou, acquired Suzhou Dialect since their early childhood, and were able to communicate freely and fluently with each other in Suzhou Dialect, Mandarin as well as English. The consonantal target segments were all the consonants of English, Mandarin and Suzhou Dialect in typical carrier words embedded in the carrier sentence Say again. The control group consisted of two Suzhou Dialect experts, two Mandarin radio broadcasters, and two British RP phoneticians, who served as the standard speakers of the three languages. The reading corpus was recorded and sampled in the phonetic laboratories at Yangzhou University, Soochow University and Cambridge University, respectively, then transcribed, segmented and analyzed acoustically via Praat software, and finally analyzed statistically via EXCEL and SPSS software. The main findings are as follows: First, in terms of correct acquisition rates (CARs) of all the consonants, Mandarin ranked top (92.83%), English second (74.81%) and Suzhou Dialect last (70.35%), and significant differences were found only between the CARs of Mandarin and English and between the CARs of Mandarin and Suzhou Dialect, demonstrating Mandarin was overwhelmingly more robust than English or Suzhou Dialect in subjects’ multilingual phonological ecology. Second, in terms of typical acoustic features, the average duration of all the consonants plus the voice onset time (VOT) of plosives, fricatives, and affricatives in 3 languages were much longer than those of standard speakers; the intensities of English fricatives and affricatives were higher than RP speakers but lower than Mandarin and Suzhou Dialect standard speakers; the formants of English nasals and approximants were significantly different from those of Mandarin and Suzhou Dialects, illustrating the inconsistent acoustic variations between the 3 languages. Thirdly, in terms of typical pronunciation variations or errors, there were significant interlingual interactions between the 3 consonant systems, in which Mandarin consonants were absolutely dominant, accounting for the strong transfer from L1 Mandarin to L2 English instead of from earlier-acquired L1 local dialect to L2 English. This is largely because the subjects were knowingly exposed to Mandarin since their nursery and were strictly required to speak in Mandarin through all the formal education periods from primary school to university.

Keywords: acquisition of L2 English consonants, role of Mandarin, role of local dialect, Chinese EFL learners from Suzhou Dialect areas

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Authors: Qi Liu, Jiqin Yao, Xiaohu Zhou, Bo Zheng

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The first artificial cell was produced by Thomas Chang in the 1950s when he was trying to make a mimic of red blood cells. Since then, many different types of artificial cells have been constructed from one of the two approaches: a so-called bottom-up approach, which aims to create a cell from scratch, and a top-down approach, in which genes are sequentially knocked out from organisms until only the minimal genome required for sustaining life remains. In this project, bottom-up approach was used to build a new cell-free expression system which mimics artificial cell that capable of protein expression and communicate with each other. The artificial cells constructed from the bottom-up approach are usually lipid vesicles, polymersomes, hydrogels or aqueous droplets containing the nucleic acids and transcription-translation machinery. However, lipid vesicles based artificial cells capable of communication present several issues in the cell communication research: (1) The lipid vesicles normally lose the important functions such as protein expression within a few hours. (2) The lipid membrane allows the permeation of only small molecules and limits the types of molecules that can be sensed and released to the surrounding environment for chemical communication; (3) The lipid vesicles are prone to rupture due to the imbalance of the osmotic pressure. To address these issues, the hydrogel-based artificial cells were constructed in this work. To construct the artificial cell, polyacrylamide hydrogel was functionalized with Acrylate PEG Succinimidyl Carboxymethyl Ester (ACLT-PEG2000-SCM) moiety on the polymer backbone. The proteinaceous factors can then be immobilized on the polymer backbone by the reaction between primary amines of proteins and N-hydroxysuccinimide esters (NHS esters) of ACLT-PEG2000-SCM, the plasmid template and ribosome were encapsulated inside the hydrogel particles. Because the artificial cell could continuously express protein with the supply of nutrients and energy, the artificial cell-artificial cell communication and artificial cell-natural cell communication could be achieved by combining the artificial cell vector with designed plasmids. The plasmids were designed referring to the quorum sensing (QS) system of bacteria, which largely relied on cognate acyl-homoserine lactone (AHL) / transcription pairs. In one communication pair, “sender” is the artificial cell or natural cell that can produce AHL signal molecule by synthesizing the corresponding signal synthase that catalyzed the conversion of S-adenosyl-L-methionine (SAM) into AHL, while the “receiver” is the artificial cell or natural cell that can sense the quorum sensing signaling molecule form “sender” and in turn express the gene of interest. In the experiment, GFP was first immobilized inside the hydrogel particle to prove that the functionalized hydrogel particles could be used for protein binding. After that, the successful communication between artificial cell-artificial cell and artificial cell-natural cell was demonstrated, the successful signal between artificial cell-artificial cell or artificial cell-natural cell could be observed by recording the fluorescence signal increase. The hydrogel-based artificial cell designed in this work can help to study the complex communication system in bacteria, it can also be further developed for therapeutic applications.

Keywords: artificial cell, cell-free system, gene circuit, synthetic biology

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Authors: Fangfang Wang, Tianjing Wang, Leyi Fu, Feng Yun, Ningning Xie, Jue Zhou, Fan Qu

Abstract:

Background: Ferroptosis, a recently discovered form of programmed cell death characterized by iron-dependent lipid peroxidation, may be linked to polycystic ovary syndrome (PCOS). Diseases marked by iron overload have been correlated with ferroptosis. Coincidently, investigations have revealed anomalies in iron metabolism among women with PCOS; however, there were inconsistencies in the evidence. Objective and Rationale: This review aimed to comprehensively explore the potential relationship between ferroptosis and PCOS by investigating the differences in iron metabolism among women with PCOS in comparison to a control group. Additionally, a narrative synthesis was provided on the past research status regarding the association between PCOS and ferroptosis. Methods: A systematic search of the literature was performed using PubMed, Embase, Web of Science from inception up to December 2022. Search terms relating to assisted PCOS, ferroptosis, and iron metabolism were used. PRISMA guidance was followed. RevMan 5.4 was utilized for conducting the meta-analysis, wherein the investigated outcomes included iron status (ferritin, iron, transferrin saturation) and a systemic iron-regulatory hormone (hepcidin). A narrative synthesis was performed to explore the correlation between PCOS and ferroptosis. Results: In the meta-analysis comprising a total of 16 studies, significant differences in serum ferritin levels between the PCOS group and the control group were observed (15 studies, standardized mean difference (SMD): 0.41, 95% CI: 0.22 to 0.59, P<0.01). This indicates elevated serum ferritin levels in PCOS patients compared to women without PCOS. The transferrin saturation in PCOS patients was significantly higher than that in the control group (3 studies, mean difference (MD): 4.39, 95% CI: 1.67 to 7.11, P<0.01). Regarding serum iron (6 studies, SMD: 0.05, 95% CI: -0.24 to 0.33, P=0.75) and serum hepcidin (4 studies, SMD: -0.44, 95% CI: -1.41 to 0.52, P=0.37), no statistically significant differences were observed between the PCOS group and the control group. Other studies have found that ferroptosis is involved in the occurrence and development of PCOS, offering valuable insights for guiding potential treatment measures and prognosis evaluation of PCOS. In addition, ferroptosis is involved in the miscarriage of PCOS-like rats; thus, controlling ferroptosis might improve pregnancy outcomes in PCOS. Conclusions: The observation of a significant elevation in serum ferritin and transferrin saturation levels in women with PCOS may suggest an underlying disturbance in iron metabolism, potentially inducing the activation of ferroptosis. Further research is imperative to elucidate the underlying pathophysiology, providing insights for potential preventive measures and therapeutic strategies. Limitation: There are some limitations as follows: First, due to limited extractable information, we excluded purely abstract publications and non-English publications. Second, the majority of original articles were case-control studies, making it difficult to determine the causal relationship between iron metabolism abnormalities and the onset of PCOS. Third, there is substantial heterogeneity in the definition of PCOS.

Keywords: polycystic ovary syndrome, ferroptosis, iron metabolism, systematic review and meta-analysis

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Authors: Adil Murtaza, Muhammad Tahir Khan, Awais Ghani, Chao Zhou, Sen Yang, Xiaoping Song

Abstract:

The morphotropic phase boundary (MPB); a boundary between two different crystallographic symmetries in the composition–temperature phase diagram has been widely studied in ferroelectrics and recently has drawn interest in ferromagnets for obtaining enhanced large field-induced strain. At MPB, the system gets a compressed free energy state, which allows the polarization to freely rotate and hence results in a high magnetoelastic response (e.g., high magnetization, low coercivity, and large magnetostriction). Based on the same mechanism, we designed MPB in a ferromagnetic Tb₁₋ₓNdₓCo₂ system. The temperature-dependent magnetization curves showed spin reorientation (SR); which can be explained by a two-sublattice model. Contrary to previously reported MPB involved ferromagnetic systems, the MPB composition of Tb₀.₃₅Nd₀.₆₅Co₂ exhibits a low saturation magnetization (MS), indicating a compensation of the Tb and Nd magnetic moments at MPB. The coercive field (HC) under a low magnetic field and first anisotropy constant (K₁) shows a minimum value at MPB composition of x=0.65. A detailed spin configuration diagram is provided for the Tb₁₋ₓNdₓCo₂ around the composition for the anisotropy compensation; this can guide the development of novel magnetostrictive materials. The anisotropic magnetostriction (λS) first decreased until x=0.8 and then continuously increased in the negative direction with further increase of Nd concentration. In addition, the large ratio between magnetostriction and the absolute values of the first anisotropy constant (λS/K₁) appears at MPB, indicating that Tb₀.₃₅Nd₀.₆₅Co₂ has good magnetostrictive properties. Present work shows an anomalous type of MPB in ferromagnetic materials, revealing that MPB can also lead to a weakening of magnetoelastic behavior as shown in the ferromagnetic Tb₁₋ₓNdₓCo₂ system. Our work shows the universal presence of MPB in ferromagnetic materials and suggests the differences between different ferromagnetic MPB systems that are important for substantial improvement of magnetic and magnetostrictive properties. Based on the results of this study, similar MPB effects might be achieved in other ferroic systems that can be used for technological applications. The finding of magnetic MPB in the ferromagnetic system leads to some important significances. First, it provides a better understanding of the fundamental concept of spin reorientation transitions (SRT) like ferro-ferro transitions are not only reorientation of magnetization but also crystal symmetry change upon magnetic ordering. Second, the flattened free energy corresponding to a low energy barrier for magnetization rotation and enhanced magnetoelastic response near MPB. Third, to attain large magnetostriction with MPB approach two terminal compounds have different easy magnetization directions below Curie temperature Tc in order to accomplish the weakening of magnetization anisotropy at MPB (as in ferroelectrics), thus easing the magnetic domain switching and the lattice distortion difference between two terminal compounds should be large enough, e.g., lattice distortion of R symmetry ˃˃ lattice distortion of T symmetry). So that the MPB composition agrees to a nearly isotropic state along with large ‘net’ lattice distortion, which is revealed in a higher value of magnetostriction.

Keywords: magnetization, magnetostriction, morphotropic phase boundary (MPB), phase transition

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Authors: Weixiao Wei, Chris Shei

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This paper describes Mandate of Heaven as a source of justification for the ruling regime from ancient China approximately three thousand years ago. Initially, the kings of Shang dynasty simply nominated themselves as the sons of Heaven sent to Earth to rule the common people. As the last generation of the kings became corrupted and ruled withbrutal force and crueltywhich directly caused their destruction, the successive kings of Zhou dynasty realised the importance of virtue and the provision of goods to the people. Legitimacy of the ruling regimes became rested not entirely on random allocation of the throne by an unknown supernatural force but on a foundation comprising morality and the ability to provide goods. The latter composite was picked up by the current ruling regime, the Chinese Communist Party, and became the cornerstone of its political legitimacy, also known as ‘performance legitimacy’ where economic development accounts for the satisfaction of the people in place of election and other democratic means of providing legal-rational legitimacy. Under this circumstance, it becomes important as well for the ruling party to use political rhetoric to convince people of the good performance of the government in the economy, morality, and foreign policy. Thus, we see a lot of propaganda materials in both government policy statements and international press conference announcements. The former consists mainly of important speeches made by prominent figures in Party conferences which are not only made publicly available on the government websites but also become obligatory reading materials for university entrance examinations. The later consists of announcements about foreign policies and strategies and actions taken by the government regarding foreign affairsmade in international conferences and offered in Chinese-English bilingual versions on official websites. This documentation strategy creates an impressive image of the Chinese Communist Party that is domestically competent and international strong, taking care of the people it governs in terms of economic needs and defending the country against any foreign interference and global adversities. This political discourse system comprising reading materials fully extractable from government websites also becomes excellent repertoire for teaching and researching in contemporary Chinese language, discourse and rhetoric, Chinese culture and tradition, Chinese political ideology, and Chinese-English translation. This paper aims to provide a detailed and comprehensive description of the current Chinese political discourse system, arguing about its lineage from the rhetorical convention of Mandate of Heaven in ancient China and its current concentration on serving the people in place of election, human rights, and freedom of speech. The paper will also provide guidelines as to how this discourse system and the manifestation of official documents created under this system can become excellent research and teaching materials in applied linguistics.

Keywords: mandate of heaven, Chinese communist party, performance legitimacy, serving the people, political discourse

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Authors: George Zhou, Yunchan Chen, Candace Chien

Abstract:

Kidney replacement therapy is the current standard of care for end-stage renal diseases. In-center or home hemodialysis remains an integral component of the therapeutic regimen. Arteriovenous fistulas (AVF) make up the vascular circuit through which blood is filtered and returned. Naturally, AVF patency determines whether adequate clearance and filtration can be achieved and directly influences clinical outcomes. Our aim was to build a deep learning model for automated AVF stenosis screening based on the sound of blood flow through the AVF. A total of 311 patients with AVF were enrolled in this study. Blood flow sounds were collected using a digital stethoscope. For each patient, blood flow sounds were collected at 6 different locations along the patient’s AVF. The 6 locations are artery, anastomosis, distal vein, middle vein, proximal vein, and venous arch. A total of 1866 sounds were collected. The blood flow sounds are labeled as “patent” (normal) or “stenotic” (abnormal). The labels are validated from concurrent ultrasound. Our dataset included 1527 “patent” and 339 “stenotic” sounds. We show that blood flow sounds vary significantly along the AVF. For example, the blood flow sound is loudest at the anastomosis site and softest at the cephalic arch. Contextualizing the sound with location metadata significantly improves classification performance. How to encode and incorporate categorical metadata is an active area of research1. Herein, we study ordinal (i.e., integer) encoding schemes. The numerical representation is concatenated to the flattened feature vector. We train a vision transformer (ViT) on spectrogram image representations of the sound and demonstrate that using scalar multiples of our integer encodings improves classification performance. Models are evaluated using a 10-fold cross-validation procedure. The baseline performance of our ViT without any location metadata achieves an AuROC and AuPRC of 0.68 ± 0.05 and 0.28 ± 0.09, respectively. Using the following encodings of Artery:0; Arch: 1; Proximal: 2; Middle: 3; Distal 4: Anastomosis: 5, the ViT achieves an AuROC and AuPRC of 0.69 ± 0.06 and 0.30 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 10; Proximal: 20; Middle: 30; Distal 40: Anastomosis: 50, the ViT achieves an AuROC and AuPRC of 0.74 ± 0.06 and 0.38 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 100; Proximal: 200; Middle: 300; Distal 400: Anastomosis: 500, the ViT achieves an AuROC and AuPRC of 0.78 ± 0.06 and 0.43 ± 0.11. respectively. Interestingly, we see that using increasing scalar multiples of our integer encoding scheme (i.e., encoding “venous arch” as 1,10,100) results in progressively improved performance. In theory, the integer values do not matter since we are optimizing the same loss function; the model can learn to increase or decrease the weights associated with location encodings and converge on the same solution. However, in the setting of limited data and computation resources, increasing the importance at initialization either leads to faster convergence or helps the model escape a local minimum.

Keywords: arteriovenous fistula, blood flow sounds, metadata encoding, deep learning

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Authors: Suliman Al-Fayoumi, Sherri Amberg, Huafeng Zhou, Jack W. Singer, James P. Dean

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Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R. In clinical studies, pacritinib was well tolerated with clinical activity in patients with myelofibrosis. The most frequent adverse events (AEs) observed with pacritinib are gastrointestinal (diarrhea, nausea, and vomiting; mostly grade 1-2 in severity) and typically resolve within 2 weeks. A human ADME mass balance study demonstrated that pacritinib is predominantly cleared via hepatic metabolism and biliary excretion (>85% of administered dose). The major hepatic metabolite identified, M1, is not thought to materially contribute to the pharmacological activity of pacritinib. Hepatic diseases are known to impair hepatic blood flow, drug-metabolizing enzymes, and biliary transport systems and may affect drug absorption, disposition, efficacy, and toxicity. This phase 1 study evaluated the pharmacokinetics (PK) and safety of pacritinib and the M1 metabolite in study subjects with mild, moderate, or severe hepatic impairment (HI) and matched healthy subjects with normal liver function to determine if pacritinib dosage adjustments are necessary for patients with varying degrees of hepatic insufficiency. Study participants (aged 18-85 y) were enrolled into 4 groups based on their degree of HI as defined by Child-Pugh Clinical Assessment Score: mild (n=8), moderate (n=8), severe (n=4), and healthy volunteers (n=8) matched for age, BMI, and sex. Individuals with concomitant renal dysfunction or progressive liver disease were excluded. A single 400 mg dose of pacritinib was administered to all participants. Blood samples were obtained for PK evaluation predose and at multiple time points postdose through 168 h. Key PK parameters evaluated included maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration time curve (AUC) from hour zero to last measurable concentration (AUC0-t), AUC extrapolated to infinity (AUC0-∞), and apparent terminal elimination half-life (t1/2). Following treatment, pacritinib was quantifiable for all study participants at 1 h through 168 h postdose. Systemic pacritinib exposure was similar between healthy volunteers and individuals with mild HI. However, there was a significant difference between those with moderate and severe HI and healthy volunteers with respect to peak concentration (Cmax) and plasma exposure (AUC0-t, AUC0-∞). Mean Cmax decreased by 47% and 57% respectively in participants with moderate and severe HI vs matched healthy volunteers. Similarly, mean AUC0-t decreased by 36% and 45% and mean AUC0-∞ decreased by 46% and 48%, respectively in individuals with moderate and severe HI vs healthy volunteers. Mean t1/2 ranged from 51.5 to 74.9 h across all groups. The variability on exposure ranged from 17.8% to 51.8% across all groups. Systemic exposure of M1 was also significantly decreased in study participants with moderate or severe HI vs. healthy participants and individuals with mild HI. These changes were not significantly dissimilar from the inter-patient variability in these parameters observed in healthy volunteers. All AEs were grade 1-2 in severity. Diarrhea and headache were the only AEs reported in >1 participant (n=4 each). Based on these observations, it is unlikely that dosage adjustments would be warranted in patients with mild, moderate, or severe HI treated with pacritinib.

Keywords: pacritinib, myelofibrosis, hepatic impairment, pharmacokinetics

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Authors: T. N. Tran Thi, J. Morse, C. Detlefs, P. K. Cook, C. Yıldırım, A. C. Jakobsen, T. Zhou, J. Hartwig, V. Zurbig, D. Caliste, B. Fernandez, D. Eon, O. Loto, M. L. Hicks, A. Pakpour-Tabrizi, J. Baruchel

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The ability to grow boron-doped diamond epilayers of high crystalline quality is a prerequisite for the fabrication of diamond power electronic devices, in particular high voltage diodes and metal-oxide-semiconductor (MOS) transistors. Boron and intrinsic diamond layers are homoepitaxially overgrown by microwave assisted chemical vapour deposition (MWCVD) on single crystal high pressure, high temperature (HPHT) grown bulk diamond substrates. Various epilayer thicknesses were grown, with dopant concentrations ranging from 1021 atom/cm³ at nanometer thickness in the case of 'delta doping', up 1016 atom/cm³ and 50µm thickness or high electric field drift regions. The crystalline quality of these overgrown layers as regards defects, strain, distortion… is critical for the device performance through its relation to the final electrical properties (Hall mobility, breakdown voltage...). In addition to the optimization of the epilayer growth conditions in the MWCVD reactor, other important questions related to the crystalline quality of the overgrown layer(s) are: 1) what is the dependence on the bulk quality and surface preparation methods of the HPHT diamond substrate? 2) how do defects already present in the substrate crystal propagate into the overgrown layer; 3) what types of new defects are created during overgrowth, what are their growth mechanisms, and how can these defects be avoided? 4) how can we relate in a quantitative manner parameters related to the measured crystalline quality of the boron doped layer to the electronic properties of final processed devices? We describe synchrotron-based techniques developed to address these questions. These techniques allow the visualization of local defects and crystal distortion which complements the data obtained by other well-established analysis methods such as AFM, SIMS, Hall conductivity…. We have used Grazing Incidence X-ray Diffraction (GIXRD) at the ID01 beamline of the ESRF to study lattice parameters and damage (strain, tilt and mosaic spread) both in diamond substrate near surface layers and in thick (10–50 µm) overgrown boron doped diamond epi-layers. Micro- and nano-section topography have been carried out at both the BM05 and ID06-ESRF) beamlines using rocking curve imaging techniques to study defects which have propagated from the substrate into the overgrown layer(s) and their influence on final electronic device performance. These studies were performed using various commercially sourced HPHT grown diamond substrates, with the MWCVD overgrowth carried out at the Fraunhofer IAF-Germany. The synchrotron results are in good agreement with low-temperature (5°K) cathodoluminescence spectroscopy carried out on the grown samples using an Inspect F5O FESEM fitted with an IHR spectrometer.

Keywords: synchrotron X-ray diffaction, crystalline quality, defects, diamond overgrowth, rocking curve imaging

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Authors: Saul Ngarava, Leocadia Zhou, Nomakhaya Monde

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Water crises have the fourth most significant societal impact after weapons of mass destruction, climate change, and extreme weather conditions, ahead of natural disasters. Intricacies between women and water are central to achieving the 2030 Sustainable Development Goals (SDGs). The majority of the 1.2 billion poor people worldwide, with two-thirds being women, and mostly located in Sub Sahara Africa (SSA) and South Asia, do not have access to safe and reliable sources of water. There exist gendered differences in water security based on the division of labour associating women with water. Globally, women and girls are responsible for water collection in 80% of the households which have no water on their premises. Women spend 16 million hours a day collecting water, while men and children spend 6 million and 4 million per day, respectively, which is time foregone in the pursuit of other livelihood activities. Due to their proximity and activities concerning water, women are vulnerable to water insecurity through exposures to water-borne diseases, fatigue from physically carrying water, and exposure to sexual and physical harassment, amongst others. Proximity to treated water and their wellbeing also has an effect on their sensitivity and adaptive capacity to water insecurity. The great distances, difficult terrain and heavy lifting expose women to vulnerabilities of water insecurity. However, few studies have quantified the vulnerabilities and burdens on women, with a few taking a phenomenological qualitative approach. Vulnerability studies have also been scanty in the water security realm, with most studies taking linear forms of either quantifying exposures, sensitivities or adaptive capacities in climate change studies. The current study argues for the need for a water insecurity vulnerability assessment, especially for women into research agendas as well as policy interventions, monitoring, and evaluation. The study sought to identify and provide pathways through which female-headed households were water insecure in South Africa, the 30th driest country in the world. This was through linking the drinking water decision as well as the vulnerability frameworks. Secondary data collected during the 2016 General Household Survey (GHS) was utilised, with a sample of 5928 female-headed households. Principal Component Analysis and Structural Equation Modelling were used to analyse the data. The results show dynamic relationships between water characteristics and water treatment. There were also associations between water access and wealth status of the female-headed households. Association was also found between water access and water treatment as well as between wealth status and water treatment. The study concludes that there are dynamic relationships in water insecurity (exposure, sensitivity, and adaptive capacity) for female-headed households in South Africa. The study recommends that a multi-prong approach is required in tackling exposures, sensitivities, and adaptive capacities to water insecurity. This should include capacitating and empowering women for wealth generation, improve access to water treatment equipment as well as prioritising the improvement of infrastructure that brings piped and safe water to female-headed households.

Keywords: gender, principal component analysis, structural equation modelling, vulnerability, water insecurity

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Authors: Zeyu Zhou, Ziyu Zhao, Xiaochen Yang, Ling AI, Heng Zhai, Stuart Holmes

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As a promising sustainable alternative to traditional fossil fuels, fuel cell technology is highly favoured due to its enhanced working efficiency and reduced emissions. In the context of high-temperature fuel cells (operating above 100 °C), the most commonly used proton exchange membrane (PEM) is the Polybenzimidazole (PBI) doped phosphoric acid (PA) membrane. Grafting is a promising strategy to advance PA-doped PBI PEM technology. The existing grafting modification on PBI PEMs mainly focuses on grafting phosphate-containing or alkaline groups onto the PBI molecular chains. However, quaternary ammonium-based grafting approaches face a common challenge. To initiate the N-alkylation reaction, deacidifying agents such as NaH, NaOH, KOH, K2CO3, etc., can lead to ionic crosslinking between the quaternary ammonium group and PBI. Polyvinylpyrrolidone (PVP) is another widely used polymer, the N-heterocycle groups within PVP endow it with a significant ability to absorb PA. Recently, PVP has attracted substantial attention in the field of fuel cells due to its reduced environmental impact and impressive fuel cell performance. However, due to the the poor compatibility of PVP in PBI, few research apply PVP in PA-doped PBI PEMs. This work introduces an innovative strategy to graft PVP onto PBI to form a network-like polymer. Due to the absence of quaternary ammonium groups, PVP does not pose issues related to crosslinking with PBI. Moreover, the nitrogen-containing functional groups on PVP provide PBI with a robust phosphoric acid retention ability. The nuclear magnetic resonance (NMR) hydrogen spectrum analysis results indicate the successful completion of the grafting reaction where N-alkylation reactions happen on both sides of the grafting agent 1,4-bis(chloromethyl)benzene. On one side, the reaction takes place with the hydrogen atoms on the imidazole groups of PBI, while on the other side, it reacts with the terminal amino group of PVP. The XPS results provide additional evidence from the perspective of the element. On synthesized PBI-g-PVP surfaces, there is an absence of chlorine (chlorine in grafting agent 1,4-bis(chloromethyl)benzene is substituted) element but a presence of sulfur element (sulfur element in terminal amino PVP appears in PBI), which demonstrates the occurrence of the grafting reaction and PVP is successfully grafted onto PBI. Prepare these modified membranes into MEA. It was found that during the fuel cell operation, all the grafted membranes showed substantial improvement in maximum current density and peak power density compared to unmodified one. For PBI-g-PVP 30, with a grafting degree of 22.4%, the peak power density reaches 1312 mW cm⁻², marking a 59.6% enhancement compared to the pristine PBI membrane. The improvement is caused by the improved PA binding ability of the membrane after grafting. The AST test result shows that the grafting membranes have better long-term durability and performance than unmodified membranes attributed to the presence of added PA binding sites, which can effectively prevent the PA leaching caused by proton migration. In conclusion, the test results indicate that grafting PVP onto PBI is a promising strategy which can effectively improve the fuel cell performance.

Keywords: fuel cell, grafting modification, PA doping ability, PVP

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Authors: Wonil Nam, Xiang Ren, Inyoung Kim, Masoud Agah, Wei Zhou

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Despite its ultrasensitive detection capability, surface-enhanced Raman spectroscopy (SERS) faces challenges as a quantitative biochemical analysis tool due to the significant dependence of local field intensity in hotspots on nanoscale geometric variations of plasmonic nanostructures. Therefore, despite enormous progress in plasmonic nanoengineering of high-performance SERS devices, it is still challenging to quantitatively correlate the measured SERS signals with the actual molecule concentrations at hotspots. A significant effort has been devoted to developing SERS calibration methods by introducing internal standards. It has been achieved by placing Raman tags at plasmonic hotspots. Raman tags undergo similar SERS enhancement at the same hotspots, and ratiometric SERS signals for analytes of interest can be generated with reduced dependence on geometrical variations. However, using Raman tags still faces challenges for real-world applications, including spatial competition between the analyte and tags in hotspots, spectral interference, laser-induced degradation/desorption due to plasmon-enhanced photochemical/photothermal effects. We show that electronic Raman scattering (ERS) signals from metallic nanostructures at hotspots can serve as the internal calibration standard to enable quantitative SERS analysis and improve biostatistical analysis. We perform SERS with Au-SiO₂ multilayered metal-insulator-metal nano laminated plasmonic nanostructures. Since the ERS signal is proportional to the volume density of electron-hole occupation in hotspots, the ERS signals exponentially increase when the wavenumber is approaching the zero value. By a long-pass filter, generally used in backscattered SERS configurations, to chop the ERS background continuum, we can observe an ERS pseudo-peak, IERS. Both ERS and SERS processes experience the |E|⁴ local enhancements during the excitation and inelastic scattering transitions. We calibrated IMRS of 10 μM Rhodamine 6G in solution by IERS. The results show that ERS calibration generates a new analytical value, ISERS/IERS, insensitive to variations from different hotspots and thus can quantitatively reflect the molecular concentration information. Given the calibration capability of ERS signals, we performed label-free SERS analysis of living biological systems using four different breast normal and cancer cell lines cultured on nano-laminated SERS devices. 2D Raman mapping over 100 μm × 100 μm, containing several cells, was conducted. The SERS spectra were subsequently analyzed by multivariate analysis using partial least square discriminant analysis. Remarkably, after ERS calibration, MCF-10A and MCF-7 cells are further separated while the two triple-negative breast cancer cells (MDA-MB-231 and HCC-1806) are more overlapped, in good agreement with the well-known cancer categorization regarding the degree of malignancy. To assess the strength of ERS calibration, we further carried out a drug efficacy study using MDA-MB-231 and different concentrations of anti-cancer drug paclitaxel (PTX). After ERS calibration, we can more clearly segregate the control/low-dosage groups (0 and 1.5 nM), the middle-dosage group (5 nM), and the group treated with half-maximal inhibitory concentration (IC50, 15 nM). Therefore, we envision that ERS calibrated SERS can find crucial opportunities in label-free molecular profiling of complicated biological systems.

Keywords: cancer cell drug efficacy, plasmonics, surface-enhanced Raman spectroscopy (SERS), SERS calibration

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Authors: Ling Ai, Ziyu Zhao, Zeyu Zhou, Xiaochen Yang, Heng Zhai, Stuart Holmes

Abstract:

Optimizing the catalyst layer structure is crucial for enhancing the performance of proton exchange membrane fuel cells (PEMFCs) with low Platinum (Pt) loading. Current works focused on the utilization, durability, and site activity of Pt particles on support, and performance enhancement has been achieved by loading Pt onto porous support with different morphology, such as graphene, carbon fiber, and carbon black. Some schemes have also incorporated cost considerations to achieve lower Pt loading. However, the design of the catalyst layer (CL) structure in the membrane electrode assembly (MEA) must consider the interactions between the layers. Addressing the crucial aspects of water management, low contact resistance, and the establishment of effective three-phase boundary for MEA, multi-walled carbon nanotubes (MWCNTs) are promising CL support due to their intrinsically high hydrophobicity, high axial electrical conductivity, and potential for ordered alignment. However, the drawbacks of MWCNTs, such as strong agglomeration, wall surface chemical inertness, and unopened ends, are unfavorable for Pt nanoparticle loading, which is detrimental to MEA processing and leads to inhomogeneous CL surfaces. This further deteriorates the utilization of Pt and increases the contact resistance. Robust chemical oxidation or nitrogen doping can introduce polar functional groups onto the surface of MWCNTs, facilitating the creation of open tube ends and inducing defects in tube walls. This improves dispersibility and load capacity but reduces length and conductivity. Consequently, a trade-off exists between maintaining the intrinsic properties and the degree of functionalization of MWCNTs. In this work, MWCNTs were modified based on the operational requirements of the MEA from the viewpoint of interlayer interactions, including the search for the optimal degree of oxidation, N-doping, and micro-arrangement. MWCNT were functionalized by oxidizing, N-doping, as well as micro-alignment to achieve lower contact resistance between CL and proton exchange membrane (PEM), better hydrophobicity, and enhanced performance. Furthermore, this work expects to construct a more continuously distributed three-phase boundary by aligning MWCNT to form a locally ordered structure, which is essential for the efficient utilization of Pt active sites. Different from other chemical oxidation schemes that used HNO3:H2SO4 (1:3) mixed acid to strongly oxidize MWCNT, this scheme adopted pure HNO3 to partially oxidize MWCNT at a lower reflux temperature (80 ℃) and a shorter treatment time (0 to 10 h) to preserve the morphology and intrinsic conductivity of MWCNT. The maximum power density of 979.81 mw cm-2 was achieved by Pt loading on 6h MWCNT oxidation time (Pt-MWCNT6h). This represented a 59.53% improvement over the commercial Pt/C catalyst of 614.17 (mw cm-2). In addition, due to the stronger electrical conductivity, the charge transfer resistance of Pt-MWCNT6h in the electrochemical impedance spectroscopy (EIS) test was 0.09 Ohm cm-2, which was 48.86% lower than that of Pt/C. This study will discuss the developed catalysts and their efficacy in a working fuel cell system. This research will validate the impact of low-functionalization modification of MWCNTs on the performance of PEMFC, which simplifies the preparation challenges of CL and contributing for the widespread commercial application of PEMFCs on a larger scale.

Keywords: carbon nanotubes, electrocatalyst, membrane electrode assembly, proton exchange membrane fuel cell

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