10,716 research outputs found

    Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

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    Abstract P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC

    The TeV Sun Rises: Discovery of Gamma rays from the Quiescent Sun with HAWC

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    We report the first detection of a TeV gamma-ray flux from the solar disk (6.3σ\sigma), based on 6.1 years of data from the High Altitude Water Cherenkov (HAWC) observatory. The 0.5--2.6 TeV spectrum is well fit by a power law, dN/dE = A(E/1 TeV)γA (E/1 \text{ TeV})^{-\gamma}, with A=(1.6±0.3)×1012A = (1.6 \pm 0.3) \times 10^{-12} TeV1^{-1} cm2^{-2} s1^{-1} and γ=3.62±0.14\gamma = -3.62 \pm 0.14. The flux shows a strong indication of anticorrelation with solar activity. These results extend the bright, hard GeV emission from the disk observed with Fermi-LAT, seemingly due to hadronic Galactic cosmic rays showering on nuclei in the solar atmosphere. However, current theoretical models are unable to explain the details of how solar magnetic fields shape these interactions. HAWC's TeV detection thus deepens the mysteries of the solar-disk emission.Comment: 15 pages, 8 figures including supplementary material. Accepted for publication in Physical Review Letter

    Magneto-transport and electronic structures in MoSi2_2 bulks and thin films with different orientations

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    We report a comprehensive study of magneto-transport properties in MoSi2_2 bulk and thin films. Textured MoSi2_2 thin films of around 70 nm were deposited on silicon substrates with different orientations. Giant magnetoresistance of 1000% was observed in sintered bulk samples while MoSi2_2 single crystals exhibit a magnetoresistance (MR) value of 800% at low temperatures. At the low temperatures, the MR of the textured thin films show weak anti-localization behaviour owing to the spin orbit coupling effects. Our first principle calculation show the presence of surface states in this material. The resistivity of all the MoSi2_2 thin films is significantly low and nearly independent of the temperature, which is important for electronic devices

    Designing the transition to operations in large inter-organizational projects: Strategy, structure, process, and people

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    The transition from projects to operations requires a spanning from more temporary, goal-oriented, and evolving organizational forms to more permanent, routine, and ongoing organizational forms. A question of practical and theoretical significance is how to organize the transition to operations in large inter-organizational projects. To answer this question, we conducted a longitudinal case study of Beijing Daxing International Airport, which is the largest transportation hub in China to date, and provides rich evidence for successfully managing the transition to operations. By analyzing the organizational design strategy, structures, processes, and management of people in the transition, we provide a synthetic framework for designing the transition to operations in large inter-organizational projects. The framework provides a set of considerations to design organizational boundaries that build connections, emphasize coordination, and achieve continuity between projects and operations. This study contributes to the nexus of operations management and project management and the organizational design of large inter-organizational projects.Design & Construction Managemen

    Correlation Between the Variability of Different Obesity Indices and Diabetic Kidney Disease: A Retrospective Cohort Study Based on Populations in Taiwan

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    Zhenzhen Sun,1,&ast; Kun Wang,1,&ast; Chuan Yun,1 Fang Bai,1 Xiaodan Yuan,2 Yaujiunn Lee,3 Qingqing Lou1 1The First Affiliated Hospital of Hainan Medical University, Hainan Clinical Research Center for Metabolic Disease, Haikou, Hainan, People’s Republic of China; 2Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Department of Endocrinology, Lee’s Clinic, Pingtung City, Pingtung County, Taiwan&ast;These authors contributed equally to this workCorrespondence: Qingqing Lou, The First Affiliated Hospital of Hainan Medical University, Hainan Clinical Research Center for Metabolic Disease, No. 31, Longhua Road, Haikou, 570102, Hainan, People’s Republic of China, Tel +86 15312019129, Email [email protected]: To investigate the association of five obesity indices and the variability of these indices with diabetic kidney disease (DKD) in patients with type 2 diabetes and compare the predictive validity of these markers for the risk of DKD in this large longitudinal cohort study.Patients and Methods: A total of 2659 patients with type 2 diabetes who did not have DKD were enrolled between 2006 and 2019 at Lee’s United Clinic in Taiwan. Data were collected for each subject, including demographic data, personal medical history, clinical parameters and calculated Body mass index (BMI), visceral adiposity index (VAI), lipid accumulation product (LAP), body roundness index (BRI) and variability of five obesity indices. Cox regression analysis was performed to determine the relationship between different obesity indicators and DKD risk. Cox’s proportional hazards model was evaluated the predictive effect of obesity indices on DKD.Results: The risk of developing DKD increased with an increase in the BRI, LAP, VAI, WC and BMI (all P trend< 0.05), and the variability of VAI was significantly associated with DKD [HR=1.132, 95% CI (1.001, 1.281)] after adjusting for corresponding variables. BRI had the strongest predictive effect on DKD. BRI had the best predictive performance, with AUC of 0.807, 0.663 and 0.673 at 1, 3 and 5 years, respectively. Cox regression analysis of risk factors for DKD in patients stratified by BRI quartiles showed that patients in the Q4 group had the highest risk of developing DKD [HR=1.356, 95% CI (1.131, 1.626)].Conclusion: BMI, WC, VAI, LAP, BRI and VAI variability were associated with a significant increase in the risk of DKD events, and BRI was superior and alternative obesity index for predicting DKD.Keywords: visceral adiposity index, lipid accumulation product, body roundness index, diabetic kidney diseas

    Leveraging base-pair mammalian constraint to understand genetic variation and human disease

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    Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease

    Third dose of BNT162b2 improves immune response in liver transplant recipients to ancestral strain but not Omicron BA.1 and XBB

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    Vaccine immunogenicity in transplant recipients can be impacted by the immunosuppressive (IS) regimens they receive. While BNT162b2 vaccination has been shown to induce an immune response in liver transplant recipients (LTRs), it remains unclear how different IS regimens may affect vaccine immunogenicity after a third BNT162b2 dose in LTRs, which is especially important given the emergence of the Omicron sublineages of SARS-CoV-2. A total of 95 LTRs receiving single and multiple IS regimens were recruited and offered three doses of BNT162b2 during the study period. Blood samples were collected on days 0, 90, and 180 after the first BNT162b2 dose. At each time point, levels of anti-spike antibodies, their neutralizing activity, and specific memory B and T cell responses were assessed. LTRs receiving single IS regimens showed an absence of poor immunogenicity, while LTRs receiving multiple IS regimens showed lower levels of spike-specific antibodies and immunological memory compared to vaccinated healthy controls after two doses of BNT162b2. With a third dose of BNT162b2, spike-specific humoral, memory B, and T cell responses in LTR significantly improved against the ancestral strain of SARS-CoV-2 and were comparable to those seen in healthy controls who received only two doses of BNT162b2. However, LTRs receiving multiple IS regimens still showed poor antibody responses against Omicron sublineages BA.1 and XBB. A third dose of BNT162b2 may be beneficial in boosting antibody, memory B, and T cell responses in LTRs receiving multiple IS regimens, especially against the ancestral Wuhan strain of SARS-CoV-2. However, due to the continued vulnerability of LTRs to presently circulating Omicron variants, antiviral treatments such as medications need to be considered to prevent severe COVID-19 in these individuals.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)National Medical Research Council (NMRC)Published versionThis work was supported by the Biomedical Research Council (BMRC), A*CRUSE (Vaccine monitoring project), the A*ccelerate GAP-funded project (ACCL/19-GAP064-R20H-H) from the Agency of Science, Technology and Research (A*STAR), Singapore National Medical Research Council COVID-19 Research Fund (COVID19RF001; COVID19RF-007; COVID19RF-011; COVID19RF-0008; COVID19RF-060), and A*STAR COVID-19 Research funding (H/ 20/04/g1/006). LR was also supported by a Start-up University Grant from Ministry of Education (SUJ #022388-00001)

    Welded steel I-section columns: residual stresses, testing, simulation and design

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    The flexural buckling behaviour and design of homogeneous and hybrid welded I-section columns, considering a wide range of steel grades, are investigated in the present study. Residual stresses are first examined through the statistical analysis of 71 existing experimental results collected from the literature; on the basis of the findings, a new residual stress model for S235 to S960 steel welded I-sections is proposed. Experiments on a total of five pin-ended homogeneous (S690) and hybrid (S355 web and S690 flanges) welded I-section columns buckling about the major axis are then presented. In parallel with the experimental programme, finite element (FE) models were created and validated against the experimental results obtained from the present study, as well as those collected from the literature. The developed FE models were shown to be capable of accurately replicating the key experimental responses, and were then utilised to carry out extensive parametric studies, through which additional 6000 numerical column buckling data covering a wide range of steel grades, cross-section geometries and member slendernesses were generated. The combined experimental and numerical data were used to evaluate the accuracy of the flexural buckling design rules for welded I-section columns set out in the current European and North American design standards, where shortcomings relating to the consideration of steel grade were identified. A modified Eurocode 3 (EC3) method was devised to reflect the influence of yield strength on the buckling resistances of welded I-section columns more systematically and shown to provide substantially improved resistance predictions in terms of accuracy and consistency; the reliability of the modified approach was statistically verified following the procedure set out in Annex D of EN 1990 and is considered to be suitable for incorporation into future revisions of Eurocode 3

    Phase engineering of metal nanocatalysts for electrochemical CO2 reduction

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    202307 bcchVersion of RecordRGCOthersCD4D; National Precious Metals Material Engineering Research Center; Research Institute for Advanced Manufacturing; Glaucoma Research Foundation; City University of Hong Kong; National Natural Science Foundation of China; Innovation and Technology Commission; Hong Kong Polytechnic University; Chinese University of Hong Kong; Science, Technology and Innovation Commission of Shenzhen MunicipalityPublishe
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