Functionalization Of 2-Azaallyl Anions, Radicals And Benzylic Chloromethyl-Coupling Polymerization

C-C bond forming reactions, under either metal catalyzed or metal free conditions, are mainstay in the construction of functionalized molecules in organic synthesis. Disubstituted methylamines are highly valuable small molecule pharmaceuticals which are widely applied in the treatment of human disease. To date, traditional synthesis of such amines requires significant effort of synthesizing pre-functionalized reagents. This dissertation describes an innovation in the construction of disubstituted methylamines via the umpolung functionalization of 2-azaallyl anions and radicals. In chapter 1, umpolung synthesis of diarylmethylamines via palladium-catalyzed arylation of 2-azaallyl anion intermediates is introduced. 2-Azaallyl anion coupling partners include 1,1,3-triaryl-2-azaallyl anions and 1,3-diaryl-2-azaallyl anions. The key to success is the advancement of NIXANTPHOS-based catalysts that enabled the arylation of aryl bromides and more challenging aryl chlorides to be conducted under mild conditions. Moreover, the identification of hindered silylamide bases ensures that products of the arylation were not deprotonated or isomerized. In chapter 2, we address the regioselectivities in the α- and γ-arylation of azapentadienyl anions. The regioselectivity was achieved by controlling the reductive elimination of the Pd-azapentadienyl intermediates using two distinct catalysts. These methods provide the first divergent synthesis of allylic amine and enamine derivatives. In chapter 3, we presented an innovative concept that 2-azaallyl anions could behave as organic super-electron-donors. Such unique behavior was illustrated in (i) generation of 2-azaallyl radicals from single-electron-transfer (SET) between 2-azaallyl anions and neutral ketimines, which then coupled with vinyl bromides; (ii) generation of 2-azaallyl radicals from SET of 2-azaallyl anions with aryl and alkyl electrophiles, which then captured aryl and alkyl radicals to form C–C bonds. The transition-metal-free vinylation, arylation and alkylation of 2-azaallyls make possible the synthesis of high-value functionalized amine derivatives in good to excellent yields. In chapter 4, a new polymerization method named benzylic-chloromethyl-coupling polymerization (BCCP) is introduced. BCCP is catalyzed by sulfenate anions, which promote an umpolung polycondensation via step-growth propagation cycles involving sulfoxide intermediates. This protocol represents a very rare example of an organocatalyst that links monomers by C=C double bonds after each enchainment

Wu Mi’s Educational Thoughts and Practice During the Period of the People’s Republic of China (PRC)

As an educator who regarded education as his life, Wu Mi made a great contribution to the development of the education of new China. This paper lays emphasis on the investigation of Wu Mi’s educational practice during the period of PRC, as well as on the expounding of the quintessence of Wu Mi’s educational practice and thoughts in allusion to then situation of education through reading up historical materials

Gastroprotective and ulcer healing properties of ethanol extract of Alpinia conchigera rhizome in experimentally induced gastric ulcer in rats

Purpose: To investigate the gastroprotective effect of Alpinia conchigera rhizome in an ulcer rat model. Method: Sprague-Dawley rats were treated with ethanol extract of Alpinia conchigera at doses of 75 and 150 mg/kg body weight. After 28 days, the rats were sacrificed. Ulcer index, total acidity, pH, hemoglobin levels, and hemorrhagic lesions were determined through macroscopic assessment and histopathological examination. The levels of lipid peroxidation (LPO), superoxide dismutase (SOD), and catalase (CAT), and inflammatory markers (TNF-α, IL-1β, and IL-6) were also determined. Results: Alpinia conchigera significantly reduced ulcer index, total acidity, pH and hemoglobin levels (p < 0.05). Results from histology revealed that the extract protected the mucosa from lesions. Moreover, the extract significantly enhanced gastric mucosal activities of SOD and CAT, and decreased LPO levels and plasma concentrations of TNF-α, IL-1β, and IL-6 (p < 0.05). Conclusion: These results validate the traditional claims on the gastroprotective effects of Alpinia conchigera as revealed through its antioxidant and ulcer-healing properties by stimulation of important cellular mechanisms

Whether and how will using social media induce social anxiety? The correlational and causal evidence from Chinese society

BackgroundPrior literature has well established the relationship between social media use and social anxiety, but little attention has been paid to the underlying mechanisms. Additionally, the causal evidence concerning the effect of social media use on social anxiety is scarce.ObjectiveGiven that, two studies were conducted to examine the effect of social media use on social anxiety and the underlying mechanisms.Methods and resultsIn Study 1, with 470 undergraduates as participants, we applied the questionnaire survey to investigate the relationship between social media use and social anxiety. The results showed that higher social media use intensity was significantly related to higher social anxiety, and social media use was related to social anxiety via two possible mediation paths: (1) social media use → upward social comparison → social anxiety, (2) and social media use → upward social comparison → self-esteem → social anxiety. In Study 2, with 180 undergraduates as participants, we conducted a lab experiment, in which participants were assigned to the experimental (exposed to the content that undergraduates frequently access on social media) or control (exposed to landscape documentaries) condition, and then measured their upward social comparison, self-esteem and social anxiety. The results showed that participants in the experimental condition reported higher social anxiety than those in the control condition, demonstrating the causality between social media exposure and social anxiety. The subsequent mediation analysis basically replicated the findings of Study 1. That is, upward social comparison played the mediating role between social media exposure and social anxiety, and upward social comparison and self-esteem played the chain-mediating role between them.ConclusionThe current research firstly demonstrated the causality between social media use and social anxiety in Chinese society, and also revealed the mediating mechanisms between them, which would deepen our understanding of how social media use will increase social anxiety

Early transition from insulin to sulfonylureas in neonatal diabetes and follow-up: experience from China

Background: Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations. As genetic testing results are often delayed, it remains controversial whether sulfonylurea treatment should be attempted immediately at diagnosis or doctors should await genetic confirmation. Objective: This study aimed to investigate the effectiveness and safety of sulfonylurea therapy in Chinese NDM patients during infancy before genetic testing results were available. Methods: The medical records of NDM patients with their follow‐up details were reviewed and molecular genetic analysis was performed. Sulfonylurea transfer regimens were applied in patients diagnosed after May 2010, and glycemic status and side effects were evaluated in each patient. Results: There were 23 NDM patients from 22 unrelated families, 10 had KCNJ11 mutations, 3 harbored ABCC8 mutations, 1 had INS mutations, 4 had chromosome 6q24 abnormalities, 1 had a deletion at chromosome 1p36.23p36.12, and 4 had no genetic abnormality identified. Sixteen NDM infants were treated with glyburide at an average age of 49 days (range 14‐120 days) before genetic confirmation. A total of 11 of 16 (69%) were able to successfully switch to glyburide with a more stable glucose profile. The responsive glyburide dose was 0.51 ± 0.16 mg/kg/d (0.3‐0.8 mg/kg/d), while the maintenance dose was 0.30 ± 0.07 mg/kg/d (0.2‐0.4 mg/kg/d). No serious adverse events were reported. Conclusions: Molecular genetic diagnosis is recommended in all patients with NDM. However, if genetic testing results are delayed, sulfonylurea therapy should be considered before such results are received, even in infants with newly diagnosed NDM

Src Family Kinases Facilitate the Crosstalk between CGRP and Cytokines in Sensitizing Trigeminal Ganglion via Transmitting CGRP Receptor/PKA Pathway

The communication between calcitonin gene-related peptide (CGRP) and cytokines plays a prominent role in maintaining trigeminal ganglion (TG) and trigeminovascular sensitization. However, the underlying regulatory mechanism is elusive. In this study, we explored the hypothesis that Src family kinases (SFKs) activity facilitates the crosstalk between CGRP and cytokines in sensitizing TG. Mouse TG tissue culture was performed to study CGRP release by enzyme-linked immunosorbent assay, cytokine release by multiplex assay, cytokine gene expression by quantitative polymerase chain reaction, and phosphorylated SFKs level by western blot. The results demonstrated that a SFKs activator, pYEEI (YGRKKRRQRRREPQY(PO3H2)EEIPIYL) alone, did not alter CGRP release or the inflammatory cytokine interleukin-1β (IL-1β) gene expression in the mouse TG. In contrast, a SFKs inhibitor, saracatinib, restored CGRP release, the inflammatory cytokines IL-1β, C-X-C motif ligand 1, C-C motif ligand 2 (CCL2) release, and IL-1β, CCL2 gene expression when the mouse TG was pre-sensitized with hydrogen peroxide and CGRP respectively. Consistently with this, the phosphorylated SFKs level was increased by both hydrogen peroxide and CGRP in the mouse TG, which was reduced by a CGRP receptor inhibitor BIBN4096 and a protein kinase A (PKA) inhibitor PKI (14-22) Amide. The present study demonstrates that SFKs activity plays a pivotal role in facilitating the crosstalk between CGRP and cytokines by transmitting CGRP receptor/PKA signaling to potentiate TG sensitization and ultimately trigeminovascular sensitization

Group-invariant Semidefinite Programming and Applications

Abstract This essay considers semidefinite programming problems that exhibit a special form of symmetry called group-invariance. We demonstrate the effect of such symmetries on certain path-following interior-point algorithms, and highlight a reduction technique that is particularly useful on certain groupinvariant semidefinite programming problems. Two applications of groupinvariant semidefinite programming problems-one in truss design and the other in graph theory-are presented. ii Acknowledgements To my supervisor, Dr. Chek Beng Chua, for his wise advice, great encouragement and continuous support during my master's study. To Professor Michael Best for his comments and careful reading of the draft. To my dear friends who gave me great help and made my life in Waterloo a wonderful experience

The association between sleep duration, respiratory symptoms, asthma, and COPD in adults

IntroductionThe association between sleep duration and cough, wheezing, and dyspnea was unclear. This research aimed to test this relationship.MethodsResearch data were obtained from people who participated in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2012. We used weighted logistic regression analysis and fitted curves to explore the association between sleep and respiratory symptoms. In addition, we investigated the association between sleep duration, chronic obstructive pulmonary disease (COPD), and asthma. The stratified analysis is used to analyze inflection points and specific populations.ResultsThe 14,742 subjects are weighted to reflect the 45,678,491 population across the United States. Weighted logistic regression and fitted curves show a U-shaped relationship between sleep duration and cough and dyspnea. This U-shaped relationship remained in people without COPD and asthma. The stratified analysis confirmed that sleep duration before 7.5 h was negatively associated with cough (HR 0.80, 95% CI 0.73–0.87) and dyspnea (HR 0.82, 95% CI 0.77–0.88). In contrast, it was positively associated with cough and (HR 1.30, 95% CI 1.14–1.48) dyspnea (HR 1.12, 95% CI 1.00–1.26) when sleep duration was >7.5 h. In addition, short sleep duration is associated with wheezing, asthma, and COPD.ConclusionBoth long and short sleep duration are associated with cough and dyspnea. And short sleep duration is also an independent risk factor for wheezing, asthma, and COPD. This finding provides new insights into the management of respiratory symptoms and diseases

Modified nusinersen intrathecal injection method: inclusion of a septal needle-free closed infusion connector

ObjectiveNusinersen, an extremely expensive biologic drug (around 100,000 US$ per dose) that needs to be administered intrathecally, is approved for the treatment of 5q-spinal muscular atrophy (SMA). Because of the low muscle tone of the back muscles of pediatric SMA patients, especially type 1 SMA patients, the safe, effective, and fast execution of sheath injection is needed. Therefore, a modified intrathecal injection method was developed accordingly. This paper aims to describe the applicability and safety of this modified method.MethodsThe modified intrathecal injection method (MIIM) mainly includes a septal needle-free closed infusion connector between the lumbar puncture needle and the syringe, besides the procedures of routine lumbar puncture. Its applicability and safety were evaluated through clinical observation.ResultsA total of 92 children with SMA have successfully received nusinersen treatment at our hospital using the modified method since 2019 without obvious adverse events related to the modified injection method. Based on the clinical feedback of operators, the advantages of the modified method include successfully injecting the total dose of nusinersen with constant injection rate and a more stable fixation of the puncture needle, as well as making the operator more relaxed. However, compared with the routine method, the procedure of the modified method has additional steps.ConclusionThe modified intrathecal injection method is an effective and safe method to inject nusinersen when weighing the pros and cons, and it may also be used for administering intrathecal injections of other expensive medicines or for patients with other strict requirements for intrathecal injection