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Reading and Writing in Negotiations: Studies in the Chinese Harry Potter Danmei Tongren Fandom
No full textUsing the Chinese "Harry Potter" danmei tongren fandom as an example, this thesis discusses the specific reading and writing habits of the Chinese danmei tongren fans. "Danmei tongren" is a Chinese umbrella term for fan fiction about male homoerotic romance that uses characters from popular texts. It is a type of popular culture appreciated mainly by young Chinese female netizens. The thesis is divided into two chapters. The first chapter discusses the reasons why danmei has become the mainstream genre/modality of tongren writing in contemporary PRC, by exploring the lineage of Chinese tongren culture and the desire and needs of its major female participants. The second chapter analyzes the specific fannish reading and writing habits fostered by online communities from the perspectives of the relationship between fans and the source texts, the interactions and conflicts between tongren readers and writers, and fans' literary innovation under communal limitations. Based on participant observation of fan practices, textual analysis of fan texts, and qualitative interviews with eight Harry Potter danmei tongren fans, I argue that danmei tongren fans' reading and writing are shaped and mediated by the complex negotiations in the intimate online community built and connected by fans' emotional investments.</p
SGC-CAMKK2-1: A Chemical Probe for CAMKK2.
No full textThe serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2
Performance and Modernity: Enacting Change on the Globalizing Stage By Julia A. Walker. Cambridge: Cambridge University Press, 2021; pp. xiii + 299, 20 illustrations. 99.99 e-book.
No full text'Minimal symptom expression' in patients with acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab.
No full textBackgroundThe efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension.MethodsAttainment of 'minimal symptom expression' was evaluated using patient-reported outcome measures of gMG symptoms [MG activities of daily living scale (MG-ADL), 15-item MG quality of life questionnaire (MG-QOL15)] at the completion of REGAIN and during the open-label extension. 'Minimal symptom expression' was defined as MG-ADL total score of 0-1 or MG-QOL15 total score of 0-3.ResultsAt REGAIN week 26, more eculizumab-treated patients achieved 'minimal symptom expression' versus placebo [MG-ADL: 21.4% vs 1.7%; difference 19.8%; 95% confidence interval (CI) 8.5, 31.0; p = 0.0007; MG-QOL15: 16.1% vs 1.7%; difference 14.4%; 95% CI 4.3, 24.6; p = 0.0069]. During the open-label extension, the proportion of patients in the placebo/eculizumab group who achieved 'minimal symptom expression' increased after initiating eculizumab treatment and was sustained through 130 weeks of open-label eculizumab (MG-ADL: 1.7 to 27.8%; MG-QOL15: 1.7 to 19.4%). At extension study week 130, similar proportions of patients in the eculizumab/eculizumab and placebo/eculizumab groups achieved 'minimal symptom expression' (MG-ADL: 22.9% and 27.8%, respectively, p = 0.7861; MG-QOL15: 14.3% and 19.4%, respectively, p = 0.7531). The long-term tolerability of eculizumab was consistent with previous reports.ConclusionsPatients with AChR+ refractory gMG who receive eculizumab can achieve sustained 'minimal symptom expression' based on patient-reported outcomes. 'Minimal symptom expression' may be a useful tool in measuring therapy effectiveness in gMG.Trial registrationClinicalTrials.gov NCT01997229, NCT02301624
Optimal tether configurations and preload tensioning to prevent proximal junctional kyphosis: A finite element analysis
No full textOBJECTIVE Proximal junctional kyphosis (PJK) is, in part, due to altered segmental biomechanics at the junction of rigid instrumented spine and relatively hypermobile non-instrumented adjacent segments. Proper application of posteriorly anchored polyethylene tethers (i.e., optimal configuration and tension) may mitigate adjacent-segment stress and help prevent PJK. The purpose of this study was to investigate the impact of different tether configurations and tensioning (preloading) on junctional range-of-motion (ROM) and other biomechanical indices for PJK in long instrumented spine constructs. METHODS Using a validated finite element model of a T7–L5 spine segment, testing was performed on intact spine, a multilevel posterior screw-rod construct (PS construct; T11–L5) without tether, and 15 PS constructs with different tether configurations that varied according to 1) proximal tether fixation of upper instrumented vertebra +1 (UIV+1) and/ or UIV+2; 2) distal tether fixation to UIV, to UIV−1, or to rods; and 3) use of a loop (single proximal fixation) or weave (UIV and/or UIV+1 fixation in addition to UIV+1 and/or UIV+2 proximal attachment) of the tether. Segmental ROM, intradiscal pressure (IDP), inter- and supraspinous ligament (ISL/SSL) forces, and screw loads were assessed under variable tether preload. RESULTS PS construct junctional ROM increased abruptly from 10% (T11–12) to 99% (T10–11) of baseline. After tethers were grouped by most cranial proximal fixation (UIV+1 vs UIV+2) and use of loop versus weave, UIV+2 Loop and/or Weave most effectively dampened junctional ROM and adjacent-segment stress. Different distal fixation and use of loop versus weave had minimal effect. The mean segmental ROM at T11–12, T10–11, and T9–10, respectively, was 6%, 40%, and 99% for UIV+1 Loop; 6%, 44%, and 99% for UIV+1 Weave; 5%, 23%, and 26% for UIV+2 Loop; and 5%, 24%, and 31% for UIV+2 Weave. Tethers shared loads with posterior ligaments; consequently, increasing tether preload tension reduced ISL/SSL forces, but screw loads increased. Further attenuation of junctional ROM and IDP reversed above approximately 100 N tether preload, suggesting diminished benefit for biomechanical PJK prophylaxis at higher preload tensioning. CONCLUSIONS In this study, finite element analysis demonstrated UIV+2 Loop and/or Weave tether configurations most effectively mitigated adjacent-segment stress in long instrumented spine constructs. Tether preload dampened ligament forces at the expense of screw loads, and an inflection point (approximately 100 N) was demonstrated above which junctional ROM and IDP worsened (i.e., avoid over-tightening tethers). Results suggest tether configuration and tension influence PJK biomechanics and further clinical research is warranted
GRIP Display: A One-Pot Library Display Platform for the Directed Evolution of Proteins
No full textLibrary display technologies have enabled the development of peptides with affinity for a given substrate. Such affinity-capture reagents have driven progress in many fields, from basic biochemistry to neuropharmacology. A major limitation in the development of neuro-pharmaceuticals has been an inability to examine how the behavioral effects of drugs are mediated by each of the distinct yet intermingled cell types in any given brain region. DART (Drugs Acutely Restricted by Tethering) is the first method to overcome this technical barrier, enabling the delivery of therapeutics to a precise genetically defined neuronal cell type. At the core of DART’s specificity is a capture of a chemical Rx-HTL (HaloTag Ligand conjugated to a drug) by a genetically encoded HTP (HaloTag protein), creating an artificial dosing window. Although the technology has already revealed novel neurobiological insights, a narrow dosing window currently limits DART to neurobiological questions where dose can be tightly controlled, such as via intracranial infusion over a small brain volume. Our goal is to adapt the principles of directed evolution and library display to improve the dosing window of DART and enable its brain-wide delivery. Moreover, using the same principles, we aim to develop an orthogonal DART pair for multiplexed delivery of any combination of drugs to two distinct cell types.
The underlying principle of a library display tool is a physical linkage between phenotype (a protein) and genotype (its corresponding nucleotide sequence). This conjugated mRNA, encoding the displayed protein, serves as a unique identifier for each variant. Over the past three decades, several display systems have been developed, each with a unique set of limitations. Typically, there is a tradeoff between the stability of this linkage and the number of unique variants (library size). Thus, no existing platform offers the desired trifecta of linkage stability, library size, and product yield.
This work introduces a novel in vitro protein display technology called GRIP Display (Gluing RNA to Its Protein) that permits the generation and simultaneous screening of vast protein libraries (~10^14 variants) against a target of interest, with minimal genetic cross-talk, significant selection enrichment, and one-step simple experimental protocol. Here, we demonstrate 1) the development of GRIP Display and its utility in the optimization of a large binding tunnel of HTP to enhance the covalent capture of its chemical ligand; 2) the development of high-affinity orthogonal HTP/HTL pairs with minimal cross-reactivity; 3) a rational design of a novel peptide/RNA interaction to promote the avidity of binding and create a “single read” display technology GRIP.2.
GRIP Display represents a valuable resource for the protein engineering community, and can substantially advance the range of neurobiological questions amenable to DART.</p
Identifying patients at risk for nonroutine discharge after surgery for cervical myelopathy: an analysis from the Quality Outcomes Database.
No full textObjectiveOptimizing patient discharge after surgery has been shown to impact patient recovery and hospital/physician workflow and to reduce healthcare costs. In the current study, the authors sought to identify risk factors for nonroutine discharge after surgery for cervical myelopathy by using a national spine registry.MethodsThe Quality Outcomes Database cervical module was queried for patients who had undergone surgery for cervical myelopathy between 2016 and 2018. Nonroutine discharge was defined as discharge to postacute care (rehabilitation), nonacute care, or another acute care hospital. A multivariable logistic regression predictive model was created using an array of demographic, clinical, operative, and patient-reported outcome characteristics.ResultsOf the 1114 patients identified, 11.2% (n = 125) had a nonroutine discharge. On univariate analysis, patients with a nonroutine discharge were more likely to be older (age ≥ 65 years, 70.4% vs 35.8%, p ConclusionsThe study results indicate that socioeconomic and demographic characteristics including age, race, gender, insurance, and employment may be the most significant drivers of a nonroutine discharge after surgery for cervical myelopathy
Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.
No full textObjectivesWe aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury.DesignRetrospective cohort study.SettingICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study.PatientsGreater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of InterventionsNone.MeasurementsPrimary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction.Main resultsOf the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes.ConclusionsAbout one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies