Sensitivity analysis for large-scale problems

The development of efficient techniques for calculating sensitivity derivatives is studied. The objective is to present a computational procedure for calculating sensitivity derivatives as part of performing structural reanalysis for large-scale problems. The scope is limited to framed type structures. Both linear static analysis and free-vibration eigenvalue problems are considered

Feminist scholarship, feminist institution-building, feminist friendships

Recollections of the daily grind and the deeper joys of editing a feminist journal

SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate

Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target/PROTAC/ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation. Here, we develop an SPR-based assay to quantify the stability of PROTAC-induced ternary complexes by measuring for the first time the kinetics of their formation and dissociation <i>in vitro</i> using purified proteins. We benchmark our assay using four PROTACs that target the bromodomains (BDs) of bromodomain and extraterminal domain proteins Brd2, Brd3, and Brd4 to the von Hippel–Lindau E3 ligase (VHL). We reveal marked differences in ternary complex off-rates for different PROTACs that exhibit either positive or negative cooperativity for ternary complex formation relative to binary binding. The positively cooperative degrader MZ1 forms comparatively stable and long-lived ternary complexes with either Brd4^BD2 or Brd2^BD2 and VHL. Equivalent complexes with Brd3^BD2 are destabilized due to a single amino acid difference (Glu/Gly swap) present in the bromodomain. We observe that this difference in ternary complex dissociative half-life correlates to a greater initial rate of intracellular degradation of Brd2 and Brd4 relative to Brd3. These findings establish a novel assay to measure the kinetics of PROTAC ternary complexes and elucidate the important kinetic parameters that drive effective target degradation

Virulence and biotype analyses of hessian fly (Diptera: Cecidomyiidae) populations from Texas, Louisiana, and Oklahoma

Citation: Garces-Carerra, S. . . . & Chen, M. (2014). Virulence and Biotype Analyses of Hessian Fly (Diptera: Cecidomyiidae) Populations From Texas, Louisiana, and Oklahoma. Journal of Economic Entomology, 107(1), 417-423. https://doi.org/10.1603/EC13372Hessian fly, Mayetiola destructor (Say, 1817), is a major pest of wheat, and is controlled mainly through deploying fly-resistant wheat cultivars. The challenge for the plant resistance approach is that virulence of Hessian fly populations in the field is dynamic, and wheat cultivars may lose resistance within 6-8 yr. To ensure continuous success of host plant resistance, Hessian fly populations in the field need to be constantly monitored to determine which resistance genes remain effective in different geographic regions. This study investigated five Hessian fly populations collected from Texas, Louisiana, and Oklahoma, where infestation by Hessian fly has been high in recent years. Eight resistance genes, H12, H13, H17, H18, H22, H25, H26, and Hdic, were found to be highly effective against all tested Hessian fly populations in this region, conferring resistance to ≥80% of plants containing one of these resistance genes. The frequencies of biotypes virulent to resistance genes H13 (biotype vH13), H18 (vH18), H21 (vH21), H25 (vH25), H26 (vH26), and Hdic (vHdic) were determined, and were found to vary from population to population, ranging from 0 to 45%. A logistic regression model was established to predict biotype frequencies based on the correlation between the percentages of susceptible plants obtained in a virulence test and the log-odds of virulent biotype frequencies determined by a traditional approach

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to no vaccination or standard three and two-dose vaccination regimens: A systematic review of evidence from clinical trials.

OBJECTIVES: This study aimed to systematically review the literature on the efficacy and immunogenicity of single-dose HPV vaccination compared to no vaccination or multi-dose schedules among vaccine trial participants. METHODS: Medline, EMBASE, Global Health Database and Cochrane Central Register of Controlled Trials were searched for publications and conference abstracts (dated January 1999-August 2018) using MeSH and non-MeSH terms for human papillomavirus AND vaccines AND (immunogenicity OR efficacy/effectiveness) AND dosage. Search results were screened against pre-specified eligibility criteria. Data were extracted from included articles, and a narrative synthesis conducted on efficacy against HPV16/18 infection and humoral immunogenicity. RESULTS: Seven of 6,523 unique records identified were included in the review. Six were nested observational studies of participants randomised to receive two or three doses in three large HPV vaccine trials, in which some participants did not complete their allocated schedules. One small pilot study prospectively allocated participants to receive one or no vaccine dose. Frequency of HPV16/18 infection was low (e.g.  0.05 in all cases). Frequency of infection was significantly lower in one-dose recipients compared to unvaccinated controls (p < 0.01 for all infection endpoints in each study). HPV16/18 seropositivity rates were high in all HPV vaccine recipients (100% in three of four studies reporting this endpoint), though antibody levels were lower with one compared to two or three doses. CONCLUSIONS: This review supports the premise that one HPV vaccine dose may be as effective in preventing HPV infection as multi-dose schedules in healthy young women. However, it also highlights the paucity of available evidence from purpose-designed, prospectively-randomised trials. Results from ongoing clinical trials assessing the efficacy and immunogenicity of single-dose HPV vaccination compared to currently-recommended schedules are awaited

Treatment fidelity monitoring, reporting and findings in a complex aphasia intervention trial: a substudy of the Very Early Rehabilitation in SpEech (VERSE) trial

Background: Treatment fidelity is inconsistently reported in aphasia research, contributing to uncertainty about the effectiveness of types of aphasia therapy following stroke. We outline the processes and outcomes of treatment fidelity monitoring in a pre-specified secondary analysis of the VERSE trial. Methods: VERSE was a 3-arm, single-blinded RCT with a 12-week primary endpoint comparing Usual Care (UC) to two higher intensity treatments: Usual Care-Plus (UC-Plus) and VERSE, a prescribed intervention. Primary outcome results were previously reported. This secondary analysis focused on treatment fidelity. Video-recorded treatment sessions in the higher intensity study arms were evaluated for treatment adherence and treatment differentiation. Treatment components were evaluated using a pre-determined fidelity checklist. Primary outcome: prescribed amount of therapy time (minutes); secondary outcomes: (i) adherence to therapy protocol (%) and (ii) treatment differentiation between control and high intensity groups. Results: Two hundred forty-six participants were randomised to Usual Care (n=81), Usual Care-Plus (n=82), and VERSE (n=83). One hundred thirty-five (82%) participants in higher intensity intervention arms received the minimum prescribed therapy minutes. From 10,805 (UC 7787; UC-Plus 1450; VERSE 1568) service events, 431 treatment protocol deviations were noted in 114 participants. Four hundred thirty-seven videos were evaluated. The VERSE therapists achieved over 84% adherence to key protocol elements. Higher stroke and aphasia severity, older age, and being in the UC-Plus group predicted more treatment deviations. Conclusions: We found high levels of treatment adherence and differentiation between the intervention arms, providing greater confidence interpreting our results. The comprehensive systems for intervention fidelity monitoring and reporting in this trial make an important contribution to aphasia research and, we argue, should set a new standard for future aphasia studies

Liberal warriors and the violent colonial logics of “partnering and advising"

Building on the feminist literature that traces the (re)production of militarized masculinities in and through military interventions, this article details some of the ways British soldiering subjects are being shaped in today's counterinsurgency context. Required now to be both nation builders and war fighters, contemporary soldiers are a “softer,” less masculinized subjectivity, and what Alison Howell has termed “liberal warriors.” British troops with their long history of colonialism and frequent overseas military campaigns are understood to be particularly suited to this role. Taking the British military's involvement in the “partnering and advising” of the Afghan National Army (ANA), this article pays attention to the interlocking gendered, raced, and sexualized discourses through which the British/Afghan encounter is experienced. Exploring first British troops' preoccupation with the perceived femininity and homosexuality of their Afghan counterparts, and second, Afghan hypermasculinity as demonstrated by the characterizations of their violent and chaotic fighting tactics, colonial logics are revealed. While British liberal warriors come to know “who they are” through these logics, (mis)represented Afghan soldiers are rendered increasingly vulnerable to the very “real,” very material violences of war

Modeling Neurodegeneration in Zebrafish

The zebrafish, Danio rerio, has been established as an excellent vertebrate model for the study of developmental biology and gene function. It also has proven to be a valuable model to study human diseases. Here, we reviewed recent publications using zebrafish to study the pathology of human neurodegenerative diseases including Parkinson’s, Huntington’s, and Alzheimer’s. These studies indicate that zebrafish genes and their human homologues have conserved functions with respect to the etiology of neurodegenerative diseases. The characteristics of the zebrafish and the experimental approaches to which it is amenable make this species a useful complement to other animal models for the study of pathologic mechanisms of neurodegenerative diseases and for the screening of compounds with therapeutic potential