Ovalization of Tubes Under Bending and Compression

An empirical equation has been developed that gives the approximate amount of ovalization for tubes under bending loads. Tests were made on tubes in the d/t range from 6 to 14, the latter d/t ratio being in the normal landing gear range. Within the range of the series of tests conducted, the increase in ovalization due to a compression load in combination with a bending load was very small. The bending load, being the principal factor in producing the ovalization, is a rather complex function of the bending moment, d/t ratio, cantilever length, and distance between opposite bearing faces. (author

The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress

The budding yeast S phase checkpoint responds to hydroxyurea-induced nucleotide depletion by preventing replication fork collapse and the segregation of unreplicated chromosomes. Although the block to chromosome segregation has been thought to occur by inhibiting anaphase, we show checkpoint-defective rad53 mutants undergo cycles of spindle extension and collapse after hydroxyurea treatment that are distinct from anaphase cells. Furthermore, chromatid cohesion, whose dissolution triggers anaphase, is dispensable for S phase checkpoint arrest. Kinetochore–spindle attachments are required to prevent spindle extension during replication blocks, and chromosomes with two centromeres or an origin of replication juxtaposed to a centromere rescue the rad53 checkpoint defect. These observations suggest that checkpoint signaling is required to generate an inward force involved in maintaining preanaphase spindle integrity during DNA replication distress. We propose that by promoting replication fork integrity under these conditions Rad53 ensures centromere duplication. Replicating chromosomes can then bi-orient in a cohesin-independent manner to restrain untimely spindle extension

PosterVote:expanding the action repertoire for local political activism

Online and digital technologies support and extend the action repertoires of localized social movements. In this paper we examine the ways by which digital technologies can support ‘on-the-ground ’ activist communities in the development of social movements. After identifying some of the challenges of deploying conventional voting and consultation technologies for activism, we examine situated political action in local communities through the design and deployment of a low-cost community voting prototype, PosterVote. We deploy PosterVote in two case studies with two local community organizations identifying the features that supported or hindered grassroots democratic practices. Through interviews with these communities, we explore the design of situated voting systems to support grassroots democratic practices and participation within an ecology of social action. Author Keywords Democracy; activism; participation; e-votin

FRI0345 HEAD-TO-HEAD STUDY EVALUATING THE COMBINED ACR50/PASI100 TREATMENT RESPONSE OF IXEKIZUMAB VERSUS ADALIMUMAB: INDIVIDUAL PATIENT DATA FROM A RANDOMIZED, OPEN-LABEL STUDY IN BIOLOGIC-NAÏVE PATIENTS WITH PSORIATIC ARTHRITIS THROUGH WEEK 52

Background:Multiple biologic DMARDs (bDMARDs) are available for the treatment of psoriatic arthritis (PsA), but there are few direct comparisons of their efficacy and safety. In SPIRIT-H2H study, ixekizumab (IXE), a high-affinity monoclonal antibody selectively targeting IL-17A, was superior to adalimumab (ADA) at Week 24 for simultaneous achievement of ACR50 and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100) in patients (pts) with active PsA. Efficacy on other PsA domains was shown.1Objectives:To provide individual patient data demonstrating the simultaneous improvement in musculoskeletal and skin symptoms as assessed by American College of Rheumatology (ACR) response criteria and Psoriasis Area and Severity Index (PASI) percent improvement, respectively.Methods:Pts with active PsA fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria, ≥3/66 tender and ≥3/68 swollen joints, ≥3% psoriasis body surface area (BSA) involvement, no prior treatment with bDMARDs, and prior inadequate response to ≥1 conventional synthetic DMARD (csDMARD), were randomized 1:1 to open-label IXE or ADA (label dosing according to presence/absence of moderate-to-severe psoriasis [baseline BSA≥10%, PASI≥12, and static Physician's Global Assessment≥3]) in Study I1F-MC-RHCF (NCT03151551). In this analysis, max ACRx was defined as the maximum ACRx response a patient can achieve where ACRx derivation follows the typical ACR response criteria: ≥x% improvement in both tender joint count (TJC) and swollen joint count (SJC) and ≥x% improvement in ≥3 of the 5 remaining components, Health Assessment Questionnaire-Disability Index total score (HAQ-DI), C-reactive protein (CRP), Patient Global Assessment (PatGA), Physician Global Assessment (PhyGA), and patient assessment of joint pain (patJP). Missing data were imputed using the last observation carried forward (LOCF) method.Results:At baseline, demographic and disease characteristics were similar across treatment groups. Mean baseline values for the ACR core data set were 20.2 (TJC), 10.4 (SJC), 63.8 (PatGA), 10.2 (CRP), 59.2 (PhyGA), 1.2 (HAQ-DI), and 61.0 (patJP). Mean PASI total score was 7.8. Figures 1 and 2 show the maximum ACR response by PASI percent improvement at Weeks 24 and 52, respectively. Independent of joint improvement, more ixekizumab-treated patients compared to adalimumab-treated patients achieved ≥PASI 90 (76.6% vs. 57.5% at week 24 and 83.0% vs. 59.6% at Week 52). Evaluation of patient-level data shows that while very few patients had joint improvement but little skin improvement (max ACRx≥50 and PASI<50; Figures 1 and 2) in both treatment arms (IXE: 1.8%; ADA: 1.4%), fewer patients treated with IXE had no to little improvement in both joint and skin symptoms (PASI<50 and max ACRx<50) than those treated with ADA at Week 24 (IXE: 3.6%; ADA: 13.3%). A similar pattern was observed at Week 52 (Figure 2).Conclusion:Ixekizumab treatment was superior to adalimumab when evaluating the combination of musculoskeletal and skin symptoms of PsA as measured by ACR response and PASI response.References:[1]Mease PJ, Smolen JS, Behrens F et al., Ann Rheum Dis 2019; 79(1):123-131.Disclosure of Interests:Arthur Kavanaugh Grant/research support from: AbbVie, Amgen, Eli Lilly, Novartis, Janssen, Pfizer, Gilead, UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Novartis, Janssen, Pfizer, Gilead, UCB, Ennio Lubrano: None declared, Talia Muram Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chen-Yen Lin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Filip van den Bosch Consultant of: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene Corporation, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Lars Erik Kristensen Consultant of: UCB Pharma (Advisory Board), Sannofi (Advisory Board), Abbvie (Advisory Board), Biogen (Advisory Board), Speakers bureau: AbbVie, Amgen, Biogen, Bristol-Myers Squibb,Celgene, Eli Lilly, Gilead, Forward Pharma, Janssen Pharmaceuticals, MSD, Novartis, Pfizer, and UCB Pharm

A Critical Site in the Core of the CCR5 Chemokine Receptor Required for Binding and Infectivity of Human Immunodeficiency Virus Type 1

Like the CCR5 chemokine receptors of humans and rhesus macaques, the very homologous (∼98–99% identical) CCR5 of African green monkeys (AGMs) avidly binds β-chemokines and functions as a coreceptor for simian immunodeficiency viruses. However, AGM CCR5 is a weak coreceptor for tested macrophage-tropic (R5) isolates of human immunodeficiency virus type 1 (HIV-1). Correspondingly, gp120 envelope glycoproteins derived from R5 isolates of HIV-1 bind poorly to AGM CCR5. We focused on a unique extracellular amino acid substitution at the juncture of transmembrane helix 4 (TM4) and extracellular loop 2 (ECL2) (Arg for Gly at amino acid 163 (G163R)) as the likely source of the weak R5 gp120 binding and HIV-1 coreceptor properties of AGM CCR5. Accordingly, a G163R mutant of human CCR5 was severely attenuated in its ability to bind R5 gp120s and to mediate infection by R5 HIV-1 isolates. Conversely, the R163G mutant of AGM CCR5 was substantially strengthened as a coreceptor for HIV-1 and had improved R5 gp120 binding affinity relative to the wild-type AGM CCR5. These substitutions at amino acid position 163 had no effect on chemokine binding or signal transduction, suggesting the absence of structural alterations. The 2D7 monoclonal antibody has been reported to bind to ECL2 and to block HIV-1 binding and infection. Whereas 2D7 antibody binding to CCR5 was unaffected by the G163R mutation, it was prevented by a conservative ECL2 substitution (K171R), shared between rhesus and AGM CCR5s. Thus, it appears that the 2D7 antibody binds to an epitope that includes Lys-171 and may block HIV-1 infection mediated by CCR5 by occluding an HIV-1-binding site in the vicinity of Gly-163. In summary, our results identify a site for gp120 interaction that is critical for R5 isolates of HIV-1 in the central core of human CCR5, and we propose that this site collaborates with a previously identified region in the CCR5 amino terminus to enable gp120 binding and HIV-1 infections

Identification of Extracellular DNA-Binding Proteins in the Biofilm Matrix.

We developed a new approach that couples Southwestern blotting and mass spectrometry to discover proteins that bind extracellular DNA (eDNA) in bacterial biofilms. Using Staphylococcus aureus as a model pathogen, we identified proteins with known DNA-binding activity and uncovered a series of lipoproteins with previously unrecognized DNA-binding activity. We demonstrated that expression of these lipoproteins results in an eDNA-dependent biofilm enhancement. Additionally, we found that while deletion of lipoproteins had a minimal impact on biofilm accumulation, these lipoprotein mutations increased biofilm porosity, suggesting that lipoproteins and their associated interactions contribute to biofilm structure. For one of the lipoproteins, SaeP, we showed that the biofilm phenotype requires the lipoprotein to be anchored to the outside of the cellular membrane, and we further showed that increased SaeP expression correlates with more retention of high-molecular-weight DNA on the bacterial cell surface. SaeP is a known auxiliary protein of the SaeRS system, and we also demonstrated that the levels of SaeP correlate with nuclease production, which can further impact biofilm development. It has been reported that S. aureus biofilms are stabilized by positively charged cytoplasmic proteins that are released into the extracellular environment, where they make favorable electrostatic interactions with the negatively charged cell surface and eDNA. In this work we extend this electrostatic net model to include secreted eDNA-binding proteins and membrane-attached lipoproteins that can function as anchor points between eDNA in the biofilm matrix and the bacterial cell surface.IMPORTANCE Many bacteria are capable of forming biofilms encased in a matrix of self-produced extracellular polymeric substances (EPS) that protects them from chemotherapies and the host defenses. As a result of these inherent resistance mechanisms, bacterial biofilms are extremely difficult to eradicate and are associated with chronic wounds, orthopedic and surgical wound infections, and invasive infections, such as infective endocarditis and osteomyelitis. It is therefore important to understand the nature of the interactions between the bacterial cell surface and EPS that stabilize biofilms. Extracellular DNA (eDNA) has been recognized as an EPS constituent for many bacterial species and has been shown to be important in promoting biofilm formation. Using Staphylococcus aureus biofilms, we show that membrane-attached lipoproteins can interact with the eDNA in the biofilm matrix and promote biofilm formation, which suggests that lipoproteins are potential targets for novel therapies aimed at disrupting bacterial biofilms

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (&#8804;100 kg/&#62;100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with &#60;5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was &#8805;20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and &#8805;75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p&#60;0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p&#60;0.001), ACR50 (p&#8804;0.05) and PASI75 (p&#60;0.001); all benefits were sustained through week 52. Among patients previously treated with &#8805;1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients

Evaluation of a new secondary dose calculation software for Gamma Knife radiosurgery

Current available secondary dose calculation software for Gamma Knife radiosurgery falls short in situations where the target is shallow in depth or when the patient is positioned with a gamma angle other than 90°. In this work, we evaluate a new secondary calculation software which utilizes an innovative method to handle nonstandard gamma angles and image thresholding to render the skull for dose calculation. 800 treatment targets previously treated with our GammaKnife Icon system were imported from our treatment planning system (GammaPlan 11.0.3) and a secondary dose calculation was conducted. The agreement between the new calculations and the TPS were recorded and compared to the original secondary dose calculation agreement with the TPS using a Wilcoxon Signed Rank Test. Further comparisons using a Mann-Whitney test were made for targets treated at a 90° gamma angle against those treated with either a 70 or 110 gamma angle for both the new and commercial secondary dose calculation systems. Correlations between dose deviations from the treatment planning system against average target depth were evaluated using a Kendall\u27s Tau correlation test for both programs. The Wilcoxon Signed Rank Test indicated a significant difference in the agreement between the two secondary calculations and the TPS, with a P-value \u3c 0.0001. With respect to patients treated at nonstandard gamma angles, the new software was largely independent of patient setup, while the commercial software showed a significant dependence (P-value \u3c 0.0001). The new secondary dose calculation software showed a moderate correlation with calculation depth, while the commercial software showed a weak correlation (Tau = -.322 and Tau = -.217 respectively). Overall, the new secondary software has better agreement with the TPS than the commercially available secondary calculation software over a range of diverse treatment geometries