Concurrent Design and Manufacturing for Mechanical Systems

The conventional product development process employs a design-build-break philosophy. The sequentially executed product development process often results in a prolonged lead-time and an elevated product cost. The proposed concurrent design and manu facturing (CDM) paradigm employs physics-based computational methods together with computer graphics techniques for product de sign. This proposed approach employs Virtual Prototyping (VP) technology to support a cross-functional team in analyzing product per formance, reliability, and manufacturing cost early in the product development stage; and in conducting quantitative trade-off for design decision making. Physical prototypes of the product design are then produced using Rapid Prototyping (RP) technique primarily for de sign verification purposes. The proposed CDM approach holds potential for shortening the overall product development cycle, improving product quality, and reducing product cost. A software tool environment that supports CDM for mechanical systems is being built at the Concurrent Design and Manufacturing Research Laboratory (http://cdm.ou.edu) at the University of Oklahoma. A snapshot of the envi ronment is illustrated using a two-stroke engine example. This paper presents three unique concepts and methods for product develop ment : (1) bringing product performance, quality, and manufacturing cost together in early design stage for design considerations, (2) supporting design decision-making through a quantitative approach, and (3) incorporating rapid prototyping for design verification through physical prototypes.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

PARP1 suppresses homologous recombination events in mice in vivo

Recent studies suggest that PARP1 inhibitors, several of which are currently in clinical trial, may selectively kill BRCA1/2 mutant cancers cells. It is thought that the success of this therapy is based on immitigable lethal DNA damage in the cancer cells resultant from the concurrent loss or inhibition of two DNA damage repair pathways: single-strand break (SSB) repair and homologous recombination repair (HRR). Presumably, inhibition of PARP1 activity obstructs the repair of SSBs and during DNA replication, these lesions cause replication fork collapse and are transformed into substrates for HRR. In fact, several previous studies have indicated a hyper-recombinogenic phenotype in the absence of active PARP1 in vitro or in response to DNA damaging agents. In this study, we demonstrate an increased frequency of spontaneous HRR in vivo in the absence of PARP1 using the pun assay. Furthermore, we found that the HRR events that occur in Parp1 nullizygous mice are associated with a significant increase in large, clonal events, as opposed to the usually more frequent single cell events, suggesting an effect in replicating cells. In conclusion, our data demonstrates that PARP1 inhibits spontaneous HRR events, and supports the model of DNA replication transformation of SSBs into HRR substrates

Rogue waters

In this essay we give an overview on the problem of rogue or freak wave formation in the ocean. The matter of the phenomenon is a sporadic occurrence of unexpectedly high waves on the sea surface. These waves cause serious danger for sailing and sea use. A number of huge wave accidents resulted in damages, ship losses and people injuries and deaths are known. Now marine researchers do believe that these waves belong to a specific kind of sea waves, not taken into account by conventional models for sea wind waves. This paper addresses to the nature of the rogue wave problem from the general viewpoint based on the wave process ideas. We start introducing some primitive elements of sea wave physics with the purpose to pave the way for the further discussion. We discuss linear physical mechanisms which are responsible for high wave formation, at first. Then, we proceed with description of different sea conditions, starting from the open deep sea, and approaching the sea cost. Nonlinear effects which are able to cause rogue waves are emphasised. In conclusion we briefly discuss the generality of the physical mechanisms suggested for the rogue wave explanation; they are valid for rogue wave phenomena in other media such as solid matters, superconductors, plasmas and nonlinear opticsComment: will be published in Contemporary Physic

The Ku Heterodimer and the Metabolism of Single-Ended DNA Double-Strand Breaks

Single-ended double-strand breaks (DSBs) are a common form of spontaneous DNA break, generated when the replisome encounters a discontinuity in the DNA template. Given their prevalence, understanding the mechanisms governing the fate(s) of single-ended DSBs is important. We describe the influence of the Ku heterodimer and Mre11 nuclease activity on processing of single-ended DSBs. Separation-of-function alleles of yku70 were derived that phenocopy Ku deficiency with respect to single-ended DSBs but remain proficient for NHEJ. The Ku mutants fail to regulate Exo1 activity, and bypass the requirement for Mre11 nuclease activity in the repair ofcamptothecin-induced single-ended DSBs. Ku mutants exhibited reduced affinity for DNA ends, manifest as both reduced end engagement and enhanced probability of diffusing inward on linear DNA. This study reveals an interplay between Ku and Mre11 in the metabolism of single-ended DSBsthat is distinct from repair pathway choice at double-ended DSBs

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

News Items about Negroes in White Urban and Rural Newspapers

Dr. Ira B Bryant's masters thesis reprinted in "The Journal of Negro Education," April, 1935. Ira B. Bryant received a masters degress from the University of Kansas in 1934