The demand for new processes to produce high strength parts, under appropriate cost and productivity, has grown with weight reduction and crash safety improvements in automobile design. The hot ...stamping processes of quenchable steel sheets potentially offer not only small forming load and high formability, but also high strength and no springback by die quenching. This paper aims to provide an overview of the state-of-the-art in such hot stamping processes, including quenchability, formability, heating and cooling approaches and lubrication. The paper also includes a description of the mechanism of formability and quenching, tailoring, analysis of hot stamping processes and applicability.
ATM signalling and cancer Cremona, C A; Behrens, A
Oncogene,
06/2014, Volume:
33, Issue:
26
Journal Article
Peer reviewed
Open access
ATM, the protein kinase mutated in the rare human disease ataxia telangiectasia (A-T), has been the focus of intense scrutiny over the past two decades. Initially this was because of the unusual ...radiosensitive phenotype of cells from A-T patients, and latterly because investigating ATM signalling has yielded valuable insights into the DNA damage response, redox signalling and cancer. With the recent explosion in genomic data, ATM alterations have been revealed both in the germline as a predisposing factor for cancer and as somatic changes in tumours themselves. Here we review these findings, as well as advances in the understanding of ATM signalling mechanisms in cancer and ATM inhibition as a strategy for cancer treatment.
We present an atlas of ultraviolet and infrared images of ∼15,750 local (d 50 Mpc) galaxies, as observed by NASA's Wide-field Infrared Survey Explorer (WISE) and Galaxy Evolution Explorer (GALEX) ...missions. These maps have matched resolution (FWHM 7 5 and 15″), matched astrometry, and a common procedure for background removal. We demonstrate that they agree well with resolved intensity measurements and integrated photometry from previous surveys. This atlas represents the first part of a program (the z = 0 Multiwavelength Galaxy Synthesis) to create a large, uniform database of resolved measurements of gas and dust in nearby galaxies. The images and associated catalogs will be publicly available at the NASA/IPAC Infrared Science Archive. This atlas allows us estimate local and integrated star formation rates (SFRs) and stellar masses (M ) across the local galaxy population in a uniform way. In the appendix, we use the population synthesis fits of Salim et al. to calibrate integrated M and SFR estimators based on GALEX and WISE. Because they leverage a Sloan Digital Sky Survey (SDSS)-based training set of >100,000 galaxies, these calibrations have high precision and allow us to rigorously compare local galaxies to SDSS results. We provide these SFR and M estimates for all galaxies in our sample and show that our results yield a "main sequence" of star-forming galaxies comparable to previous work. We also show the distribution of intensities from resolved galaxies in NUV-to-WISE1 versus WISE1-to-WISE3 space, which captures much of the key physics accessed by these bands.
Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma
. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours ...a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II
. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)
tumours in syngeneic MHC-humanized mice
. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)
astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG
and CXCL13
T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
Public health initiatives require coordinated efforts from healthcare, social services and other service providers. Organisational theory tells us that trust is essential for reaching collaborative ...effectiveness. This paper explores the drivers for initiating and sustaining trust in a temporary public health partnership, in response to a sudden health threat.
This qualitative study analysed the formation process of a multisector partnership for a Covid-19 contact tracing service. Data was collected through 12 interviews, two focus groups, one feedback workshop, and an online survey with workforce members from all seven partner organisations. Purposive maximum variation sampling was used to capture the reflections and experiences of workforce members from all seven partner organisations. A deductive code scheme was used to identify drivers for building and sustaining trust in inter-organisational collaboration.
Relational mechanisms emanating from the commitment to the common aim, shared norms and values, and partnership structures affected trust-building. Shared values and the commitment to the common aim appeared to channel partners' behaviour when interacting, resulting in being perceived as a fair, reliable and supportive partner. Shared values were congruent with the design of the partnership in terms of governance structure and communication lines reflecting flat hierarchies and shared decision-making power. Tensions between partner organisations arose when shared values were infringed.
When managing trust in a collaboration, partners should consider structural components like governance structure, organisational hierarchy, and communication channels to ensure equal power distribution. Job rotation, recruitment of candidates with the desired personality traits and attitudes, as well as training and development, encourage inter-organisational networking among employees, which is essential for building and strengthening relationships with partner organisations. Partners should also be aware of managing relational dynamics, channelling behaviours through shared values, objectives and priorities and fostering mutual support and equality among partner organisations.
Bulk forming of sheet metal Merklein, M.; Allwood, J.M.; Behrens, B.-A. ...
CIRP annals,
2012, 2012-00-00, 20120101, Volume:
61, Issue:
2
Journal Article, Conference Proceeding
Peer reviewed
Ever increasing demands on functional integration of high strength light weight products leads to the development of a new class of manufacturing processes. The application of bulk forming processes ...to sheet or plate semi-finished products, sometimes in combination with conventional sheet forming processes creates new products with the requested properties. The paper defines this new class of sheet-bulk metal forming processes, gives an overview of the existing processes belonging to this class, highlights the tooling aspects as well as the resulting product properties and presents a short summary of the relevant work that has been done towards modeling and simulation.
In recent years, the requirements for technical components have been increasing steadily. This development is intensified by the desire for products with lower weight, smaller size and extended ...functionality, but at the same time higher resistance against specific loads. Mono-material components manufactured according to established processes reach their limits regarding conflicting requirements. It is, for example, hardly possible to combine excellent mechanical properties with lightweight construction using mono-materials. Thus, a significant increase in production quality, lightweight design, functionality and efficiency can only be reached by combining different materials in one component. The superior aim of the Collaborative Research Centre (CRC) 1153 is to develop novel process chains for the production of hybrid solid components. In contrast to existing process chains in bulk metal forming, in which the joining process takes place during forming or at the end of the process chain, the CRC 1153 uses tailored semi-finished workpieces which are joined before the forming process. This results in a geometric and thermomechanical influence on the joining zone during the forming process which cannot be created by conventional joining techniques. The present work gives an overview of the CRC and the Tailored Forming approach including the applied joining, forming and finishing processes as well as a short summary of the accompanying design and evaluation methods.
Intramedullary nailing of diaphyseal femoral fractures is a commonly used treatment method in dogs because of its biological and biomechanical advantages compared to bone plating. To achieve adequate ...resistance of the intramedullary nail against torsional and axial compressive forces, additional application of transcortical screws is needed. As these interlocking screws represent a frequent cause of post-operative complications, a new expandable intramedullary nail (EXPN) was developed, which was designed to provide adequate fracture stabilisation without the need for transcortical fixation. The evaluation of the biomechanical properties of the new EXPN with regard to torsional, compressive and bending stability as well as direct comparison to the biomechanical properties of conventional Steinmann (STMN)- and interlocking (ILN) nails was carried out with different biomechanical test arrangements. No significant statistical differences regarding the torsional and bending resistance between the EXPN and ILN group were seen, which indicates that rotatory as well as bending stability of the innovative EXPN is similar to the conventional ILN. Nevertheless, the percentage deviation between the attempted and successfully reached physiological compressive forces was significantly higher (p = 0.045) in the EXPN group compared to the ILN group, which indicates that the compressive stability of the innovative EXPN might be weaker compared to the ILN. In summary, the new EXPN represents an interesting alternative to conventional intramedullary nails. However, in direct comparison to conventional interlocking nails, the EXPN has shown weaknesses in the neutralization of axial compressive forces, which indicates that at least biomechanically the interlocking nail seems advantageous. Further in-vitro and in-vivo investigations are required before clinical use can be recommended.
The hereditary autosomal recessive disease ataxia telangiectasia (A-T) is caused by mutation in the DNA damage kinase ATM. ATM's main function is to orchestrate DNA repair, thereby maintaining ...genomic stability. ATM activity is increased in response to several stimuli, including ionising radiation (IR) and hypotonic stress. DNMT1-associated protein 1 (DMAP1) is a member of the TIP60-p400 histone acetyl transferase (HAT) complex, which acetylates histone H4 at lysine 16 (H4K16) to affect chromatin relaxation and modulate ATM activation. Here we demonstrate that DMAP1 is required for both modes of ATM activation. Knockdown of DMAP1 impaired IR-induced ATM activation and consequently resulted in radiosensitivity and impaired the G2/M checkpoint. Moreover, DMAP1 was also required for efficient ATM signalling in response to hypotonic stress. Overexpression of DMAP1 increased IR-induced ATM substrate phosphorylation, suggesting that DMAP1 function is rate limiting for ATM signalling. DMAP1 associated with TIP60-dependent HAT activity, and depletion of DMAP1 reduced H4K16 acetylation in response to DNA damage. Treatment with histone deacetylase inhibitors rescued IR-induced ATM signalling in Dmap1-depleted cells. These results suggest that DMAP1 is a critical regulator of ATM activity and function.
Static light scattering (SLS) combined with structure-based Monte Carlo (MC) simulations provide new insights into mechanisms behind anisotropic, attractive protein interactions. A nonmonotonic ...behavior of the osmotic second virial coefficient as a function of ionic strength is here shown to originate from a few charged amino acids forming an electrostatic attractive patch, highly directional and complementary. Together with Coulombic repulsion, this attractive patch results in two counteracting electrostatic contributions to the interaction free energy which, by operating over different length scales, is manifested in a subtle, salt-induced minimum in the second virial coefficient as observed in both experiment and simulations.
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