A Size Effect on the Fatigue Crack Growth Rate Threshold of Alloy 718

Fatigue crack growth rate (FCGR) tests were conducted on Alloy 718 in the solution annealed and aged condition at room temperature. In each test, the FCGR threshold was measured using the decreasing (Delta)K method. Initial testing was at two facilities, one of which used C(T) specimens with W = 127 mm. Previous data at the other facility had been obtained with specimens with W = 50.8 mm. A comparison of test results at R = 0.1 showed that the threshold for the 127 mm specimen was considerably higher than that of the 50.8 mm specimen. A check showed that this difference was not due to a heat-to-heat or lab-to-lab variation. Additional tests were conducted on specimens with W = 25.4 mm and at other R values. Data for the various specimens is presented along with parameters usually used to describe threshold behavior

NASA Contractor Report: Guidelines for Proof Test Analysis

These Guidelines integrate state-of-the-art Elastic-Plastic Fracture Mechanics (EPFM) and proof test implementation issues into a comprehensive proof test analysis procedure in the form of a Road Map which identifies the types of data, fracture mechanics based parameters, and calculations needed to perform flaw screening and minimum proof load analyses of fracture critical components. Worked examples are presented to illustrate the application of the Road Map to proof test analysis. The state-of-the-art fracture technology employed in these Guidelines is based on the EPFM parameter, J, and a pictorial representation of a J fracture analysis, called the Failure Assessment Diagram (FAD) approach. The recommended fracture technology is validated using finite element J results, and laboratory and hardware fracture test results on the nickel-based superalloy IN-718, the aluminum alloy 2024-T351 1, and ferritic pressure vessel steels. In all cases the laboratory specimens and hardware failed by ductile mechanisms. Advanced proof test analyses involving probability analysis and Multiple Cycle Proof Testing (MCPT) are addressed. Finally, recommendations are provided on to how to account for the effects of the proof test overload on subsequent service fatigue and fracture behaviors

Guidelines for Proof Test Analysis

These guidelines integrate state-of-the-art elastic-plastic fracture mechanics (EPFM) and proof test implementation issues into a comprehensive proof test analysis procedure in the form of a road map which identifies the types of data, fracture mechanics based parameters, and calculations needed to perform flaw screening and minimum proof load analyses of fracture critical components. Worked examples are presented to illustrate the application of the road map to proof test analysis. The state-of-the art fracture technology employed in these guidelines is based on the EPFM parameter, J, and a pictorial representation of a J fracture analysis, called the failure assessment diagram (FAD) approach. The recommended fracture technology is validated using finite element J results, and laboratory and hardware fracture test results on the nickel-based superalloy Inconel 718, the aluminum alloy 2024-T3511, and ferritic pressure vessel steels. In all cases the laboratory specimens and hardware failed by ductile mechanisms. Advanced proof test analyses involving probability analysis and multiple-cycle proof testing (MCPT) are addressed. Finally, recommendations are provided on how to account for the effects of the proof test overload on subsequent service fatigue and fracture behaviors

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease.

We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. Patients with localized germinoma (n 190) received either CSI alone (n 125) or combined therapy (n 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 0.02 vs 0.88 0.04; P .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n 45) had 0.98 0.023 event-free and overall survival. Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease

Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration

Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB), ameliorating disease phenotype in multiple ND models, but its mechanism is still obscure. We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP). This effect correlated with the calcium-dependent phosphatase PPP3/calcineurin activation, TFEB dephosphorylation and nuclear translocation. Trehalose upregulated genes for the TFEB target and regulator Ppargc1a, lysosomal hydrolases and membrane proteins (Ctsb, Gla, Lamp2a, Mcoln1, Tpp1) and several autophagy-related components (Becn1, Atg10, Atg12, Sqstm1/p62, Map1lc3b, Hspb8 and Bag3) mostly in a PPP3- and TFEB-dependent manner. TFEB silencing counteracted the trehalose prodegradative activity on misfolded protein causative of motoneuron diseases. Similar effects were exerted by trehalase-resistant trehalose analogs, melibiose and lactulose. Thus, limited lysosomal damage might induce autophagy, perhaps as a compensatory mechanism, a process that is beneficial to counteract neurodegeneration

Binge-Like Alcohol Exposure During Adolescence Disrupts Dopaminergic Neurotransmission in the Adult Prelimbic Cortex

Repeated binge-like exposure to alcohol during adolescence has been reported to perturb prefrontal cortical development, yet the mechanisms underlying these effects are unknown. Here we report that adolescent intermittent ethanol exposure induces cellular and dopaminergic abnormalities in the adult prelimbic cortex (PrL-C). Exposing rats to alcohol during early-mid adolescence (PD28–42) increased the density of long/thin dendritic spines of layer 5 pyramidal neurons in the adult PrL-C. Interestingly, although AIE exposure did not alter the expression of glutamatergic proteins in the adult PrL-C, there was a pronounced reduction in dopamine (DA) D1 receptor modulation of both intrinsic firing and evoked NMDA currents in pyramidal cells, whereas D2 receptor function was unaltered. Recordings from fast-spiking interneurons also revealed that AIE reduced intrinsic excitability, glutamatergic signaling, and D1 receptor modulation of these cells. Analysis of PrL-C tissue of AIE-exposed rats further revealed persistent changes in the expression of DA-related proteins, including reductions in the expression of tyrosine hydroxylase and catechol-O-methyltransferase (COMT). AIE exposure was associated with hypermethylation of the COMT promoter at a conserved CpG site in exon II. Taken together, these findings demonstrate that AIE exposure disrupts DA and GABAergic transmission in the adult medial prefrontal cortex (mPFC). As DA and GABA work in concert to shape and synchronize neuronal ensembles in the PFC, these alterations could contribute to deficits in behavioral control and decision-making in adults who abused alcohol during adolescence

Nosocomial or not? A combined epidemiological and genomic investigation to understand hospital-acquired COVID-19 infection on an elderly care ward.

BACKGROUND: COVID-19 has the potential to cause outbreaks in hospitals. Given the comorbid and elderly cohort of patients hospitalized, hospital-acquired COVID-19 infection is often fatal. Pathogen genome sequencing is becoming increasingly important in infection prevention and control (IPC). AIM: To inform the understanding of in-hospital SARS-CoV-2 transmission in order to improve IPC practices and to inform the future development of virological testing for IPC. METHODS: Patients detected COVID-19 positive by polymerase chain reaction on Ward A in April and May 2020 were included with contact tracing to identify other potential cases. Genome sequencing was undertaken for a subgroup of cases. Epidemiological, genomic, and cluster analyses were performed to describe the epidemiology and to identify factors contributing to the outbreak. FINDINGS: Fourteen cases were identified on Ward A. Contact tracing identified 16 further patient cases; in addition, eight healthcare workers (HCWs) were identified as being COVID-19 positive through a round of asymptomatic testing. Genome sequencing of 16 of these cases identified viral genomes differing by two single nucleotide polymorphisms or fewer, with further cluster analysis identifying two groups of infection (a five-person group and a six-person group). CONCLUSION: Despite the temporal relationship of cases, genome sequencing identified that not all cases shared transmission events. However, 11 samples were found to be closely related and these likely represented in-hospital transmission. This included three HCWs, thereby confirming transmission between patients and HCWs.S.R. and A.B. are part-funded from Research England’s Expanding Excellence in England (E3) Fund. The sequencing costs were funded by the COVID-19 Genomics UK (COG-UK) Consortium which is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute for Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

STEM education in the twenty-first century: learning at work-an exploration of design and technology teacher perceptions and practices

Teachers’ knowledge of STEM education, their understanding, and pedagogical application of that knowledge is intrinsically linked to the subsequent effectiveness of STEM delivery within their own practice; where a teacher’s knowledge and understanding is deficient, the potential for pupil learning is ineffective and limited. Set within the context of secondary age phase education in England and Wales (11–16 years old), this paper explores how teachers working within the field of design and technology education acquire new knowledge in STEM; how understanding is developed and subsequently embedded within their practice to support the creation of a diverse STEM-literate society. The purpose being to determine mechanisms by which knowledge acquisition occurs, to reconnoitre potential implications for education and learning at work, including consideration of the role which new technologies play in the development of STEM knowledge within and across contributory STEM subject disciplines. Underpinned by an interpretivist ontology, work presented here builds upon the premise that design and technology is an interdisciplinary educational construct and not viewed as being of equal status to other STEM disciplines including maths and science. Drawing upon the philosophical field of symbolic interactionism and constructivist grounded theory, work embraces an abductive methodology where participants are encouraged to relate design and technology within the context of STEM education. Emergent findings are discussed in relation to their potential to support teachers’ educational development for the advancement of STEM literacy, and help secure design and technology’s place as a subject of value within a twenty-first Century curriculum