A Genre-aware Approach to Online Journalism Education

Revised paperpublished_or_final_versio

‘May I speak Cantonese?’ – Co-constructing a scientific proof in an EFL junior secondary science classroom

In this paper, an excerpt of teacher–student interaction in an EFL junior secondary science classroom in Hong Kong is analysed using the conversation analytic method of sequential analysis. The fine-grained analysis reveals that in the teacher's effort to engage her students in the co-construction of a scientific proof, the students' familiar everyday discourses (e.g. students' examples and experiences as expressed in their familiar language) need to be allowed to play a significant role. It also shows how translanguaging can be well-coordinated with multimodal practices (using blackboard drawings, gestures) to facilitate students' meaning-making in the inquiry-based teacher–student dialogue.postprin

Calibration of the Aronson 6-DOF robotic platform

A discussion is presented of the calibration of the Aronson six-degree-of-freedom platform. Absolute encoders are used to determine the starting positions of all six joints. The hardware implemented are described in detail. Software programs are used to calibrate the hardware and to build the look-up tables that are needed in determining the initial joint positions. The descriptions of all software routines used are given

Ten-year trends in traumatic brain injury: a retrospective cohort study of California emergency department and hospital revisits and readmissions.

OBJECTIVE:To describe visits and visit rates of adults presenting to emergency departments (EDs) with a diagnosis of traumatic brain injury (TBI). TBI is a major cause of death and disability in the USA; yet, current literature is limited because few studies examine longer-term ED revisits and hospital readmission patterns of TBI patients across a broad spectrum of injury severity, which can help inform potential unmet healthcare needs. DESIGN:We performed a retrospective cohort study. SETTING:We analysed non-public patient-level data from California's Office of Statewide Health Planning and Development for years 2005 to 2014. PARTICIPANTS:We identified 1.2 million adult patients aged ≥18 years presenting to California EDs and hospitals with an index diagnosis of TBI. PRIMARY AND SECONDARY OUTCOME MEASURES:Our main outcomes included revisits, readmissions and mortality over time. We also examined demographics, mechanism and severity of injury and disposition at discharge. RESULTS:We found a 57.7% increase in the number of TBI ED visits, representing a 40.5% increase in TBI visit rates over the 10-year period (346-487 per 100 000 residents). During this time, there was also a 33.8% decrease in the proportion of patients admitted to the hospital. Older, publicly insured and black populations had the highest visit rates, and falls were the most common mechanism of injury (45.5% of visits). Of all patients with an index TBI visit, 40.5% of them had a revisit during the first year, with 46.7% of them seeking care at a different hospital from their initial hospital or ED visit. Additionally, of revisits within the first year, 13.4% of them resulted in hospital readmission. CONCLUSIONS:The large proportion of patients with TBI who are discharged directly from the ED, along with the high rates of revisits and readmissions, suggest a role for an established system for follow-up, treatment and care of TBI

Enhancing HIV Communication between Parents and Children: Efficacy of the Parents Matter!

We examine efficacy of the Parents Matter! Program (PMP), a program to teach African-American parents of preadolescents sexual communication and HIV-prevention skills, through a multicenter, randomized control trial. A total of 1115 parent-child participants were randomized to one of three intervention arms (enhanced, brief, control). Percentages and 95% confidence intervals compare parents’ perception of child readiness to learn about sexual issues, communication effectiveness, and dyad concordance from baseline to 12 months postintervention. Wilcoxon rank sum tests compare the changes in scores measuring communication content in HIV/ AIDS, abstinence, and condom use. Compared to control, parents in the enhanced arm increased perception of child readiness to learn about sex (16% vs. 29%; p \u3c .001), and a greater proportion of parent-child dyads reported concordant responses on communication topics: HIV/AIDS (15%, 95% CI = 8-21%; p \u3c .001), abstinence (13%, 95% CI = 7-20%; p \u3c .001), condoms (15%, 95% CI = 9-22%; p \u3c .001). Increases in communication scores in HIV/AIDS, abstinence, and condom use were greater in the enhanced arm than control (p \u3c 0.01). We conclude that the enhanced PMP can help parents educate children about HIV and prepare children to avoid sexual risk

Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort.

Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) -positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus -negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC

Topoisomerase 1 Inhibition in MYC-Driven Cancer Promotes Aberrant R-Loop Accumulation to Induce Synthetic Lethality

CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors. MYC is a central regulator of gene transcription and is frequently dysregulated in human cancers. As targeting MYC directly is challenging, an alternative strategy is to identify specific proteins or processes required for MYC to function as a potent cancer driver that can be targeted to result in synthetic lethality. To identify potential targets in MYC-driven cancers, we performed a genome-wide CRISPR knockout screen using an isogenic pair of breast cancer cell lines in which MYC dysregulation is the switch from benign to transformed tumor growth. Proteins that regulate R-loops were identified as a potential class of synthetic lethal targets. Dysregulated MYC elevated global transcription and coincident R-loop accumulation. Topoisomerase 1 (TOP1), a regulator of R-loops by DNA topology, was validated to be a vulnerability in cells with high MYC activity. Genetic knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation compared with control cells, demonstrating synthetic lethality. Overexpression of RNaseH1, a riboendonuclease that specifically degrades R-loops, rescued the reduction in clonogenicity induced by TOP1 deficiency, demonstrating that this vulnerability is driven by aberrant R-loop accumulation. Genetic and pharmacologic TOP1 inhibition selectively reduced the fitness of MYC-transformed tumors in vivo. Finally, drug response to TOP1 inhibitors (i.e., topotecan) significantly correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids. Together, these results highlight TOP1 as a promising target for MYC-driven cancers.Significance: CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors

Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL

Timed degradation of the cyclin-dependent kinase inhibitor p27^(Kip1) by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27^(Kip1) pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL)

Super-resolution fluorescence microscopy reveals clustering behaviour of Chlamydia pneumoniae’s major outer membrane protein

Chlamydiapneumoniaeis a Gram-negative bacterium responsible for a number of humanrespiratory diseases and linked to some chronic inflammatory diseases. The major outer membraneprotein (MOMP) ofChlamydiais a conserved immunologically dominant protein located in the outermembrane, which, together with its surface exposure and abundance, has led to MOMP being themain focus for vaccine and antimicrobial studies in recent decades. MOMP has a major role in thechlamydial outer membrane complex through the formation of intermolecular disulphide bonds,although the exact interactions formed are currently unknown. Here, it is proposed that due to thelarge number of cysteines available for disulphide bonding, interactions occur between cysteine-richpockets as opposed to individual residues. Such pockets were identified using a MOMP homologymodel with a supporting low-resolution (~4 Å) crystal structure. The localisation of MOMP in theE. colimembrane was assessed using direct stochastic optical reconstruction microscopy (dSTORM),which showed a decrease in membrane clustering with cysteine-rich regions containing two mutations.These results indicate that disulphide bond formation was not disrupted by single mutants locatedin the cysteine-dense regions and was instead compensated by neighbouring cysteines within thepocket in support of this cysteine-rich pocket hypothesis