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Objective: To investigate the anti-cancer efficacy of ENB101-LNP, an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16, in combination therapy with cisplatin in cervical cancer in vitro and in vivo. Methods: CaSki cells were treated with ENB101-LNP, cisplatin, or combination. Cell viability assessed the cytotoxicity of the treatment. HPV16 E6/E7 gene knockdown was verified with RT-PCR both in vitro and in vivo. HLA class I and PD-L1 were checked by flow cytometry. A xenograft model was made using CaSki cells in BALB/c nude mice. To evaluate anticancer efficacy, mice were grouped. ENB101-LNP was given three times weekly for 3 weeks intravenously, and cisplatin was given once weekly intraperitoneally. Tumor growth was monitored. On day 25, mice were euthanized; tumors were collected, weighed, and imaged. Tumor samples were analyzed through histopathology, immunostaining, and western blot. Results: ENB101-LNP and cisplatin synergistically inhibit CaSki cell growth. The combination reduces HPV 16 E6/E7 mRNA and boosts p21 mRNA, p53, p21, and HLA class I proteins. In mice, the treatment significantly blocked tumor growth and promoted apoptosis. Tumor inhibition rates were 29.7% (1 mpk ENB101-LNP), 29.6% (3 mpk), 34.0% (cisplatin), 47.0% (1 mpk ENB101-LNP-cisplatin), and 68.8% (3 mpk ENB101-LNP-cisplatin). RT-PCR confirmed up to 80% knockdown of HPV16 E6/E7 in the ENB101-LNP groups. Immunohistochemistry revealed increased p53, p21, and HLA-A expression with ENB101-LNP treatments, alone or combined. Conclusion: The combination of ENB101-LNP, which inhibits E6/E7 of HPV 16, with cisplatin, demonstrated significant anticancer activity in the xenograft mouse model of cervical cancer. [ABSTRACT FROM AUTHOR]

This paper aims to identify what aviation experts consider to be the key features of effective communication by examining in detail their commentary on a 17-minute segment of recorded radiotelephony discourse between a Russian pilot and a Korean air traffic controller. The segment was played to three practising pilots and three air traffic controllers. Their commentary on the qualities of communication displayed in the interaction was recorded and coded thematically, using a grounded ethnography approach. The analysis revealed that although the Russian pilot was viewed as having limited English proficiency, the strategies he used to make himself understood were evaluated positively as fulfilling the requirements of the professional role. By contrast, the Korean air traffic controller, although not evaluated as having limited proficiency, was criticized for his lack of professional knowledge. The discourse analysis and the feedback given by these expert informants highlight not only the nature of the miscommunication arising in unexpected situations, but also the multiple factors that may contribute to it. While language proficiency is clearly an issue, there are many other sources of miscommunication that emerge during the exchange. These findings are used to critique the narrow, language-focused oral proficiency construct as articulated in the holistic descriptors and the rating scale stipulated by the International Civil Aviation Organization (ICAO, 2010) as the basis for tests of aviation English worldwide. Instead the paper proposes an expanded construct of oral communication incorporating elements of professional knowledge and behaviour with a focus on interactional competence specific to this context.

This article explores the issues of pronunciation and comprehension in the English as a lingua franca (ELF) context of pilot--air traffic controller radiotelephony communication, and how these are handled in the proficiency rating scale globally used to assess pilots and air traffic controllers engaging in international flight and air traffic control. Based on an analysis of live radiotelephony discourse, feedback from aviation experts on sources of miscommunication, and an investigation of the phonetic features of key turns in the discourse, we present results indicating that L1-influenced pronunciation is one of the major factors causing miscommunication on the part of the speaker, together with unfamiliarity with the pronunciation on the part of the listener. Findings also suggest the descriptors for the "Pronunciation" and "Comprehension" criteria in the rating scale do not reflect the ways language users deal with these matters in their work. This study therefore argues that a new conceptualization of proficiency is needed for taking up the real matters in the assessment of ELF in the aviation context and other ELF contexts at large.

This study presents an approach to better characterize the P‐wave and S‐wave velocity structure of the seafloor sediment layer using ocean bottom seismometers. The presence of low‐velocity seafloor sediment layers influences the observed seismic record at the seafloor over a broad frequency range, such that detailed knowledge of this sediment structure is essential to predict its effect on teleseismic records. We use the radial component of teleseismic P waves and autocorrelation functions of the radial, vertical, and pressure components of teleseismic P and S waves to obtain sediment layer models using the Markov chain Monte Carlo approach with parallel tempering. Synthetic tests show that the body waves constrain the P‐ and S‐wave impedances and travel times and the P‐ to S‐wave velocity ratio of the sediment layers. The proposed method resolves thin layers at a high resolution, including the uppermost thin (∼50 m to a few hundred meters) low S‐wave velocity layer. Real data applications at sites across the Pacific Ocean that are coincident with previous in situ studies demonstrate the effectiveness of this method in characterizing the seafloor sediment unit. The sediment models characterized by this new approach will allow us to more accurately predict and correct the effects of sediment layers in generating P‐ and S‐wave reverberations. Plain Language Summary: Ocean bottom seismometers are powerful tools for investigating the detailed structure of the oceanic mantle. However, most ocean bottom seismometers are placed above the low‐velocity water‐saturated sediment layer, such that their seismic records are inevitably affected by this seafloor sediment layer. Detailed constraints on the structure of the seafloor sediment layer allow us to accurately predict its effects on the observed seismic records. The seafloor sediment layer may consist of multiple discontinuities and vary regionally. This study proposes a new approach for characterizing the seismic properties of the seafloor sediment layer using teleseismic body waves recorded at ocean bottom seismometers. Synthetic tests show that the method can resolve thin sublayers within the sediment layer, such as a very thin low shear‐wave velocity layer and sharp seismic velocity jumps. Real data applications show that the sediment models obtained using this approach are in good agreement with those obtained from direct measurements and previous body‐wave analyses. Our proposed method will enable more detailed prediction and correction of the influence of the sediment layer on ocean bottom seismometer records, thereby providing more accurate constraints on deeper Earth structures. Key Points: The seismic properties of the seafloor sediment layer are characterized using ocean bottom seismometer teleseismic body‐wave recordsThe P‐ and S‐wave impedances and travel times and the VP/VS values of each sublayer within the sediment layer are resolvedIn situ seafloor sediment structure constraints will enable accurate correction and prediction of shallow structure effects [ABSTRACT FROM AUTHOR]

Acute stroke management is critically time-sensitive and challenging. Blood-based biomarkers that can differentiate acute ischemic stroke (IS) from hemorrhagic stroke (HS) can greatly facilitate triage and early management. Admission blood samples obtained within 6 h of stroke symptom onset were analyzed in a derivation/validation design. GFAP, N-FL, NT-proBNP, copeptin, neutrophils (%), NLR, and platelet counts were assessed in the derivation cohort. The informative markers and the derived cutoff values were evaluated in the validation cohort. GFAP > 703 pg/mL showed a PPV of 76.9% and NPV of 95.8% for differentiating HS from IS. Multiple logistic regression analysis showed that GFAP and NT-proBNP were independent variables associated with IS and HS differentiation. Furthermore, applying a combined cutoff (GFAP > 703 pg/mL and NT-proBNP ≤ 125 pg/mL) for HS detection increased the PPV in both the derivation and validation cohorts (93.3% and 100%, respectively). GFAP and NT-proBNP levels were validated as informative blood biomarkers in the differentiation of IS and HS and using a combination of GFAP and NT-proBNP is suggested as a feasible strategy to differentiate stroke subtypes in the hyperacute phase of stroke. [ABSTRACT FROM AUTHOR]

This paper explores the underlying construct of both the English proficiency test for pilot and air traffic controller radiotelephony communication developed and administered in Korea and the ICAO language proficiency testing policy on which the test in Korea is based. It does so by canvassing the opinions of Korean airline pilots and air traffic controllers through 400 questionnaire and 22 interview sources. Results reveal a lack of fit between the policy construct and the reality through which the goals and objectives of the policy are accomplished and strong disapproval of the ICAO's espoused construct and the associated Korean English test from language users in the target domain. This study confirms the importance of eliciting views from such stakeholders (i.e., domain experts) who are well-placed to determine what really matters for communicative success in the context of concern.

While there have been a number of studies exploring the impact of time-on-task and language background on language achievement for both English and other languages, the Student Achievement in Asian Languages Education (SAALE) project constitutes the first systematic attempt to gather empirical evidence of these effects for four Asian languages (Chinese, Indonesian, Japanese and Korean) in Australian schools. The paper focuses on the approach adopted to measure and exemplify the diverse nature of learner achievements in the context of concern. This approach involved a) the gathering of information about the language background and prior learning experience of the study's participants in order to establish learner sub-groups for subsequent analysis, b) the use of common assessment procedures at each level of schooling to compare levels of achievement across learner sub-groups and c) the analysis of samples of each sub-group's performance by teams of teacher experts to develop rich descriptions of achievement reflecting the different dimensions of diversity relevant to each language. The paper outlines the methodology adopted for the study, and reports briefly on the overall findings. Particular attention is paid to the challenges encountered in undertaking the research and to the further efforts that are needed to build on the project outcomes. (Contains 1 table.)

Researchers exploring the use of language use in radiotelephony communication have tended to focus on the limitations of the non-native English user and the threats which their limited control of English may pose for aviation safety (e.g. Atsushi, 2003, 2004). Hence the recent International Civil Aviation Organization (ICAO) policy places the onus on non-native users to bring their English to an appropriate standard. The present paper argues that there is a need for a broader perspective on this issue and supports this case with reference to two sources of data: a) episodes of radiotelephony discourse recorded in two air traffic control centres in Korea exemplifying non-routine, abnormal and emergency situations involving NS of English and NNS from different language backgrounds, b) focus group and individual interviews with selected Korean aviation personnel eliciting their interpretations of these episodes and of issues in aviation English more generally. Findings suggest that responsibilities for communication problems in aviation English are distributed across NS and NNS users, and may be partly due to the absence of shared assumptions about efficient and appropriate communication practices in an environment where English is a lingua franca (ELF). Implications are drawn for the communication training of all aviation personnel, regardless of language background. (Contains 1 endnote and 2 tables.)

RNA recombination in positive-strand RNA viruses is a molecular-genetic process, which permits the greatest evolution of the genome and may be essential to stabilizing the genome from the deleterious consequences of accumulated mutations. Enteroviruses represent a useful system to elucidate the details of this process. On the biochemical level, it is known that RNA recombination is catalyzed by the viral RNA-dependent RNA polymerase using a template-switching mechanism. For this mechanism to function in cells, the recombining genomes must be located in the same subcellular compartment. How a viral genome is trafficked to the site of genome replication and recombination, which is membrane associated and isolated from the cytoplasm, is not known. We hypothesized that genome translation was essential for colocalization of genomes for recombination. We show that complete inactivation of internal ribosome entry site (IRES)-mediated translation of a donor enteroviral genome enhanced recombination instead of impairing it. Recombination did not occur by a nonreplicative mechanism. Rather, sufficient translation of the nonstructural region of the genome occurred to support subsequent steps required for recombination. The noncanonical translation initiation factors, eIF2A and eIF2D, were required for IRES-independent translation. Our results support an eIF2A/eIF2D-dependent mechanism under conditions in which the eIF2-dependent mechanism is inactive. Detection of an IRES-independent mechanism for translation of the enterovirus genome provides an explanation for a variety of debated observations, including nonreplicative recombination and persistence of enteroviral RNA lacking an IRES. The existence of an eIF2A/eIF2D-dependent mechanism in enteroviruses predicts the existence of similar mechanisms in other viruses. This study of enterovirus presents evidence for a cap-independent strategy of translation initiation that functions when eIF2α has been inactivated, identifying an RNA element upstream of the initiation codon that enables translation initiation using the non-canonical initiation factors eIF2A or eIF2D. [ABSTRACT FROM AUTHOR]

Clean water for human consumption is, in many places, a scarce resource, and efficient schemes to purify water are in great demand. Here, we describe a method to dramatically increase the efficiency of a photocatalytic water purification microreactor. Our hierarchical optofluidic microreactor combines the advantages of a nanostructured photocatalyst with light harvesting by base substrates, together with a herringbone micromixer for the enhanced transport of reactants. The herringbone micromixer further improves the reaction efficiency of the nanostructured photocatalyst by generating counter-rotating vortices along the flow direction. In addition, the use of metal-based substrates underneath the nanostructured catalyst increases the purification capacity by improving the light-harvesting efficiency. The photocatalyst is grown from TiO2 as a nanohelix film, which exhibits a large surface-to-volume ratio and a reactive microstructure. We show that the hierarchical structuring with micro- to nanoscale features results in a device with markedly increased photocatalytic activity as compared with a solid unstructured catalyst surface. This is evidenced by the successful degradation of persistent aqueous contaminants, sulfamethoxazole, and polystyrene microplastics. The design can potentially be implemented with solar photocatalysts in flow-through water purification systems. [ABSTRACT FROM AUTHOR]

Author(s): Jing Li [1, 6]; Bing Hou [1, 6]; Sarka Tumova [1]; Katsuhiko Muraki [2]; Alexander Bruns [1]; Melanie J. Ludlow [1]; Alicia Sedo [1]; Adam J. Hyman [1]; Lynn [...]

Lab-on-a-CD (LOCD) is gaining importance as a diagnostic platform due to being low-cost, easy-to-use, and portable. During LOCD usage, mixing and reaction are two processes that play an essential role in biochemical applications such as point-of-care diagnosis. In this paper, we numerically and experimentally investigate the effects of the Coriolis and Euler forces in the mixing chamber during the acceleration and deceleration of a rotating disk. The mixing performance is investigated under various conditions that have not been reported, such as rotational condition, chamber aspect ratio at a constant volume, and obstacle arrangement in the chamber. During disk acceleration and deceleration, the Euler force difference in the radial direction causes rotating flows, while the Coriolis force induces perpendicular vortices. Increasing the maximum rotational velocity improves the maximum rotational displacement, resulting in better mixing performance. A longer rotational period increases the interfacial area between solutions and enhances mixing. Mixing performance also improves when there is a substantial difference between Euler forces at the inner and outer radii. Furthermore, adding obstacles in the angular direction also passively promotes or inhibits mixing by configuration. This quantitative investigation provides valuable information for designing and developing high throughput and multiplexed point-of-care LOCDs. [ABSTRACT FROM AUTHOR]

This study presents reflectivity images of the northeast (NE) Japan subduction zone continuous across the ocean and land. As nearly half of its forearc region is under the ocean, data from ocean bottom seismometers (OBSs) must be utilized to fully image the region by passive seismic analysis. The use of OBS data has been a challenge due to inherent characters of the ocean bottom observations: high noise level and effects of seafloor sediment. Now, decent imaging is possible in NE Japan overcoming the high level noise due to the accumulated data set of the OBSs. The low‐velocity of seafloor sediment significantly delays and amplifies S waves passing through them, and thus complicates teleseismic waveforms. We identify and correct these effects to produce coherent receiver function images throughout the amphibious subduction zone. Our images provide a potential for discussing new structural features and will help better understanding of the dynamics of the NE Japan subduction zone. Plain Language Summary: In northeast Japan, the Pacific plate is subducting beneath the Japanese arc, and delineating how the actual subduction is taking place at depths has been the target of many seismological studies. This study presents our effort of continuous imaging of subsurface interfaces across the ocean and land employing an amphibious data set. On the land side, there are dense seismic networks that have been used to reveal the seismic interfaces using converted phases of distant earthquakes. On the ocean side, the accumulation of data from temporary ocean bottom seismometers in the last decade and the recently installed ocean bottom cable network has made it possible to use a similar approach as on the land. However, the low‐velocity sediment beneath the seafloor causes systematic slower arrivals and larger amplitudes of the seismic phases of interest that result in highly disturbed images if we analyze them in the same way as the land. Here, we identify and correct the effects of the seafloor sediment to analyze the seismic interfaces across the ocean and land. As a result, we succeed in imaging the interfaces of the subducting oceanic crust throughout the region, as well as previously unidentified features under the ocean that may deserve future investigation. Key Points: The northeast Japan subduction zone is imaged using receiver functions (RFs) of an amphibious data setWe identify significant amplitude and time delay effects on RFs from seafloor sedimentCorrections of the sediment effects significantly improve images across an amphibious region [ABSTRACT FROM AUTHOR]

IgE multiple myeloma is a rare subtype of myeloma, accounting for <0.1% of all myeloma cases. Difficulties in diagnosing and monitoring this rare myeloma type are recognized, including the need of heightened awareness for initial diagnosis, performing a reflex immunofixation test using an anti-IgE antisera, and recognizing the possibility of the prozone phenomenon. Here, we report a rare case of IgE multiple myeloma with the prozone phenomenon. This case was characterized by a paradoxical increase in IgE levels with a progressive increase in the dilution factor. Moreover, serial monitoring of IgE levels correlated with the trend in the serum free light chain ratio, especially when the monoclonal protein was no longer detectable. This case highlights the need for laboratory professionals to be vigilant about the occurrence of the prozone phenomenon in IgE multiple myeloma. [ABSTRACT FROM AUTHOR]

Endothelial barrier integrity is important for vascular homeostasis, and hyperpermeability participates in the progression of many pathological states, such as diabetic retinopathy, ischemic stroke, chronic bowel disease, and inflammatory disease. Here, using drug repositioning, we discovered that primaquine diphosphate (PD), previously known as an antimalarial drug, was a potential blocker of vascular leakage. PD inhibited the linear pattern of vascular endothelial growth factors (VEGF)-induced disruption at the cell boundaries, blocked the formation of VEGF-induced actin stress fibers, and stabilized the cortactin actin rings in endothelial cells. PD significantly reduced leakage in the Miles assay and mouse model of streptozotocin (STZ)-induced diabetic retinopathy. Targeted prediction programs and deubiquitinating enzyme activity assays identified a potential mechanism of action for PD and demonstrated that this operates via ubiquitin specific protease 1 (USP1). USP1 inhibition demonstrated a conserved barrier function by inhibiting VEGF-induced leakage in endothelial permeability assays. Taken together, these findings suggest that PD could be used as a novel drug for vascular leakage by maintaining endothelial integrity. [ABSTRACT FROM AUTHOR]

Abstract Background In mammalian cells, the integrity of the primary cilium is critical for proper regulation of the Hedgehog (Hh) signal transduction pathway. Whether or not this dependence on the primary cilium is a universal feature of vertebrate Hedgehog signalling has remained contentious due, in part, to the apparent divergence of the intracellular transduction pathway between mammals and teleost fish. Results Here, using a functional Gli2-GFP fusion protein, we show that, as in mammals, the Gli2 transcription factor localizes to the primary cilia of cells in the zebrafish embryo and that this localization is modulated by the activity of the Hh pathway. Moreover, we show that the Igu/DZIP1protein, previously implicated in the modulation of Gli activity in zebrafish, also localizes to the primary cilium and is required for its proper formation. Conclusion Our findings demonstrate a conserved role of the primary cilium in mediating Hedgehog signalling activity across the vertebrate phylum and validate the use of the zebrafish as a representative model for the in vivo analysis of vertebrate Hedgehog signalling.

Blocking the immune evasion mechanism of tumor cells has become an attractive means for treating cancers. However, the usage of a drug such as nivolumab (αPD-1), which blocks programmed cell death protein 1 (PD-1), turned out to be only effective against certain types of cancer. Especially, vascular abnormal structures of which deter delivery route by leakage and cause the poor perfusion were considered to be environment unfavorable to T cells and immune checkpoint blockade (ICB) delivery within the tumor microenvironment (TME). Herein, we report stabilization of tumor blood vessels by endothelial dysfunctional blocker CU06-1004, which modified the TME and showed synergistic effects with immunotherapy anti-PD-1 antibody. CU06-1004 combination therapy consistently prolonged the survival of tumor-bearing mice by decreasing tumor growth. T-cell infiltration increased in the tumors of the combination group, with cytotoxic CD8+ T cell activity within the tumor parenchyma upregulated compared with anti-PD-1 monotherapy. Tumor inhibition was associated with reduced hypoxia and reduced vessel density in the central region of the tumor. These effects correlated significantly with enhanced expression of IFN gamma and PD-L1 in tumors. Taken together, our findings suggest that CU06-1004 is a potential candidate drug capable of improving therapeutic efficacy of anti-PD-1 through beneficial changes in the TME. [ABSTRACT FROM AUTHOR]

The versatile design of stimuli‐responsive microparticles embedding valuable biomolecules has great potential in a variety of engineering fields, such as sensors, actuators, drug delivery, and catalysis. Here, results are reported on thermoresponsive core–gap–shell (TCGS) microcapsules made of poly(N‐isopropylacrylamide) (PNIPAm), which encapsulate hydrophilic payloads in a simple and stable manner. These are realized by a one‐step microfluidic approach using the phase separation of a supersaturated aqueous solution of NIPAm. Various designs of the microcapsules are achieved by individual control of the swelling or by incorporating pH‐responsive comonomers of the inner core and outer shell. The gap, i.e., the space between the inner core and outer shell, can be loaded with cargo‐like nanoparticles. The outer shell can serve as a stimuli‐responsive gateway for the transport of smaller molecules from the external solution. It is shown that the TCGS microcapsules are suitable as temperature controllable glucose sensors and hold promise in the design of controllable enzymatic reactions. The proposed platform provides an avenue for developing a new‐generation of microparticles for diverse and efficient engineering applications. [ABSTRACT FROM AUTHOR]

This article explores the issues of pronunciation and comprehension in the English as a lingua franca (ELF) context of pilot-air traffic controller radiotelephony communication, and how these are handled in the proficiency rating scale globally used to assess pilots and air traffic controllers engaging in international flight and air traffic control. Based on an analysis of live radiotelephony discourse, feedback from aviation experts on sources of miscommunication, and an investigation of the phonetic features of key turns in the discourse, we present results indicating that L1-influenced pronunciation is one of the major factors causing miscommunication on the part of the speaker, together with unfamiliarity with the pronunciation on the part of the listener. Findings also suggest the descriptors for the Pronunciation and Comprehension criteria in the rating scale do not reflect the ways language users deal with these matters in their work. This study therefore argues that a new conceptualization of proficiency is needed for taking up the real matters in the assessment of ELF in the aviation context and other ELF contexts at large. [ABSTRACT FROM AUTHOR]