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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 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]

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]

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]

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]

Metastasising cells express the intermediate filament protein vimentin, which is used to diagnose invasive tumours in the clinic. We aimed to clarify how vimentin regulates the motility of metastasising fibroblasts. STED super-resolution microscopy, live-cell imaging and quantitative proteomics revealed that oncogene-expressing and metastasising fibroblasts show a less-elongated cell shape, reduced cell spreading, increased cell migration speed, reduced directionality, and stronger coupling between these migration parameters compared to normal control cells. In total, we identified and compared 555 proteins in the vimentin interactome. In metastasising cells, the levels of keratin 18 and Rab5C were increased, while those of actin and collagen were decreased. Inhibition of HDAC6 reversed the shape, spreading and migration phenotypes of metastasising cells back to normal. Inhibition of HDAC6 also decreased the levels of talin 1, tropomyosin, Rab GDI β, collagen and emilin 1 in the vimentin interactome, and partially reversed the nanoscale vimentin organisation in oncogene-expressing cells. These findings describe the changes in the vimentin interactome and nanoscale distribution that accompany the defective cell shape, spreading and migration of metastasising cells. These results support the hypothesis that oncogenes can act through HDAC6 to regulate the vimentin binding of the cytoskeletal and cell–extracellular matrix adhesion components that contribute to the defective motility of metastasising cells. [ABSTRACT FROM AUTHOR]