Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation

The planar cell polarity (PCP) pathway is conserved throughout evolution, but it mediates distinct developmental processes. In Drosophila, members of the PCP pathway localize in a polarized fashion to specify the cellular polarity within the plane of the epithelium, perpendicular to the apicobasal axis of the cell. In Xenopus and zebrafish, several homologs of the components of the fly PCP pathway control convergent extension. We have shown previously that mammalian PCP homologs regulate both cell polarity and polarized extension in the cochlea in the mouse. Here we show, using mice with null mutations in two mammalian Dishevelled homologs, Dvl1 and Dvl2, that during neurulation a homologous mammalian PCP pathway regulates concomitant lengthening and narrowing of the neural plate, a morphogenetic process defined as convergent extension. Dvl2 genetically interacts with Loop-tail, a point mutation in the mammalian PCP gene Vangl2, during neurulation. By generating Dvl2 BAC (bacterial artificial chromosome) transgenes and introducing different domain deletions and a point mutation identical to the dsh1 allele in fly, we further demonstrated a high degree of conservation between Dvl function in mammalian convergent extension and the PCP pathway in fly. In the neuroepithelium of neurulating embryos, Dvl2 shows DEP domain-dependent membrane localization, a pre-requisite for its involvement in convergent extension. Intriguing, the Loop-tail mutation that disrupts both convergent extension in the neuroepithelium and PCP in the cochlea does not disrupt Dvl2 membrane distribution in the neuroepithelium, in contrast to its drastic effect on Dvl2 localization in the cochlea. These results are discussed in light of recent models on PCP and convergent extension

Fan similarity model for the fan-intake interaction problem

Very high bypass ratio turbofans with large fan tip diameter are an effective way of improving the propulsive efficiency of civil aero-engines. Such engines, however, require larger and heavier nacelles, which partially offset any gains in specific fuel consumptions. This drawback can be mitigated by adopting thinner walls for the nacelle and by shortening the intake section. This binds the success of very high bypass ratio technologies to the problem of designing an intake with thin lips and short diffuser section, which is well matched to a low speed fan. Consequently, the prediction of the mutual influence between the fan and the intake flow represents a crucial step in the design process. Considerable effort has been devoted in recent years to the study of models for the effects of the fan on the lip stall characteristics and the operability of the whole installation. The study of such models is motivated by the wish to avoid the costs incurred by full, three-dimensional (3D) computational fluid dynamics (CFD) computations. The present contribution documents a fan model for fan–intake computations based on the solution of the double linearization problem for unsteady, transonic flow past a cascade of aerofoils with finite mean load. The computation of the flow in the intake is reduced to a steady problem, whereas the computation of the flow in the fan is reduced to one steady problem and a set of solutions of the linearized model in the frequency domain. The nature of the approximations introduced in the fan representation is such that numerical solutions can be computed inexpensively, while the main feature of the flow in the fan passage, namely the shock system and an approximation of the unsteady flow encountered by the fan are retained. The model is applied to a well-documented test case and compares favorably with much more expensive 3D, time-domain computations

Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model

Formyl peptide receptor 2/lipoxin A4 (LXA4) receptor (Fpr2/ALX) co-ordinates the transition from inflammation to resolution during acute infection by binding to distinct ligands including serum amyloid A (SAA) and Resolvin D1 (RvD1). Here, we evaluated the proresolving actions of aspirin-triggered RvD1 (AT-RvD1) in an acute coinfection pneumonia model. Coinfection with Streptococcus pneumoniae and influenza A virus (IAV) markedly increased pneumococcal lung load and neutrophilic inflammation during the resolution phase. Fpr2/ALX transcript levels were increased in the lungs of coinfected mice, and immunohistochemistry identified prominent Fpr2/ALX immunoreactivity in bronchial epithelial cells and macrophages. Levels of circulating and lung SAA were also highly increased in coinfected mice. Therapeutic treatment with exogenous AT-RvD1 during the acute phase of infection (day 4–6 post-pneumococcal inoculation) significantly reduced the pneumococcal load. AT-RvD1 also significantly reduced neutrophil elastase (NE) activity and restored total antimicrobial activity in bronchoalveolar lavage (BAL) fluid (BALF) of coinfected mice. Pneumonia severity, as measured by quantitating parenchymal inflammation or alveolitis was significantly reduced with AT-RvD1 treatment, which also reduced the number of infiltrating lung neutrophils and monocytes/macrophages as assessed by flow cytometry. The reduction in distal lung inflammation in AT-RvD1-treated mice was not associated with a significant reduction in inflammatory and chemokine mediators. In summary, we demonstrate that in the coinfection setting, SAA levels were persistently increased and exogenous AT-RvD1 facilitated more rapid clearance of pneumococci in the lungs, while concurrently reducing the severity of pneumonia by limiting excessive leukocyte chemotaxis from the infected bronchioles to distal areas of the lungs

Fan similarity model for the fan-intake interaction problem

Very high bypass ratio turbofans with large fan tip diameter are an effective way of improving the propulsive efficiency of civil aero-engines. Such engines, however, require larger and heavier nacelles, which partially offset any gains in specific fuel consumptions. This drawback can be mitigated by adopting thinner walls for the nacelle and by shortening the intake section. This binds the success of very high bypass ratio technologies to the problem of designing an intake with thin lips and short diffuser section, which is well matched to a low speed fan. Consequently, the prediction of the mutual influence between the fan and the intake flow represents a crucial step in the design process. Considerable effort has been devoted in recent years to the study of models for the effects of the fan on the lip stall characteristics and the operability of the whole installation. The study of such models is motivated by the wish to avoid the costs incurred by full, threedimensional (3D) computational fluid dynamics (CFD) computations. The present contribution documents a fan model for fan-intake computations based on the solution of the double linearization problem for unsteady, transonic flow past a cascade of aerofoils with finite mean load. The computation of the flow in the intake is reduced to a steady problem, whereas the computation of the flow in the fan is reduced to one steady problem and a set of solutions of the linearized model in the frequency domain. The nature of the approximations introduced in the fan representation is such that numerical solutions can be computed inexpensively, while the main feature of the flow in the fan passage, namely the shock system and an approximation of the unsteady flow encountered by the fan are retained. The model is applied to a well-documented test case and compares favorably with much more expensive 3D, time-domain computations.</p

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

PurposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.MethodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5&nbsp;mg once daily (QD) + uprosertib 50&nbsp;mg QD.ResultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was &lt; 5% (1 complete response, 5 partial responses).ConclusionsContinuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested

MEMS based fabrication of high-frequency integrated inductors on Ni–Cu–Zn ferrite substrates

A surface micro-machining process is described to realize planar inductors on ferrite (Ni0.49Zn0.33Cu0.18 Fe2O4) for high-frequency applications (14 at 30 MHz) and ~244 nH (DC resistance~0.86 Ω and Q-value~18 at 30 MHz) at 1 MHz for elongated racetrack (10.75 nH/mm2) and racetrack inductors (12.5 nH/mm2), respectively show good agreement with simulated finite element method analysis. This device can be integrated with power management ICs PMICs for cost-effective, high-performance realization of power-supply in package (PSiP) or on-chip (PSoC). This simple process lays the foundation for fabricating closed core ferrite nano-crystalline core micro-inductors

The Abl-related gene (Arg) requires its F-actin–microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion

Microtubules (MTs) help establish and maintain cell polarity by promoting actin-dependent membrane protrusion at the leading edge of the cell, but the molecular mechanisms that mediate cross-talk between actin and MTs during this process are unclear. We demonstrate that the Abl-related gene (Arg) nonreceptor tyrosine kinase is required for dynamic lamellipodial protrusions after adhesion to fibronectin. arg−/− fibroblasts exhibit reduced lamellipodial dynamics as compared with wild-type fibroblasts, and this defect can be rescued by reexpression of an Arg-yellow fluorescent protein fusion. We show that Arg can bind MTs with high affinity and cross-link filamentous actin (F-actin) bundles and MTs in vitro. MTs concentrate and insert into Arg-induced F-actin–rich cell protrusions. Arg requires both its F-actin–binding domains and its MT-binding domain to rescue the defects in lamellipodial dynamics of arg−/− fibroblasts. These findings demonstrate that Arg can mediate physical contact between F-actin and MTs at the cell periphery and that this cross-linking activity is required for Arg to regulate lamellipodial dynamics in fibroblasts

Fitness of INTERGROWTH-21st birth weight standards for Chinese-ethnicity babies

OBJECTIVE: To determine the fitness of the INTERGROWTH-21st birth weight standards (INTERGROWTH21) for ethnic Chinese babies compared with a local reference (FOK2003). DESIGN: Population-based analysis of territory-wide birth data. SETTING: All public hospitals in Hong Kong. PARTICIPANTS: Live births between 24 and 42 complete weeks' gestation during 2006-2017. MAIN OUTCOME MEASURES: Babies' birth weight Z-scores were calculated using published methods. The two references were compared in three aspects: (1) the proportions of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) infants, (2) the gestation-specific and sex-specific mean birth weight Z-scores and (3) the predictive power for SGA-related complications. RESULTS: 488 896 infants were included. Using INTERGROWTH21, among neonates born <33 weeks' gestation, the mean birth weight Z-scores per week were closer to zero (-0.2 to 0.05), while most of them were further from zero (0.06 to 0.34) after excluding infants with a high risk of abnormal intrauterine growth. Compared with FOK2003, INTERGROWTH21 classified smaller proportions of infants as SGA (8.3% vs 9.6%) and LGA (6.6% vs 7.9%), especially SGA among preterm infants (13.1% vs 17.0%). The area under the receiver operating characteristic curve for predicting SGA-related complications was greater with FOK2003 (0.674, 95% CI 0.670 to 0.677) than INTERGROWTH21 (0.658, 95% CI 0.655 to 0.661) (p<0.001). CONCLUSIONS: INTERGROWTH21 performed less well than FOK2003, a local reference for ethnic Chinese babies, especially in infants born <33 weeks' gestation. Although the differences are clinically small, both these references performed poorly for extremely preterm infants, and thus a more robust chart based on a larger sample of appropriately selected infants is needed