We present an unconditionally energy stable finite difference scheme for the Modified Phase Field Crystal equation, a generalized damped wave equation for which the usual Phase Field Crystal equation ...is a special degenerate case. The method is based on a convex splitting of a discrete pseudoenergy and is semi-implicit. The equation at the implicit time level is nonlinear but represents the gradient of a strictly convex function and is thus uniquely solvable, regardless of time step-size. We present a local-in-time error estimate that ensures the pointwise convergence of the scheme.
Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo ...tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. Celastrol, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity. Celastrol also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway.
We present an unconditionally energy stable and solvable finite difference scheme for the Cahn-Hilliard-Hele-Shaw (CHHS) equations, which arise in models for spinodal decomposition of a binary fluid ...in a Hele-Shaw cell, tumor growth and cell sorting, and two phase flows in porous media. We show that the CHHS system is a specialized conserved gradient-flow with respect to the usual Cahn-Hilliard (CH) energy, and thus techniques for bistable gradient equations are applicable. In particular, the scheme is based on a convex splitting of the discrete CH energy and is semi-implicit. The equations at the implicit time level are nonlinear, but we prove that they represent the gradient of a strictly convex functional and are therefore uniquely solvable, regardless of time step-size. Owing to energy stability, we show that the scheme is stable in the
norm, and, assuming two spatial dimensions, we show in an appendix that the scheme is also stable in the
norm. We demonstrate an efficient, practical nonlinear multigrid method for solving the equations. In particular, we provide evidence that the solver has nearly optimal complexity. We also include a convergence test that suggests that the global error is of first order in time and of second order in space.
•Light goods vehicles have seen the greatest growth across London.•Walking can account for 62% of a parcel carrier’s round.•Urban centres are being designed around walking, cycling and public ...transport.•Collaboration over the last-mile could aid carriers.
Growth in e-commerce has led to increasing use of light goods vehicles for parcel deliveries in urban areas. This paper provides an insight into the reasons behind this growth and the resulting effort required to meet the exacting delivery services offered by e-retailers which often lead to poor vehicle utilisation in the last-mile operation, as well as the duplication of delivery services in urban centres as competitors vie for business. A case study investigating current parcel delivery operations in central London identified the scale of the challenge facing the last-mile parcel delivery driver, highlighting the importance of walking which can account for 62% of the total vehicle round time and 40% of the total round distance in the operations studied. The characteristics of these operations are in direct conflict with the urban infrastructure which is being increasingly redesigned in favour of walking, cycling and public transport, reducing the kerbside accessibility for last-mile operations. The paper highlights other pressures on last-mile operators associated with managing seasonal peaks in demand; reduced lead times between customers placing orders and deliveries being made; meeting delivery time windows; first-time delivery failure rates and the need to manage high levels of product returns. It concludes by describing a range of initiatives that retailers and parcel carriers, sometimes in conjunction with city authorities, can implement to reduce the costs associated with last-mile delivery, without negatively impacting on customer service levels.
Aphasic deficits are usually only interpreted in terms of domain-specific language processes. However, effective human communication and tests that probe this complex cognitive skill are also ...dependent on domain-general processes. In the clinical context, it is a pragmatic observation that impaired attention and executive functions interfere with the rehabilitation of aphasia. One system that is important in cognitive control is the salience network, which includes dorsal anterior cingulate cortex and adjacent cortex in the superior frontal gyrus (midline frontal cortex). This functional imaging study assessed domain-general activity in the midline frontal cortex, which was remote from the infarct, in relation to performance on a standard test of spoken language in 16 chronic aphasic patients both before and after a rehabilitation programme. During scanning, participants heard simple sentences, with each listening trial followed immediately by a trial in which they repeated back the previous sentence. Listening to sentences in the context of a listen-repeat task was expected to activate regions involved in both language-specific processes (speech perception and comprehension, verbal working memory and pre-articulatory rehearsal) and a number of task-specific processes (including attention to utterances and attempts to overcome pre-response conflict and decision uncertainty during impaired speech perception). To visualize the same system in healthy participants, sentences were presented to them as three-channel noise-vocoded speech, thereby impairing speech perception and assessing whether this evokes domain general cognitive systems. As expected, contrasting the more difficult task of perceiving and preparing to repeat noise-vocoded speech with the same task on clear speech demonstrated increased activity in the midline frontal cortex in the healthy participants. The same region was activated in the aphasic patients as they listened to standard (undistorted) sentences. Using a region of interest defined from the data on the healthy participants, data from the midline frontal cortex was obtained from the patients. Across the group and across different scanning sessions, activity correlated significantly with the patients' communicative abilities. This correlation was not influenced by the sizes of the lesion or the patients' chronological ages. This is the first study that has directly correlated activity in a domain general system, specifically the salience network, with residual language performance in post-stroke aphasia. It provides direct evidence in support of the clinical intuition that domain-general cognitive control is an essential factor contributing to the potential for recovery from aphasic stroke.
In this paper we present and compare two unconditionally energy stable finite-difference schemes for the phase field crystal equation. The first is a one-step scheme based on a convex splitting of a ...discrete energy by Wise et al. S.M. Wise, C. Wang, J.S. Lowengrub, An energy stable and convergent finite-difference scheme for the phase field crystal equation, SIAM J. Numer. Anal., in press. In this scheme, which is first order in time and second order in space, the discrete energy is non-increasing for any time step. The second scheme we consider is a new, fully second-order two-step algorithm. In the new scheme, the discrete energy is bounded by its initial value for any time step. In both methods, the equations at the implicit time level are nonlinear but represent the gradients of strictly convex functions and are thus uniquely solvable, regardless of time step-size. We solve the nonlinear equations using an efficient nonlinear multigrid method. Numerical simulations are presented and confirm the stability, efficiency and accuracy of the schemes.
As more floating farms are being developed, the wake interaction between multiple floating wind turbines (FWTs) is becoming increasingly relevant. FWTs have long natural periods in certain degrees of ...freedom, and the large‐scale movement of the wake, known as wake meandering, occurs at very low frequencies. In this study, we use FAST.Farm to simulate a two‐turbine case with three different FWT concepts: a semisubmersible (semi), a spar, and a tension leg platform (TLP), separated by eight rotor diameters in the wind direction. Since wake meandering varies depending on the environmental conditions, three different wind speeds (for all three concepts) as well as two different turbulence levels (for the semi) are considered. For the below‐rated wind speed, when wake meandering was most extreme, yaw motion standard deviations for the downstream semi were approximately 40% greater in high turbulence and over 100% greater in low turbulence when compared with the upstream semi. The low yaw natural frequency (0.01 Hz) of the semi was excited by meandering, while quasi‐static responses resulted in approximately 20% increases in yaw motion standard deviations for the spar and TLP. Differences in fatigue loading between the upstream and downstream turbines for the mooring line tension and tower base fore‐aft bending moment mostly depended on the velocity deficit and were not directly affected by meandering. However, wake meandering did affect fatigue loading related to the tower top yaw moment and the blade root out‐of‐plane moment.
We present an unconditionally energy stable finite-difference scheme for the phase field crystal equation. The method is based on a convex splitting of a discrete energy and is semi-implicit. The ...equation at the implicit time level is nonlinear but represents the gradient of a strictly convex function and is thus uniquely solvable, regardless of time step size. We present local-in-time error estimates that ensure the convergence of the scheme. While this paper is primarily concerned with the phase field crystal equation, most of the theoretical results hold for the related Swift–Hohenberg equation as well.
Sleep is essential for optimal health in children and adolescents. Members of the American Academy of Sleep Medicine developed consensus recommendations for the amount of sleep needed to promote ...optimal health in children and adolescents using a modified RAND Appropriateness Method. The recommendations are summarized here. A manuscript detailing the conference proceedings and the evidence supporting these recommendations will be published in the Journal of Clinical Sleep Medicine.
We used whole-genome design and complete chemical synthesis to minimize the 1079-kilobase pair synthetic genome of Mycoplasma mycoides JCVI-syn1.0. An initial design, based on collective knowledge of ...molecular biology combined with limited transposon mutagenesis data, failed to produce a viable cell. Improved transposon mutagenesis methods revealed a class of quasi-essential genes that are needed for robust growth, explaining the failure of our initial design. Three cycles of design, synthesis, and testing, with retention of quasi-essential genes, produced JCVI-syn3.0 (531 kilobase pairs, 473 genes), which has a genome smaller than that of any autonomously replicating cell found in nature. JCVI-syn3.0 retains almost all genes involved in the synthesis and processing of macromolecules. Unexpectedly, it also contains 149 genes with unknown biological functions. JCVI-syn3.0 is a versatile platform for investigating the core functions of life and for exploring whole-genome design.
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