bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Wnt Signaling Activation Promotes Inner Ear Differentiation via Cell Caudalization in Mouse Stem Cell-Derived Organoids
Authors: Tang Pei-Ciao , Chen Li , Singh Sunita , Groves Andrew K , Koehler Karl R , Liu Xue Zhong , Nelson Rick F 
Published: September 2022

AbstractThe inner ear is derived from the otic placode, one of the numerous cranial sensory placodes that emerges from the pre-placodal ectoderm (PPE) along its anterior-posterior axis. However, the molecular dynamics underlying how the PPE is regionalized are poorly resolved. We used stem cell-derived organoids to investigate the effects of Wnt signaling on early PPE differentiation and found that modulating Wnt signaling significantly increased inner ear organoid induction efficiency and reproducibility. Alongside single-cell RNA sequencing, our data reveal that the canonical Wnt signaling pathway leads to PPE regionalization and, more specifically, medium Wnt levels during the early stage induce (1) expansion of the caudal neural plate border (NPB), which serves as a precursor for the posterior PPE, and (2) a caudal microenvironment that is required for otic specification. Our data further demonstrate Wnt-mediated induction of rostral and caudal cells in organoids and more broadly suggest that Wnt signaling is critical for anterior-posterior patterning in the PPE.
Dietary fenugreek seed extract improves dry matter intake, apparent total tract nutrient digestibility, and alters whole blood transcriptome of Holstein dairy heifers
Authors: Taiwo Godstime , Sidney Taylor , Idowu Modoluwamu , Eichie Francisca , Karnezos Theodore P , Ogunade Ibukun M 
Published: September 2022

AbstractThis study was conducted to evaluate the effects of dietary supplementation of a fenugreek seed extract (SAP) as a source of saponins on dry matter intake, blood metabolites, apparent total tract nutrient digestibility, and whole blood transcriptome of Holstein dairy heifers. Eight heifers (BW = 477 ± 23.8 kg) were stratified by BW and then randomly assigned to one of two treatments in a cross-over design with two 35-d experimental periods and a 14-d wash-out between the two periods. The heifers were housed individually in eight dry lot pens. Each pen was equipped with one GrowSafe intake node. Treatments were 1) corn silage-based diet with no additive (CON) and 2) corn silage-based diet plus 2 g per hd per d of SAP. Dairy heifers fed supplemental SAP had higher (P ≤ 0.05) DMI and apparent total tract digestibility of dry matter, crude protein, and neutral detergent fiber compared to CON. Dairy heifers fed supplemental SAP had lower (P = 0.03) blood urea nitrogen and higher (P = 0.01) blood glucose concentration compared to CON. Pathway analysis via gene set enrichment analysis revealed increased (FDR ≤ 0.05) transcript levels for gene sets belonging to ISG15 antiviral mechanism, metabolism of proteins, citric acid cycle and respiratory electron transport, ATP synthesis by chemiosmotic coupling, and complex I biogenesis in dairy heifers fed supplemental SAP compared to CON. Decreased (FDR ≤ 0.05) transcript levels for gene sets associated with erythrocytes take up/release carbon dioxide, release/take up oxygen, and O2/CO2 exchange in erythrocytes were also observed with SAP supplemental group. Taken together, our results revealed that fenugreek seed extract can be used as an effective dietary supplement for dairy heifers to improve intake and digestibility, and alter the host transcriptome toward improved energy and amino acid metabolism, improved antiviral immune status, and reduced oxidative stress damage.
A stochastic regularized second-order iterative scheme for optimal control and inverse problems in stochastic partial differential equations
Authors: Dambrine Marc , Khan Akhtar A. , Sama Miguel 
Published: September 2022

Numerous applied models used in the study of optimal control problems, inverse problems, shape optimization, machine learning, fractional programming, neural networks, image registration and so on lead to stochastic optimization problems in Hilbert spaces. Under a suitable convexity assumption on the objective function, a necessary and sufficient optimality condition for stochastic optimization problems is a stochastic variational inequality. This article presents a new stochastic regularized second-order iterative scheme for solving a variational inequality in a stochastic environment where the primary operator is accessed by employing sampling techniques. The proposed iterative scheme, which fits within the general framework of the stochastic approximation approach, has its almost-sure convergence analysis given in a Hilbert space. We test the feasibility and the efficacy of the proposed stochastic approximation approach for a stochastic optimal control problem and a stochastic inverse problem, both associated with a second-order stochastic partial differential equation.
This article is part of the theme issue ‘Non-smooth variational problems and applications’.
A generalized Stokes system with a non-smooth slip boundary condition
Authors: Zhao Jing , Migórski Stanislaw , Dudek Sylwia 
Published: September 2022

A class of quasi variational–hemivariational inequalities in reflexive Banach spaces is studied. The inequalities contain a convex potential, a locally Lipschitz superpotential and an implicit obstacle set of constraints. Results on the well-posedness including existence, uniqueness, dependence of solution on the data and the compactness of the solution set in the strong topology are established. The applicability of the results is illustrated by the steady-state generalized Stokes model of a generalized Newtonian incompressible fluid with a non-monotone slip boundary condition.
This article is part of the theme issue ‘Non-smooth variational problems and applications’.
On a frictional unilateral contact problem in nonlinear elasticity—existence and smoothing procedure
Authors: Gwinner Joachim 
Published: September 2022

This note is devoted to a novel frictional unilateral contact problem in finite-strain elasticity. Here, we adopt the Tresca friction model from linear elasticity. Our analysis relies on the polyconvexity approach to nonlinear elasticity due to J. Ball. We include the delicate case where the elastic body neither is fixed nor has a deformation prescribed along some part of its boundary, but rests on a rigid foundation with a free boundary and is only submitted to forces and loads acting in the interior (like gravity) and at the boundary, respectively. This leads to a loss of coercivity and necessitates an extra condition that prevents the body from escaping by the geometry of the obstacle. This new condition extends a similar condition of Ciarlet and Nečas from the frictionless case to the case of Tresca friction. In addition, as a first step towards a numerical treatment of such nonlinear problems, we present a smoothing procedure that tackles the non-smooth term from Tresca friction and provide a convergence result for the novel smoothing method.This article is part of the theme issue ‘Non-smooth variational problems and applications’.
Junction problem for thin elastic and volume rigid inclusions in elastic body
Authors: Khludnev A. M. 
Published: September 2022

The article concerns a junction problem for two-dimensional elastic body with a thin elastic inclusion and a volume rigid inclusion. It is assumed that the inclusions have a common point. A delamination of the thin inclusion from the surrounding elastic body is assumed thus forming an interfacial crack. Constraint-type boundary conditions are imposed at the crack faces to prevent interpenetration between the faces. Moreover, a connection between the crack faces is characterized by a positive damage parameter. Limit transitions are justified as the damage parameter tends to infinity and to zero. In addition to this, a transition to limit is analysed as a rigidity parameter of the thin inclusion tends to infinity. Limit models are investigated. In particular, junction conditions at the common point are found for all cases considered.This article is part of the theme issue ‘Non-smooth variational problems and applications’.
Fully discrete approximation schemes for rate-independent crack evolution
Authors: Knees Dorothee , Schröder Andreas , Shcherbakov Viktor 
Published: September 2022

Over the past two decades, several distinct solution concepts for rate-independent evolutionary systems driven by non-convex energies have been suggested in an attempt to model properly jump discontinuities in time. Much attention has been paid in this context to the modelling of crack propagation. This paper studies two fully discrete (in time and space) approximation schemes for the rate-independent evolution of a single crack in a two-dimensional linear elastic material. The crack path is assumed to be known in advance, and the evolution of the crack tip along it relies on the Griffith theory. On the time-discrete level, the first scheme is based on local minimization, whereas the second scheme is a regularized version of the first one. The crucial feature of the schemes is their adaptive time-stepping nature, with finer time steps at those points where the evolution of the crack tip might develop a discontinuity. The set of discretization parameters includes the mesh size, crack increment, locality parameter and regularization parameter. In both cases, we explore the interplay between the discretization parameters and derive sufficient conditions on them ensuring the convergence of discrete interpolants to parametrized balanced viscosity solutions of the continuous model. To illustrate the performance of the approximation schemes, we support our theoretical analysis with numerical simulations.
This article is part of the theme issue ‘Non-smooth variational problems and applications’.
Equilibrium problem for a thermoelastic Kirchhoff–Love plate with a delaminated flat rigid inclusion
Authors: Lazarev Nyurgun P. 
Published: September 2022

A new mathematical model describing an equilibrium of a thermoelastic heterogeneous Kirchhoff–Love plate is considered. A corresponding nonlinear variational problem is formulated with respect to a two-dimensional domain with a cut. This cut corresponds to an interfacial crack located on a given part of the boundary of a flat rigid inclusion. The flat inclusion is described by a cylindrical surface. Due to the presence of the flat rigid inclusion in the plate, restrictions of the functions describing displacements to the corresponding curves satisfy special constraints having a linear form. Displacement boundary conditions of an inequality type are set on the crack faces that ensure a mutual non-penetration of opposite crack faces. Solvability of the problem is proved. Under the assumption that the solution of the variational problem is smooth enough, an equivalent differential formulation is found.
This article is part of the theme issue ‘Non-smooth variational problems and applications’.
Non-smooth variational problems and applications
Authors: Kovtunenko Victor A. , Itou Hiromichi , Khludnev Alexander M. , Rudoy Evgeny M. 
Published: September 2022

Mathematical methods based on the variational approach are successfully used in a broad range of applications, especially those fields that are oriented on partial differential equations. Our problem area addresses a wide class of nonlinear variational problems described by all kinds of static and evolution equations, inverse and ill-posed problems, non-smooth and non-convex optimization, and optimal control including shape and topology optimization. Within these directions, we focus but are not limited to singular and unilaterally constrained problems arising in mechanics and physics, which are governed by complex systems of generalized variational equations and inequalities. Whereas classical mathematical tools are not applicable here, we aim at a non-standard well-posedness analysis, numerical methods, asymptotic and approximation techniques including homogenization, which are successful within the primal as well as the dual variational formalism. In a broad scope, the theme issue objectives are directed toward advances that are attained in the mathematical theory of non-smooth variational problems, its physical consistency, numerical simulation and application to engineering sciences.This article is part of the theme issue ‘Non-smooth variational problems and applications’.
Interaction of scales for a singularly perturbed degenerating nonlinear Robin problem
Authors: Musolino Paolo , Mishuris Gennady 
Published: September 2022

We study the asymptotic behaviour of solutions of a boundary value problem for the Laplace equation in a perforated domain inRn,n≥3, with a (nonlinear) Robin boundary condition on the boundary of the small hole. The problem we wish to consider degenerates in three respects: in the limit case, the Robin boundary condition may degenerate into a Neumann boundary condition, the Robin datum may tend to infinity, and the size ϵ of the small hole where we consider the Robin condition collapses to 0. We study how these three singularities interact and affect the asymptotic behaviour as ϵ tends to 0, and we represent the solution and its energy integral in terms of real analytic maps and known functions of the singular perturbation parameters.This article is part of the theme issue ‘Non-smooth variational problems and applications’.
Moderate activity of RNA chaperone maximizes the yield of self-spliced pre-RNA in vivo
Authors: Song Yonghyun , Thirumalai D. , Hyeon Changbong 
Published: September 2022

CYT-19 is a DEAD-box protein whose ATP-dependent helicase activity facilitates the folding of group I introns in precursor RNA (pre-RNA) of Neurospora crassa. In the process they consume a substantial amount of ATP. While much of the mechanistic insights into CYT-19 activity has been gained through the studies on the folding of Tetrahymena group I intron ribozyme, the more biologically relevant issue, namely the effect of CYT-19 on the self-splicing of pre-RNA, remains largely unexplored. Here, we employ a kinetic network model, based on the generalized iterative annealing mechanism, to investigate the relation between CYT-19 activity, rate of ribozyme folding, and the kinetics of the self-splicing reaction. The network rate parameters are extracted by analyzing the recent biochemical data for CYT-19-facilitated folding of T. ribozyme. We then build extended models to explore the metabolism of pre-RNA. We show that the timescales of chaperone-mediated folding of group I ribozyme and self-splicing reaction compete with each other. As a consequence, in order to maximize the self-splicing yield of group I introns in pre-RNA, the chaperone activity must be sufficiently large to unfold the misfolded structures, but not too large to unfold the native structures prior to the self-splicing event. We discover that despite the promiscuous action on structured RNAs, the helicase activity of CYT-19 on group I ribozyme gives rise to self-splicing yields that are close to the maximum.Significance StatementIn cells, RNA chaperones assist misfolding-prone ribozymes to fold correctly to carry out its biological function. CYT-19 is an ATP-consuming RNA chaperone that accelerates the production of native group I intron ribozyme by partially unfolding the kinetically trapped structures. Using the theoretical framework based on the iterative annealing mechanism, we establish that to maximize the processing of pre-RNA, an optimal balance should exist between the timescales of self-splicing activity and CYT-19-mediated production of the native ribozyme. Remarkably, the activity of CYT-19 has been optimized to unfold the misfolded structures but is not so high that it disrupts the native ribozyme, which ensures that the yield of the self-splicing reaction is maximized in a biologically relevant time scale.
The joint associations of physical activity, sedentary time, and sleep on VO2maxin trained and untrained children and adolescents: A novel five-part compositional analysis
Authors: Runacres A. , Mackintosh K.A. , Chastin S. , McNarry M.A. 
Published: September 2022

AbstractThe benefits of physical activity (PA) and the negative impacts of sedentary time (SED) on both short- and long-term health in youth are well established. However, uncertainty remains about how PA and SED jointly influence maximal oxygen uptake (VO2max). Therefore, the aim of this study was to determine the joint influence of PA and SED on peak VO2using compositional analyses. 176 adolescents (84 girls, 13.8 ± 1.8 years) completed an incremental ramp test, and supramaximal validation bout, on cycle ergometer with PA and SED recorded for seven consecutive days on the right hip using a ActiGraph GT3X accelerometer. Time spent in sleep, SED, light, moderate and vigorous PA was analysed using a compositional linear regression model. Compositions with 10 minutes more time in vigorous PA (> 27.5 mins·day-1) compared to the average 17.5 mins·day-1were associated with a + 2.9% - 11.1% higher absolute and allometrically scaled peak VO2. Whereas compositions with less (> −10 mins·day-1) VPA were associated with a reduced absolute and allometrically scaled VO2max(−4.6% - 24.4%). All associations were irrespective of sex, maturity, and training status. The proportion of time spent sedentary had little impact on absolute and scaled peak VO2(0.01 – 1.98%). These findings therefore highlight that intensity of PA may be of greater importance for increases in VO2maxthan reductions in SED and should be incorporated into future intervention designs.
Neural correlates of an illusionary sense of agency caused by virtual reality
Authors: Cai Yiyang , Yang Huichao , Wang Xiaosha , Xiong Ziyi , Kühn Simone , Bi Yanchao , Wei Kunlin 
Published: September 2022

AbstractSense of agency (SoA) is the sensation that self-actions lead to ensuing perceptual consequences. The prospective mechanism emphasizes that SoA arises from motor prediction and its comparison with actual action outcomes, while the reconstructive mechanism stresses that SoA emerges from retrospective causal processing about the action outcomes. Consistent with the prospective mechanism, motor planning regions were identified by neuroimaging studies using the temporal binding effect, a behavioral measure often linked to implicit SoA. Yet, temporal binding also occurs during passive observation of another’s action, lending support to the reconstructive mechanism, but its neural correlates remain unexplored. Here, we employed virtual reality (VR) to modulate such observation-based SoA and examined it with functional magnetic resonance imaging. After manipulating an avatar hand in VR, participants passively observed an avatar’s “action” and showed a significant increase in temporal binding. The binding effect was associated with the right angular gyrus and inferior parietal lobule, which are critical nodes for inferential and agency processing. These results suggest that the experience of controlling an avatar may potentiate inferential processing within the right inferior parietal cortex and give rise to the illusionary sense of agency without voluntary action.
Discovery of homogentisic acid as a precursor in trimethoprim metabolism and natural product biosynthesis
Authors: McAvoy Andrew C. , Threatt Paxton H. , Kapcia Joseph , Garg Neha 
Published: September 2022

AbstractOpportunistic infections by Burkholderia cenocepacia are life threatening for patients suffering from cystic fibrosis and chronic granulomatous disease. These infections are often associated with variable clinical outcomes, prompting an interest into molecular investigations of phenotypes associated with disease severity. The production of the pyomelanin pigment is one such phenotype, which was recently linked to the ability of clinical strains to carry out biotransformation of the antibiotic trimethoprim. However, this biotransformation product was not identified, and differences in metabolite production associated with pyomelanin pigmentation are poorly understood. Here, we identify several key metabolites produced exclusively by the pyomelanin-producing strains. To provide insight into the structures and biosynthetic origin of these metabolites, we developed a mass spectrometry-based strategy coupling unsupervised in silico substructure prediction with stable isotope labeling referred to as MAS-SILAC (Metabolite Annotation assisted by Substructure discovery and Stable Isotope Labeling by Amino acids in Cell culture). This approach led to discovery of homogentisic acid as a precursor for biosynthesis of several natural products and for biotransformation of trimethoprim, representing a previously unknown mechanism of antibiotic tolerance. This work presents application of computational methods for analysis of untargeted metabolomic data to link the chemotype of pathogenic microorganisms with a specific phenotype. The observations made in this study provide insights into the clinical significance of the melanated phenotype.
Multisensory inputs control the regulation of time investment for mating by sexual experience in male Drosophila melanogaster
Authors: Lee Seung Gee , Kang Changku , Saad Baraa , Nguyen Khoi-Nguyen Ha , Guerra-Phalen Adrian , Bui Dorothy , Abbas Al-Hassan , Trinh Brian , Malik Ashvent , Zeghal Mahdi , Auge Anne-Christine , Islam Md Ehteshamul , Wong Kyle , Stern Tiffany , Lebedev Elizabeth , Sun Dongyu , Miao Hongyu , Wu Zekun , Sherratt Thomas N. , Kim Woo Jae 
Published: September 2022

ABSTRACTMales have finite resources to spend on reproduction. Thus, males rely on a ‘time investment strategy’ to maximize their reproductive success. For example, male Drosophila melanogaster extends their mating duration when surrounded by conditions enriched with rivals. Here we report a novel form of behavioral plasticity whereby male fruit flies exhibit a shortened duration of mating when they are sexually experienced; we refer to this plasticity as ‘shorter-mating-duration (SMD)’. SMD is a plastic behavior and requires sexually dimorphic taste neurons. We identified several neurons in the male foreleg and midleg that express specific sugar, pheromone and mechanosensory receptors. Using a cost-benefit model and behavioral experiments, we further show that SMD behavior exhibits adaptive behavioral plasticity in male flies. Thus, our study delineates the molecular and cellular basis of the sensory inputs required for SMD; this represents a plastic interval timing behavior that could serve as a model system to study how multisensory inputs converge to modify interval timing behavior for improved adaptation.ONE SENTENCE SUMMARYMale flies use information derived from their previous sexual experiences from multiple sensory inputs to optimize their investment in mating.
Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibition
Authors: Arabanian Laleh S. , Adamsson Jenni , Unger Anke , Lucrezia Raffaella Di , Bergbrede Tim , Ashouri Arghavan , Larsson Erik , Nussbaumer Peter , Klebl Bert M. , Palmqvist Lars , Gustafsson Claes M. 
Published: September 2022

AbstractOvercoming drug-resistance and the subsequent relapse that often occurs with monotherapy is crucial in the treatment of acute myeloid leukemia. We here demonstrate that therapy-resistant leukemia initiating cells can be targeted using a novel inhibitor of mitochondrial transcription (IMT). The compound inhibits mitochondrial RNA polymerase activity and sensitizes the resistant population to the induction of apoptosis.In vitrostudies on acute myeloid leukemia cells demonstrate that IMT prevents cell proliferation, and together with a selective BCL-2 inhibitor, venetoclax, induces apoptosis and suppress oxidative phosphorylation (OXPHOS) synergistically. AML mouse models treated with IMT in combination with venetoclax show prolonged survival in venetoclax-resistant models. Our findings suggest that certain therapy-resistant leukemia cell populations display a unique dependency on mitochondrial transcription and can be targeted with IMT.