bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor BOLD connectivity profile correlates with glioma patients’ survival
Authors: Sprugnoli Giulia , Rigolo Laura , Faria Meghan , Juvekar Parikshit , Tie Yanmei , Rossi Simone , Sverzellati Nicola , Golby Alexandra J , Santarnecchi Emiliano
Published: September 2022

Background

Presence of residual neurovascular activity within glioma lesions have been recently demonstrated via functional MRI (fMRI) along with active electrical synapses between glioma cells and healthy neurons that influence survival. In this study, we aimed to investigate whether gliomas demonstrate synchronized neurovascular activity with the rest of the brain, by measuring Blood Oxygen Level Dependent (BOLD) signal synchronization, that is, functional connectivity (FC), while also testing whether the strength of such connectivity might predict patients’ overall survival (OS).

Methods

Resting-state fMRI scans of patients who underwent pre-surgical brain mapping were analyzed (total sample, n = 54; newly diagnosed patients, n = 18; recurrent glioma group, n = 36). A seed-to-voxel analysis was conducted to estimate the FC signal profile of the tumor mass. A regression model was then built to investigate the potential correlation between tumor FC and individual OS. Finally, an unsupervised, cross-validated clustering analysis was performed including tumor FC and clinical OS predictors (e.g., Karnofsky Performance Status - KPS - score, tumor volume, and genetic profile) to verify the performance of tumor FC in predicting OS with respect to validated radiological, demographic, genetic and clinical prognostic factors.

Results

In both newly diagnosed and recurrent glioma patients a significant pattern of BOLD synchronization between the solid tumor and distant brain regions was found. Crucially, glioma-brain FC positively correlated with variance in individual survival in both newly diagnosed glioma group (r = 0.90–0.96; P < .001; R2 = 81–92%) and in the recurrent glioma group (r = 0.72; P < .001; R2 = 52%), outperforming standard clinical, radiological and genetic predictors.

Conclusions

Results suggest glioma’s synchronization with distant brain regions should be further explored as a possible diagnostic and prognostic biomarker.
Factors affecting the radiation response in glioblastoma
Authors: Aiyappa-Maudsley Radhika , Chalmers Anthony J , Parsons Jason L
Published: September 2022

Glioblastoma (GBM) is a highly invasive primary brain tumor in adults with a 5-year survival rate of less than 10%. Conventional radiotherapy with photons, along with concurrent and adjuvant temozolomide, is the mainstay for treatment of GBM although no significant improvement in survival rates has been observed over the last 20 years. Inherent factors such as tumor hypoxia, radioresistant GBM stem cells, and upregulated DNA damage response mechanisms are well established as contributing to treatment resistance and tumor recurrence. While it is understandable that efforts have focused on targeting these factors to overcome this phenotype, there have also been striking advances in precision radiotherapy techniques, including proton beam therapy and carbon ion radiotherapy (CIRT). These enable higher doses of radiation to be delivered precisely to the tumor, while minimizing doses to surrounding normal tissues and organs at risk. These alternative radiotherapy techniques also benefit from increased biological effectiveness, particularly in the case of CIRT. Although not researched extensively to date, combining these new radiation modalities with radio-enhancing agents may be particularly effective in improving outcomes for patients with GBM.
Stroke-associated infections in patients with and without cancer
Authors: Seystahl Katharina , Schweizer Juliane , Katan Mira , Weber Sung Ju , Hug Alessia , Wanner Miriam , Luft Andreas R , Rohrmann Sabine , Wegener Susanne , Weller Michael
Published: September 2022

Background

Cancer in stroke patients is associated with higher levels of inflammatory biomarkers and unfavorable poststroke outcomes. We thus explored whether there is a link between cancer and stroke-associated infections.

Methods

Medical records of patients with ischemic stroke in 2014–2016 registered in the Swiss Stroke Registry of Zurich were retrospectively analyzed. Incidence, characteristics, treatment, and outcome of stroke-associated infections diagnosed within 7 days after stroke onset were tested for an association with cancer.

Results

Among 1181 patients with ischemic stroke, 102 patients with cancer were identified. Stroke-associated infections occurred in 179 and 19 patients (17% and 19%) without and with cancer (P = .60), respectively, among them pneumonia in 95 and 10 patients (9% and 10%) and urinary tract infections in 68 and 9 patients (6% and 9%) (P = .74 and P = .32). Use of antibiotics was similar between groups. Levels of C-reactive protein (CRP) (P < .001), erythrocyte sedimentation rate (ESR) (P = .014) and procalcitonin (P = .015) were higher and levels of albumin (P = .042) and protein (P = .031) were lower in patients with cancer than without cancer. Among patients without cancer, higher CRP (P < .001), ESR (P < .001) and procalcitonin (P = .04) and lower albumin (P < .001) were associated with stroke-associated infections. Among cancer patients with or without infections, no significant differences in these parameters were observed. In-hospital mortality was associated with cancer (P < .001) and with stroke-associated infections (P < .001). However, among patients with stroke-associated infections, cancer was not associated with in-hospital mortality (P = .24) or 30-day mortality (P = .66).

Conclusions

Cancer does not represent a risk factor for stroke-associated infections in this patient cohort.
Navigating disability insurance in the American healthcare system for the low-grade glioma patient
Authors: Yogendran Lalanthica , Rudolf Mark , Yeannakis Drew , Fuchs Kathleen , Schiff David
Published: September 2022

In the United States, diagnosis of grade 3 or 4 glioma qualifies patients for Social Security disability benefits. Low-grade gliomas (LGGs) can be similarly debilitating, with at least 31% of patients presenting with cognitive deficits and 80% with tumor-related epilepsy. A diagnosis of LGG does not in and of itself qualify patients for disability benefits; the burden of proof is substantially higher. We outline the American healthcare system process of medical documentation to support disability benefits, Social Security Disability Insurance (SSDI) and Supplemental Security Income (SSI). We provide a template to assist providers in facilitating the application process for patients with LGG. The provider’s role is not to simply “declare” a patient disabled, but to provide comprehensive documentation regarding diagnosis, treatment, disease status, symptoms, and functional status in the medical record. As cognitive symptoms and seizures are 2 key sources of disability in LGG patients, selective referrals to neuropsychology and epileptology may improve patient care and bolster documentation of the patient’s symptoms in these domains. Likewise, connecting patients with social workers and disability claims representatives can assist them in navigating the complicated application process. We provide an extensive review for patient eligibility in the United States to receive disability. We map a comprehensive care process that may have relevance to multiple regions outside the United States. Providers are better able to help their patients navigate the disability application process when they understand how to address physical and cognitive changes for thorough care of their patient.
Multidisciplinary care of patients with narcolepsy during coronavirus disease 2019 pandemic in Italy via televisit: the TElemedicine for NARcolepsy feasibility study
Authors: Pizza Fabio , Vignatelli Luca , Oriolo Claudia , Zenesini Corrado , Mangiaruga Anastasia , Rossetti Andrea , Moresco Monica , Vandi Stefano , Citeroni Francesca , Pagotto Uberto , Ingravallo Francesca , Plazzi Giuseppe
Published: September 2022

Study Objectives

Narcolepsy is a rare chronic central disorder of hypersomnolence with frequent endocrine-metabolic comorbidities. To address the complex care needs of patients during the COVID-19 emergency, we carried out a feasibility study of the TElemedicine for NARcolepsy (TENAR) protocol with the aim of assessing the feasibility of a multidisciplinary care approach via televisit for patients with narcolepsy.

Methods

A feasibility single open-arm study on the multidisciplinary care of children (>7 y.o.) and adults with narcolepsy who required a follow-up visit was realized during the COVID-19 pandemic emergency period in Italy. The study included a sleep, metabolic, and psychosocial assessment via televisit at baseline, at 6, and at 12 months from the study inclusion period (15th May–26th June 2020).

Results

In total 39 out of 44 eligible patients (89%) entered the study (30 adults, nine children); 37 patients (95%) ended the 12-month follow-up. At baseline, the median Epworth sleepiness scale score (ESS) was 10 (IQR 8–14), and the median body mass index (BMI) was 25.6 (IQR 22.1–30.9). During the follow-up period, the ESS score decreased from the 6th month onward (p = 0.003), and BMI decreased at the 1-year follow-up (p = 0.047), while there were no differences in depressive and anxiety symptoms, quality of life, compliance with treatment, adverse drug reactions, or accidents.

Conclusions

High response and retention rates, stability of ESS, and lack of side effects indicate that telemedicine is a feasible and safe approach for adults and children with narcolepsy.
The Continued Absence of Functional Germline Stem Cells in Adult Ovaries
Authors: Yoshihara Masahito , Wagner Magdalena , Damdimopoulos Anastasios , Zhao Cheng , Petropoulos Sophie , Katayama Shintaro , Kere Juha , Lanner Fredrik , Damdimopoulou Pauliina
Published: September 2022

Ovaries are central to development, fertility, and reproduction of women. A particularly interesting feature of ovaries is their accelerated aging compared to other tissues, leading to loss of function far before other organs senesce. The limited pool of ovarian follicles is generated before birth and once exhausted, menopause will inevitably commence around the age of 50 years marking the end of fertility. Yet, there are reports suggesting the presence of germline stem cells and neo-oogenesis in adult human ovaries. These observations have fueled a long debate, created experimental fertility treatments, and opened business opportunities. Our recent analysis of cell types in the ovarian cortex of women of fertile age could not find evidence of germline stem cells. Like before, our work has been met with critique suggesting methodological shortcomings. We agree that excellence starts with methods and welcome discussion on the pros and cons of different protocols. In this commentary, we discuss the recent re-interpretation of our work.
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

The 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

This 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.
On solutions for a generalized Navier–Stokes–Fourier system fulfilling the entropy equality
Authors: Abbatiello Anna , Bulíček Miroslav , Kaplický Petr
Published: September 2022

We consider a flow of a non-Newtonian heat conducting incompressible fluid in a bounded domain subjected to the homogeneous Dirichlet boundary condition for the velocity field and the Dirichlet boundary condition for the temperature. In three dimensions, for a power-law index greater or equal to

11

/

5

, we show the existence of a solution fulfilling the entropy equality. The entropy equality can be formally deduced from the energy equality by renormalization. However, such a procedure can be justified by the DiPerna–Lions theory only for

p
>
5

/

2

. The main novelty is that we do not renormalize the temperature equation, but rather construct a solution which fulfils the entropy equality.

This article is part of the theme issue ‘Non-smooth variational problems and applications’.
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’.
Multiscale analysis of stationary thermoelastic vibrations of a composite material
Authors: Fankina Irina V. , Furtsev Alexey I. , Rudoy Evgeny M. , Sazhenkov Sergey A.
Published: September 2022

The problem of description of stationary vibrations is studied for a planar thermoelastic body incorporating thin inclusions. This problem contains two small positive parameters

δ

and

ε

, which describe the thickness of an individual inclusion and the distance between two neighbouring inclusions, respectively. Relying on the variational formulation of the problem, by means of the modern methods of asymptotic analysis, we investigate the behaviour of solutions as

δ

and

ε

tend to zero. As the result, we construct two models corresponding to the limit cases. At first, as

δ
→
0

, by the version of the method of formal asymptotic expansions we derive a limit model in which inclusions are thin (of zero width). Then, from this limit model, as

ε
→
0

, we derive a homogenized model, which describes effective behaviour on the macroscopic scale, i.e. on the scale where there is no need to take into account each individual inclusion. The limiting passage as

ε
→
0

is based on the use of the two-scale convergence theory.

This article is part of the theme issue ‘Non-smooth variational problems and applications’.
Lagrange multipliers and nonlinear variational inequalities with gradient constraints
Authors: Giuffrè Sofia , Marcianò Attilio
Published: September 2022

The paper deals with nonlinear monotone variational inequalities with gradient constraints. In particular, using a new strong duality principle, the equivalence between the problem under consideration and a suitable double obstacle problem is proved. Moreover, the existence of

L
2

Lagrange multipliers is achieved.

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’.
An inverse coefficient problem of identifying the flexural rigidity in damped Euler–Bernoulli beam from measured boundary rotation
Authors: Hasanov Alemdar
Published: September 2022

We present a new mathematical model and method for identifying the unknown flexural rigidity

r
(
x
)

in the damped Euler–Bernoulli beam equation

ρ
(
x
)

w

t
t

+
μ
(
x
)

w

t

+

(
r
(
x
)

w

x
x

)

x
x

−

(

T
r

(
x
)

w
x

)

x

=
F
(
x
,
t
)
,
(
x
,
t
)

∈

Ω
T

:=
(
0
,
ℓ
)
×
(
0
,
T
)

, subject to the simply supported boundary conditions

w
(
0
,
t
)
=

w

x
x

(
0
,
t
)
=
0

,

w
(
ℓ
,
t
)
=

w

x
x

(
ℓ
,
t
)
=
0

, from the available measured boundary rotation

θ
(
t
)
:=

w
x

(
0
,
t
)

. We prove the existence of a quasi-solution and derive an explicit gradient formula for the Fréchet derivative of the Tikhonov functional

J
(
r
)
=
‖

w
x

(
0
,
⋅
;
r
)
−
θ

‖

L
2

(
0
,
T
)

2

. The results obtained here also form the basis of gradient-based computational methods for solving this class of inverse coefficient problems.

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’.
Quasi-variational inequality for the nonlinear indentation problem: a power-law hardening model
Authors: Kovtunenko Victor A.
Published: September 2022

The Boussinesq problem, which describes quasi-static indentation of a rigid punch into a deformable body, is studied within the context of nonlinear constitutive equations. By this, the material response expresses the linearized strain in terms of the stress and cannot be inverted in general. A contact area between the punch and the body is unknown
a priori
, whereas the total contact force is prescribed and yields a non-local integral condition. Consequently, the unilateral indentation problem is stated as a quasi-variational inequality for unknown variables of displacement, stress and indentation depth. The Lagrange multiplier approach is applied in order to establish well-posedness to the underlying physically and geometrically nonlinear problem based on augmented penalty regularization and applying the minimax theorem of Ekeland and Témam. A sufficient solvability condition implies response functions that are bounded, hemi-continuous, coercive and obey a convex potential. A typical example is power-law hardening models for titanium alloys, Norton–Hoff and Ramberg–Osgood materials.

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’.
Unique solvability of a crack problem with Signorini-type and Tresca friction conditions in a linearized elastodynamic body
Authors: Kashiwabara Takahito , Itou Hiromichi
Published: September 2022

We consider dynamic motion of a linearized elastic body with a crack subject to a modified contact law, which we call
the Signorini contact condition of dynamic type
, and to the Tresca friction condition. Whereas the modified contact law involves both displacement and velocity, it formally includes the usual non-penetration condition as a special case. We prove that there exists a unique strong solution to this model. It is remarkable that not only existence but also uniqueness is obtained and that no viscosity term that serves as a parabolic regularization is added in our model.

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 Statement

In 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

The 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

Sense 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

Opportunistic 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

Males 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 SUMMARY

Male 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

Overcoming 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.
Chemical bonds in collagen rupture selectively under tensile stress
Authors: Rowe James , Röder Konstantin
Published: September 2022

Collagen fibres are the main constituent of the extracellular matrix, and fulfil an important role in the structural stability of living multicellular organisms. An open question is how collagen absorbs pulling forces, and if the applied forces are strong enough to break bonds, what mechanisms underlie this process. As experimental studies on this topic are challenging, simulations are an important tool to further our understanding of these mechanisms. Here, we present pulling simulations of collagen triple helices, revealing the molecular mechanisms induced by tensile stress. At lower forces, pulling alters the configuration of proline residues leading to an effective absorption of applied stress. When forces are strong enough to introduce bond ruptures, these are located preferentially in X-position residues. Reduced backbone flexibility, for example through mutations or cross linking, weakens tensile resistance, leading to localised ruptures around these perturbations. In fibre-like segments, a significant overrepresentation of ruptures in proline residues compared to amino acid contents is observed. This study confirms the important role of proline in the structural stability of collagen, and adds detailed insight into the molecular mechanisms underlying this observation.
Assembly and architecture of the type III secretion sorting platform
Authors: Soto J. Eduardo , Galán Jorge E. , Lara-Tejero María
Published: September 2022

Type III secretion systems are bacterial nanomachines specialized in protein delivery into target eukaryotic cells. The structural and functional complexity of these machines demand highly coordinated mechanisms for their assembly and operation. The sorting platform is a critical component of type III secretion machines that ensures the timely engagement and secretion of proteins destined to travel this export pathway. However, the mechanisms that lead to the assembly of this multi-component structure have not been elucidated. Herein, employing structure modeling and an extensive in vivo crosslinking strategy, we provide a detailed inter-subunit-contact survey of the entire sorting platform complex. Using the identified crosslinks as signatures for pairwise inter-subunit interactions in combination with systematic genetic deletions, we mapped the assembly process of this unique bacterial structure. Insights generated by this study could serve as the bases for the development of anti-virulence strategies to combat several medically important bacterial pathogens.
Metallothionein-3 attenuates the effect of Cu2+ ions on actin filaments
Authors: Lakha Rabina , Hachicho Carla , Mehlenbacher Matthew R. , Wilcox Dean E. , Austin Rachel N. , Vizcarra Christina L.
Published: September 2022

Metallothionein 3 (MT-3) is a cysteine-rich metal-binding protein that is expressed in the mammalian central nervous system and kidney. Various reports have posited a role for MT-3 in regulating the actin cytoskeleton by promoting the assembly of actin filaments. We generated purified, recombinant mouse MT-3 of known metal compositions, either with zinc (Zn), lead (Pb), or copper/zinc (Cu/Zn) bound. None of these forms of MT-3 accelerated actin filament polymerization in vitro, either with or without the actin binding protein profilin. Furthermore, using a co-sedimentation assay, we did not observe Zn-bound MT-3 in complex with actin filaments. Cu2+ ions on their own induced rapid actin polymerization, an effect that we attribute to filament fragmentation. This effect of Cu2+ is reversed by adding either EGTA or Zn-bound MT-3, indicating that either molecule can chelate Cu2+ from actin. Altogether, our data indicate that recombinant MT-3 does not directly bind actin but it does attenuate the Cu-induced fragmentation of actin filaments.
Estradiol (E2) concentration shapes the chromatin binding landscape of the estrogen receptor
Authors: Han Amy L. , Vinod-Paul Kiran , Rao Satyanarayan , Brechbuhl Heather M. , Sartorius Carol A. , Ramachandran Srinivas , Kabos Peter
Published: September 2022

How transcription factors (TF) selectively occupy a minute subset of their binding sites from a sizeable pool of putative sites in large mammalian genomes remains an important unanswered question. In part, nucleosomes help by creating formidable barriers to TF binding. TF concentration itself plays a crucial role in the competition between TFs and nucleosomes. In the case of nuclear receptors, the ligand adds another layer of complexity. Estrogen receptor alpha (ER) is a classic example where its main ligand estradiol (E2) can modulate ER binding on chromatin. Here we show a complete rewiring of ER binding as a function of E2 concentration. As E2 concentration increases by two orders of magnitude, ER levels decrease, and ER binding localizes to promoter-distal sites with strong ER motifs. At low E2 levels, abundant levels of ER are present in the nucleus, and ER binding occurs mostly at sites without an identifiable ER binding motif, potentially in cooperation with other TFs like STAT1. We propose that E2’s effect on ER activity plays a major role in defining genome-wide ER binding profiles. Thus, variations in E2 concentrations in ER-positive breast tumors could be a significant factor driving heterogeneity in tumor phenotype, treatment response, and potentially drug resistance.
Reevaluation of Piezo1 as a gut RNA sensor
Authors: Nickolls AR , O’Brien GS , Shnayder S , Zhang Y , Nagel M , Patapoutian A , Chesler AT
Published: September 2022

Piezo1 is a stretch-gated ion channel required for mechanosensation in many organ systems. Recent provocative findings describe a new role for Piezo1 in the gut, suggesting that it is a sensor of microbial single-stranded RNA (ssRNA) rather than mechanical force. If true, this would redefine the scope of Piezo biology. Here, we sought to replicate the central finding that fecal ssRNA is a natural agonist of Piezo1. While we observed that fecal extracts and ssRNA stimulate calcium influx in certain cell lines, this response was independent of Piezo1. Additionally, sterilized dietary extracts devoid of gut biome RNA showed similar cell line-specific stimulatory activity to fecal extracts. Together, our data highlight potential confounds inherent to gut-derived extracts, exclude Piezo1 as a receptor for ssRNA in the gut, and support a dedicated role for Piezo channels in mechanosensing.