bluuebunny/crossref_metadata_2025 huggingface dataset:
Lubricated viscous gravity currents of power-law fluids. Part 1. Self-similar flow regimes
Authors: Leung Lucas Tsun-yin , Kowal Katarzyna N.
Published: April 2022

We examine the gravity-driven flow of thin films of viscous fluid of power-law rheology, lubricated by another power-law viscous fluid from below. Such flows are relevant to a range of geophysical and industrial settings, including the flow of ice sheets and fast-flowing ice streams lubricated from below by a layer of subglacial till. We model both layers using lubrication theory in two-dimensional and axisymmetric settings, in the limit in which vertical shear provides the dominant resistance to the flow. The flow is self-similar if the power-law exponents, describing the rheology of the two layers of fluid, are equal. We examine the similarity solutions in both geometries and describe the flow in terms of four distinct flow regimes ranging from thin films of viscous fluid coating a more viscous fluid from above, to thin layers of fluid lubricating a more viscous fluid from below. In contrast to the former scenario, a thin film of a low-viscosity fluid strikingly alters the dynamics of a more viscous fluid when it lubricates it from below: the overlying layer thins, the upper surface gradients lessen and most of the shear is confined to the lower layer. Such features amplify, and this flow regime becomes increasingly dominant when the viscous fluids are shear thinning, like the deformation of glacial ice on the large scale. This flow regime is most relevant to the flow of lubricated ice sheets, which thin and accelerate, forming fast-flowing ice streams, when they are well lubricated from below.
Leading-edge vortex dynamics on plunging airfoils and wings
Authors: Son O. , Gao A.-K. , Gursul I. , Cantwell C.D. , Wang Z. , Sherwin S.J.
Published: April 2022

The vortex dynamics of leading-edge vortices on plunging high-aspect-ratio (AR = 10) wings and airfoils were investigated by means of volumetric velocity measurements, numerical simulations and stability analysis to understand the deformation of the leading-edge vortex filament and spanwise instabilities. The vortex filaments on both the wing and airfoil exhibit spanwise waves, but with different origins. The presence of a wing-tip causes the leg of the vortex to remain attached to the wing upper surface, while the initial deformation of the filament near the wing tip resembles a helical vortex. The essential features can be modelled as the deformation of an initially L-shaped semi-infinite vortex column. In contrast, the instability of the vortices is well captured by the instability of counter-rotating vortex pairs, which are formed either by the trailing-edge vortices or the secondary vortices rolled-up from the wing surface. The wavelengths observed in the experiments and simulations are in agreement with the stability analysis of counter-rotating vortex pairs of unequal strength.
Granular surface flows confined between flat, frictional walls. Part 1. Kinematics
Authors: Richard Patrick , Valance Alexandre , Delannay Renaud , Boltenhagen Philippe
Published: April 2022

We report and analyse the results of extensive discrete element method simulations of three-dimensional gravity driven flows of cohesionless granular media over an erodible bed, the whole being confined between two flat and frictional sidewalls. We focus on the role of sidewalls by performing simulations for different gap widths (

$W$

) between the two confining sidewalls: from

$5$

to

$30$

grain sizes (

$d$

). Our results indicate the existence of two distinct regimes: regime I for flow angles smaller than the critical angle

$\theta_c\approx 40^\circ$

and regime II at flow angles larger than

$\theta_c$

. Regime I corresponds to dense flows whereas flows belonging to regime II exhibit a strong variation of the volume fraction through the depth. Three relevant lengths are identified in the system:

$W$

the gap between sidewalls,

$l$

the length characterizing the vertical variation of the volume fraction and

$h$

a characteristic length associated with the vertical variation of the streamwise velocity. Using these lengths we can rescale the profiles of various flow properties (e.g. streamwise velocity, granular temperature, particle rotation…). In regime II, in contrast to regime I,

$l$

and

$h$

have a similar behaviour. As a consequence, the rescaled profiles in regime II only involve

$h$

(or equivalently

$l$

) and

$W$

. Other dissimilarities exist between regimes I and II. In particular, the scaling of the flow rate with

$h$

(at fixed

$W$

) differs in the two regimes, although they display a similar scaling with

$W$

(at fixed flow angle).
Repicturing viscoelastic drag-reducing turbulence by introducing dynamics of elasto-inertial turbulence
Authors: Zhang Wen-Hua , Zhang Hong-Na , Wang Zi-Mu , Li Yu-Ke , Yu Bo , Li Feng-Chen
Published: April 2022

Recently, the nature of viscoelastic drag-reducing turbulence (DRT), especially the maximum drag reduction (MDR) state, has become a focus of controversy. It has long been regarded as polymer-modulated inertial turbulence (IT), but is challenged by the newly proposed concept of elasto-inertial turbulence (EIT). This study is to repicture DRT in parallel plane channels by introducing dynamics of EIT through statistical, structural and budget analysis for a series of flow regimes from the onset of drag reduction to EIT. Some underlying mechanistic links between DRT and EIT are revealed. Energy conversion between velocity fluctuations and polymers as well as pressure redistribution effects are of particular concern, based on which a new energy self-sustaining process (SSP) of DRT is repictured. The numerical results indicate that at low Reynolds number (

$Re$

), weak IT flow is replaced by a laminar regime before the barrier of EIT dynamics is established with the increase of elasticity, whereas, at moderate

$Re$

, EIT-related SSP can get involved and survive from being relaminarized. This further explains the reason why relaminarization phenomenon is observed for low

$Re$

while the flow directly enters MDR and EIT at moderate

$Re$

. Moreover, with the proposed energy picture, the newly discovered phenomenon that streamwise velocity fluctuations lag behind those in the wall-normal direction can be well explained. The repictured SSP certainly justifies the conjecture that IT nature is gradually replaced by that of EIT in DRT with the increase of elasticity.
THE PERSISTENT BONDS OF THEOIKOSIN EURIPIDES’HERACLES
Authors: Moore Jocelyn
Published: April 2022

Interpretations of Euripides’Heraclesoften focus on Theseus’ and Heracles’ cooperative social values in the final scene as a culmination of themes ofphilia. I argue that the relationship Theseus forges competes with Heracles’ attachment to his household,oikos, which is the central social relationship Euripides describes. The drama consistently develops Heracles as his household's leader by inviting the audience to compare Heracles with interim caretakers Megara and Amphitryon, and later through the protagonist's performance of emotional attachment before and after his madness. The closing scene continues to reveal the value and vulnerability of household attachment by accentuating Heracles’ exclusion from the identity of human family member. This trajectory suggests a painful misalignment between Heracles’ experience in theoikosand the public position Theseus offers at Athens: of a semi-divine hero receiving public cult and honours. Euripides emphasizes this tension to distinguish the experience ofoikos-membership.
In Pursuit of Laicized Urban Administration: The Muhtar System in Istanbul and Ottoman Attitudes toward Non-Muslim Religious Authorities in the Nineteenth Century
Authors: Ueno Masayuki
Published: April 2022

The Ottoman Empire introduced the muhtar system in Istanbul in 1829, appointing lay headmen, called muhtar, to the lowest levels of urban administration: Muslim neighborhoods; Orthodox, Armenian, and Catholic parishes; and Jewish congregations. This reform resulted in the overlapping of state responsibilities and those of non-Muslim religious authorities, later leading to disputes between the groups. This article investigates such disagreements in an effort to understand how state officials perceived non-Muslim religious authorities’ participation in imperial governance. In so doing, this article argues that, as non-Muslim political movements began developing during the late nineteenth century, state officials adopted a cautious attitude toward non-Muslim clergy, viewing the latter as requiring more careful handling than the layman. This take on clergymen was a shift, a reconsideration of the exceptional treatment they had previously enjoyed, and ignited a growing desire to sever the ties, formerly tolerated, between muhtars and religious authorities.
Energetic bounds on gyrokinetic instabilities. Part 1. Fundamentals
Authors: Helander P. , Plunk G.G.
Published: April 2022

Upper bounds on the growth of free energy in gyrokinetics are derived. These bounds apply to all local gyrokinetic instabilities in the geometry of a flux tube, i.e. a slender volume of plasma aligned with the magnetic field, regardless of the geometry of field, the number of particle species or collisions. The results apply both to linear instabilities and to the nonlinear growth of finite-amplitude fluctuations.
Proficiency of allocentric and egocentric wayfinding: a comparison of schoolchildren with young adults and older adults
Authors: Rinne Klara , Memmert Daniel , Bock Otmar
Published: April 2022

Wayfinding skills decay in old age, more so for wayfinding in an allocentric than an egocentric reference frame. This study investigates whether wayfinding deficits of schoolchildren mimic those of older adults. Schoolchildren were tested on two wayfinding tasks: one could only be mastered in an allocentric, and the other only in an egocentric reference frame. The results were compared with those from a previous study of young and older adults who had been tested on the same two wayfinding tasks. It was found that wayfinding performance improved somewhat from school age to young adulthood and that this improvement proceeded more or less in parallel for the allocentric and the egocentric tasks. It was further found that wayfinding performance decayed from young to older adulthood and that this decay was more dramatic for the allocentric than for the egocentric task. This pattern of findings does not support the hypothesis that the wayfinding performance of schoolchildren mimics that of older adults.
Uncovering Public Perceptions of Older Adults’ Vaccines in Canada: A Study of Online Discussions from National Media Sources
Authors: Lynch Meghan , Thomas Maddi , Allin Sara
Published: April 2022

This study explored how a subsection of Canadians perceive older adults’ vaccines through a qualitative analysis of comments posted in response to national online news articles. We used reflexive thematic analysis to analyse 147 comments from 31 news article comments sections published between 2015 and 2020 from five different national online news sources (CBC, National Post, Global News, Globe & Mail, and Huffington Post Canada) that focused on three older adults’ diseases and vaccines: influenza, pneumococcal pneumonia, and herpes-zoster. Three themes encompassed the similarities and differences in how these three diseases were discussed: (1) the importance of personal experiences on stated stance in vaccine uptake or refusal, (2) questioning vaccine research and recommendations, and (3) criticisms of the government’s unequal vaccine opportunities across different Canadian provinces. Our findings identified that perceptions regarding older adult vaccination were dependent on the vaccine type, and, therefore, we make suggestions for future researchers to build on our findings, particularly the need not to treat the research subject of “older adults’ vaccines” as one entity. Gaining a better understanding of how older adults’ vaccines are perceived in Canada will enable public health professionals to develop effective communication strategies that should ultimately improve vaccination rates for older adults.
A Tale of Two Houses: Opera Houses in Cairo and Cape Town
Authors: Somma Donato
Published: April 2022

This article considers the parallel histories of the opera houses in Cairo, Egypt and Cape Town, South Africa. Their respective stories reflect common and divergent experiences of the colonial and postcolonial and the emergent national and nationalist identities at the terminal cities of Africa. Considered separately from the content performed on their stages, the article traces the significance of the buildings as part of their cities. In each city the opera house has been destroyed and rebuilt, under new regimes with new purposes. The discursive value of opera houses is considered more broadly, with evidence presented for the houses as functionaries of the ‘operatic state’ or impresarialist institutions. Who is welcomed in and courted at the opera house is investigated as part of the phenomenon of a nominally public space with conventionalised issues of access.
On the Lie symmetries of characteristic function hierarchy in compressible turbulence
Authors: PRATURI D.S. , PLÜMACHER D. , OBERLACK M.
Published: April 2022

We compute the Lie symmetries of characteristic function (CF) hierarchy of compressible turbulence, ignoring the effects of viscosity and heat conductivity. In the probability density function (PDF) hierarchy, a typical non-local nature is observed, which is naturally eliminated in the CF hierarchy. We observe that the CF hierarchy retains all the symmetries satisfied by compressible Euler equations. Broadly speaking, four types of symmetries can be discerned in the CF hierarchy: (i) symmetries corresponding to coordinate system invariance, (ii) scaling/dilation groups, (iii) projective groups and (iv) statistical symmetries, where the latter define measures of intermittency and non-gaussianity. As the multi-point CFs need to satisfy additional constraints such as the reduction condition, the projective symmetries are only valid for monatomic gases, that is, the specific heat ratio,
$\gamma = 5/3$
. The linearity of the CF hierarchy results in the statistical symmetries due to the superposition principle. For all of the symmetries, the global transformations of the CF and various key compressible statistics are also presented.
Quality of energy intake in Malaysian adolescents: prevalence, characteristics, determinants and impact of implausible reporters
Authors: Zulfarina Mohamed S , Sharif Razinah , Sharkawi Ahmad Mohd , Mokhtar Sabarul Afian , Shuid Ahmad Nazrun , Naina-Mohamed Isa
Published: April 2022

Objective:

Misreporting of energy intake (EI) in nutritional epidemiology is common and even severe among adolescents. Thus, the current study aims to examine the presence, bias and impact introduced by implausible reporters.

Design:

Cross-sectional.

Setting:

Central and eastern regions of Peninsular Malaysia.

Participants:

A stratified random sampling was employed to select 917 secondary school-going adolescents (aged 15–17 years).

Results:

The prevalence of under-reporters was 17·4 %, while no over-reporters were identified. Under-reporters had higher body composition and lower dietary intakes (except for vitamin C, Cr and Fl) compared with plausible reporters (P< 0·05). Adolescents with overweight and obesity had a higher odds of under-reporting compared with under-/normal weight adolescents (P< 0·001). In model 3, the highest regression coefficient (R2= 0·404,P< 0·001) was obtained after adjusting for reporting status.

Conclusions:

Overweight and obese adolescents were more likely to under-report their food intake and consequently affect nutrient intakes estimates. Future analyses that include nutrient intake data should adjust for reporting status so that the impact of misreporting on study outcomes can be conceded and consequently improve the accuracy of dietary-related results.
A Model for Characteristic X-Ray Emission in Electron Probe Microanalysis Based on the (Filtered) Spherical Harmonic () Method for Electron Transport
Authors: Bünger Jonas , Richter Silvia , Torrilhon Manuel
Published: April 2022

Classical$k$-ratio models, for example, ZAF and$\phi ( \rho z)$, used in electron probe microanalysis (EPMA) assume a homogeneous or multilayered material structure, which essentially limits the spatial resolution of EPMA to the size of the interaction volume where characteristic X-rays are produced. We present a new model for characteristic X-ray emission that avoids assumptions on the material structure to not restrict the resolution of EPMAa priori. Our model bases on the spherical harmonic ($P_{\rm N}$) approximation of the Boltzmann equation for electron transport in continuous slowing down approximation.$P_{\rm N}$models have a simple structure, are hierarchical in accuracy and well-suited for efficient adjoint-based gradient computation, which makes our model a promising alternative to classical models in terms of improving the resolution of EPMA in the future. We present results of various test cases including a comparison of the$P_{\rm N}$model to a minimum entropy moment model as well as Monte-Carlo (MC) trajectory sampling, a comparison of$P_{\rm N}$-based$k$-ratios to$k$-ratios obtained with MC, a comparison with experimental data of electron backscattering yields as well as a comparison of$P_{\rm N}$and MC based on characteristic X-ray generation in a three-dimensional material probe with fine structures.
Evaluating user experiences of SHaRON: an online CBT-based peer support platform
Authors: Browne Natasha L. , Carragher Nick O. , O’Toole Annette , Pimm John , Ryder Joanne , Thew Graham R.
Published: April 2022

Online peer support platforms have been shown to provide a supportive space that can enhance social connectedness and personal empowerment. Some studies have analysed forum messages, showing that users describe a range of advantages, and some disadvantages to their use. However, the direct examination of users’ experiences of such platforms is rare and may be particularly informative for enhancing their helpfulness. This study aimed to understand users’ experiences of the Support, Hope and Recovery Online Network (SHaRON), an online cognitive behavioural therapy-based peer support platform for adults with mild to moderate anxiety or depression. Platform users (n = 88) completed a survey on their use of different platform features, feelings about using the platform, and overall experience. Responses were analysed descriptively and using thematic analysis. Results indicated that most features were generally well used, with the exception of private messaging. Many participants described feeling well supported and finding the information and resources helpful; the majority of recent users (81%) rated it as helpful overall. However, some participants described feeling uncomfortable about posting messages, and others did not find the platform helpful and gave suggestions for improvements. Around half had not used the platform in the past 3 months, for different reasons including feeling better or forgetting about it. Some described that simply knowing it was there was helpful, even without regular use. The findings highlight what is arguably a broader range of user experiences than observed in previous studies, which may have important implications for the enhancement of SHaRON and other platforms.

Key learning aims

(1)

To understand what an online peer support platform is and how this can be used to support users’ mental health.

(2)

To learn how users described their experience of the SHaRON platform.

(3)

To understand the benefits that online peer support may provide.

(4)

To consider what users found helpful and unhelpful, and how this might inform the further development of these platforms.
Comparing the effectiveness and predictors of cognitive behavioural therapy-enhanced between patients with various eating disorder diagnoses: a naturalistic study
Authors: Melisse Bernou , Dekker Jack , van den Berg Elske , de Jonge Margo , van Furth Eric F. , Peen Jaap , de Beurs Edwin
Published: April 2022

Cognitive behaviour therapy-enhanced (CBT-E) is an effective treatment for non-underweight patients with eating disorders. Its efficacy and effectiveness is investigated mostly among transdiagnostic samples and remains unknown for binge eating disorder. The aim of the present study was to assess several treatment outcome predictors and to compare effectiveness of CBT-E among adult out-patients with bulimia nervosa (n=370), binge eating disorder (n=113), and those with a restrictive food pattern diagnosed with other specified feeding and eating disorders (n=139). Effectiveness of CBT-E was assessed in routine clinical practice in a specialised eating disorders centre. Eating disorder pathology was measured with the EDEQ pre- and post-treatment, and at 20 weeks follow-up. Linear mixed model analyses with fixed effect were performed to compare treatment outcome among the eating disorder groups. Several predictors of treatment completion and outcome were examined with a regression analysis. No predictors for drop-out were found, except the diagnosis of bulimia nervosa. Eating disorder pathology decreased among all groups with effect sizes between 1.43 and 1.70 on the EDE-Q total score. There were no differences in remission rates between the three groups at end of treatment or at follow-up. Eating disorder severity at baseline affected treatment response. The results can be generalised to other specialised treatment centres. No subgroup of patients differentially benefited from CBT-E supporting the transdiagnostic perspective for the treatment of eating disorders. Longer-term follow-up data are necessary to measure persistence of treatment benefits.

Key learning aims

(1)

What is the effectiveness of CBT-E among patients suffering from binge eating disorder?

(2)

Does any subgroup of patients suffering from an eating disorder differentially benefit from CBT-E?

(3)

What factors predict treatment response?
A compact SWB MIMO antenna with 45° clock-wise square patch inclusions for polarization diversity applications
Authors: Agarwal Shobit , Sharma Ashwani , Zuazola Ignacio J. Garcia , Kumar Manoj
Published: April 2022

In this paper, a compact super wideband annular ring antenna using 45° clock-wise square patch inclusions for super high frequency and polarization diversity applications is proposed. The inclusions consist of a combination of squares and circles into one another in the inner area of a main annular ring radiator. The antenna uses a partial ground plane having a stair-type defected ground structure, is designed on an FR-4 substrate, and has a total size of 25 × 26 × 1.6 mm3 (0.17λ × 0.18λ). The design was fabricated and experimental results fairly agreed with simulations and resulted in an antenna with an operating frequency from 2.07 to 30 GHz; that is, a large fractional bandwidth of 174.2$\%$ with a bandwidth (BW) ratio of 14.5:1 and a high BW dimension ratio, BW per unit electrical length of 5693, and a measured peak gain of 8 dBi with an average gain of 5 dBi for the overall operating frequency. For the polarization diversity, a 4 × 4 multiple input-multiple output configuration is additionally presented, offering an effective isolation of ≥ 22.5 dB between ports and corroborated by measurements.
Impacts of Storm Surge Barriers on Drag, Mixing, and Exchange Flow in a Partially Mixed Estuary
Authors: Ralston David K.
Published: April 2022

Storm surge barriers are increasingly being considered as risk mitigation measures for coastal population centers. During non‐storm periods, permanent barrier infrastructure reduces the flow cross‐sectional area and affects tidal exchange. Effects of barrier structures on estuarine tidal and salinity dynamics have not been extensively examined, particularly for partially mixed estuaries. A nested, high‐resolution model is used to characterize impacts of a potential storm surge barrier near the mouth of the Hudson River estuary. Maximum tidal velocities through barrier openings are more than double those in the base case. Landward of the barrier, tidal amplitude decreases on average by about 6% due to increased drag. The drag coefficient with the barrier is about 5 times greater than the base case due primarily to form drag from flow separation at barrier structures rather than increased bottom friction. The form drag scales with barrier geometry similar to previous studies of flow around headlands. Tidal water levels are reduced particularly during spring tides, such that marsh inundation frequency is reduced up to 25%. Strong tidal velocities through barrier openings enhance salinity mixing locally, but overall mixing in the estuary decreases due to reduced tidal velocities. Correspondingly, stratification decreases near the barrier and increases landward in the estuary. The salinity intrusion length increases by 5%–15% depending on discharge due to the decreased mixing and increased exchange flow. Exchange flow increases near the barrier due reflux into the lower layer with the increased mixing, which has the potential to increase estuarine residence times.
An Advanced Discrete Fracture Methodology for Fast, Robust, and Accurate Simulation of Energy Production From Complex Fracture Networks
Authors: de Hoop S. , Voskov D. V. , Bertotti G. , Barnhoorn A.
Published: April 2022

Fracture networks are abundant in subsurface applications (e.g., geothermal energy production, CO2 sequestration). Fractured reservoirs often have a very complex structure, making modeling flow and transport in such networks slow and unstable. Consequently, this limits our ability to perform uncertainty quantification and increases development costs and environmental risks. This study provides an advanced methodology for simulation based on Discrete Fracture Model approach. The preprocessing framework results in a fully conformal, uniformly distributed grid for realistic 2D fracture networks at a required level of precision. The simplified geometry and topology of the resulting network are compared with input (i.e., unchanged) data to evaluate the preprocessing influence. The resulting mesh‐related parameters, such as volume distributions and orthogonality of control volume connections, are analyzed. Furthermore, changes in fluid‐flow response related to preprocessing are evaluated using a high‐enthalpy two‐phase flow geothermal simulator. The simplified topology directly improves meshing results and, consequently, the accuracy and efficiency of numerical simulation. The main novelty of this work is the introduction of an automatic preprocessing framework allowing us to simplify the fracture network down to required level of complexity and addition of a fracture aperture correction capable of handling heterogeneous aperture distributions, low connectivity fracture networks, and sealing fractures. The graph‐based framework is fully open‐source and explicitly resolves small‐angle intersections within the fracture network. A rigorous analysis of changes in the static and dynamic impact of the preprocessing algorithm demonstrates that explicit fracture representation can be computationally efficient, enabling their use in large‐scale uncertainty quantification studies.
Intense Energy Conversion Events at the Magnetopause Boundary Layer
Authors: Man Hengyan , Zhou Meng , Zhong Zhihong , Deng Xiaohua
Published: April 2022

This paper investigates intense energy conversion events (IECEs) at the dayside magnetopause boundary layer (MBL) using high‐resolution data from the Magnetospheric Multiscale (MMS) spacecraft. Most events were detected by MMS in a duration less than 0.5 s, corresponding to a thickness below one ion inertia length. About three‐quarters of the events occurred in local reconnecting current sheets. Interestingly, there are more electron‐only reconnections than standard reconnections. Most of the reconnection IECEs are within the exhaust of the primary reconnection and the Kelvin‐Helmholtz vortices, suggesting that secondary reconnections are important building blocks for the overall energy conversion at the magnetopause. The nonreconnection events are also primarily within the reconnection exhaust and the Kelvin‐Helmholtz vortices, highlighting the importance of reconnection and Kelvin‐Helmholtz instability in regulating the energy conversion at the MBL.
NEDD9 sustains hexokinase expression to promote glycolysis
Authors: Deneka Alexander Y. , Nikonova Anna S. , Lee Hyung-Ok , Kruger Warren D. , Golemis Erica A.
Published: April 2022

Elevated rates of glycolysis in cancer cells support tumor growth, in a process that typically depends on oncogene-induced increases in the expression and/or activity of enzymes in the glycolytic pathway. The NEDD9 scaffolding protein is upregulated in many advanced tumors, with increased NEDD9 promoting the activity of SRC and other effectors that promote invasion and metastasis. We here define a new role for NEDD9 in support of glycolysis. NEDD9 knockdown significantly impaired glycolysis in multiple lung cancer cell lines This was accompanied by post-transcriptional downregulation of steady-state levels of hexokinases (HK1 and HK2), which catalyze early steps in the glycolytic cascade, key rate limiting enzyme phosphofructokinase (PFK1), and downstream glyceraldehyde phosphate dehydrogenase (GAPDH). In mice, protein levels of HK1, HK2, PFK1, and GAPDH were depressed in Krastm4Tyj/J/Trp53tm1Brn/J (KP) non-small cell lung tumors with null versus wild type Nedd9. Reciprocally, depletion of HK1 or HK2 elevated NEDD9 expression, as did the treatment of cells with 2-deoxyglucose (2DG), an inhibitor of glycolysis; whereas overexpression of hexokinases promoted NEDD9 dephosphorylation, associated with reduced NEDD9 activity. Together, these data for the first time suggest a negative feedback circuit involving NEDD9 and glycolytic enzymes that may contribute to NEDD9 action in promoting the aggressive growth of advanced tumors.
The association between midlife living arrangement and psychiatrist-diagnosed depression in later life: who among your family members reduces the risk of depression?
Authors: Ogawa Kento , Shirai Kokoro , Nozaki Shoko , Shikimoto Ryo , Sawada Norie , Mimura Masaru , Iso Hiroyasu , Tsugane Shoichiro ,   for the Japan Public Health Center-based Prospective Study Group
Published: April 2022

This study investigates the longitudinal association between living arrangements and psychiatrists’ diagnosis of depression in the general population. In 1990, 1254 Japanese men and women aged 40–59 years were enroled and completed questionnaires on the living arrangement in the Japan Public Health Center-based Prospective Study (JPHC Study) and participated in a mental health screening (2014–2015). The study diagnosed a major depressive disorder (MDD) assessed by well-trained certified psychiatrists through medical examinations. During the follow-up, a total of 105 participants (36 men and 69 women) aged 64–84 years were diagnosed with MDD by psychiatrists. Living with a child (ren) was associated with a reduced risk of MDD for men but not for women; the respective multivariable ORs (95% CIs) were 0.42 (0.19–0.96) and 0.59 (0.32–1.09). These associations remained unchanged after adjusting for living with spouse and parent(s). In conclusion, living with a child (ren) was associated with a reduced risk of MDD in men, suggesting the role of a child (ren) in the prevention of MDD.
Large-scale real-world data analysis identifies comorbidity patterns in schizophrenia
Authors: Lu Chenyue , Jin Di , Palmer Nathan , Fox Kathe , Kohane Isaac S. , Smoller Jordan W. , Yu Kun-Hsing
Published: April 2022

Schizophrenia affects >3.2 million people in the USA. However, its comorbidity patterns have not been systematically characterized in real-world populations. To address this gap, we conducted an observational study using a cohort of 86 million patients in a nationwide health insurance dataset. We identified participants with schizophrenia and those without schizophrenia matched by age, sex, and the first three digits of zip code. For each phenotype encoded in phecodes, we compared their prevalence in schizophrenia patients and the matched non-schizophrenic participants, and we performed subgroup analyses stratified by age and sex. Results show that anxiety, posttraumatic stress disorder, and substance abuse commonly occur in adolescents and young adults prior to schizophrenia diagnoses. Patients aged 60 and above are at higher risks of developing delirium, alcoholism, dementia, pelvic fracture, and osteomyelitis than their matched controls. Type 2 diabetes, sleep apnea, and eating disorders were more prevalent in women prior to schizophrenia diagnosis, whereas acute renal failure, rhabdomyolysis, and developmental delays were found at higher rates in men. Anxiety and obesity are more commonly seen in patients with schizoaffective disorders compared to patients with other types of schizophrenia. Leveraging a large-scale insurance claims dataset, this study identified less-known comorbidity patterns of schizophrenia and confirmed known ones. These comorbidity profiles can guide clinicians and researchers to take heed of early signs of co-occurring diseases.
The role of ADHD genetic risk in mid-to-late life somatic health conditions
Authors: Garcia-Argibay Miguel , du Rietz Ebba , Lu Yi , Martin Joanna , Haan Elis , Lehto Kelli , Bergen Sarah E. , Lichtenstein Paul , Larsson Henrik , Brikell Isabell
Published: April 2022

Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42–88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors.
Cutaneous manifestations of monoclonal gammopathy
Authors: Claveau Jean-Sebastien , Wetter David A. , Kumar Shaji
Published: April 2022

Monoclonal gammopathy associated with dermatological manifestations are a well-recognized complication. These skin disorders can be associated with infiltration and proliferation of a malignant plasma cells or by a deposition of the monoclonal immunoglobulin in a nonmalignant monoclonal gammopathy. These disorders include POEMS syndrome, light chain amyloidosis, Schnitzler syndrome, scleromyxedema and TEMPI syndrome. This article provides a review of clinical manifestations, diagnostics criteria, natural evolution, pathogenesis, and treatment of these cutaneous manifestations.
Neurotropic EV71 causes encephalitis by engaging intracellular TLR9 to elicit neurotoxic IL12-p40-iNOS signaling
Authors: Lai Rai-Hua , Chow Yen-Hung , Chung Nai-Hsiang , Chen Tsan-Chi , Shie Feng-Shiun , Juang Jyh-Lyh
Published: April 2022

Brainstem encephalitis, a manifestation of severe enterovirus 71 (EV71) infection, is an acute excessive inflammatory response. The mechanisms underlying its development remain poorly understood. Usually neurotropic viruses trigger acute host immune response by engaging cell surface or intracellular receptors. Here, we show that EV71 engagement with intracellular receptor TLR9 elicits IL-12p40-iNOS signaling causing encephalitis in mice. We identified IL-12p40 to be the only prominent cytokine-induced at the early infection stage in the brainstem of mice subjected to a lethal dose of EV71. The upregulated IL-12p40 proteins were expressed in glial cells but not neuronal cells. To better understand the role of IL-12p40 in severe EV71 infection, we treated the EV71-infected mice with an antibody against IL-12p40 and found the mortality rate, brainstem inflammation, and gliosis to be markedly reduced, suggesting that the acute IL-12p40 response plays a critical role in the pathogenesis of brainstem encephalitis. Mechanistically, intracellular TLR9 was found essential to the activation of the IL-12p40 response. Blocking TLR9 signaling with CpG-ODN antagonist ameliorated IL-12p40 response, brainstem inflammation, and limb paralysis in mice with EV71-induced encephalitis. We further found the glial IL-12p40 response might damage neurons by inducing excess production of neurotoxic NO by iNOS. Overall, EV71 engagement with intracellular TLR9 was found to elicit a neurotoxic glial response via IL12p40-iNOS signaling contributing to the neurological manifestation of EV71 infection. This pathway could potentially be targeted for the treatment of brainstem encephalitis.
Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis
Authors: Wang Bo , Xu Jun , Ren Qian , Cheng Lu , Guo Fan , Liang Yan , Yang Letian , Tan Zhouke , Fu Ping , Ma Liang
Published: April 2022

Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) significantly increases morbidity and mortality. Growing evidence suggests that fatty acid-binding protein 4 (FABP4) is critically involved in kidney diseases, while its role in septic AKI remains unknown. Here, FABP4 was mainly upregulated in renal tubular epithelial cells (RTECs) following cecal ligation and puncture (CLP)- or lipopolysaccharide (LPS)-induced septic AKI. FABP4 inhibition by genetic deletion or BMS309403 treatment both attenuated kidney dysfunction and pathological injury in CLP- or LPS-treated mice. Notably, RTEC-specific deletion of FABP4 also showed similar renoprotective effects. Moreover, FABP4 inhibition alleviated inflammation and apoptosis in CLP-injured kidneys and LPS-stimulated mouse tubular epithelial cells. Mechanistically, TLR4 blockage improved sepsis-induced kidney injury, as well as suppressed c-Jun phosphorylation and FABP4 expression, where c-Jun knockdown also inhibited LPS-stimulated FABP4 level. Meanwhile, FABP4 inhibition reduced the elevated phosphorylated c-Jun, while the levels of TLR4 and MyD88 were uninfluenced. Collectively, the increased FABP4 in RTECs is dependent on TLR4/c-Jun signaling activation and contributes to kidney injury, by forming a positive feedback loop with c-Jun to aggravate inflammation and apoptosis in septic AKI. Thus, FABP4 may be a therapeutic target for septic AKI.
BNIP3 (BCL2 interacting protein 3) regulates pluripotency by modulating mitochondrial homeostasis via mitophagy
Authors: Liu Kun , Zhao Qian , Sun Hongyan , Liu Lei , Wang Chaoqun , Li Zheng , Xu Youqing , Wang Liang , Zhang Lin , Zhang Honghai , Chen Quan , Zhao Tongbiao
Published: April 2022

Autophagy-mediated mitochondrial degradation plays pivotal roles in both the acquisition and maintenance of pluripotency, but the molecular mechanisms that link autophagy-mediated mitochondrial homeostasis to pluripotency regulation are unclear. Here, we identified that the mitophagy receptor BNIP3 regulates pluripotency. In mouse ESCs, depletion of BNIP3 caused accumulation of aberrant mitochondria accompanied by decreased mitochondrial membrane potential, increased production of reactive oxygen species (ROS), and reduced ATP generation, which led to compromised self-renewal and differentiation. Impairment of mitophagy by knockdown of BNIP3 inhibited mitochondrial clearance during pluripotency induction, resulting in decreased reprogramming efficiency. These defects were rescued by reacquisition of wild-type but not LIR-deficient BNIP3 expression. Taken together, our findings highlight a critical role of BNIP3-mediated mitophagy in the induction and maintenance of pluripotency.
Silencing of lncRNA MALAT1 facilitates erastin-induced ferroptosis in endometriosis through miR-145-5p/MUC1 signaling
Authors: Liang Zongwen , Wu Qiong , Wang Honglin , Tan Jiahuan , Wang Han , Gou Yanling , Cao Yingying , Li Zhi , Zhang Zongfeng
Published: April 2022

Endometriosis is a chronic disorder characterized by the implantation of endometrial glands and stroma outside the uterus. However, the pathogenesis of endometriosis is still unclear. To date, there is no fully effective treatment without trauma because of various side effects. Recent data suggest that ferroptosis is a novel recognized form of nonapoptosis-regulated cell death characterized by iron-dependent and lethal lipid peroxidation accumulation, showing great promise in the treatment of many diseases. In the present study, we verified that erastin induced ferroptosis in ectopic endometrial stromal cells (EESCs). Furthermore, we found that the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was decreased during erastin-induced ferroptosis. Knockdown of MALAT1 significantly aggravated the inhibition of cell viability and increased intracellular iron, Liperfluo, and MDA levels in EESCs upon erastin treatment. Mechanistically, we demonstrated that MALAT1 served as a competing endogenous RNA of miR-145-5p to regulate the expression of MUC1, a suppressor of ferroptosis. MALAT1 knockdown-mediated ferroptotic cell death and MUC1 downregulation could be abrogated by inhibition of miR-145-5p. In addition, miR-145-5p inhibition-mediated ferroptotic cell death could be abolished by MUC1 knockdown. Furthermore, erastin-induced ferroptosis shrunk endometriotic lesions via the MALAT1/miR-145-5p/MUC1 axis in vivo. Taken together, our data indicate that knockdown of MALAT1 facilitates ferroptosis upon erastin treatment via miR-145-5p/MUC1 signaling. The synergistic effect of MALAT1 knockdown and erastin induction in ferroptosis may be a new therapeutic strategy for endometriosis.
NAMPT-dependent NAD+ salvage is crucial for the decision between apoptotic and necrotic cell death under oxidative stress
Authors: Nishida Takuto , Naguro Isao , Ichijo Hidenori
Published: April 2022

Oxidative stress is a state in which the accumulation of reactive oxygen species exceeds the capacity of cellular antioxidant systems. Both apoptosis and necrosis are observed under oxidative stress, and we have reported that these two forms of cell death are induced in H2O2-stimulated HeLa cells depending on the concentration of H2O2. Weak H2O2stimulation induces apoptosis, while strong H2O2stimulation induces necrosis. However, the detailed mechanisms controlling the switching between these forms of cell death depending on the level of oxidative stress remain elusive. Here, we found that NAD+metabolism is a key factor in determining the form of cell death in H2O2-stimulated HeLa cells. Under both weak and strong H2O2stimulation, intracellular nicotinamide adenine dinucleotide (NAD+) was depleted to a similar extent by poly (ADP-ribose) (PAR) polymerase 1 (PARP1)-dependent consumption. However, the intracellular NAD+concentration recovered under weak H2O2stimulation but not under strong H2O2stimulation. NAD+recovery was mediated by nicotinamide (NAM) phosphoribosyltransferase (NAMPT)-dependent synthesis via the NAD+salvage pathway, which was suggested to be impaired only under strong H2O2stimulation. Furthermore, downstream of NAD+, the dynamics of the intracellular ATP concentration paralleled those of NAD+, and ATP-dependent caspase-9 activation via apoptosome formation was thus impaired under strong H2O2stimulation. Collectively, these findings suggest that NAD+dynamics balanced by PARP1-dependent consumption and NAMPT-dependent production are important to determine the form of cell death activated under oxidative stress.
3D nanoprinting via spatially controlled assembly and polymerization
Authors: Pattison Thomas G. , Wang Shuo , Miller Robert D. , Liu Gang-yu , Qiao Greg G.
Published: April 2022

Macroscale additive manufacturing has seen significant advances recently, but these advances are not yet realized for the bottom-up formation of nanoscale polymeric features. We describe a platform technology for creating crosslinked polymer features using rapid surface-initiated crosslinking and versatile macrocrosslinkers, delivered by a microfluidic-coupled atomic force microscope known as FluidFM. A crosslinkable polymer containing norbornene moieties is delivered to a catalyzed substrate where polymerization occurs, resulting in extremely rapid chemical curing of the delivered material. Due to the living crosslinking reaction, construction of lines and patterns with multiple layers is possible, showing quantitative material addition from each deposition in a method analogous to fused filament fabrication, but at the nanoscale. Print parameters influenced printed line dimensions, with the smallest lines being 450 nm across with a vertical layer resolution of 2 nm. This nanoscale 3D printing platform of reactive polymer materials has applications for device fabrication, optical systems and biotechnology.
Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86
Authors: Liu Haiyin , Wilson Kayla R. , Firth Ashley M. , Macri Christophe , Schriek Patrick , Blum Annabelle B. , Villar Javiera , Wormald Samuel , Shambrook Mitch , Xu Bangyan , Lim Hui Jing , McWilliam Hamish E. G. , Hill Andrew F. , Edgington-Mitchell Laura E. , Caminschi Irina , Lahoud Mireille H. , Segura Elodie , Herold Marco J. , Villadangos Jose A. , Mintern Justine D.
Published: April 2022

The MARCH E3 ubiquitin (Ub) ligase MARCH1 regulates trafficking of major histocompatibility complex class II (MHC II) and CD86, molecules of critical importance to immunity. Here we show, using a genome-wide CRISPR knockout screen, that ubiquitin-like protein 3 (UBL3) is a necessary component of ubiquitination-mediated trafficking of these molecules in mice and in humans. Ubl3-deficient mice have elevated MHC II and CD86 expression on the surface of professional and atypical antigen presenting cells. UBL3 also regulates MHC II and CD86 in human dendritic cells (DCs) and macrophages. UBL3 impacts ubiquitination of MARCH1 substrates, a mechanism that requires UBL3 plasma membrane anchoring via prenylation. Loss of UBL3 alters adaptive immunity with impaired development of thymic regulatory T cells, loss of conventional type 1 DCs, increased number of trogocytic marginal zone B cells, and defective in vivo MHC II and MHC I antigen presentation. In summary, we identify UBL3 as a conserved, critical factor in MARCH1-mediated ubiquitination with important roles in immune responses.