bluuebunny/crossref_metadata_2025 huggingface dataset:
Academic Freedom and the Transnational Production of Knowledge
Authors: Kiwan Dina
Published: January 2024

Public debates on academic freedom have become increasingly contentious, and understandings of what it is and its purposes are contested within the academy, policymakers and the general public. Drawing on rich empirical interview data, this book critically examines the understudied relationship between academic freedom and its role in knowledge production across four country contexts - Lebanon, the UAE, the UK and the US - through the lived experiences of academics conducting 'controversial' research. It provides an empirically-informed transnational theory of academic freedom, contesting the predominantly national constructions of academic freedom and knowledge production and the methodological nationalism of the field. It is essential reading for academics and students of the sociology of education, as well as anyone interested in this topic of global public concern. This title is part of the Flip it Open Programme and may also be available Open Access. Check our website Cambridge Core for details.
The importance of sub-meter-scale snow roughness on conductive heat flux of Arctic sea ice
Authors: Clemens-Sewall David , Polashenski Chris , Perovich Don , Webster Melinda Anne
Published: January 2024

The conductive heat flux through the snow and ice is a critical component of the mass and energy budgets in the Arctic sea ice system. We use high horizontal resolution (3–15 cm) measurements of snow topography to explore the impacts of sub-meter-scale snow surface roughness on heat flux as simulated by the Finite Element method. Simulating horizontal heat flux in a variable snow cover modestly increases the total simulated heat flux. With horizontal heat flux, as opposed to simple 1D-vertical heat flux modeling, the simulated heat flux is 10% greater than that for uniform snow with the same mean snow thickness for a 31.5 × 21 m region of sea ice (the largest region we studied). Vertical-only (1D) heat flux simulates just a 6% increase for the same region. However, this is highly dependent on observation resolution. Had we measured the snow cover at 1 m horizontal spacing or greater, simulating horizontal heat flux would not have changed the net heat flux from that simulated with vertical-only heat flux. These findings suggest that measuring and modeling snow roughness at sub-meter horizontal scales may be necessary to accurately represent horizontal heat flux on level Arctic sea ice.
Performance characterization of a new, low-cost multi-GNSS instrument for the cryosphere
Authors: Pickell Derek James , Hawley Robert Lyman
Published: January 2024

We developed a multi-frequency, multi-Global Navigation Satellite System (GNSS) positioning instrument optimized for autonomous applications in the cryosphere. At lower power requirements and a fraction of the cost and weight compared to commercially available options, this instrument simplifies field usage and associated logistics. In this paper, we assess several baseline aspects of performance in a polar environment relative to geodetic receivers commonly used for glaciological applications. Evaluations of precision and relative accuracy of positioning show millimeter to centimeter-level (‘geodetic-grade’) quality of this instrument, making it a competitive alternative for GNSS glaciological and geophysical applications such as monitoring surface elevation change and ice flow. An array of these instruments, tested in the field on the Greenland Ice Sheet, also demonstrated robustness throughout the polar winter and met power and reliability requirements.
What emerging technologies and innovations present opportunities for economic repurposing of mined land, assets, and waste materials?
Authors: Perlatti Fabio , Gagen Emma J.
Published: January 2024

The definition of the future use of mined lands should be considered early in the life cycle of a mine. Well-established concepts, such as “Begin with the end in mind” or “Design for closure,” have at their core the idea of having in mind the intended use of the mined area before the cessation of operational activities. However, closure is complex and the optimal future use of a mined area involves evaluation of environmental, social, and economic aspects, all of which change through the life of a mine. Closure is also a dynamic and iterative process that needs to be integrated into operations, while accounting for the possibility of temporary or sudden closure (ICMM, 2019).
The practice of polygyny on the utilisation of reproductive health services among married women in Ghana
Authors: Kumbeni Maxwell Tii , Alem John Ndebugri , Ziba Florence Assibi , Afaya Agani , Apanga Paschal Awingura
Published: January 2024

While the practice of polygyny is common in Ghana, little is known about its impact on the use of reproductive health services. The aim of this study was to assess the relationship between polygynous marriage and the utilisation of skilled antenatal care (ANC), assisted skilled birth, and modern contraceptive services among married women in Ghana. Secondary data from the 2017 Ghana Maternal Health Survey were used for this study. The study included a weighted sample of 9,098 married women aged 15–49 years. We used multivariable logistic regression models to assess the association between polygyny and each outcome variables. Sensitivity analysis was conducted to assess the dose–response relationship between polygyny and each outcome variable. The prevalence of eight or more ANC contacts, assisted skilled births, and use of modern contraception were 47.0%, 81.4%, and 25.4%, respectively. The prevalence of women in polygynous marriages was 15.3%. Compared to monogynous marriage, polygynous marriage was associated with 19% lower odds of having eight plus ANC contacts (adjusted odds ratio [aOR] 0.81, 95% CI: 0.69, 0.96), 25% lower odds of having assisted skilled birth (aOR 0.75, 95% CI: 0.63, 0.89), and 19% lower odds of modern contraceptive utilisation (aOR 0.81, 95% CI: 0.66, 0.99). Interventions on reproductive health may need to prioritise women in polygynous marriages in order to improve the utilisation of skilled ANC, assisted skilled birth, and modern contraceptive services.
Bioclimatic predictors of forest structure, composition and phenology in the Paraguayan Dry Chaco
Authors: Ruiz-Díaz Susana , Pérez de Molas Lidia Florencia , Benítez-León Enrique , Almeyda Zambrano Angélica María , Johnson Daniel J. , Bohlman Stephanie , Broadbent Eben North
Published: January 2024

One of the largest remnants of tropical dry forest is the South American Gran Chaco. A quarter of this biome is in Paraguay, but there have been few studies in the Paraguayan Chaco. The Gran Chaco flora is diverse in structure, function, composition and phenology. Fundamental ecological questions remain in this biome, such as what bioclimatic factors shape the Chaco’s composition, structure and phenology. In this study, we integrated forest inventories from permanent plots with monthly high-resolution NDVI from PlanetScope and historical climate data from WorldClim to identify bioclimatic predictors of forest structure, composition and phenology. We found that bioclimatic variables related to precipitation were correlated with stem density and Pielou evenness index, while temperature-related variables correlated with basal area. The best predictor of forest phenology (NDVI variation) was precipitation lagged by 1 month followed by temperature lagged by 2 months. In the period with most water stress, the phenological response correlates with diversity, height and basal area, showing links with dominance and tree size. Our results indicate that even if the ecology and function of Dry Chaco Forest is characterised by water limitation, temperature has a moderating effect by limiting growth and influencing leaf flush and deciduousness.
Transatlanticism: A fading paradigm?
Authors: Scott-Smith Giles
Published: January 2024

In 2018, the first full year of the Trump presidency, it became abundantly clear that the transatlantic relationship had entered a period of intense discord, causing a series of pessimistic reports and commentary in the mainstream Anglo-American media. With this as the starting point, the article re-examines the study of the ‘transatlantic’ as a region. It engages with thinking of time (periodisation), space (scale), and discipline (methodology) in order to question standard assumptions and open up new avenues for research, identity-formation, and emancipatory commitment.
Stress and emotion recognition predict the relationship between a history of maltreatment and sensitive parenting behaviors: A moderated-moderation
Authors: Bérubé Annie , Pearson Jessica , Blais Caroline , Forget Hélène
Published: January 2024

Our study proposes to examine how stress and emotion recognition interact with a history of maltreatment to influence sensitive parenting behaviors. A sample of 58 mothers and their children aged between 2 and 5 years old were recruited. Parents’ history of maltreatment was measured using the Child Trauma Questionnaire. An emotion recognition task was performed. Mothers identified the dominant emotion in morphed facial emotion expressions in children. Mothers and children interacted for 15 minutes. Salivary cortisol levels of mothers were collected before and after the interaction. Maternal sensitive behaviors were coded during the interaction using the Coding Interactive Behavior scheme. Results indicate that the severity of childhood maltreatment is related to less sensitive behaviors for mothers with average to good abilities in emotion recognition and lower to average increases in cortisol levels following an interaction with their children. For mothers with higher cortisol levels, there is no association between a history of maltreatment and sensitive behaviors, indicating that higher stress reactivity could act as a protective factor. Our study highlights the complex interaction between individual characteristics and environmental factors when it comes to parenting. These results argue for targeted interventions that address personal trauma.
Exploring genetic diversity of Centella asiatica (L.) Urb. across six Korean island regions: implications for conservation and utilization
Authors: Lee Shin Ae , Seo Hyemin , Han Seahee , Jeong Jun Seong , Jung Tae Won , Lee Kyung Jun
Published: January 2024

Despite the increasing demand for diverse Centella asiatica (L.) Urb. species in Korea, studies on related topics are limited, with the majority of studies focusing on functional evaluations, rather than genetic diversity. Therefore, in this study, we explored the genetic diversity of C. asiatica, a valuable medicinal plant collected from six island regions in Korea, using genotyping-by-sequencing analysis. Specifically, we aimed to understand plant genetic variations, population structure and the potential for conservation and genetic improvement. The results indicated relatively high genetic diversity among the samples collected from the six island regions but low genetic differentiation among their populations. Two distinct genetic clusters were identified; however, even within these clusters, genetic differentiation was minimal. The lack of significant isolation-by-distance patterns and evidence of potential clonal spread suggested that some individuals that adapted to colder Korean conditions achieved dominance. This study highlights the importance of assessing the genetic diversity of native C. asiatica in Korea and explores the possibility of conducting follow-up studies to understand the phytochemical content and bioactivity variations among the individuals. This information can aid in the selection of superior resources and effective utilization of plant genetic resources for cultivar development and other applications.
Controlling Factors on REY Enrichments in Basins From the Pacific Ocean: Early Diagenesis and Local Constraints
Authors: Liao Jianlin , Chen Jieyun , Sun Xiaoming , Deng Yinan , Wang Yanjingyu , Wang Dajin , Hong Gang , Klose Lukas , Koschinsky Andrea
Published: January 2024

Increasing interest in high‐tech metals (e.g., rare earth elements and yttrium, REY) has triggered extensive research on the enrichment of these metals in pelagic sediments. In the sediments collected worldwide, Ca‐phosphate and Fe‐Mn (oxyhydr)oxides are targeted as the two most important REY carriers based on multiple geochemical and mineralogical analyses. However, the formation of the REY‐rich stratum remains enigmatic as the influences of diagenesis and the local restrictions of different oceanic basins are complex, which require further investigation. In our study, we analyzed four sediment cores from the Western, Central North, and Eastern South Pacific (WP, CNP, and ESP), which are three of the most promising REY‐rich regions in global oceans. Sequential leaching quantifies the dominance of Ca‐phosphate by controlling ∼73.9%–93.3% of ΣREY and the secondary role of Fe‐Mn (oxyhydr)oxides by holding up to ∼97.8% of Ce and ∼4.82%–13.9% of ΣREY. The shallowly and deeply buried sediments show similar features regarding the REY proportions hosted by different phases, which indicates that the REY accumulation by Ca‐phosphate might majorly occur on the seawater‐sediment interface. The geochemistry of the studied sediment cores reveals that (a) REY enrichment in ESP is affected by hydrothermal Fe‐Mn (oxyhydr)oxides which can promote adsorptions of P and REY. (b) The Fe and Mn contents in WP sediments show an inverse relationship against REY enrichment which might be explained by the dust input from Central Asia. (c) The slow sedimentation rate of CNP enables the extraordinary REY‐uptake by Ca‐phosphate, but the low flux of phosphorus constrains the formation of high‐grade REY deposits.
Precipitation Scaling in Extreme Rainfall Events and the Implications for Future Indian Monsoon: Analysis of High‐Resolution Global Climate Model Simulations
Authors: Varghese Stella Jes , Surendran Sajani , Rajendran Kavirajan , Ghosh Subimal , Kitoh Akio , Ashok Karumuri
Published: January 2024

The increase in water holding capacity of the atmosphere with temperature, given by the Clausius‐Clapeyron (CC) relationship, describes the changes in extreme rainfall intensities at warmer atmospheric states. We study the characteristics of extreme rainfall events (EREs) during the Indian summer monsoon season with respect to thermodynamic changes and precipitation‐scaling over the Indian subcontinent and its homogeneous rainfall zones. We utilize outputs from a present‐day climate simulation and a time‐slice future climate change projection experiments of a high‐resolution global climate model. Large changes are seen for very EREs (vEREs) which suggests their sensitivity to warmer temperatures. In future, the altered radiative forcing will heat up the upper atmosphere, stabilize it and offset the effect of increasing humidity on precipitation intensity. Our analysis also suggests that more convective clouds and the interplay of increased moisture content and circulation will result in future changes in EREs.
Understanding Rapid Intensification of Typhoon Mujigae in 2015: Insights From Kinetic and Potential Energy Budgets
Authors: Zhang Chi , Li Xiaofan , Zhai Guoqing , Shen Xinyong
Published: January 2024

This study investigated the kinetic and potential energy budgets during the slow (SI) and rapid intensification (RI) periods of Typhoon Mujigae, which occurred in October 2015, by conducting a Weather Research and Forecasting model simulation. We found that the kinetic energy conversion between asymmetric and symmetric rotational circulations in the lower troposphere plays a pivotal role in initiating the difference in the tendency of symmetric rotational kinetic energy between the RI and SI via the horizontal advection process of asymmetric circulations. Southerly and easterly environmental flows transported asymmetric anticyclonic flows in SI and cyclonic flows in RI to the radius of maximum wind, respectively, where asymmetric rotational circulation was developed by vertical shear of environmental flow. Such transports initiate the growth of symmetric cyclonic rotational circulation from SI to RI. The kinetic energy conversion of symmetric divergent circulations supported by symmetric potential energy accelerates the growth of symmetric rotational kinetic energy from SI to RI. These findings can shed light on the fundamental dynamics of the RI of tropical cyclones.
WTAP-mediated m6A modification of FRZB triggers the inflammatory response via the Wnt signaling pathway in osteoarthritis
Authors: An Xueying , Wang Rongliang , Lv Zhongyang , Wu Wenshu , Sun Ziying , Wu Rui , Yan Wenjin , Jiang Qing , Xu Xingquan
Published: January 2024

Osteoarthritis (OA) is the most common form of arthritis. However, the exact pathogenesis remains unclear. Emerging evidence shows that N6-methyladenosine (m6A) modification may have an important role in OA pathogenesis. This study aimed to investigate the role of m6A writers and the underlying mechanisms in osteoarthritic cartilage. Among m6A methyltransferases, Wilms tumor 1-associated protein (WTAP) expression most significantly differed in clinical osteoarthritic cartilage. WTAP regulated extracellular matrix (ECM) degradation, inflammation and antioxidation in human chondrocytes. Mechanistically, the m6A modification and relative downstream targets in osteoarthritic cartilage were assessed by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing, which indicated that the expression of frizzled-related protein (FRZB), a secreted Wnt antagonist, was abnormally decreased and accompanied by high m6A modification in osteoarthritic cartilage. In vitro dysregulated WTAP had positive effects on β-catenin expression by targeting FRZB, which finally contributed to the cartilage injury phenotype in chondrocytes. Intra-articular injection of adeno-associated virus-WTAP alleviated OA progression in a mouse model, while this protective effect could be reversed by the application of a Wnt/β-catenin activator. In summary, this study revealed that WTAP-dependent RNA m6A modification contributed to Wnt/β-catenin pathway activation and OA progression through post-transcriptional regulation of FRZB mRNA, thus providing a potentially effective therapeutic strategy for OA treatment.
4-1BB immunotherapy: advances and hurdles
Authors: Singh Rohit , Kim Young-Ho , Lee Sang-Jin , Eom Hyeon-Seok , Choi Beom K.
Published: January 2024

Since its initial description 35 years ago as an inducible molecule expressed in cytotoxic and helper T cells, 4-1BB has emerged as a crucial receptor in T-cell-mediated immune functions. Numerous studies have demonstrated the involvement of 4-1BB in infection and tumor immunity. However, the clinical development of 4-1BB agonist antibodies has been impeded by the occurrence of strong adverse events, notably hepatotoxicity, even though these antibodies have exhibited tremendous promise in in vivo tumor models. Efforts are currently underway to develop a new generation of agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while mitigating adverse effects. In this review, we briefly examine the role of 4-1BB in T-cell biology, explore its clinical applications, and discuss future prospects in the field of 4-1BB agonist immunotherapy.
GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents
Authors: Klein Adam K. , Austin Eric W. , Cunningham Michael J. , Dvorak Dino , Gatti Silvia , Hulls Sarah K. , Kiss Laszlo , Kruegel Andrew C. , Marek Gerard J. , Papp Mariusz , Sporn Jonathan , Hughes Zoë A.
Published: January 2024

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.
Parental and child genetic burden of glycaemic dysregulation and early-life cognitive development: an Asian and European prospective cohort study
Authors: Huang Jian , Kee Michelle Z. L. , Law Evelyn C. , Sum Ka Kei , Silveira Patricia Pelufo , Godfrey Keith M. , Daniel Lourdes Mary , Tan Kok Hian , Chong Yap Seng , Chan Shiao-Yng , Eriksson Johan G. , Meaney Michael J. , Huang Jonathan Yinhao
Published: January 2024

Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at ~7 years (β = −0. 141, p-value = 0.024, 95% CI −0. 264 to −0. 018) and a lower WIAT-III mean score at ~9 years (β = −0.222, p-value = 0.001, 95% CI −0.357 to −0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at ~7 years (β = −0.172, p-value = 0.002, 95% CI −0.280 to −0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at ~8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better.
Resistance to BRAF inhibition explored through single circulating tumour cell molecular profiling in BRAF-mutant non-small-cell lung cancer
Authors: Mezquita Laura , Oulhen Marianne , Aberlenc Agathe , Deloger Marc , Aldea Mihaela , Honore Aurélie , Lecluse Yann , Howarth Karen , Friboulet Luc , Besse Benjamin , Planchard David , Farace Françoise
Published: January 2024

Background

Resistance mechanisms to combination therapy with dabrafenib plus trametinib remain poorly understood in patients with BRAFV600E-mutant advanced non-small-cell lung cancer (NSCLC). We examined resistance to BRAF inhibition by single CTC sequencing in BRAFV600E-mutant NSCLC.

Methods

CTCs and cfDNA were examined in seven BRAFV600E-mutant NSCLC patients at failure to treatment. Matched tumour tissue was available for four patients. Single CTCs were isolated by fluorescence-activated cell sorting following enrichment and immunofluorescence (Hoechst 33342/CD45/pan-cytokeratins) and sequenced for mutation and copy number-alteration (CNA) analyses.

Results

BRAFV600E was found in 4/4 tumour biopsies and 5/7 cfDNA samples. CTC mutations were mostly found in MAPK-independent pathways and only 1/26 CTCs were BRAFV600E mutated. CTC profiles encompassed the majority of matched tumour biopsy CNAs but 72.5% to 84.5% of CTC CNAs were exclusive to CTCs. Extensive diversity, involving MAPK, MAPK-related, cell cycle, DNA repair and immune response pathways, was observed in CTCs and missed by analyses on tumour biopsies and cfDNA. Driver alterations in clinically relevant genes were recurrent in CTCs.

Conclusions

Resistance was not driven by BRAFV600E-mutant CTCs. Extensive tumour genomic heterogeneity was found in CTCs compared to tumour biopsies and cfDNA at failure to BRAF inhibition, in BRAFV600E-mutant NSCLC, including relevant alterations that may represent potential treatment opportunities.
Bivalent activity of super-enhancer RNA LINC02454 controls 3D chromatin structure and regulates glioma sensitivity to temozolomide
Authors: Shi Tengfei , Guo Dianhao , Zheng Yaoqiang , Wang Wenbin , Bi Jinfang , He Anshun , Fan Sibo , Su Guangsong , Zhao Xueyuan , Zhao Zhenhao , Song Yingjie , Sun Shupeng , Li Peng , Zhao Zhongfang , Shi Jiandang , Lu Wange , Zhang Lei
Published: January 2024

Glioma cell sensitivity to temozolomide (TMZ) is critical for effective treatment and correlates with patient survival, although mechanisms underlying this activity are unclear. Here, we reveal a new mechanism used by glioma cells to modulate TMZ sensitivity via regulation of SORBS2 and DDR1 genes by super-enhancer RNA LINC02454. We report that LINC02454 activity increases glioma cell TMZ sensitivity by maintaining long-range chromatin interactions between SORBS2 and the LINC02454 enhancer. By contrast, LINC02454 activity also decreased glioma cell TMZ sensitivity by promoting DDR1 expression. Our study suggests a bivalent function for super-enhancer RNA LINC02454 in regulating glioma cell sensitivity to TMZ.
A cross-scale framework for evaluating flexibility values of battery and fuel cell electric vehicles
Authors: Liu Ruixue , He Guannan , Wang Xizhe , Mallapragada Dharik , Zhao Hongbo , Shao-Horn Yang , Jiang Benben
Published: January 2024

Flexibility has become increasingly important considering the intermittency of variable renewable energy in low-carbon energy systems. Electrified transportation exhibits great potential to provide flexibility. This article analyzed and compared the flexibility values of battery electric vehicles and fuel cell electric vehicles for planning and operating interdependent electricity and hydrogen supply chains while considering battery degradation costs. A cross-scale framework involving both macro-level and micro-level models was proposed to compute the profits of flexible EV refueling/charging with battery degradation considered. Here we show that the flexibility reduction after considering battery degradation is quantified by at least 4.7% of the minimum system cost and enlarged under fast charging and low-temperature scenarios. Our findings imply that energy policies and relevant management technologies are crucial to shaping the comparative flexibility advantage of the two transportation electrification pathways. The proposed cross-scale methodology has broad implications for the assessment of emerging energy technologies with complex dynamics.
VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity
Authors: Bapat Ojasee , Purimetla Tejas , Kruessel Sarah , Shah Monil , Fan Ruolin , Thum Christina , Rupprecht Fiona , Langer Julian D. , Rangaraju Vidhya
Published: January 2024

Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.
Longevity interventions modulate mechanotransduction and extracellular matrix homeostasis in C. elegans
Authors: Teuscher Alina C. , Statzer Cyril , Goyala Anita , Domenig Seraina A. , Schoen Ingmar , Hess Max , Hofer Alexander M. , Fossati Andrea , Vogel Viola , Goksel Orcun , Aebersold Ruedi , Ewald Collin Y.
Published: January 2024

Dysfunctional extracellular matrices (ECM) contribute to aging and disease. Repairing dysfunctional ECM could potentially prevent age-related pathologies. Interventions promoting longevity also impact ECM gene expression. However, the role of ECM composition changes in healthy aging remains unclear. Here we perform proteomics and in-vivo monitoring to systematically investigate ECM composition (matreotype) during aging in C. elegans revealing three distinct collagen dynamics. Longevity interventions slow age-related collagen stiffening and prolong the expression of collagens that are turned over. These prolonged collagen dynamics are mediated by a mechanical feedback loop of hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression and longevity via the transcriptional co-activator YAP-1 across tissues. Our results provide in-vivo evidence that coordinated ECM remodeling through mechanotransduction is required and sufficient to promote longevity, offering potential avenues for interventions targeting ECM dynamics.
Muscle abnormalities worsen after post-exertional malaise in long COVID
Authors: Appelman Brent , Charlton Braeden T. , Goulding Richie P. , Kerkhoff Tom J. , Breedveld Ellen A. , Noort Wendy , Offringa Carla , Bloemers Frank W. , van Weeghel Michel , Schomakers Bauke V. , Coelho Pedro , Posthuma Jelle J. , Aronica Eleonora , Joost Wiersinga W. , van Vugt Michèle , Wüst Rob C. I.
Published: January 2024

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
Stalled response near thermal equilibrium in periodically driven systems
Authors: Dabelow Lennart , Reimann Peter
Published: January 2024

The question of how systems respond to perturbations is ubiquitous in physics. Predicting this response for large classes of systems becomes particularly challenging if many degrees of freedom are involved and linear response theory cannot be applied. Here, we consider isolated many-body quantum systems which either start out far from equilibrium and then thermalize, or find themselves near thermal equilibrium from the outset. We show that time-periodic perturbations of moderate strength, in the sense that they do not heat up the system too quickly, give rise to the following phenomenon of stalled response: While the driving usually causes quite considerable reactions as long as the unperturbed system is far from equilibrium, the driving effects are strongly suppressed when the unperturbed system approaches thermal equilibrium. Likewise, for systems prepared near thermal equilibrium, the response to the driving is barely noticeable right from the beginning. Numerical results are complemented by a quantitatively accurate analytical description and by simple qualitative arguments.
TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence
Authors: Ren Jiang , Wang Shuai , Zong Zhi , Pan Ting , Liu Sijia , Mao Wei , Huang Huizhe , Yan Xiaohua , Yang Bing , He Xin , Zhou Fangfang , Zhang Long
Published: January 2024

Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NP’s ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviral immune response is suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation and a newly identified SUMO-interacting motif in SARS2-NP. Importantly, the widespread SARS2-NP R203K mutation gains a novel site of SUMOylation which further increases SARS2-NP’s LLPS and immunosuppression. Notably, the SUMO E3 ligase TRIM28 is responsible for catalyzing SARS2-NP SUMOylation. An interfering peptide targeting the TRIM28 and SARS2-NP interaction was screened out to block SARS2-NP SUMOylation and LLPS, and consequently inhibit SARS-CoV-2 replication and rescue innate antiviral immunity. Collectively, these data support SARS2-NP SUMOylation is critical for SARS-CoV-2 virulence, and therefore provide a strategy to antagonize SARS-CoV-2.
Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
Authors: Luo Zhangyi , Huang Yixian , Batra Neelu , Chen Yuang , Huang Haozhe , Wang Yifei , Zhang Ziqian , Li Shichen , Chen Chien-Yu , Wang Zehua , Sun Jingjing , Wang Qiming Jane , Yang Da , Lu Binfeng , Conway James F. , Li Lu-Yuan , Yu Ai-Ming , Li Song
Published: January 2024

The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. iRhom1 plays a role in cancer cell proliferation and its expression is negatively correlated with immune cell infiltration. Here we show that iRhom1 decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by reducing the stability of ERAP1 protein and the ERAP1-mediated antigen processing and presentation. To facilitate the therapeutic translation of these findings, we develop a biodegradable nanocarrier that is effective in codelivery of iRhom pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. This nanocarrier is effective in tumor targeting and penetration through both enhanced permeability and retention effect and CD44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of iRhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment.
Temporal dendritic heterogeneity incorporated with spiking neural networks for learning multi-timescale dynamics
Authors: Zheng Hanle , Zheng Zhong , Hu Rui , Xiao Bo , Wu Yujie , Yu Fangwen , Liu Xue , Li Guoqi , Deng Lei
Published: January 2024

It is widely believed the brain-inspired spiking neural networks have the capability of processing temporal information owing to their dynamic attributes. However, how to understand what kind of mechanisms contributing to the learning ability and exploit the rich dynamic properties of spiking neural networks to satisfactorily solve complex temporal computing tasks in practice still remains to be explored. In this article, we identify the importance of capturing the multi-timescale components, based on which a multi-compartment spiking neural model with temporal dendritic heterogeneity, is proposed. The model enables multi-timescale dynamics by automatically learning heterogeneous timing factors on different dendritic branches. Two breakthroughs are made through extensive experiments: the working mechanism of the proposed model is revealed via an elaborated temporal spiking XOR problem to analyze the temporal feature integration at different levels; comprehensive performance benefits of the model over ordinary spiking neural networks are achieved on several temporal computing benchmarks for speech recognition, visual recognition, electroencephalogram signal recognition, and robot place recognition, which shows the best-reported accuracy and model compactness, promising robustness and generalization, and high execution efficiency on neuromorphic hardware. This work moves neuromorphic computing a significant step toward real-world applications by appropriately exploiting biological observations.
Cation-π interactions enabled water-stable perovskite X-ray flat mini-panel imager
Authors: Pan Wanting , He Yuhong , Li Weijun , Liu Lulu , Guo Keke , Zhang Jianglei , Wang Chao , Li Bao , Huang Hu , Zhang Junhu , Yang Bai , Wei Haotong
Published: January 2024

Sensitive and stable perovskite X-ray detectors are attractive in low-dosage medical examinations. The high sensitivity, tunable chemical compositions, electronic dimensions, and low-cost raw materials make perovskites promising next-generation semiconductors. However, their ionic nature brings serious concerns about their chemical and water stability, limiting their applications in well-established technologies like crystal polishing, micro-processing, photolithography, etc. Herein we report a one-dimensional tryptamine lead iodide perovskite, which is stable in water for several months as the strong cation-π interactions between organic cations. The one-dimensional and two-dimensional tryptamine lead iodide perovskite tablets are switchable through thermal-annealing or water-soaking treatments to relax microstrains. The water-stable and microstrain-free one-dimensional perovskite tablets yield a large sensitivity of 2.5 × 106 μC Gyair−1 cm−2 with the lowest detectable dose rate of 5 nGyair s−1. Microelectrode arrays are realized by surface photolithography to construct high-performance X-ray flat mini-panels with good X-ray imaging capability, and a record spatial resolution of 17.2 lp mm−1 is demonstrated.
Dynamic predictors of COVID-19 vaccination uptake and their interconnections over two years in Hong Kong
Authors: Yuan Jiehu , Xu Yucan , Wong Irene Oi Ling , Lam Wendy Wing Tak , Ni Michael Y. , Cowling Benjamin J. , Liao Qiuyan
Published: January 2024

The global rollout of COVID-19 vaccines faces a significant barrier in the form of vaccine hesitancy. This study adopts a dynamic and network perspective to explore the determinants of COVID-19 vaccine uptake in Hong Kong, focusing on multi-level determinants and their interconnections. Following the framework proposed by the Strategic Advisory Group of Experts (SAGE), the study used repeated cross-sectional surveys to map these determinants at multiple levels and investigates their interconnections simultaneously in a sample of 15,179 over two years. The results highlight the dynamic nature of COVID-19 vaccine hesitancy in an evolving pandemic. The findings suggest that vaccine confidence attitudes play crucial roles in vaccination uptake, with their importance shifting over time. The initial emphasis on vaccine safety gradually transitioned to heightened consideration of vaccine effectiveness at a later stage. The study also highlights the impact of chronic condition, age, COVID-19 case numbers, and non-pharmaceutical preventive behaviours on vaccine uptake. Higher educational attainment and being married were associated with primary and booster vaccine uptake and it may be possible to leverage these groups as early innovation adopters. Trust in government acts as a crucial bridging factor linking various variables in the networks with vaccine confidence attitudes, which subsequently closely linked to vaccine uptake. This study provides insights for designing future effective vaccination programmes for changing circumstances.
Multimodal profiling reveals site-specific adaptation and tissue residency hallmarks of γδ T cells across organs in mice
Authors: du Halgouet Anastasia , Bruder Kerstin , Peltokangas Nina , Darbois Aurélie , Obwegs David , Salou Marion , Thimme Robert , Hofmann Maike , Lantz Olivier , Sagar
Published: January 2024

γδ T cells perform heterogeneous functions in homeostasis and disease across tissues. However, it is unclear whether these roles correspond to distinct γδ subsets or to a homogeneous population of cells exerting context-dependent functions. Here, by cross-organ multimodal single-cell profiling, we reveal that various mouse tissues harbor unique site-adapted γδ subsets. Epidermal and intestinal intraepithelial γδ T cells are transcriptionally homogeneous and exhibit epigenetic hallmarks of functional diversity. Through parabiosis experiments, we uncovered cellular states associated with cytotoxicity, innate-like rapid interferon-γ production and tissue repair functions displaying tissue residency hallmarks. Notably, our observations add nuance to the link between interleukin-17-producing γδ T cells and tissue residency. Moreover, transcriptional programs associated with tissue-resident γδ T cells are analogous to those of CD8+ tissue-resident memory T cells. Altogether, this study provides a multimodal landscape of tissue-adapted γδ T cells, revealing heterogeneity, lineage relationships and their tissue residency program.
Transcription-induced domains form the elementary constraining building blocks of bacterial chromosomes
Authors: Bignaud Amaury , Cockram Charlotte , Borde Céline , Groseille Justine , Allemand Eric , Thierry Agnès , Marbouty Martial , Mozziconacci Julien , Espéli Olivier , Koszul Romain
Published: January 2024

Transcription generates local topological and mechanical constraints on the DNA fiber, leading to the generation of supercoiled chromosome domains in bacteria. However, the global impact of transcription on chromosome organization remains elusive, as the scale of genes and operons in bacteria remains well below the resolution of chromosomal contact maps generated using Hi-C (~5–10 kb). Here we combined sub-kb Hi-C contact maps and chromosome engineering to visualize individual transcriptional units. We show that transcriptional units form discrete three-dimensional transcription-induced domains that impose mechanical and topological constraints on their neighboring sequences at larger scales, modifying their localization and dynamics. These results show that transcriptional domains constitute primary building blocks of bacterial chromosome folding and locally impose structural and dynamic constraints.
Dynamic network curvature analysis of gene expression reveals novel potential therapeutic targets in sarcoma
Authors: Elkin Rena , Oh Jung Hun , Dela Cruz Filemon , Norton Larry , Deasy Joseph O. , Kung Andrew L. , Tannenbaum Allen R.
Published: January 2024

Network properties account for the complex relationship between genes, making it easier to identify complex patterns in their interactions. In this work, we leveraged these network properties for dual purposes. First, we clustered pediatric sarcoma tumors using network information flow as a similarity metric, computed by the Wasserstein distance. We demonstrate that this approach yields the best concordance with histological subtypes, validated against three state-of-the-art methods. Second, to identify molecular targets that would be missed by more conventional methods of analysis, we applied a novel unsupervised method to cluster gene interactomes represented as networks in pediatric sarcoma. RNA-Seq data were mapped to protein-level interactomes to construct weighted networks that were then subjected to a non-Euclidean, multi-scale geometric approach centered on a discrete notion of curvature. This provides a measure of the functional association among genes in the context of their connectivity. In confirmation of the validity of this method, hierarchical clustering revealed the characteristic EWSR1-FLI1 fusion in Ewing sarcoma. Furthermore, assessing the effects of in silico edge perturbations and simulated gene knockouts as quantified by changes in curvature, we found non-trivial gene associations not previously identified.
Evodiae Fructus extract suppresses inflammatory response in HaCaT cells and improves house dust mite-induced atopic dermatitis in NC/Nga mice
Authors: Jin Seong Eun , Seo Chang-Seob , Jeon Woo-Young , Oh Yong Jin , Shin Hyeun-Kyoo , Jeong Hye Gwang , Ha Hyekyung
Published: January 2024

This study was conducted to assess the effect of Evodiae Fructus 70% ethanol extract (EFE) on the pathology of atopic dermatitis using in vitro and in vivo models. The major compounds in EFE were identified by ultra-performance liquid chromatography with tandem mass spectrometry as rutaecarpine, evodiamine, evodol, dehydroevodiamine, limonin, synephrine, evocarpine, dihydroevocarpine, and hydroxyevodiamine. EFE significantly decreased chemokine levels in tumor necrosis factor-α/interferon-γ-stimulated HaCaT cells. In house dust mite-treated NC/Nga mice, topical application of EFE significantly decreased the dermatitis score, epidermal hyperplasia and thickening, mast cell infiltration, and plasma levels of histamine and corticosterone. Thymic stromal lymphopoietin, CD4+ T cells, interleukin-4, and intercellular adhesion molecule-1 expression in the lesioned skin was reduced in the treated mice. The mechanism of EFE was elucidated using transcriptome analysis, followed by experimental validation using Western blotting in HaCaT cells. EFE down-regulated the activation of Janus kinase (JAK)-signal transducers and activators of transcription (STAT) and mitogen-activated protein kinases (MAPK) signaling pathways in HaCaT cells. EFE improves atopic dermatitis-like symptoms by suppressing inflammatory mediators, cytokines, and chemokines by regulating the JAK-STAT and MAPK signaling pathways, suggesting its use as a potential agent for the treatment of atopic dermatitis.