bluuebunny/crossref_metadata_2025 huggingface dataset:
Coxiella burnetii
inhibits nuclear translocation of TFEB, the master transcription factor for lysosomal biogenesis
Authors: Killips Brigham , Heaton Emily J. Bremer , Augusto Leonardo , Omsland Anders , Gilk Stacey D.
Published: July 2024

Coxiella burnetii
is a highly infectious, Gram-negative, obligate intracellular bacterium and the causative agent of human Q fever. The
Coxiella
Containing Vacuole (CCV) is a modified phagolysosome that forms through fusion with host endosomes and lysosomes. While an initial acidic pH < 4.7 is essential to activate
Coxiella
metabolism, the mature, growth-permissive CCV has a luminal pH of ~5.2 that remains stable throughout infection. Inducing CCV acidification to a lysosomal pH (~4.7) causes
Coxiella
degradation, suggesting that
Coxiella
regulates CCV pH. Supporting this hypothesis,
Coxiella
blocks host lysosomal biogenesis, leading to fewer host lysosomes available to fuse with the CCV. Host cell lysosome biogenesis is primarily controlled by the transcription factor EB (TFEB), which binds Coordinated Lysosomal Expression And Regulation (CLEAR) motifs upstream of genes involved in lysosomal biogenesis and function. TFEB is a member of the microphthalmia/transcription factor E (MiT/TFE) protein family, which also includes MITF, TFE3, and TFEC. This study examines the roles of MiT/TFE proteins during
Coxiella
infection. We found that in cells lacking TFEB, both
Coxiella
growth and CCV size increase. Conversely, TFEB overexpression or expression in the absence of other family members leads to significantly less bacterial growth and smaller CCVs. TFE3 and MITF do not appear to play a significant role during
Coxiella
infection. Surprisingly, we found that
Coxiella
actively blocks TFEB nuclear translocation in a Type IV Secretion System-dependent manner, thus decreasing lysosomal biogenesis. Together, these results suggest that
Coxiella
inhibits TFEB nuclear translocation to limit lysosomal biogenesis, thus avoiding further CCV acidification through CCV-lysosomal fusion.

IMPORTANCE

The obligate intracellular bacterial pathogen
Coxiella burnetii
causes the zoonotic disease Q fever, which is characterized by a debilitating flu-like illness in acute cases and life-threatening endocarditis in patients with chronic disease. While
Coxiella
survives in a unique lysosome-like vacuole called the
Coxiella
Containing Vacuole (CCV), the bacterium inhibits lysosome biogenesis as a mechanism to avoid increased CCV acidification. Our results establish that transcription factor EB (TFEB), a member of the microphthalmia/transcription factor E (MiT/TFE) family of transcription factors that regulate lysosomal gene expression, restricts
Coxiella
infection. Surprisingly,
Coxiella
blocks TFEB translocation from the cytoplasm to the nucleus, thus downregulating the expression of lysosomal genes. These findings reveal a novel bacterial mechanism to regulate lysosomal biogenesis.
Spatial technologies to evaluate the HIV-1 reservoir and its microenvironment in the lymph node
Authors: Zaman Fatima , Smith Melissa L. , Balagopal Ashwin , Durand Christine M. , Redd Andrew D. , Tobian Aaron A. R.
Published: July 2024

The presence of the HIV-1 reservoir, a group of immune cells that contain intact, integrated, and replication-competent proviruses, is a major challenge to cure HIV-1. HIV-1 reservoir cells are largely unaffected by the cytopathic effects of viruses, antiviral immune responses, or antiretroviral therapy (ART). The HIV-1 reservoir is seeded early during HIV-1 infection and augmented during active viral replication. CD4+ T cells are the primary target for HIV-1 infection, and recent studies suggest that memory T follicular helper cells within the lymph node, more precisely in the B cell follicle, harbor integrated provirus, which contribute to viral rebound upon ART discontinuation. The B cell follicle, more specifically the germinal center, possesses a unique environment because of its distinct property of being partly immune privileged, potentially allowing HIV-1-infected cells within the lymph nodes to be protected from CD8+ T cells. This modified immune response in the germinal center of the follicle is potentially explained by the exclusion of CD8+ T cells and the presence of T regulatory cells at the junction of the follicle and extrafollicular region. The proviral makeup of HIV-1-infected cells is similar in lymph nodes and blood, suggesting trafficking between these compartments. Little is known about the cell-to-cell interactions, microenvironment of HIV-1-infected cells in the follicle, and trafficking between the lymph node follicle and other body compartments. Applying a spatiotemporal approach that integrates genomics, transcriptomics, and proteomics to investigate the HIV-1 reservoir and its neighboring cells in the lymph node has promising potential for informing HIV-1 cure efforts.
Global evaluation and outcomes of cholecystectomy: protocol for a multicentre, international, prospective cohort study (GlobalSurg 4)
Authors: Harrison Ewen , Kathir Kamarajah Sivesh
Published: July 2024

Introduction

Cholecystectomy is one of the most common operations performed worldwide. Although laparoscopic surgery has been the ‘gold-standard’ approach for this operation, there is a paucity of global evidence around the variations of safe provision of cholecystectomy, including low-income and middle-income countries. This international collaborative study will allow contemporaneous data collection on the quality of cholecystectomies using measures covering infrastructure, care processes and outcomes, with the primary aim define the global variation in compliance with preoperative, intraoperative and postoperative audit standards.

Methods and analysis

Global Evaluation of Cholecystectomy Knowledge and Outcomes is a prospective, international, multicentre, observational cohort study delivered by the GlobalSurg Collaborative. Consecutive patients undergoing cholecystectomy between 31 July 2023 and 19 November 2023 will be recruited, with follow-up at 30 days and 1-year postoperatively. The study will be undertaken at any hospital providing emergency or elective surgical services for biliary disease. The primary endpoint of this study is compliance with preoperative, intraoperative and postoperative audit standards. Secondary outcomes include rates of 30-day complications, achievement of critical view of safety and rates of gallbladder cancer.

Ethics and dissemination

This project will not affect clinical practice and has been classified as clinical audit following research ethics review at University Hospital Birmingham NHS Trust. The protocol will be disseminated through the international GlobalSurg and CovidSurg network.

Trial registration number

NCT06223061
.
Methodological quality of research on perioperative immunomodulatory supplementation in oncological gastrointestinal tract surgery: a meta-research protocol
Authors: Lima Luana Pucci de , Mello Arthur Thives , Nascimento Giovanna Mozzaquattro , Trindade Erasmo B S de Moraes
Published: July 2024

Introduction

One of the topics that show differences of opinion in the scientific field of nutrition is the recommendation by clinical practice guidelines (CPGs) of an immunomodulatory diet with arginine, nucleotides and omega-3 for individuals diagnosed with cancer undergoing major surgery. The quality of the recommendations is directly related to credibility, transparency and rigour in their development, but also to the quality of the studies published and available for inclusion in the recommendation, such as systematic reviews (SRs) and randomised clinical trials. The aim of this study is to evaluate the methodological quality of the recommendation of perioperative immunomodulatory supplementation for individuals with gastrointestinal and head and neck cancer, the CPGs, and the studies that support the recommendations.

Methods and analysis

We will conduct a systematic search for CPGs. Recommendations for nutritional supplementation with immunomodulatory substrates for individuals undergoing major oncological surgery will be analysed using the Appraisal of Guidelines Research and Evaluation-Recommendations Excellence tool. CPGs will be analysed using the Appraisal of Guidelines Research and Evaluation II tool. The SRs cited in the recommendations will be analysed using the A Measurement Tool to Assess Systematic Reviews II tool and additional questions regarding heterogeneity in reviews. The clinical trials cited in the SRs and in the guideline recommendations (when applicable) will be analysed according to questions regarding heterogeneity in trials. The results will be presented in tables or charts using descriptive analyses.

Ethics and dissemination

The results of this study will be disseminated through relevant conferences and peer-reviewed journals.

Protocol registration number

10.17605/OSF.IO/X2GYT.
Disparity between statistical and clinical significance in published randomised controlled trials indexed in PubMed: a protocol for a cross-sectional methodological survey
Authors: Esterhuizen Tonya Marianne , Mbuagbaw Lawrence , Thabane Lehana
Published: July 2024

Introduction

The commonly used frequentist paradigm of null hypothesis statistics testing with its reliance on the p-value and the corresponding notion of ‘statistical significance’ has been under ongoing criticism. Misinterpretation and misuse of the p-value have contributed to publication bias, unreliable studies, frequent false positives, fraud and mistrust in results of scientific studies. While p-values themselves are still useful, part of the problem may be the confusion between statistical and clinical significance. In randomised controlled trials of health interventions, this confusion could lead to erroneous conclusions about treatment efficacy, research waste and compromised patient outcomes. The extent to which clinical and statistical significance of published randomised clinical trials do not match is not known. This is a protocol for a methodological study to understand the extent of the problem of disparities between statistical and clinical significance in published clinical trials, and to identify and assess the factors associated with discrepant results in these studies.

Methods and analysis

A methodological survey of published randomised controlled trials is planned. Trials published between 2018 and 2022 and their protocols will be searched and screened for inclusion, with a planned sample size of 500 studies. The reported minimum clinically important difference, the study effect size and confidence intervals will be used to assess clinical importance of trial results. Comparison of statistical significance and clinical importance of the trial results will be used to determine disparity. Data will be analysed to estimate the outcomes, and factors associated with disparate study results will be assessed using logistic regression analysis.

Ethics and dissemination

Ethical approval for the study has been granted by Stellenbosch University’s Health Research Ethics Committee. This is part of a larger study towards a PhD in Biostatistics and will be disseminated as a thesis, conference abstract and peer-reviewed manuscript.
Prognostic value of angiographic based quantitative flow ratio and anatomic features in intracranial atherosclerotic stenosis
Authors: Huang Kangmo , Yao Weihe , Song Zhiruo , Jia Xuerong , Gao Jie , Liu Rui , Han Yunfei , Liu Xinfeng , Du Juan , Tu Shengxian , Zhu Wusheng
Published: July 2024

Background

Patients with intracranial atherosclerotic stenosis (ICAS) are prone to stroke recurrence despite aggressive medical treatment. Further assessment of the anatomy and physiology of ICAS is urgently needed to facilitate individualized therapy. We explored the predictive value of angiography based hemodynamic and anatomical features for ICAS patients.

Methods

In this retrospective study, patients with moderate-to-severe stenosis of the middle cerebral artery (MCA) were enrolled. The hemodynamic assessment was performed using the single view Murray’s law based quantitative flow ratio (μQFR) approach. The locations of lesions were categorized as perforator rich segments of the MCA (pMCA) and others. Multivariate Cox models were developed to identify significant predictors. The primary outcomes were defined as stroke and transient ischemic attack.

Results

Among the 333 patients (median (IQR) age, 56 (49–63) years, 70.3% men) over a median follow-up period of 64.5 months, 50 (15.0%) had the primary outcomes, and 80.0% occurred within 5 years. Patients with lower μQFR values (dichotomized at 0.73) had a higher risk of the 5 year primary outcomes (log rank P=0.023), and good collateral circulation may have attenuated the risk. In the multivariate analyses, μQFR (adjusted HR=0.345; 95% CI 0.155 to 0.766; P=0.009), lesion located in pMCA (adjusted HR=0.377; 95% CI 0.190 to 0.749; P=0.005), and diameter ratio of the internal carotid artery (adjusted HR=4.187; 95% CI 1.071 to 16.370; P=0.040) were significantly associated with the 5 year primary outcomes.

Conclusions

Angiography based μQFR and anatomical features, namely plaque localization and internal carotid artery expansion, could serve as promising prognostic indexes for MCA atherosclerosis.
Prion diseases motor and neuropsychiatric symptom cluster pharmacotherapy: structured scoping review
Authors: Hogg Roseanagh , Centola John , McDermott Eugene Ace , Mastaglio Francesca , Grundy Anna , Awe Terri , Carey Matthew , Miller Mary , Chin Chloe Antoinette , Quibell Rachel , Bajorek Tomasz , Pal Suvankar , Bradley Victoria
Published: July 2024

Background

Prion diseases are a group of rare, neurodegenerative conditions that are invariably fatal and cause a variety of symptoms, which can prove challenging to control. Through this paper, we aim to review the current evidence regarding pharmacological management of neuropsychiatric and motor symptoms of prion disease as well as draw on experts’ and relatives’ experience, to evaluate the current evidence and provide recommendations moving forwards.

Methods

A scoping review of the literature for pharmacological management of symptoms was conducted using the systematic review tool, COVIDENCE, with searches conducted through four databases. 120 papers were selected for inclusion, and data extraction was carried out by two independent reviewers. Given the lack of high-quality data and small numbers, no further attempt at statistical analysis was made, and results are presented in a thematic synthesis.

Results

Although a broad range of approaches and pharmacotherapies are trialled to manage these challenging symptoms, there are patterns emerging of some efficacy seen with the use of benzodiazepines, antipsychotic and anticonvulsant medications in both motor and neuropsychiatric symptoms in prion disease. These approaches and associated challenges were reflected in international expert opinion that was gathered via online survey.

Conclusion

There continues to be a paucity of good-quality evidence and we suggest a need for longitudinal, population-based and standardised research to allow a robust evidence base, which in turn will guide excellent symptom control and end of life care for this group of complex patients.
Global policy scan of commercial combustible tobacco product retailing regulations by WHO region
Authors: Canty Ruth , Gartner Coral E , Hoek Janet , Hefler Marita
Published: July 2024

Background/aims

Regulatory schemes for tobacco retailing help restrict the supply and availability of smoked tobacco products. Tobacco retailer density and the proximity of tobacco outlets to youth spaces, such as schools, are greater in more disadvantaged areas. Exposure to tobacco retailing normalises smoking and increases ease of access, thus increasing smoking uptake and undermining quitting. To inform future policy, we conducted a global scan of combustible tobacco retail regulatory schemes (We use the term schemes to refer to any kind of relevant initiative, policy, regulations or legislation that we found).

Methods

All types of English language records concerning the regulation of commercial tobacco product availability were considered, including peer-reviewed journal articles, key reports and policy documents. The key features of regulatory schemes were documented. In addition, we contacted key informants in different countries and regions for advice on additional sources and undertook targeted searching in regions where we initially found little data.

Results/findings

Although many countries have well-established and comprehensive tobacco control programmes, tobacco retail policy that actively addresses the availability of tobacco is underutilised. Many jurisdictions have implemented a minimum purchase age and restricted point-of-sale advertising and marketing. Other tobacco retailing regulations also included licensing systems with licence fees, caps on licences and restrictions on store location, type and retailer density/proximity. A very small number of jurisdictions have ended tobacco retailing altogether.

Conclusions

At a minimum, policy-makers should implement licensing schemes, licence caps and proximity limits and invest in robust monitoring systems and compliance enforcement. Tobacco products’ ubiquity is incompatible with its status as a dangerous addictive substance and does not align with tobacco endgame goals.
Three-dimensional voxel geological modelling for subsurface stratigraphy: a graph convolutional network approach
Authors: Wang Lai , Pan Qiujing , Su Dong , Huang Shan
Published: July 2024

Three-dimensional (3D) geological modelling enhances the understanding and visualisation of complex subsurface stratigraphy, which underpins geotechnical digital twin and resilience design. Existing methods for 3D geological modelling suffer from either high computational burden or low modelling accuracy in large-scale region with complex subsurface stratigraphy. This paper presents a novel deep learning method that applies the graph convolutional network to 3D voxel geological modelling using limited boreholes. A topological graph is firstly constructed, with spatial points encoded as graph nodes. The soil types and spatial coordinates are incorporated into the feature vector of each node. Spatial correlations are quantified through weighted edges by connecting pairs of nodes within a cuboid neighbouring system. Besides, the occurrence probability of soil types in all boreholes is embedded into the feature vector of each graph node to further improve the model robustness. A series of comparisons shows that the proposed method outperforms traditional two-point statistic and multi-point statistic methods in terms of modelling accuracy. The proposed method is finally applied to a real tunnel engineering in Changsha City, which demonstrates the effectiveness of the proposed method in complex 3D geological scenario.
Assessing Onsager’s reciprocity difference in signal transduction cascade model: a new metric for evaluating cellular response dynamics
Authors: Taga Masataka , Kobayashi Go , Yano Shiho , Koyama Kazuaki , Tsuruyama Tatsuaki
Published: July 2024

The cell signaling system translates extracellular changes into biochemical reactions within the cell, ultimately affecting gene expression. This system is crucial for responding to environmental stressors through a series of chemical interactions among intracellular molecules. Although Onsager’s reciprocity theorem is foundational in analyzing non-equilibrium systems, its limitations are evident in the nonlinear responses characteristic of the chemical reactions essential for signal transduction. In this study, we demonstrate that the reciprocity coefficients between signal molecule Xj, Lj:j+1 in the transmission from the jth step to the j + 1th step and molecule Xj+1, Lj+1:j from the j + 1th step to the jth step are not necessarily equal due to nonlinear interactions. This disparity, quantified as Jj:j+1 = −Lj:j+1 + Lj+1:j, reflects the amount of signal transduced between these steps, coupled with the phosphorylation rate of signaling molecules. Through kinetic model simulations, we analyzed the cellular response to external radiation exposure, monitoring how signal transduction progresses via phosphorylation reactions over time. The simulation showed a transition from an unstable to a stable, unimodal signaling pattern at varying radiation doses, correlating well with actual cellular responses. In conclusion, our findings suggest that the discrepancy in Onsager’s reciprocity coefficients correlates with signal transduction velocity, providing novel insights into the thermodynamic underpinnings of cellular signaling mechanisms.
Exploring the impact of multiplicative white noise on novel soliton solutions with the perturbed Triki–Biswas equation
Authors: Arnous Ahmed H. , Ahmed Manar S. , Nofal Taher A. , Yildirim Yakup
Published: July 2024

This study examines the effects of multiplicative white noise on soliton perturbations governed by the Triki–Biswas equation for the first time. Triki–Biswas equation advances research on ultrashort pulse propagation in optical fibers. It modifies the nonlinear Schrödinger equation to describe the behavior of femtosecond pulses more accurately in optical media, becoming a critical tool in the field. The paper employs two innovative methods, the enhanced direct algebraic method and the new projective Riccati equations method to uncover a broad range of soliton solutions, including bright, dark, and singular solitons. The solutions are expressed in terms of Jacobi elliptic functions and exhibit a transition to soliton-type solutions as the elliptic modulus approaches unity. This investigation is the first of its kind to explore the effects of multiplicative white noise within this context, providing new perspectives and methodologies for future research in the field. The study sheds light on previously unexplored aspects of multiplicative white noise and contributes significantly to the body of knowledge in soliton theory and its application to optical fiber technology.
On validity of quantum partial adiabatic search
Authors: Sun Jie , Cai Dunbo , Lu Songfeng , Qian Ling , Zhang Runqing
Published: July 2024

In this paper, we further verify the validity of the quantum partial adiabatic search algorithm which was initialized in the previous related works by revisiting its quantum circuit model. The main results got here are as follows. When considering implementing quantum partial adiabatic evolution on a quantum circuit, a correction is given for the time slice estimation for the first stage during this approximation in the previous related works, new evidence is provided for a time complexity cost $O(\sqrt{N}/M)$
O
(

N

/
M
)
of quantum partial adiabatic algorithm is impossible, and the correct time complexity $O(\sqrt{N/M})$
O
(

N
/
M

)
of it is emphasized once more according to its circuit correspondence, in which N is the total number of elements in the search problem of which M of them are the marked ones. The findings exposed are hopeful for revisiting quantum partial adiabatic evolution and its connection with the quantum circuit model.
ARQUIN: Architectures for Multinode Superconducting Quantum Computers
Authors: Ang James , Carini Gabriella , Chen Yanzhu , Chuang Isaac , Demarco Michael , Economou Sophia , Eickbusch Alec , Faraon Andrei , Fu Kai-Mei , Girvin Steven , Hatridge Michael , Houck Andrew , Hilaire Paul , Krsulich Kevin , Li Ang , Liu Chenxu , Liu Yuan , Martonosi Margaret , McKay David , Misewich Jim , Ritter Mark , Schoelkopf Robert , Stein Samuel , Sussman Sara , Tang Hong , Tang Wei , Tomesh Teague , Tubman Norm , Wang Chen , Wiebe Nathan , Yao Yongxin , Yost Dillon , Zhou Yiyu
Published: July 2024

Many proposals to scale quantum technology rely on modular or distributed designs wherein individual quantum processors, called nodes, are linked together to form one large multinode quantum computer (MNQC). One scalable method to construct an MNQC is using superconducting quantum systems with optical interconnects. However, internode gates in these systems may be two to three orders of magnitude noisier and slower than local operations. Surmounting the limitations of internode gates will require improvements in entanglement generation, use of entanglement distillation, and optimized software and compilers. Still, it remains unclear what performance is possible with current hardware and what performance algorithms require. In this article, we employ a systems analysis approach to quantify overall MNQC performance in terms of hardware models of internode links, entanglement distillation, and local architecture. We show how to navigate tradeoffs in entanglement generation and distillation in the context of algorithm performance, lay out how compilers and software should balance between local and internode gates, and discuss when noisy quantum internode links have an advantage over purely classical links. We find that a factor of 10–100× better link performance is required and introduce a research roadmap for the co-design of hardware and software towards the realization of early MNQCs. While we focus on superconducting devices with optical interconnects, our approach is general across MNQC implementations.
“Robots Can Do Disgusting Things, but Also Good Things”: Fostering Children’s Understanding of AI through Storytelling
Authors: Arn Luise , Huang Elaine M.
Published: July 2024

In this research, we explore the use of storybooks as an educational tool for fostering a meaningful understanding of artificial intelligence (AI) technologies for children and consider how AI should be depicted in storybook narratives to achieve this. We present guidelines for the depiction of AI in narratives for four- to six-year-old children and deploy the guidelines to support the creation of two picture books. We assess both the guidelines and the resulting stories with children as experts and domain experts in the fields of education, technology, and storytelling. Our findings suggest there are advantages to using stories to communicate AI concepts due to their engaging and stimulating nature and that the guidelines were useful and could be easily applied. The feedback from subject matter experts highlighted the value of the guidelines but also reflected the ongoing challenges in defining a conceptually sound and meaningful depiction of AI for children.
Asymmetries in Nominally Symmetric Flows
Authors: Williams Owen J.H. , Smits Alexander J.
Published: July 2024

Many flows that are expected to be symmetric are actually observed to be asymmetric. The appearance of asymmetry in the face of no particular cause is a widespread although underappreciated occurrence. This rather puzzling and sometimes frustrating phenomenon can occur in wide-angle diffusers, over the forebody of axisymmetric bodies at high angles of attack, in the wake downstream of streamlined as well as bluff bodies, and in the flow over three-dimensional bumps and ramps. We review some notable examples and highlight the extreme sensitivity of many such flows to small disturbances in the body geometry or the incoming flow. Some flows appear to be permanently asymmetric, while others are bistable on timescales that are orders of magnitude longer than any convective timescale. Convective or global instabilities can occur, bistability is common, and mode interactions become important when multiple similar but distinct timescales and length scales are present. Our understanding of these phenomena is still very limited, and further research is urgently required; asymmetries in otherwise symmetric flows can have serious real-world consequences on vehicle control and performance.
Biventricular responses to exercise and their relation to cardiorespiratory fitness in pediatric pulmonary hypertension
Authors: Pieles Guido E. , Dorobantu Dan-Mihai , Caterini Jessica E. , Cifra Barbara , Reyes Janette , Roldan Ramos Sara , Hannon Eilis , Williams Craig A. , Humpl Tilman , Mertens Luc , Wells Greg D. , Friedberg Mark K.
Published: July 2024

In children with pulmonary arterial hypertension, there is a marked increase in pulmonary artery pressure during physical activity, but this is not the underlying mechanism that limits exercise. Instead, right ventricle-to-pulmonary artery uncoupling occurs at the transition from moderate to high-intensity exercise and correlates with lower peak oxygen uptake. This highlights the more complex underlying pathological responses and the need for multiparametric assessment of cardiac function reserve in these patients when feasible.
Promoting Articular Cartilage Regeneration through Microenvironmental Regulation
Authors: Liu Kai , Zhang Bingjun , Zhang Xiaoling
Published: July 2024

In recent years, as the aging population continues to grow, osteoarthritis (OA) has emerged as a leading cause of disability, with its incidence rising annually. Current treatments of OA include exercise and medications in the early stages and total joint replacement in the late stages. These approaches only relieve pain and reduce inflammation; however, they have significant side effects and high costs. Therefore, there is an urgent need to identify effective treatment methods that can delay the pathological progression of this condition. The changes in the articular cartilage microenvironment, which are complex and diverse, can aggravate the pathological progression into a vicious cycle, inhibiting the repair and regeneration of articular cartilage. Understanding these intricate changes in the microenvironment is crucial for devising effective treatment modalities. By searching relevant research articles and clinical trials in PubMed according to the keywords of articular cartilage, microenvironment, OA, mechanical force, hypoxia, cytokine, and cell senescence. This study first summarizes the factors affecting articular cartilage regeneration, then proposes corresponding treatment strategies, and finally points out the future research direction. We find that regulating the opening of mechanosensitive ion channels, regulating the expression of HIF‐1, delivering growth factors, and clearing senescent cells can promote the formation of articular cartilage regeneration microenvironment. This study provides a new idea for the treatment of OA in the future, which can promote the regeneration of articular cartilage through the regulation of the microenvironment so as to achieve the purpose of treating OA.
Phenomenological Model of Electrotechnical Systems Based on a Synchronous Generator With an Excitation System
Authors: Moroz Volodymyr , Paranchuk Yaroslav , Konoval Volodymyr , Kuznyetsov Oleksiy
Published: July 2024

We propose a variant of the application of a phenomenological approach using the “black box” concept to the modeling of electrotechnical systems. The method enables obtaining simplified models of a complex electrotechnical system based on a synchronous generator (SG) with an excitation system and an integral estimation of the accuracy of the reproduction of the original step response. The compromise between complexity and accuracy is the basis for obtaining the computer model of different orders utilizing the proposed method. The application of the proposed phenomenological approach is illustrated by the examples.
Associations Between Postnatal Pollution Exposures, 24‐h Movement Behaviours, and Motor Development Outcomes Among Children (0–12 Years Old): A Systematic Review
Authors: Maddren Claudia I. , Dhamrait Gursimran , Elliott Kayla , Toledo-Vargas Marcelo , Gryech Ihsane , Okely Anthony D.
Published: July 2024

Background: Little is known about how exposure to different types of pollution is associated with motor development in children or how pollution may be related to time spent in physical activity, sedentary behaviour—including screen time, and sleep. The purpose of this study was to review the evidence on these associations, especially in light of the World Health Organization (WHO) Guidelines for these behaviours.

Methods: We searched eight electronic databases: CINAHL, Embase, ERIC, Global Health, MEDLINE, PsycINFO, Scopus, and Web of Science, from inception to May 2023. Studies that reported an association between a pollution measure (air, water, noise, or land) and at least one movement behaviour (physical activity, sleep, or sedentary time) or motor development outcome (fine or gross motor) among apparently healthy children from birth to 12 years were included. Eligibility of the studies was assessed, and extracted data was based on the study design, sample characteristics, pollution type, and type of association reported.

Results: The search returned 5358 studies, of which 18 were eligible for inclusion. Most studies were conducted in high‐income countries (n = 13). Studies reported measures of outdoor air (n = 7), indoor air (n = 4), land (n = 3), and noise pollution (n = 4). Findings from the review were mixed and inconsistent. Most studies reported associations between a pollution measure and motor development outcomes (n = 12), followed by sleep (n = 5) and physical activity and sedentary behaviour (n = 1).

Conclusions: There is limited evidence regarding associations between pollution measures, 24‐h movement behaviours, and motor development. Future research should pay more attention to postnatal exposure to different types of pollution and its impact on healthy levels of physical activity, sedentary behaviour, sleep, and motor development and consider confounders such as geographic location, weather conditions, and country income level.

Trial Registration: PROSPERO: CRD42022340130.
Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy
Authors: Reinstein Zachary Z. , Zhang Yue , Ospina Oscar E. , Nichols Matt D. , Chu Victoria A. , Pulido Alvaro de Mingo , Prieto Karol , Nguyen Jonathan V. , Yin Rui , Moran Segura Carlos , Usman Ahmed , Sell Brittney , Ng Spencer , de la Iglesia Janis V. , Chandra Sunandana , Sosman Jeffrey A. , Cho Raymond J. , Cheng Jeffrey B. , Ivanova Ellie , Koralov Sergei B. , Slebos Robbert J.C. , Chung Christine H. , Khushalani Nikhil I. , Messina Jane L. , Sarnaik Amod A. , Zager Jonathan S. , Sondak Vernon K. , Vaske Charles , Kim Sungjune , Brohl Andrew S. , Mi Xinlei , Pierce Brian G. , Wang Xuefeng , Fridley Brooke L. , Tsai Kenneth Y. , Choi Jaehyuk
Published: July 2024

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ∼50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (RNA-seq) with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1. Responders have increased type I/II interferons and preexisting tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public T-cell receptors. Spatial transcriptomics demonstrated colocalization of T cells with B and dendritic cells, which supply chemokines and costimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC.

Significance: MCC serves as a model of ICB response. We utilized the largest-to-date, multimodal MCC dataset (n = 116 patients) to uncover unique tumor-intrinsic properties and immune circuits that predict response. We identified CD8 Trm and Vδ1 T cells as clinically actionable mediators of ICB response in major histocompatibility complex–high and –low MCCs, respectively.
MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer
Authors: Klingbeil Olaf , Skopelitis Damianos , Tonelli Claudia , Yoshimoto Toyoki , Alpsoy Aktan , Panepinto Maria C. , Minicozzi Francesca , Merrill Joseph R. , Cafiero Amanda M. , Aggarwal Disha , Russo Suzanne , Ha Taehoon , Demerdash Osama E. , Wee Tse-Luen , Spector David L. , Lyons Scott K. , Tuveson David A. , Cifani Paolo , Vakoc Christopher R.
Published: July 2024

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. In this study, we used paralog cotargeting CRISPR screens to identify kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is the direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from Helicobacter pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful codependencies of YAP/TAZ in human cancer, targets that may allow for pharmacology that restores Hippo pathway–mediated tumor suppression.

Significance: We show how genetic redundancy conceals tight functional relationships between signaling and transcriptional activation in cancer. Blocking the function of MARK2/3 kinases leads to the reactivation of the Hippo tumor suppressive pathway and may have therapeutic potential in YAP/TAZ-dysregulated carcinomas and sarcomas.

See related commentary by Gauthier-Coles and Sheltzer, p. 2312
Supplementary Figure 6 from Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma
Authors: Lai Thomas J. , Sun Lu , Li Kevin , Prins Terry J. , Treger Janet , Li Tie , Sun Matthew Z. , Nathanson David A. , Liau Linda M. , Lai Albert , Prins Robert M. , Everson Richard G.
Published: July 2024

Fig S6 A-F
Supplementary Data 1 from Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma
Authors: Lai Thomas J. , Sun Lu , Li Kevin , Prins Terry J. , Treger Janet , Li Tie , Sun Matthew Z. , Nathanson David A. , Liau Linda M. , Lai Albert , Prins Robert M. , Everson Richard G.
Published: July 2024

Isoplexis fluorescence values per cytokine per cell
Figure 4 from Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma
Authors: Lai Thomas J. , Sun Lu , Li Kevin , Prins Terry J. , Treger Janet , Li Tie , Sun Matthew Z. , Nathanson David A. , Liau Linda M. , Lai Albert , Prins Robert M. , Everson Richard G.
Published: July 2024

DAC induces multiple CTA for potential polyclonal antigen targeting in gliomaspheres. A, UMAP and (B) percent of cells with at least one read for seven differentially expressed CTA (CTAG1B, MAGEA4, CTAG2 (LAGE-1), PAGE5, PAGE2, PAGE2B, and MAEL). C, Heatmap of CTA expression per cell.
Figure 3 from Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma
Authors: Lai Thomas J. , Sun Lu , Li Kevin , Prins Terry J. , Treger Janet , Li Tie , Sun Matthew Z. , Nathanson David A. , Liau Linda M. , Lai Albert , Prins Robert M. , Everson Richard G.
Published: July 2024

DAC induces NY-ESO-1 and other CTA homogeneously in serum-free patient derived gliomaspheres. A, UMAP of primary gliomasphere lines (GS025, GS243) treated with DAC or DMSO (n = 22,313; B) UMAP of cells expressing CTAG1B (red). C, 35% (n = 1,487 CTAG1B+ cells of 4,190 DAC-treated cells) of treated cells demonstrate CTAG1B upregulation. D, UMAP and (E) proportion of cell populations as determined by Seurat and differentially expressed cluster markers. F, Relative gene expression of cells expressing CTAG1B and pan-MHC class 1 (HLA-A, HLA-B, HLA-C) in GS025_DMSO (light blue), GS025_DAC (light red), GS243_DMSO (dark blue), and GS243_DAC (dark red) across defined cell populations.
Nanoparticles with lipid core can enhance the infection of epithelial cells with an enterovirus.
Authors: Vergez Inès , Nekoua Magloire Pandoua , Rubrecht Cédric , Fasquelle François , Scuotto Angelo , Alidjinou Enagnon Kazali , Betbeder Didier , Hober Didier
Published: July 2024

Introduction: The effect of maltodextrin-based nanoparticles with an anionic phospholipid core (NPLs) on the infection of a human tumoral cell line with poliovirus (PV) has been studied. Methods: NPLs were synthesized and associated with PV type 1 Sabin strain and the formulations were characterized. PV and PV/NPL formulations were inoculated to HEp-2 cells. Results: The surface charge and the diameter of PV/NPL formulation suggest that viral particles were adsorbed onto NPLs. When HEp-2 cells were inoculated with 1 TCID50/mL PV associated with NPLs, the cytopathic effect appeared obvious; the levels of infectious titer of culture supernatants, and the proportion of VP1-positive cells were higher. The level of intracellular viral RNA extracted from HEp-2 cells inoculated with PV/NPL formulation was higher as well. Conclusion: These results show that NPLs can enhance the infection with a virus and suggest that they might be used in virotherapy to increase the virus-mediated lysis of tumor cells.
How Do Physical Activity and Exercise Affect Fabry Disease? Exploring a New Opportunity
Authors: Baciga Federica , Marchi Giacomo , Caccia Federica , Momentè Claudia , Esposito Pasquale , Aucella Filippo , Vitturi Nicola , Pederzoli Laura , Shakkour Meilad , Granata Antonio , Zicarelli Maria Teresa , Girelli Domenico , Andreucci Michele , Carraro Gianni , Battaglia Yuri
Published: July 2024

Background: Fabry disease (FD) is a multisystem, monogenic, X-linked storage disorder caused by mutations in the GLA gene, resulting in reduced alfa-galactosidase A enzyme activity. This effect leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide, in various tissues, including the heart, kidney, vasculature, smooth muscle, and peripheral nervous system. Hemizygous males are usually more severely affected than females, in whom random inactivation of an X chromosome may lead to variable phenotype. Summary: Among the manifestations of FD, exercise intolerance is commonly diagnosed but often underestimated, even though it significantly limits quality of life, especially in young patients. This review primarily discusses the various pathophysiological mechanisms involved in exercise intolerance in FD patients, such as altered muscle composition, compromised cardiopulmonary framework, and peripheral neuropathy. Secondarily, it explores the potential effect of available therapy, including enzyme replacement therapy and chaperone therapy (migalastat), in reducing exercise intolerance while considering the potential impact of physical activity and exercise training as adjunctive treatments. Conclusion: Exercise intolerance has a major impact on the well-being of people with FD. Exercise training can play an important role in addition to drug therapy.
Sementes da arte-educação-ambiental
Authors: Willms Elni Elisa ,   Universidade Federal de Mato Grosso, Costa Rafael Nogueira , Almeida Rogério de , Sato Michèle ,   Universidade Federal do Rio de Janeiro. Instituto de Biodiversidade e Sustentabilidade NUPEM,   Universidade de São Paulo. Faculdade de Educação,   Universidade Federal de Mato Grosso
Published: July 2024

Este livro certamente pode contribuir para a busca por respostas para perguntas e inquietações que acometem a pessoa educadora ambiental, a artista ou ambientalista, cidadã. A coletânea de textos que constituem a obra "Sementes da arte-educação-ambiental" faz parte de um reflorestamento. São sementes, que foram protegidas em nossas mentes durante a pandemia do Covid-19, adormecidas enquanto o Brasil assistia a descrença na ciência e a tentativa de destruição das imagens das universidades públicas. É direcionada a professoras e professores, bem como a cientistas com diferentes formações e orientações teóricas. Assim, os capítulos contribuem com a ampliação da nossa maneira de fazer pesquisa, por meio da interlocução acadêmica e no respeito às diversidades teóricas.
Claude Lefort e a democracia selvagem
Authors: Passos Eduardo
Published: July 2024

In this article, we will discuss and contextualize the notion of savage democracy within Claude Lefort's democratic theory. The text will be divided into three parts. Firstly, we will present the fundamental ideas of the author's political thought. Next, we will analyze the role of the notion of savage democracy in three texts by Lefort: two dedicated to the May 68 events, A desordem nova and Releitura as well as the preface to the second edition of the work Éléments d'une critique de la bureaucratie. Finally, we will present the recent discussion in Lefortian studies regarding the fertility of the term savage democracy mainly relating to two important themes for Lefort: the dimension of conflict in democracies and the relationship of law with democratic struggles.
Trazer de volta o conflito: Schmitt sobre o político
Authors: Silva Felipe Alves da
Published: July 2024

This paper proposes an analysis of the essential criteria for defining the concept of the political as formulated by Carl Schmitt. The friend and enemy duality, as a criterion of differentiation par excellence, consists of the elementary foundation for the definition of the political. Schmitt seeks to highlight the controversial nature of a conflictual dimension underlying the political, turning against the alleged attempts of liberalism to try to remote not only the centrality of the conflict, but also its autonomous character, promoting depoliticization and transforming the enemy into an adversary. Then, the aim is to reconstruct part of Schmitt’s argument in his search for an identification criterion for demonstrating the autonomy of the political.
Maria Tereza Horta e a Intervenção Crítica por meio do Romance As Luzes de Leonor
Authors: Lima Jaqueline Vieira de
Published: July 2024

Este artigo objetiva mostrar como a autora Maria Teresa Horta utiliza determinadas estratégias para fazer crítica literária por meio do romance As Luzes de Leonor, a Marquesa de Alorna, uma sedutora de anjos, poetas e heróis (2012). Para tanto, fazemos um breve recorte sobre a Crítica Literária Feminista em Portugal, mostrando como essa vertente vem sendo construída no país. Em um segundo momento, focamos, especificamente, nos aspectos relacionados à autora e ao romance em estudo. Para embasar à nossa discussão, buscamos suporte nos estudos críticos e reflexivos de Teresa Almeida (2016), Vanda Anastácio (2012; 2013; 2015; 2019), Ana Gabriela Macedo e Ana Luísa Amaral (2005), Conceição Flores e Fabio Mario da Silva (2019), dentre outros.
Marx, Nietzsche e a dialética do estado em Henri Lefebvre
Authors: Castelhano Pedro Jablinski , Fiorin Evandro
Published: July 2024

This study seeks to understand Henri Lefebvre’s theory of the State through a dialectical analysis of the theories of two of his main influences: Karl Marx and Friedrich Nietzsche. Through a literature review, the study aims to comprehend how both philosophers explain the public institution and how Lefebvre interprets their theories. It is understood that while Marx sees the origin of the State in materiality, Nietzsche sees it in the will to power. However, both thinkers understand the State as a limiting entity: for the development of social classes in Marx’s case, and for individual development and overcoming in Nietzsche’s. The analysis of Lefebvre’s State theory shows that he absorbed such contradiction, where the curbing of individual development is precisely the means used by the State to limit the development of a social class submissive to a dominant class.