bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal anxiety during pregnancy is associated with weaker prefrontal functional connectivity in adult offspring
Authors: Turk Elise , van den Heuvel Marion I. , Sleurs Charlotte , Billiet Thibo , Uyttebroeck Anne , Sunaert Stefan , Mennes Maarten , Van den Bergh Bea R.H.
Published: June 2023

Background

The connectome, constituting a unique fingerprint of a person’s brain, may be influenced by its prenatal environment, potentially affecting later-life resilience and mental health.

Methods

We conducted a prospective resting-state functional Magnetic Resonance Imaging study in 28-year-old offspring (N = 49) of mothers whose anxiety was monitored during pregnancy. Two offspring anxiety subgroups were defined: “High anxiety” (n = 13) group versus “low-to-medium anxiety” (n = 36) group, based on maternal self-reported state anxiety at 12–22 weeks of gestation. To predict resting-state functional connectivity of 32 by 32 ROIs, maternal state anxiety during pregnancy was included as a predictor in general linear models for both ROI-to-ROI and graph theoretical metrics. Sex, birth weight and postnatal anxiety were included as covariates.

Results

Higher maternal anxiety was associated with weaker functional connectivity of medial prefrontal cortex with left inferior frontal gyrus (t = 3.45, pFDR < 0.05). Moreover, network-based statistics (NBS) confirmed our finding and revealed an additional association of weaker connectivity between left lateral prefontal cortex with left somatosensory motor gyrus in the offspring. While our results showed a general pattern of lower functional connectivity in adults prenatally exposed to maternal anxiety, we did not observe significant differences in global brain networks between groups.

Conclusions

Weaker (medial) prefrontal cortex functional connectivity in the high anxiety adult offspring group suggests a long-term negative impact of prenatal exposure to high maternal anxiety, extending into adulthood. To prevent mental health problems at population level, universal primary prevention strategies should aim at lowering maternal anxiety during pregnancy.
Potential Uses of Local Clay Materials for the Production of Porcelain Electrical Insulators, Ethiopia
Authors: Wondemagegnehu Eshetu Bekele , Addis Tamirat , Zereffa Enyew Amare , Tullu Andualem Merga , Brehane Belay , Tufa Lemma Teshome , Lee Jaebeom
Published: June 2023

Clays are extremely variable materials with different mineral compositions, and they are the main ingredients in ceramics applications. Their properties play specific roles in influencing the technological properties and performance of ceramics products. Evaluating the various properties can help to determine the best way to utilize clay materials, such as the locally available Bombawuha (BC) and Denkaka (DC) clays mined from Ethiopia's Bombawuha and Denkaka areas, respectively. The objective of this study was to examine these materials for the purpose of using them to produce quality electrical porcelain insulators. The clay samples were characterized for their chemical composition, mineralogy, thermal properties, plasticity, and particle-size distribution, using atomic absorption spectrometry (AAS), X-ray diffractometry (XRD), differential thermal analysis coupled with thermogravimetric analysis (DTA-TGA), the Atterberg plasticity test, and sieve hydrometer analysis. Based on the characteristics, suitable clay materials were selected and mixed with feldspar and quartz to formulate various porcelain body compositions which were fired at three different temperatures (1200, 1250, and 1300°C) and dwell times (1.5, 2.0, and 2.5 h). The mineralogy, water adsorption, apparent porosity, bulk density, dielectric strength, flexural strength, and microstructure of the fired bodies were measured. The results revealed that, compared to DC, BC contains kaolinite as the major mineral with appreciable amounts of silica (46.72 wt.%), alumina (35.32 wt.%), and fluxing oxides but smaller amounts of CaO. BC contains greater clay fractions (20.58 wt.%); and has a middle-range plasticity index (PI = 11.2 wt.%), thus making BC suitable for producing porcelain insulators. A test-body composition of 40 wt.% BC, 40 wt.% feldspar, and 20 wt.% quartz, fired at 1250°C for 2 h, exhibited water adsorption of 0.17 wt.%, apparent porosity of 0.42 wt.%, bulk density of 2.45 g/cm3, a dielectric strength of 8.22 kV/mm, and flexural strength of 43.63 MPa and, thus, satisfied the required properties for quality porcelain insulators.
Discovery of ferroelectricity in natural product androstane
Authors: Xiong Ren-Gen , Zhang Han-Yue , Jiang Huan-Huan
Published: June 2023

Progesterone and its derivatives attracted widespread interest because of their applications in medicine, health care and birth control, which is the main active ingredient of contraceptive pills known as one of the five chemistry discoveries that changed human life. Although the research of pharmacological effects on contraceptive pill-related compounds has been around for decades, their ferroelectricity has long been overlooked. Here, we report that 4-androsten-3-one-5-ene-17-carboxylic acid, a derivative of progesterone, is an organic single-component ferroelectric, as confirmed by the polarization–electric field hysteresis loops. It crystallizes in the monoclinic space group P21 with a polar packing structure and undergoes a reversible structural phase transition at a high temperature of 489 K. Thermal analysis revealed that its ferroelectricity can persist up to 533 K, giving a wide working temperature range. As the first ferroelectric in steroid biomaterials, 4-androsten-3-one-5-ene-17-carboxylic acid shows great potential in applications for flexible devices, biomedical devices, bio-machines and so on.
Acute hyperthermia and hypoxia tolerance of two improved strains of nile tilapia (Oreochromis niloticus)
Authors: Obirikorang Kwasi Adu , Appiah-Kubi Richard , Adjei-Boateng Daniel , Sekey Wonder , Duodu Collins Prah
Published: June 2023

Tilapia production in Ghana has been hit with episodes of stress and pathogen-induced mass fish kills which have anecdotally been linked to the culture of illegally imported Genetically Improved Farmed Tilapia (GIFT) strains of Nile tilapia, Oreochromis niloticus. This study was thus set up to comprehensively assess the stress tolerance of the GIFT strain and a native strain of Nile tilapia (the Akosombo strain) following exposures to hyperthermic and hypoxic stressors. In a series of experiments, oxygen consumption (MO2), aquatic surface respiration (ASR), thermal limits and hypoxia tolerance were assessed. The effects of these stressors on haematological parameters were also assessed. The GIFT strain was less tolerant of hypoxia and performed ASR at higher O2 levels than the Akosombo strain. Under progressive hypoxia, the GIFT strain exhibited higher gill ventilations frequencies (fV) than the Akosombo strain. The thermal tolerance trial indicated that the Akosombo strain of O. niloticus has higher thermotolerance than the GIFT strain and this was reflective in the higher LT50 (45.1℃) and LTmax (48℃), compared to LT50 and LTmax of 41.5℃ and 46℃ respectively. These results imply that it is crucial to consider how the GIFT strain performs under various environmental conditions and changes during culture. Particularly, raising the GIFT strain of Nile tilapia in earthen ponds rich in phytoplankton and subject to protracted episodes of extreme hypoxia may have a detrimental physiological impact on its growth and welfare.
A cross-sectional study of the relationship between depression status, health care coverage, and sexual orientation
Authors: Liu Yang , O’Grady Megan A.
Published: June 2023

Health care coverage is an important factor in receipt of behavioral healthcare. This study uses data from the New York City Community Health Survey to examine how sexual minority status impacts the relationship between depression status and having health care coverage. Approximately 10% of the sample (n = 9571; 47% 45+ years old; 35% White Non-Hispanic; 7% sexual minority) reported probable depression and low health care coverage. Compared to heterosexual participants, a greater proportion of sexual minority participants had low health care coverage (17% vs. 9%) and probable depression (19% vs. 9%). Logistic regression examining the association between probable depression status and health care coverage showed that those with probable depression have odds of low health care coverage that are were 3.08 times those who did not have probable depression; this relationship was not modified by sexual orientation. Continued research to understand the interplay of health care coverage, mental health, and sexual orientation is needed.
Space-filling and print path generation methods for large-area 3D concrete printing pavements
Authors: Huang Shuyi , Xu Weiguo , Hu Hanyang
Published: June 2023

3D concrete printing (3DCP) technology is a construction method that offers a unique combination of automation and customization. However, when the printing area goes large, generating the print path becomes a sophisticated work. That’s because the customized print path should not only be expandable but also printable, such rules are hard to follow as both the printing area and construction requirements increase. In this paper, the Shenzhen Baoan 3D Printing Park project serves as a case study to introduce space-filling and print path generation methods for three types of large-area concrete pavement. The space-filling methods utilize geometry-based rules to generate complex and expandable paving patterns, while the print path generation methods utilize construction-oriented rules to convert these patterns into print paths. The research provides easy-to-operate design and programming workflows to achieve a pavement printing area of 836 sqm, which significantly increases the construction scale of large-format additive manufacturing (LFAM) and shows the potential of 3D printing technology to reach non-standard results by using standard workflows.
Prosthetic Agency
Authors: Plain Gill
Published: June 2023

Prosthetic Agency: Literature, Culture and Masculinity after World War II examines the social and psychic upheaval of demobilisation. It maps the rapid transition from wartime regimentation to individual responsibility, from intense homosociality to heteronormative expectations, from normativity to disability and from uniformed masculinity to domestic citizenship. This book considers some of the many ways in which popular culture of the time sought to mediate these difficult transitions, exploring films, popular fiction, memoir and biography. In particular, the book explores how technology was imagined as a new space of masculine becoming and how disability was written, represented and assimilated. Through a focus on popular narrative, this book explores the modes of masculinity promoted as ideally suited to national reconstruction and tries to make sense of a culture of rehabilitation that could not name or know itself as such.
Decisions about Decisions
Authors: Sunstein Cass R.
Published: June 2023

Here is one of the most fundamental questions in human life: How do we decide how we decide? We make such decisions all the time. If you trust your doctor, you might decide to follow a simple rule for medical decisions: Do whatever your doctor suggests. If you like someone a lot, and maybe love them, but are not sure whether you want to marry them, you might do this: Live with them first. Some of these strategies are wise. They prevent error. They improve your emotional well-being. Some of these strategies are foolish. They lead you in the direction of terrible mistakes. They prevent you from learning. They might make you miserable. Decisions about Decisions explores how people do, and should, make decisions about decisions. It aims to see what such decisions are, to explore how they go right, and see where they go wrong.
Characteristics of patients associated with any outpatient antibiotic prescribing among Medicare Part D enrollees, 2007–2018
Authors: Kim Christine Y. , Gouin Katryna A. , Hicks Lauri A. , Kabbani Sarah
Published: June 2023

The 2007–2018 National Health Interview Survey data linked with Medicare claims were used to examine older adults’ characteristics and assess their associations with receiving an antibiotic prescription. This analysis shows variation in antibiotic prescribing among adults enrolled in Medicare Part D by race and ethnicity, sex, geography, and health status.
Impact of a pharmacy resident on a transitions of care rotation for inpatients enrolled in an outpatient parenteral antimicrobial therapy (OPAT) program
Authors: Britt Rachel S. , Pearson Jeffrey C. , LaSalvia Mary T. , Mahoney Monica V. , McCoy Christopher , Padival Simi
Published: June 2023

A novel pharmacy residency rotation was created to meet the needs of patients enrolled in an outpatient parenteral antimicrobial therapy (OPAT) program but not yet discharged from the inpatient setting. This service resulted in a high number of antimicrobial stewardship interventions identified and accepted by the primary team(s).
Antibiotic prescribing behavior among physicians in Asia: a multinational survey
Authors: Wiboonchutikula Chonlanan , Kim Hong Bin , Honda Hitoshi , Xin Loo Audrey Yong , Chi-Chung Cheng Vincent , Camins Bernard , Jantarathaneewat Kittiya , Apisarnthanarak Piyaporn , Rutjanawech Sasinuch , Apisarnthanarak Anucha
Published: June 2023

Objective:

To evaluate antibiotic prescribing behavior (APB) among physicians with various specialties in five Asian countries.

Design:

Survey of antibiotics prescribing behavior in three stages (initial, on-treatment, and de-escalation stages).

Methods:

Participants included internists, infectious diseases (ID) specialists, hematologists, intensivists, and surgeons. Participants’ characteristics, patterns of APB, and perceptions of antimicrobial stewardship were collected. A multivariate analysis was conducted to evaluate factors associated with appropriate APB.

Results:

There were 367 participants. The survey response rate was 82.5% (367/445). For the initial stage, different specialties had different choices for empiric treatment. For the on-treatment stage, if the patient does not respond to empiric treatment, most respondents will step up to broader-spectrum antibiotics (273/367: 74.39%). For the de-escalation stage, the rate of de-escalation was 10%–60% depending on the specialty. Most respondents would de-escalate antibiotics based on guidelines (250/367: 68.12%). De-escalation was mostly reported by ID specialists (66/106: 62.26%). Respondents who reported that they performed laboratory investigations prior to empirical antibiotic prescriptions (aOR = 2.83) were associated with appropriate use, while respondents who reported ID consultation were associated with appropriate antibiotic management for infections not responding to empiric treatment (aOR = 40.87); adherence with national guidelines (aOR = 2.57) was associated with reported successful carbapenem de-escalation.

Conclusion:

This study highlights the variation in practices and gaps in appropriate APB on three stages of antibiotic prescription among different specialties. Education on appropriate investigation, partnership with ID specialist, and availability and adherence with national guidelines are critical to help guide appropriate APB among different specialties.
Trust, distrust, and mass atrocity prevention: The Central African Republic
Authors: Gallagher Adrian
Published: June 2023

The article calls on academics and policymakers who focus on mass atrocity prevention to engage with Trust Studies. This is needed because trust and distrust are commonly identified as a significant factor in destruction processes, yet there remains no substantive engagement with these concepts. The article combines Trust Studies, interdisciplinary research on the Central African Republic (Anthropology, Sociology, African Studies, and Political Science), and primary sources to analyse social and political trust dynamics through an exploration of (a) leadership, (b) outsourcing, (c) identity politics, and (d) witchcraft. It makes a twofold contribution. First, it provides a more informed understanding of the mass violence that took place in the Central African Republic through a historical analysis of trust dynamics. Second, it considers the implications for mass atrocity prevention, as it argues that the mainstream commitment to ‘rebuilding trust’ is built on misguided assumptions. The case study holds broader implications for both Trust Studies and mass atrocity prevention. Ultimately, it calls for interdisciplinary research to aid our collective understanding of the multifaceted roles that trust and distrust play in mass violence.
The ordoliberal internet? Continuity and change in the EU’s approach to the governance of cyberspace
Authors: Farrand Benjamin
Published: June 2023

This Article considers the role of ideas in shaping law and policy processes, serving to facilitate certain actions or approaches while curtailing others. Using the development of the EU’s governance approach to online service providers and platforms, this Article demonstrates how ordoliberalism as a set of beliefs regarding the regulation of market activity through law have shaped the understanding of appropriate measures for combating hybrid threats such as disinformation. Highlighting the origins of the E-Commerce Directive and the influence of ordoliberalism in the application of a regulated self-regulation model, the Article explores how ordoliberal philosophical ideas have influenced programme and policy level ideas concerning EU cyberspace governance as it relates to online platform activities. Even where there has been discursive change regarding the role of online platforms in contributing to an environment of insecurity, there has nevertheless been ideational continuity in the approach to their regulation, dictating the legal response in the Digital Services Act.
Knowledge and Disinformation
Authors: Simion Mona
Published: June 2023

This paper develops a novel account of the nature of disinformation that challenges several widely spread theoretical assumptions, such as that disinformation is a species of information, a species of misinformation, essentially false or misleading, essentially intended/aimed/having the function of generating false beliefs in/misleading hearers. The paper defends a view of disinformation as ignorance generating content: on this account, X is disinformation in a context C iff X is a content unit communicated at C that has a disposition to generate ignorance at C in normal conditions. I also offer a taxonomy of disinformation, and a view of what it is for a signal to constitute disinformation for a particular agent in a particular context. The account, if correct, carries high stakes upshots, both theoretically and practically: disinformation tracking will need to go well beyond mere fact checking.
Continuum dynamics of suspensions at low Reynolds number
Authors: Wolgemuth Charles W. , Palos-Chavez Jorge I.
Published: June 2023

The dynamics of suspensions of particles has been an active area of research since Einstein first calculated the leading-order correction to the viscosity of a suspension of spherical particles (Einstein, Proc. R. Soc., vol. A102, 1906, pp. 161–179). Since then, researchers have strived to develop an accurate description of the behaviours of suspensions that goes beyond just leading order in the particle volume fraction. Here, we consider the low-Reynolds-number behaviour of a suspension of spherical particles. Working from the Green's functions for the flow due to a single particle, we derive a continuum-level description of the dynamics of suspensions. Our analysis corrects an error in the derivation of these equations in the work of Jackson (Chem. Engng Sci., vol. 52, 1997, pp. 2457–2469) and leads to stable equations of motion for the particles and fluid. In addition, our resulting equations naturally give the sedimentation speed for suspended particles and correct a separate error in the calculation by Batchelor (J. Fluid Mech., vol. 52, 1972, pp. 245–268). Using the pair-correlation function for hard spheres, we are able to compute the sedimentation speed out to seventh order in the volume fraction, which agrees with experimental data up to 30 %–35 %, and also get higher-order corrections to the suspension viscosity, which agree with experiments up to

$\sim$

15 %. Then, using the pair distribution for spheres in shear flow, we find alterations to both the first and second normal stresses.
On–off pumping for drag reduction in a turbulent channel flow
Authors: Foggi Rota Giulio , Monti Alessandro , Rosti Marco E. , Quadrio Maurizio
Published: June 2023

We show that the energy required by a turbulent flow to displace a given amount of fluid through a straight duct in a given time interval can be reduced by modulating in time the pumping power. The control strategy is hybrid: it is passive, as it requires neither a control system nor control energy, but it manipulates how pumping energy is delivered to the system (as in active techniques) to increase the pumping efficiency. Our control employs a temporally periodic pumping pattern, where a short and intense acceleration (in which the pumping system is on) followed by a longer deceleration (in which the pumping system is off) makes the flow alternately visit a quasi-laminar and a turbulent state. The computational study is for a plane channel flow, and employs direct numerical simulations, which present specific computational challenges, for example the highly varying instantaneous value of the Reynolds number, and the importance of discretisation effects. Particular care is devoted to a meaningful definition of drag reduction in the present context. The ability of the forcing to yield significant savings is demonstrated. Since only a small portion of the parameter space is investigated, the best performance of the control technique remains to be assessed.
The prognostic significance of early troponin levels in patients undergoing aortic ridge surgery
Authors: Kara Kenan Abdurrahman , Arslanoglu Ergin , Yigit Fatih , Arkan Cuneyt , Ozcan Esra , Akardere Omer Faruk , Cine Nihat , Tuncer Eylem , Cetiner Nilufer , Ceyran Hakan
Published: June 2023

Subaortic stenosis is a CHD that can lead to left ventricular hypertrophy, heart failure, and aortic valve damage if left untreated. The gold standard treatment for subaortic stenosis is septal myectomy. However, there is no clear consensus on the surgical margins required for adequate muscle resection. In this retrospective study, we reviewed the records of 83 patients who underwent subaortic stenosis surgery between 2012 and 2020 to investigate the effect of early troponin levels on prognosis. We excluded patients with additional cardiac pathologies, hypertrophic obstructive cardiomyopathy, and valvular aortic stenosis.

Troponin levels were recorded in the early post-operative period, and patients were monitored for complications such as ventricular arrhythmia, left ventricular systolic dysfunction, infective endocarditis, and pacemaker implantation. The troponin levels were significantly higher in the patients who had septal myectomy. The degree of myectomy affected the risk of complications in the early post-operative period and recurrence in the later period. However, when the gradient was substantially or completely removed by myectomy, patients experienced significant symptom improvement in the early post-operative period, and their late survival was equivalent to that of healthy individuals of the same age.

Our findings suggest that monitoring troponin levels in patients undergoing septal myectomy may be beneficial in predicting the risk of complications. However, further studies are needed to establish the optimal surgical technique and extent of muscle resection required for subaortic stenosis treatment. Our study adds to the existing knowledge of the benefits and risks associated with septal myectomy as a treatment option for subaortic stenosis.
Analysis of genetic diversity and population structure using glutenin protein markers in various wheat varieties
Authors: Rai Anjali , Singh Santosh K. , Singh Sumit K. , Sharma Poornima , Ahlawat Arvind K. , Han Sung Soo , Mahendru-Singh Anju
Published: June 2023

The study of polymorphism of glutenin makes it possible to identify and isolate desirable genotypes with higher grain quality. In the last few years, only a part of the genetic diversity among the modern and popular wheat germplasm and varieties based on the polymorphism of glutenin subunits are captured. To address this 107 wheat varieties released across different agricultural zones in India, were used to investigate HMW-GS and LMW-GS allele polymorphism, gene diversity and genetic variation in the Glu-1 and Glu-3 loci. Among the different HMW-GS, the highest genetic variation was observed at the Glu-D1 locus with both Glu-D1a and Glu-D1d possessing genetic variation of 0.490, 0.484 respectively. The highest genetic variation at the Glu-A3 locus was observed at the Glu-A3c and GluA3b possessing a genetic variation of 0.463, 0.411 respectively. This was followed by the Glu-B3j having a genetic variation of 0.386 at the Glu-B3 locus. Over 20 years a remarkable increase in the Glu-D1d allele is observed in the newly released varieties in India. Among all the zones, Glu-A1-null is the least frequent allele at the Glu-1 locus, however, it is present as the predominant allele in the NHZ of India. This study elucidates the relationships of these HMW and LMW allelic frequencies and genetic variation with their geographical distribution over the two different periods. This study provides reference data that can be used to assist the breeding, quality evaluation and development of good-quality wheat varieties.
Autophagy in BRAF-mutant cutaneous melanoma: recent advances and therapeutic perspective
Authors: Fratta Elisabetta , Giurato Giorgio , Guerrieri Roberto , Colizzi Francesca , Dal Col Jessica , Weisz Alessandro , Steffan Agostino , Montico Barbara
Published: June 2023

Macroautophagy, hereafter referred to as autophagy, represents a highly conserved catabolic process that maintains cellular homeostasis. At present, the role of autophagy in cutaneous melanoma (CM) is still controversial, since it appears to be tumor-suppressive at early stages of malignant transformation and cancer-promoting during disease progression. Interestingly, autophagy has been found to be often increased in CM harboring BRAF mutation and to impair the response to targeted therapy. In addition to autophagy, numerous studies have recently conducted in cancer to elucidate the molecular mechanisms of mitophagy, a selective form of mitochondria autophagy, and secretory autophagy, a process that facilitates unconventional cellular secretion. Although several aspects of mitophagy and secretory autophagy have been investigated in depth, their involvement in BRAF-mutant CM biology has only recently emerged. In this review, we aim to overview autophagy dysregulation in BRAF-mutant CM, along with the therapeutic advantages that may arise from combining autophagy inhibitors with targeted therapy. In addition, the recent advances on mitophagy and secretory autophagy involvement in BRAF-mutant CM will be also discussed. Finally, since a number of autophagy-related non-coding RNAs (ncRNAs) have been identified so far, we will briefly discussed recent advances linking ncRNAs to autophagy regulation in BRAF-mutant CM.
Aurora kinase A/AURKA functionally interacts with the mitochondrial ATP synthase to regulate energy metabolism and cell death
Authors: Sharma Rakesh Kumar , Chafik Abderrahman , Bertolin Giulia
Published: June 2023

Cancer cells often hijack metabolic pathways to obtain the energy required to sustain their proliferation. Understanding the molecular mechanisms underlying cancer cell metabolism is key to fine-tune the metabolic preference of specific tumors, and potentially offer new therapeutic strategies. Here, we show that the pharmacological inhibition of mitochondrial Complex V delays the cell cycle by arresting breast cancer cell models in the G0/G1 phase. Under these conditions, the abundance of the multifunctional protein Aurora kinase A/AURKA is specifically lowered. We then demonstrate that AURKA functionally interacts with the mitochondrial Complex V core subunits ATP5F1A and ATP5F1B. Altering the AURKA/ATP5F1A/ATP5F1B nexus is sufficient to trigger G0/G1 arrest, and this is accompanied by decreased glycolysis and mitochondrial respiration rates. Last, we discover that the roles of the AURKA/ATP5F1A/ATP5F1B nexus depend on the specific metabolic propensity of triple-negative breast cancer cell lines, where they correlate with cell fate. On one hand, the nexus induces G0/G1 arrest in cells relying on oxidative phosphorylation as the main source of energy. On the other hand, it allows to bypass cell cycle arrest and it triggers cell death in cells with a glycolytic metabolism. Altogether, we provide evidence that AURKA and mitochondrial Complex V subunits cooperate to maintain cell metabolism in breast cancer cells. Our work paves the way to novel anti-cancer therapies targeting the AURKA/ATP5F1A/ATP5F1B nexus to lower cancer cell metabolism and proliferation.
Targeting lysine-specific demethylase 1 (KDM1A/LSD1) impairs colorectal cancer tumorigenesis by affecting cancer cells stemness, motility, and differentiation
Authors: Antona Annamaria , Leo Giovanni , Favero Francesco , Varalda Marco , Venetucci Jacopo , Faletti Stefania , Todaro Matilde , Mazzucco Eleonora , Soligo Enrica , Saglietti Chiara , Stassi Giorgio , Manfredi Marcello , Pelicci Giuliana , Corà Davide , Valente Guido , Capello Daniela
Published: June 2023

Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A also known as LSD1), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC samples, KDM1A overexpression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted multi-omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype, supporting the role of KDM1A in CRC cells stemness maintenance. Also, KDM1A silencing resulted in up-regulation of miR-506-3p, previously reported to play a tumor-suppressive role in CRC. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A impacts CRC progression in several non-overlapping ways, and therefore it represents a promising epigenetic target to prevent tumor relapse.
Neutrophil diversity and plasticity: Implications for organ transplantation
Authors: Qu Junwen , Jin Jingsi , Zhang Ming , Ng Lai Guan
Published: June 2023

Neutrophils, as the first defenders against external microbes and stimuli, are highly active and finely regulated innate immune cells. Emerging evidence has challenged the conventional dogma that neutrophils are a homogeneous population with a short lifespan that promotes tissue damage. Recent findings on neutrophil diversity and plasticity in homeostatic and disease states have centered on neutrophils in the circulation. In contrast, a comprehensive understanding of tissue-specialized neutrophils in health and disease is still lacking. This article will first discuss how multiomics advances have contributed to our understanding of neutrophil heterogeneity and diversification in resting and pathological settings. This discussion will be followed by a focus on the heterogeneity and role of neutrophils in solid organ transplantation and how neutrophils may contribute to transplant-related complications. The goal of this article is to provide an overview of the research on the involvement of neutrophils in transplantation, with the aim that this may draw attention to an underappreciated area of neutrophil research.
Immunobiology of a rationally-designed AAV2 capsid following intravitreal delivery in mice
Authors: Whitehead Michael , Sage Andrew , Burgoyne Tom , Osborne Andrew , Yu-Wai-Man Patrick , Martin Keith R.
Published: June 2023

Adeno-associated virus serotype 2 (AAV2) is a viral vector that can be used to deliver therapeutic genes to diseased cells in the retina. One strategy for altering AAV2 vectors involves the mutation of phosphodegron residues, which are thought to be phosphorylated/ubiquitinated in the cytosol, facilitating degradation of the vector and the inhibition of transduction. As such, mutation of phosphodegron residues have been correlated with increased transduction of target cells, however, an assessment of the immunobiology of wild-type and phosphodegron mutant AAV2 vectors following intravitreal (IVT) delivery to immunocompetent animals is lacking in the current literature. In this study, we show that IVT of a triple phosphodegron mutant AAV2 capsid is associated with higher levels of humoral immune activation, infiltration of CD4 and CD8 T-cells into the retina, generation of splenic germinal centre reactions, activation of conventional dendritic cell subsets, and elevated retinal gliosis compared to wild-type AAV2 capsids. However, we did not detect significant changes in electroretinography arising after vector administration. We also demonstrate that the triple AAV2 mutant capsid is less susceptible to neutralisation by soluble heparan sulphate and anti-AAV2 neutralising antibodies, highlighting a possible utility for the vector in terms of circumventing pre-existing humoral immunity. In summary, the present study highlights novel aspects of rationally-designed vector immunobiology, which may be relevant to their application in preclinical and clinical settings.
Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid
Authors: Wei Wenchao , Wong Chi Chun , Jia Zhongjun , Liu Weixin , Liu Changan , Ji Fenfen , Pan Yasi , Wang Feixue , Wang Guoping , Zhao Liuyang , Chu Eagle S. H. , Zhang Xiang , Sung Joseph J. Y. , Yu Jun
Published: June 2023

Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of 13C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by 13C-inulin. Integration of 13C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease.
An anti-biofilm cyclic peptide targets a secreted aminopeptidase from P. aeruginosa
Authors: Harding Christopher John , Bischoff Marcus , Bergkessel Megan , Czekster Clarissa Melo
Published: June 2023

Pseudomonas aeruginosa is an opportunistic pathogen that causes serious illness, especially in immunocompromised individuals. P. aeruginosa forms biofilms that contribute to growth and persistence in a wide range of environments. Here we investigated the aminopeptidase, P. aeruginosa aminopeptidase (PaAP) from P. aeruginosa, which is highly abundant in the biofilm matrix. PaAP is associated with biofilm development and contributes to nutrient recycling. We confirmed that post-translational processing was required for activation and PaAP is a promiscuous aminopeptidase acting on unstructured regions of peptides and proteins. Crystal structures of wild-type enzymes and variants revealed the mechanism of autoinhibition, whereby the C-terminal propeptide locks the protease-associated domain and the catalytic peptidase domain into a self-inhibited conformation. Inspired by this, we designed a highly potent small cyclic-peptide inhibitor that recapitulates the deleterious phenotype observed with a PaAP deletion variant in biofilm assays and present a path toward targeting secreted proteins in a biofilm context.
Readout of histone methylation by Trim24 locally restricts chromatin opening by p53
Authors: Isbel Luke , Iskar Murat , Durdu Sevi , Weiss Joscha , Grand Ralph S. , Hietter-Pfeiffer Eric , Kozicka Zuzanna , Michael Alicia K. , Burger Lukas , Thomä Nicolas H. , Schübeler Dirk
Published: June 2023

The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually diverse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as DNA methylation, do not influence the binding of p53 across the genome. Instead, the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated histone 3 lysine 4 (H3K4), thereby preferentially localizing to those p53 sites that reside in closed chromatin, whereas it is deterred from accessible chromatin by H3K4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to affect gene expression as a function of the local chromatin state. These findings link H3K4 methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors that locally modulate TF function.
Touch events and human activities for continuous authentication via smartphone
Authors: Gattulli Vincenzo , Impedovo Donato , Pirlo Giuseppe , Volpe Francesco
Published: June 2023

The security of modern smartphones is related to the combination of Continuous Authentication approaches, Touch events, and Human Activities. The approaches of Continuous Authentication, Touch Events, and Human Activities are silent to the user but are a great source of data for Machine Learning Algorithms. This work aims to develop a method for continuous authentication while the user is sitting and scrolling documents on the smartphone. Touch Events and Smartphone Sensor Features (from the well-known H-MOG Dataset) were used with the addition, for each sensor, of the feature called Signal Vector Magnitude. Several Machine Learning Models have been considered with different experiment setups, 1-class, and 2-class, for evaluation. The results show that the 1-class SVM achieves an accuracy of 98.9% and an F1-score of 99.4%, considering the selected features and the feature Signal Vector Magnitude very significant.
A composite fishing index to support the monitoring and sustainable management of world fisheries
Authors: Ye Yimin , Link Jason S.
Published: June 2023

Overfishing has severe social, economic, and environmental ramifications. Eliminating global overfishing is one of the United Nations’ Sustainable Development Goals (SDGs). The SDGs require effective policy and progress monitoring. However, current indicators are issue-specific and cannot be utilized to measure fisheries efficacy holistically. This study develops a comprehensive index that takes into account the inputs, outputs, and ecological implications of fisheries. These components are then merged to form a single composite fishing index that evaluates both total fishing pressure on the ecosystem and historical patterns. The global fishing intensity grew by a factor of eleven between 1950 and 2017, and geographical differences emerged. The fishing intensity of developed countries peaked in 1997 and has since fallen due to management, but developing countries’ fishing intensity has increased continuously over the whole research period, with quasi-linear growth after 1980. Africa has experienced the most rapid expansion in fishing activity and now has the highest fishing intensity. This index takes a more comprehensive and objective look at fisheries. Its worldwide spatial–temporal comparison enables the identification of similar temporal trends across countries or regions, as well as areas of uneven development and hotspot sites for targeted policy action.
Impact of sea level rise on the Mediterranean Lithophyllum byssoides rims
Authors: Blanfuné Aurélie , Boudouresque Charles-François , Verlaque Marc , Minne Antoine , Noisette Fanny , Thibaut Thierry
Published: June 2023

The calcified red macroalga Lithophyllum byssoides, a very common midlittoral species in the western Mediterranean Sea, is a significant ecosystem engineer capable, under exposed and dim light conditions, of building wide and solid endemic bioconstructions near the mean sea level: the L. byssoides rims or 'trottoirs à L. byssoides'. Although the growth of the species is relatively rapid for a calcified alga, the construction of a large rim requires several centuries of near stable or slowly rising sea level. As the time scale of their formation is measured in centuries, L. byssoides bioconstructions constitute valuable and sensitive sea level markers. The health status of L. byssoides rims has been studied at two sites located far apart from each other (Marseille and Corsica), both in areas heavily impacted by humans and in areas with little impact (MPAs and unprotected areas). A health index is proposed: Lithophylum byssoides Rims Health Index. The main and inevitable threat is the rise in the sea level. This ecosystem would be the first case worldwide of marine ecosystem collapse resulting, indirectly, from man-induced global change.
Establishment of a protocol to administer immunosuppressive drugs for iPS cell-derived cardiomyocyte patch transplantation in a rat myocardial infarction model
Authors: Ito Emiko , Kawamura Ai , Kawamura Takuji , Takeda Maki , Harada Akima , Mochizuki-Oda Noriko , Sawa Yoshiki , Miyagawa Shigeru
Published: June 2023

Transplantation of human allogeneic induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is a new, promising treatment for severe heart failure. However, immunorejection is a significant concern in allogeneic hiPSC-CM transplantation, requiring the administration of several immunosuppressive agents. An appropriate protocol for the administration of immunosuppressants may substantially affect the efficacy of hiPSC-CM transplantation in case of heart failure owing to allogeneic transplantation. In this study, we investigated the effect of immunosuppressant administration duration on the efficacy and safety of allogenic hiPSC-CM patch transplantation. We used a rat model of myocardial infarction to evaluate cardiac function using echocardiography six months after the transplantation of hiPSC-CM patches with immunosuppressant administration for either two or four months and compared them to control rats (sham operation, no immunosuppressant administration). Histological analysis performed at 6 months after hiPSC-CM patch transplantation revealed significant improvement in cardiac function in immunosuppressant-treated rats compared with those in the control group. Moreover, fibrosis and cardiomyocyte size was significantly reduced and the number of structurally mature blood vessels was significantly increased in the immunosuppressant-treated rats compared to control rats. However, there were no significant differences between the two immunosuppressant-treated groups. Our results show that prolonged administration of immunosuppressive agents did not enhance the effectiveness of hiPSC-CM patch transplantation, and therefore, highlight the importance of an appropriate immunological regimen for the clinical application of such transplantation.
Combination of expert guidelines-based and machine learning-based approaches leads to superior accuracy of automated prediction of clinical effect of copy number variations
Authors: Sládeček Tomáš , Gažiová Michaela , Kucharík Marcel , Zaťková Andrea , Pös Zuzana , Pös Ondrej , Krampl Werner , Tomková Erika , Hýblová Michaela , Minárik Gabriel , Radvánszky Ján , Budiš Jaroslav , Szemes Tomáš
Published: June 2023

Clinical interpretation of copy number variants (CNVs) is a complex process that requires skilled clinical professionals. General recommendations have been recently released to guide the CNV interpretation based on predefined criteria to uniform the decision process. Several semiautomatic computational methods have been proposed to recommend appropriate choices, relieving clinicians of tedious searching in vast genomic databases. We have developed and evaluated such a tool called MarCNV and tested it on CNV records collected from the ClinVar database. Alternatively, the emerging machine learning-based tools, such as the recently published ISV (Interpretation of Structural Variants), showed promising ways of even fully automated predictions using broader characterization of affected genomic elements. Such tools utilize features additional to ACMG criteria, thus providing supporting evidence and the potential to improve CNV classification. Since both approaches contribute to evaluation of CNVs clinical impact, we propose a combined solution in the form of a decision support tool based on automated ACMG guidelines (MarCNV) supplemented by a machine learning-based pathogenicity prediction (ISV) for the classification of CNVs. We provide evidence that such a combined approach is able to reduce the number of uncertain classifications and reveal potentially incorrect classifications using automated guidelines. CNV interpretation using MarCNV, ISV, and combined approach is available for non-commercial use at https://predict.genovisio.com/.