bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling Sales of Multigeneration Technology Products in the Presence of Frequent Repeat Purchases: A Fractional Calculus-Based Approach
Authors: Lotfi Ali , Jiang Zhengrui , Naoum-Sawaya Joe , Begen Mehmet A
Published: March 2024

Frequently releasing a new product generation has become a common practice to sustain sales over time, thus accurately forecasting the sales trajectory of each product generation plays a vital role in the short-, medium-, and long-term planning of a firm. Classic multigeneration diffusion models do not incorporate within-generation repeat purchases, making them unusable for product lines with high rates of such purchases. Concentrating on technology products, we develop a multigeneration sales model to fill this void. We demonstrate that the new model can be used for predictive and prescriptive analytics. Our empirical results show that the new model estimates and forecasts sales more accurately than a state-of-the-art benchmark model that does not account for within-generation repeat purchases, underscoring the importance of incorporating repeat purchases. Furthermore, we use two different versions of our model to examine market entry timing under two main strategies, that is, (i) a phase-out transition strategy in which firms continue to sell the old generation after the release of the new generation, and (ii) a total transition strategy in which firms discontinue the old generation after the introduction of the new generation. Our results indicate that the repeat purchases rate determines whether it is optimal to expedite or delay the new product launch, underscoring the importance of incorporating repeat purchases in market entry strategies.
Stories to Prevent Cancer: A Pilot Study Using Cancer Survivor Narratives to Increase Human Papillomavirus Vaccine Intentions
Authors: Bufalini Chelsea M. , Kraschnewski Jennifer L. , Riley Timothy D. , Wile Kevin , Spanos Katherine , Wong Ashley , Myrick Jessica Gall , Schaefer Eric W. , Calo William A.
Published: March 2024

Introduction

Human papillomavirus (HPV) vaccination rates are lower than other recommended adolescent vaccines. Cancer survivor narratives are used to promote cancer prevention and control, but little is known about their impact on adolescent HPV vaccination.

Objective

This pilot study explored the feasibility and effects of a video education intervention using a cancer survivor narrative to improve parents’ attitudes toward and intentions to get the HPV vaccine.

Methods

This study utilized a one-group design; participants completed a pre-intervention survey, watched the video before attending their sons’ wellness visits, and completed a post-intervention survey within one week of their appointment. Using the narrative persuasion framework, we developed a 4-minute video of a local HPV-related cancer survivor to promote the HPV vaccine as cancer prevention. We recruited 37 participants between June and October 2020. Participants were parents of males ages 9-17 who had not yet initiated HPV vaccination.

Results

After the video, more parents agreed that HPV vaccination is safe (pre: 66% vs. post: 82%; P = .045) and that their child’s chances of getting HPV-related cancer in the future are high (pre: 24% vs. post: 46%; P = .014). Overall, 91% of parents felt the cancer survivor story helped them understand the risks of HPV cancers, and 52% said the story influenced their decision to start HPV vaccination for their child.

Conclusions

Our findings suggest that cancer survivor narratives influence parents’ vaccine opinions and understanding of their child’s risk of HPV infection, leading to increased parental intent to get the HPV vaccine for their adolescent males.
Creative Ecologies in Borderline Personality Disorder Research: Just What the Doctor Ordered
Authors: Harris Daniel X. , Holman Jones Stacy , Borovica Tamara
Published: March 2024

This article draws on the power of creative methods to call for a more collaborative, ecological approach to awareness, education, and research analysis of Borderline Personality Disorder (BPD). Drawing on affect theory and empirical research using a co-creation methodology, we advocate for the power of peer-directed support provision for those experiencing BPD. Through recognition and advocacy for this emerging area, the article advances the ways in which more holistic, ecological protocols can help shift research into BPD from a deficit-framed diagnostic approach to a more strengths-based agentic approach that recognizes the wider context and multiple factors beyond the individual.
Successful Treatment of Erosive Lichen Planus With Tofacitinib: A Case Series and Review of the Literature
Authors: Mansouri Parvin , Jafari Mohammad Amin , Chalangari Reza , Roohaninasab Masoumeh , Goodarzi Azadeh
Published: March 2024

Lichen planus (LP) is an inflammatory disease that affects the skin, hair, nails and mucous membranes. Erosive LP is a chronic and difficult-to-treat subtype of lichen planus, characterized by lesions on mucosal surfaces, particularly in the oral and genital areas. The prevalence of erosive LP has not been determined. To date, treatment has consisted of surgical intervention, photodynamic therapy, laser therapy, and systemic or topical drugs, including steroids and immunomodulatory agents. LP usually need longer periods of treatment and are known as precancerous lesions with a 0.4% to 12% conversion rate. In addition, nearly 25% of patients who develop erosive LP of the vulva are resistant to topical corticosteroids, which are the first choice of treatment. This study reports 6 cases with a mean age of 3.33 years, who were diagnosed with erosive LP lesions and previously failed in treatment with local, intralesional, and systemic steroids, and hydroxychloroquine. These patients were then treated with 10 mg of tofacitinib per day. Interestingly, with the new treatment, the patients’ mean overall satisfaction score was 9.16 out of 10 (range: 8-10), the mean pain relief score was 9.16 out of 10 (range: 9-10) and patients’ symptom improvement also began an average of 1.33 months after starting treatment (range: 1-2.5 months).
How do we speak about algorithms and algorithmic media futures? Using vignettes and scenarios in a citizen council on data-driven media personalisation
Authors: Das Ranjana , Wong Yen Nee , Jones Rhianne , Jackson Philip JB
Published: March 2024

‘New’ media and algorithmic rules underlying many emerging technologies present particular challenges in fieldwork, because the opacity of their design, and, sometimes, their real or perceived status as ‘not quite here yet’ – makes speaking about these challenging in the field. In this article, we use insights from a three-stage citizens council investigating citizens’ views on developments in data-driven media personalisation to reflect on the potentials of using future-orientated vignettes and scenarios in data collection on user experiences, expectations and the ethics of algorithms. We present the possibilities and potentials of using vignettes as part of a data collection approach in user-centric algorithm studies which invites users’ contextual experiences of algorithms but also enables more normative reflections on what good looks like in contemporary datafied societies.
Influence of overlapping friction stir processing on microstructural evolution, texture development, and mechanical performance in Al6061
Authors: Satyanarayana Marukurti VNV , Vijayakrishna Begari , Srinivasnaik Mukuloth , Kolagotla Rajani K. , Janaki Durga V. , Prakash Putta
Published: March 2024

In the current examination, a large-area stirred zone has been created in Al6061 through the application of overlapping friction stir processing. The investigation focused on examining the microstructural and texture changes in friction stir processed Al6061, using the electron backscattered diffraction technique. Electron backscattered diffraction images provided valuable insights into the recrystallization process, revealing the presence of fine-grained structure with high-angle boundaries in the large-area stirred zone attributed to intense plastic straining and dynamic recrystallization. The use of the tool caused significant plastic straining, resulting in the development of the A- (1 1 1) {1 1 0} texture component. Mechanical testing demonstrated a noteworthy increase in ductility after processing. However, the microhardness and strength were observed to be inferior to the base material due to elevated thermal cycling.
Visual-related conflicts in close relationships
Authors: Lucchesi Federico , Lobinger Katharina
Published: March 2024

This study explores visual-related conflicts, that is, interpersonal conflicts arising from the problematic use of visual communication and visual practices in close relationships. A total of 90 semi-structured pair and individual in-depth interviews with romantic partners and friends were conducted by applying a repertoire-oriented approach. The article explores how the polysemic nature of visuals and different visual practices (e.g. sharing, archiving and deleting visuals), especially related to mundane everyday visual content, contribute to conflictual situations among partners and friends. Specifically, the results highlight that visual-related conflicts occur around miscommunication through interpersonal communication, non-negotiation around visual sharing, not including partners in online relational presentations, online monitoring activities on social network sites and intrusive requests to delete visuals. This study extends the understanding of potential risks to close relationships from problematic uses of visual communication.
Environmentally friendly greener approach toward sustainable application of amaltas brown pod-based natural colorant for wool yarn dyeing
Authors: Adeel Shahid , Younis Mariam , Mia Rony , Özomay Meral , Mirnezhad Somayeh , Imran Muhammad
Published: March 2024

The escalating concerns over the environmental impacts of synthetic dyes have catalyzed a shift toward sustainable and eco-friendly alternatives in the textile industry. Within this framework, the purpose of this research article is to investigate the environmentally friendly application of brown pods generated from amaltas ( Cassia fistula) as a natural pigment for the purpose of dyeing wool yarn. The purpose of this study is to investigate the possibility of obtaining the reddish-brown anthraquinone-based pigment that is found in Cassia fistula pods by the application of microwave-assisted extraction process. The efficacy of microwave radiation in enhancing the extraction process is evaluated, highlighting its potential for expediting and improving the yield of the natural colorant. In addition, the response surface methodology is utilized in order to optimize the dyeing conditions. Particular attention is paid to characteristics like as temperature, duration, pH, and salt content. In addition, the study investigates the function of mordants, notably salt of Fe, salt of Al, and tartaric acid, in the process of improving colorfastness and generating shades that are both brilliant and long-lasting. The scope of the work is expanded to include the impacts of plant-based extracts as a biomordants, such as pomegranate, red sumac, and hulela zard, for the purpose of producing a wide variety of colors. Additionally, the impact of microwave treatment on wool yarn dyeability is explored, emphasizing improvements in surface morphology and dye absorption. The yarn analysis encompasses color strength, shade variation, and surface morphology, employing techniques such as Fourier transform infrared spectroscopy (FTIR) to elucidate chemical interactions. The study’s findings contribute to the growing body of knowledge on sustainable dyeing practices, highlighting the viability of amaltas-based natural pigments and environmentally friendly mordants in textile applications. Ultimately, this research underscores the significance of adopting ecologically conscious dyeing methods and paves the way for a more sustainable approach to coloration in the textile industry.
Developing initial programme theories for a realist synthesis on digital clinical consultations in maternity care: contributions from stakeholder involvement
Authors: Evans Catrin , Clancy Georgia , Evans Kerry , Booth Andrew , Nazmeen Benash , Timmons Stephen , Sunney Candice , Clowes Mark , Jones Nia Wyn , Spiby Helen
Published: March 2024

Background:

The COVID pandemic prompted an increase in the use of digital clinical consultations (telephone or video calls) within midwifery and nursing care. This paper reports on a realist review project related to maternity care that seeks to illuminate for whom such consultations can safely and acceptably be used, how, for what purposes and in what contexts.

Aims:

This paper addresses the first phase of a realist enquiry – initial programme theory development – focusing particularly on the role of stakeholder involvement (including digital transformation leaders, midwives, obstetricians, service users and community organisations).

Methods:

Three sub-stages of initial programme theory development are described highlighting the contribution of stakeholder groups to each stage: (i) consultation to focus the review question, (ii) focused searching and (iii) further consultation.

Results:

Realist literature searching strategies yielded limited theory-rich evidence on digital consultations. Stakeholders provided essential additional contributions resulting in the development of 13 initial programme theories and a conceptual framework.

Conclusions:

More research on the implementation of virtual midwifery/nursing consultations is needed. Nursing/midwifery digital researchers should involve stakeholders to help shape research priorities, deepen contextual understanding and sense-check emerging findings.
Nusinersen therapy changed the natural course of spinal muscular atrophy type 1: What about spine and hip?
Authors: Yasar Niyazi Erdem , Ozdemir Guzelali , Uzun Ata Elif , Ayvali Mustafa Okan , Ata Naim , Ulgu Mahir , Dumlupınar Ebru , Birinci Suayip , Bingol Izzet , Bekmez Senol
Published: March 2024

Purpose:

Spinal muscular atrophy type 1 has a devastating natural course and presents a severe course marked by scoliosis and hip subluxation in nonambulatory patients. Nusinersen, Food and Drug Administration-approved spinal muscular atrophy therapy, extends survival and enhances motor function. However, its influence on spinal and hip deformities remains unclear.

Methods:

In a retrospective study, 29 spinal muscular atrophy type 1 patients born between 2017 and 2021, confirmed by genetic testing, treated with intrathecal nusinersen, and had registered to the national electronic health database were included. Demographics, age at the first nusinersen dose, total administrations, and Children’s of Philadelphia Infant Test of Neuromuscular Disorders scores were collected. Radiological assessments included parasol rib deformity, scoliosis, pelvic obliquity, and hip subluxation.

Results:

Mean age was 3.7 ± 1.1 (range, 2–6), and average number of intrathecal nusinersen administration was 8.9 ± 2.9 (range, 4–19). There was a significant correlation between Children’s of Philadelphia Infant Test of Neuromuscular Disorders score and the number of nusinersen administration ( r = 0.539, p = 0.05). The correlation between Children’s of Philadelphia Infant Test of Neuromuscular Disorders score and patient age ( r = 0.361) or the time of first nusinersen dose ( r = 0.39) was not significant ( p = 0.076 and p = 0.054, respectively). While 93.1% had scoliosis, 69% had pelvic obliquity, and 60.7% had hip subluxation, these conditions showed no significant association with patient age, total nusinersen administrations, age at the first dose, or Children’s of Philadelphia Infant Test of Neuromuscular Disorders scores.

Conclusion:

Disease-modifying therapy provides significant improvements in overall survival and motor function in spinal muscular atrophy type 1. However, progressive spine deformity and hip subluxation still remain significant problems in the majority of cases which would potentially need to be addressed.
Love and ‘Spiritual Ecumenism’: A Foundational Backdrop for Underhill’s The Spiritual Life
Authors: Wrigley-Carr Robyn
Published: March 2024

One foundational backdrop for Evelyn Underhill’s BBC radio talks, 'The Spiritual Life' (1937), is her posture of ‘spiritual ecumenism’ (prayer for Church unity). In 1936, Underhill had published 'Worship' and participated in various worship practices, plus prayer groups for Church unity. During these years, loving rather than critiquing Christians different to herself had become an area of growth for Underhill (outlined in her spiritual journals). Bérulle’s three types of generous love - adoration, communion and co-operation - provided Underhill’s macro structure for 'The Spiritual Life.' Through the lens of ‘spiritual ecumenism’, Underhill emphasised the centrality of love in ‘the spiritual life’ – love of God and neighbour – particularly fellow Christians. Underhill encourages us to pray for Church unity and engage in spiritual understanding rather than judgment, competition and ‘mud-slinging’. In the context of growing secularism, individualism, and Church disunity, ‘spiritual ecumenism’ has the potential to enhance the Church’s missional impact.
Promotive and Buffering Effects of Protective and Compensatory Experiences on Mental Health and Adjustment in Young Adults
Authors: Ratliff Erin L. , Jespersen Jens E. , Addante Samantha , Watrous Jennifer N. H. , Morris Michael , Beasley Lana O. , Ciciolla Lucia , Hays-Grudo Jennifer , Morris Amanda S.
Published: March 2024

Adverse childhood Experiences (ACEs) are considered a major public health crisis. Protective and Compensatory Experiences (PACEs) may help to ameliorate the effects of ACEs on young adult well-being. This study examined the moderating role of childhood PACEs on the effects of ACEs on depression, anxiety, substance use, and emotion regulation (ER) difficulties in a sample of 550 (73% female, m age = 20 yrs.) undergraduate students. ACEs were associated with greater symptoms of anxiety and depression, substance use, and ER difficulties whereas PACEs were associated with fewer symptoms of depression and anxiety, substance use, and ER difficulties. Protective and compensatory experiences significantly moderated the relationship between ACEs and depression, such that greater PACEs weakened the relationship between ACES and depression. Protective and compensatory experiences did not significantly moderate relationships between ACEs and anxiety, substance use, or ER difficulties. These findings suggest PACEs promote adjustment in young adults and can buffer the deleterious effects of ACEs.
An Epistemic Look at Parental Conceptual Knowledge and Oral Health Outcomes in Children
Authors: Brown Untray T. , Spivakovsky Silvia , Janal Malvin
Published: March 2024

Objective. This study explores the impact of parental oral health knowledge on children’s oral health, investigating if limited knowledge contributes to poor outcomes. The CAMBRA caries risk assessment and the World Health Organization dmft/DMFT index measure oral health. Methods. Over 23 months, the Knowledge Related to Oral Health Literacy (KROHL) questionnaire assesses parental knowledge in 4 domains and 5 oral health conditions. Pearson Correlation Coefficient analyzes the association between KROHL scores and CAMBRA outcomes. Results. Positive correlation emerges between parental oral health knowledge levels and children’s dental caries risk, indicating the KROHL questionnaire’s utility in identifying knowledge gaps. No standardized method for measuring oral health knowledge exists, although various tools claim to address aspects of the issue. This study pioneers the correlation between oral health knowledge and CAMBRA outcomes. Conclusion. The KROHL questionnaire proves a practical, disease-specific tool for research, emphasizing parental oral health knowledge’s pivotal role in children’s oral health. It serves as a valuable means to identify knowledge gaps and potential areas for intervention and education in oral health.
Water Supply Systems in Urban Slum Communities in Lagos, Nigeria: Between Self-supply and Co-production
Authors: Hoelzel Fabienne
Published: March 2024

By investigating the contribution of the ‘informal sector’, this article explores the resourcefulness of place-based practices and how they shape the urban water provision in Lagos. It also provides a detailed and critical view of the enormous efforts of inhabitants in urban slums in the daily water provision. Analysing the qualitative field data collected from observations, 89 semi-structured interviews (field notes), 6 focus group discussions and 12 expert interviews, water supply systems, the utilisation in slum communities and power and politics around it are exposed. Even if people can afford to pay the bills, the provision of urban services by state actors (or commissioned firms) is erratic and often not available. The daily infrastructure provision remains the responsibility of individuals and groups, mostly organised in complex yet fragile and changing networks. Drawing from the research on the existing, largely informal water supply in slum communities, this article argues for the recognition and pro-active implementation of hybrid approaches in the planning, implementation and administration of urban infrastructure. It calls for co-production and ‘hybrid water governance’.
The crystal structure of charmarite – the first case of a 11 × 11 Å superstructure mesh in layered double hydroxides
Authors: Zhitova Elena S. , Zolotarev Andrey A. , Kasatkin Anatoly V. , Sheveleva Rezeda M. , Krivovichev Sergey V. , Pekov Igor V. , Bocharov Vladimir N.
Published: March 2024

Charmarite, Mn4Al2(OH)12CO3⋅3H2O, is a hydrotalcite supergroup member (or layered double hydroxide, LDH) with a previously unknown crystal structure and a Mn2+-analogue of quintinite (commonly erroneously reported as ‘2:1 hydrotalcite’). The single-crystal X-ray diffraction (XRD) data were obtained from the specimen from Mont Saint-Hilaire, Québec, Canada and are best processed in the space group P$\bar{3}$, a = 10.9630(4), c = 15.0732(5) Å and V = 1568.89(12) Å3. The crystal structure has been solved by direct methods and refined to R1 = 0.0750 for 3801 unique reflections with Fo > 2σ(Fo). The charmarite structure has long-range periodicity in the xy plane due to $2\sqrt 3$a’ × $2\sqrt 3$a’ scheme (or 11 × 11 Å) determined for LDHs for the first time (where a’ is a subcell parameter ≈ 3.2 Å). This periodicity is produced by the combination of two superstructures formed by: (1) Mn2+ and Al3+ ordering in the metal-hydroxide layers [Mn4Al2(OH)12]2+ according to the $\sqrt 3$a’ × $\sqrt 3$a’ pattern and (2) the (CO3)2– ordering according to the 2a’ × 2a’ pattern in the [CO3(H2O)3]2– interlayer sheet in order to avoid close contacts between adjacent carbonate groups. The $2\sqrt 3$a’ × $2\sqrt 3$a’ superstructure is an example of the adaptability of the components of the interlayer space to the charge distribution of the metal-hydroxyl layers. The Mn2+ and Al3+ cations have a large difference in size, which apparently leads to the considerable degree of their order as di- and trivalent cations resulting in a higher degree of statistical order of the interlayer components. Both powder and single-crystal XRD data show that the samples studied belong to the hexagonal branch of two-layer polytypes (2T or 2H) with d00n ≈ 7.57 Å. The chemical composition of the samples studied is close to the ideal formula. The Raman spectrum of charmarite is reported and the band assignment is provided.
DNA damage response defects in hematologic malignancies: mechanistic insights and therapeutic strategies
Authors: Kwok Marwan , Agathanggelou Angelo , Stankovic Tatjana
Published: March 2024

The DNA damage response (DDR) encompasses the detection and repair of DNA lesions and is fundamental to the maintenance of genome integrity. Germ line DDR alterations underlie hereditary chromosome instability syndromes by promoting the acquisition of pathogenic structural variants in hematopoietic cells, resulting in increased predisposition to hematologic malignancies. Also frequent in hematologic malignancies are somatic mutations of DDR genes, typically arising from replication stress triggered by oncogene activation or deregulated tumor proliferation that provides a selective pressure for DDR loss. These defects impair homology–directed DNA repair or replication stress response, leading to an excessive reliance on error-prone DNA repair mechanisms that results in genomic instability and tumor progression. In hematologic malignancies, loss-of-function DDR alterations confer clonal growth advantage and adverse prognostic impact but may also provide therapeutic opportunities. Selective targeting of functional dependencies arising from these defects could achieve synthetic lethality, a therapeutic concept exemplified by inhibition of poly-(adenosine 5′-diphosphate ribose) polymerase or the ataxia telangiectasia and Rad 3 related-CHK1-WEE1 axis in malignancies harboring the BRCAness phenotype or genetic defects that increase replication stress. Furthermore, the role of DDR defects as a source of tumor immunogenicity, as well as their impact on the cross talk between DDR, inflammation, and tumor immunity are increasingly recognized, thus providing rationale for combining DDR modulation with immune modulation. The nature of the DDR–immune interface and the cellular vulnerabilities conferred by DDR defects may nonetheless be disease-specific and remain incompletely understood in many hematologic malignancies. Their comprehensive elucidation will be critical for optimizing therapeutic strategies to target DDR defects in these diseases.
Epigenetic control over the cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia
Authors: Felipe Fumero Eloísa , Walter Carolin , Frenz Joris Maximillian , Seifert Franca , Alla Vijay , Hennig Thorben , Angenendt Linus , Hartmann Wolfgang , Wolf Sebastian , Serve Hubert , Oellerich Thomas , Lenz Georg , Müller-Tidow Carsten , Schliemann Christoph , Huber Otmar , Dugas Martin , Mann Matthias , Jayavelu Ashok Kumar , Mikesch Jan-Henrik , Arteaga Maria Francisca
Published: March 2024

Epigenetic modulation of the cell-intrinsic immune response holds promise as a therapeutic approach for leukemia. However, current strategies designed for transcriptional activation of endogenous transposons and subsequent interferon type-I (IFN-I) response, show limited clinical efficacy. Histone lysine methylation is an epigenetic signature in IFN-I response associated with suppression of IFN-I and IFN-stimulated genes, suggesting histone demethylation as key mechanism of reactivation. In this study, we unveil the histone demethylase PHF8 as a direct initiator and regulator of cell-intrinsic immune response in acute myeloid leukemia (AML). Site-specific phosphorylation of PHF8 orchestrates epigenetic changes that upregulate cytosolic RNA sensors, particularly the TRIM25-RIG-I-IFIT5 axis, thereby triggering the cellular IFN-I response-differentiation-apoptosis network. This signaling cascade largely counteracts differentiation block and growth of human AML cells across various disease subtypes in vitro and in vivo. Through proteome analysis of over 200 primary AML bone marrow samples, we identify a distinct PHF8/IFN-I signature in half of the patient population, without significant associations with known clinically or genetically defined AML subgroups. This profile was absent in healthy CD34+ hematopoietic progenitor cells, suggesting therapeutic applicability in a large fraction of patients with AML. Pharmacological support of PHF8 phosphorylation significantly impairs the growth in samples from patients with primary AML. These findings provide novel opportunities for harnessing the cell-intrinsic immune response in the development of immunotherapeutic strategies against AML.
Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT
Authors: Bernabéu-Herrero Maria E. , Patel Dilipkumar , Bielowka Adrianna , Zhu JiaYi , Jain Kinshuk , Mackay Ian S. , Chaves Guerrero Patricia , Emanuelli Giulia , Jovine Luca , Noseda Michela , Marciniak Stefan J. , Aldred Micheala A. , Shovlin Claire L.
Published: March 2024

For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.
IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation
Authors: Hong Lih En , Wechalekar Mihir D. , Kutyna Monika , Small Annabelle , Lim Kelly , Thompson-Peach Chloe , Li Joule J. , Chhetri Rakchha , Scott Hamish S. , Brown Anna , Hahn Christopher N. , Yeung David T. , Sajid Salvia , Robinson Nirmal , Thomas Ranjeny , Branford Susan , D’Andrea Richard J. , Samaraweera Saumya E. , Patnaik Mrinal , Proudman Susanna , Thomas Daniel , Kok Chung Hoow , Shah Mithun V. , Hiwase Devendra K.
Published: March 2024

High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.
Architecture and sedimentary evolution of the Ladinian Kobilji curek basin (External Dinarides, central Slovenia)
Authors: Rožič Boštjan , Kocjančič Anja , Gale Luka , Zupančič Nina , Popit Tomislav , Vodnik Primož , Kolar-Jurkovšek Tea , Brajkovič Rok , Žvab Rožič Petra
Published: March 2024

The study area is located in cental Slovenia, and geologically located at the junction between the Alps and the Dinarides. The Middle Triassic of this region is characterised by intense rifting manifested by differential subsidence and volcanism. This led to a major paleogeographic reorganisation of the region, where three paleogeographic domains formed in the Upper Triassic: The Julian Carbonate Platform in the north, the intermediate Slovenian Basin, both parts of the Southern Alps, and the Dinaric (Adriatic, Friuli) Carbonate Platform in the south, which today is a part of the External Dinarides that host the area of investigation. Prior to the installation of the Dinaric Carbonate Platfrom, i.e. in the Ladinian, the entire area of the preset-day External Dinarides broke up into numerous tectonic blocks that were exposed to either erosion or continental, shallow-marine, and deep-marine sedimentation. In this study, we analyse at small scale a complex transitional area between a local carbonate platform and the Kobilji curek basin (depositional area dominated by deeper marine sediments), located in the Rute Plateau in central Slovenia south of Ljubljana. During enhanced subsidence, the basin was filled with volcanic material (tuffs and volcanogenic clays and subordinate extrusive material), while the adjacent platform aggraded. The slope was positioned above active paleofaults. During relative sea level lowstand, the platform prograded across the basin. The study area is divided into four major tectonic paleoblocks. The NW paleoblock experienced the most enhanced subsidence, and the platform prograded twice in this area and was submerged again by the rejuvenated subsidence and/or sea-level rise. The second and third paleoblocks subsided only during discrete major subsidence events, and the carbonates of the platform and slope were soon reinstated therein. In the fourth paleoblock to the east the platform persisted during the Ladinian. In the Carnian, the entire study area became emerged, and continental clastics were deposited. These were then replaced by a uniform shallow marine/intertidal Hauptdolomit (Dolomia Principale) formation at the onset of the Norian. This study provides the first detailed reconstruction of the sedimentary evolution of small-scale Ladinian basin and platforms system in the northern External Dinarides.
Huntingtin HTT1a is generated in a CAG repeat-length-dependent manner in human tissues
Authors: Hoschek Franziska , Natan Julia , Wagner Maximilian , Sathasivam Kirupa , Abdelmoez Alshaimaa , von Einem Björn , Bates Gillian P. , Landwehrmeyer G. Bernhard , Neueder Andreas
Published: March 2024

Background

The disease-causing mutation in Huntington disease (HD) is a CAG trinucleotide expansion in the huntingtin (HTT) gene. The mutated CAG tract results in the production of a small RNA, HTT1a, coding for only exon 1 of HTT. HTT1a is generated by a block in the splicing reaction of HTT exon 1 to exon 2 followed by cleavage in intron 1 and polyadenylation. Translation of HTT1a leads to the expression of the highly toxic HTT exon 1 protein fragment. We have previously shown that the levels of HTT1a expression in mouse models of HD is dependent on the CAG repeat length. However, these data are lacking for human tissues.

Methods

To answer this question, we developed highly sensitive digital PCR assays to determine HTT1a levels in human samples. These assays allow the absolute quantification of transcript numbers and thus also facilitate the comparison of HTT1a levels between tissues, cell types and across different studies. Furthermore, we measured CAG repeat sizes for every sample used in the study. Finally, we analysed our data with ANOVA and linear modelling to determine the correlation of HTT1a expression levels with CAG repeat sizes.

Results

In summary, we show that HTT1a is indeed expressed in a CAG repeat-length-dependent manner in human post mortem brain tissues as well as in several peripheral cell types. In particular, PBMCs show a statistically significant positive correlation of HTT1a expression with CAG repeat length, and elevated HTT1a expression levels even in the adult-onset CAG repeat range.

Conclusions

Our results show that HTT1a expression occurs throughout a wide range of tissues and likely with all CAG lengths. Our data from peripheral sample sources demonstrate that HTT1a is indeed generated throughout the body in a CAG repeat-length-dependent manner. Therefore, the levels of HTT1a might be a sensitive marker of disease state and/or progression and should be monitored over time, especially in clinical trials targeting HTT expression.
Differential association between physical activity behaviours and dynapenia by comorbid diseases in community-dwelling Korean older adults
Authors: Park Jae Hyeon , Nam Hyung Seok , Park Mina , Kim Yeo Hyung
Published: March 2024

Background

Physical activity (PA) behaviours and comorbid diseases are associated with muscle strength. However, the association between dynapenia and detailed PA behaviours, including participation in aerobic and resistance exercises and sedentary behaviour (SB), in relation to comorbid diseases has not yet been investigated. Using nationwide data, this study aimed to evaluate the independent association of dynapenia with detailed PA behaviour (participation in aerobic and resistance exercises and SB), and assess the differential associations of detailed PA behaviour with dynapenia according to comorbid diseases with prevalent sarcopenia.

Methods

A total of 7,558 community-dwelling older adults aged ≥ 65 years who were included in the Korea National Health and Nutrition Examination Survey from 2014 to 2019 were included in the present study. Cross-sectional associations between PA behaviours (participation in aerobic exercise, participation in resistance exercise, and SB) and dynapenia were analysed using complex-sample multivariable-adjusted logistic regression models according to the type of comorbid disease (cardiovascular disease [CVD], diabetes mellitus [DM], and chronic lung disease [CLD]).

Results

Sufficient aerobic exercise, sufficient resistance exercise, and low sedentary time of < 420 min/day showed independent negative associations with dynapenia (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.60–0.83; OR, 0.54; 95% CI, 0.42–0.69; and OR, 0.84; 95% CI, 0.72–0.97, respectively). Among the participants with CVD or CLD, the associations of sufficient resistance exercise (OR, 0.46; 95% CI, 0.26–0.82 and OR, 0.51; 95% CI, 0.35–0.75 for CVD and CLD, respectively) and low sedentary time (OR, 0.66; 95% CI, 0.45–0.98 and OR, 0.71; 95% CI, 0.55–0.93 for CVD and CLD, respectively) with dynapenia were significant, whereas the association of sufficient aerobic exercise with dynapenia was insignificant. Meanwhile, in participants with DM, sufficient aerobic exercise (OR, 0.70; 95% CI, 0.52–0.94) and sufficient resistance exercise (OR, 0.45; 95% CI, 0.29–0.70) were independently associated with dynapenia, whereas no association between SB and dynapenia was found.

Conclusion

We observed an independent inverse association between PA behaviours and dynapenia. Disease-specific associations between each PA behaviour (sufficient aerobic exercise, sufficient resistance exercise, and low sedentary time) and dynapenia differed in the older adults. Therefore, these differences should be acknowledged during interventions for this population.
Bayesian inference for identifying tumour-specific cancer dependencies through integration of ex-vivo drug response assays and drug-protein profiling
Authors: Xing Hanwen , Yau Christopher
Published: March 2024

The identification of tumor-specific molecular dependencies is essential for the development of effective cancer therapies. Genetic and chemical perturbations are powerful tools for discovering these dependencies. Even though chemical perturbations can be applied to primary cancer samples at large scale, the interpretation of experiment outcomes is often complicated by the fact that one chemical compound can affect multiple proteins. To overcome this challenge, Batzilla et al. (PLoS Comput Biol 18(8): e1010438, 2022) proposed DepInfeR, a regularized multi-response regression model designed to identify and estimate specific molecular dependencies of individual cancers from their ex-vivo drug sensitivity profiles. Inspired by their work, we propose a Bayesian extension to DepInfeR. Our proposed approach offers several advantages over DepInfeR, including e.g. the ability to handle missing values in both protein-drug affinity and drug sensitivity profiles without the need for data pre-processing steps such as imputation. Moreover, our approach uses Gaussian Processes to capture more complex molecular dependency structures, and provides probabilistic statements about whether a protein in the protein-drug affinity profiles is informative to the drug sensitivity profiles. Simulation studies demonstrate that our proposed approach achieves better prediction accuracy, and is able to discover unreported dependency structures.
scFSNN: a feature selection method based on neural network for single-cell RNA-seq data
Authors: Peng Minjiao , Lin Baoqin , Zhang Jun , Zhou Yan , Lin Bingqing
Published: March 2024

While single-cell RNA sequencing (scRNA-seq) allows researchers to analyze gene expression in individual cells, its unique characteristics like over-dispersion, zero-inflation, high gene-gene correlation, and large data volume with many features pose challenges for most existing feature selection methods. In this paper, we present a feature selection method based on neural network (scFSNN) to solve classification problem for the scRNA-seq data. scFSNN is an embedded method that can automatically select features (genes) during model training, control the false discovery rate of selected features and adaptively determine the number of features to be eliminated. Extensive simulation and real data studies demonstrate its excellent feature selection ability and predictive performance.
Genome-wide analysis of acid tolerance genes of Enterococcus faecalis with RNA-seq and Tn-seq
Authors: Chen Zhanyi , Niu Chenguang , Wei Lifan , Huang Zhengwei , Ran Shujun
Published: March 2024

Enterococcus faecalis, a formidable nosocomial and community-acquired opportunistic pathogen, can persist a wide range of extreme environments, including low pH and nutrient deficiency. Clarifying the survival mechanism of E. faecalis in low-pH conditions is the key to combating the infectious diseases caused by E. faecalis. In this study, we combined transcriptome profiling (RNA-seq) and transposon insertion sequencing (TIS) to comprehensively understand the genes that confer these features on E. faecalis. The metadata showed that genes whose products are involved in cation transportation and amino acid biosynthesis were predominantly differentially expressed under acid conditions. The products of genes such as opp1C and copY reduced the hydrion concentration in the cell, whereas those of gldA2, gnd2, ubiD, and ubiD2 mainly participated in amino metabolism, increasing matters to neutralize excess acid. These, together with the folE and hexB genes, which are involved in mismatch repair, form a network of E. faecalis genes necessary for its survival under acid conditions.
Childbirth experiences of women with a history of physical, sexual, and child abuse: a cross-sectional study of 2,575 Russian women
Authors: Suarez Anna , Yakupova Vera
Published: March 2024

Background

A substantial number of women who subsequently become pregnant and give birth have a history of physical, sexual, and/or child abuse. This study investigated the associations of these types of traumas and their cumulative effect with childbirth experiences, namely, mode of birth, maternal and child complications during pregnancy/childbirth, preterm birth, medical procedures, and obstetric violence during labour.

Methods

A group of Russian women (n = 2,575) who gave birth within the previous 12 months, completed a web-based survey, where they provided demographic information, details about their childbirth experiences, and a history of trauma.

Results

Women with any type of past abuse were at higher risk for maternal complications during pregnancy/childbirth (exp(β) < 0.73, p < 0.010 for all). More specific to the type of trauma were associations of physical abuse with caesarean birth, child abuse with complications during pregnancy/childbirth for the baby, and physical and child abuse with obstetric violence (exp(β) < 0.54, p < 0.022 for all). There was a cumulative effect of trauma for all the outcomes except for medical procedures during childbirth and preterm birth.

Conclusion

This study provides insights into potential different individual effects of physical, sexual, and/or child abuse as well as their cumulative impact on the childbirth experiences. The robust findings about maternal complications during pregnancy/childbirth and obstetric violence highlight the importance of trauma-informed care, supportive policies, and interventions to create safe and empowering birthing environments that prioritise patient autonomy, dignity, and respectful communication.
Regulation of metastatic potential by drug repurposing and mitochondrial targeting in colorectal cancer cells
Authors: Mathur Shashank , Srivastava Pransu , Srivastava Anubhav , Rai Neeraj Kumar , Abbas Sabiya , kumar Ashok , Tiwari Meenakshi , Sharma Lokendra Kumar
Published: March 2024

Background

Increased mitochondrial activities contributing to cancer cell proliferation, invasion, and metastasis have been reported in different cancers; however, studies on the therapeutic targeting of mitochondria in regulating cell proliferation and invasiveness are limited. Because mitochondria are believed to have evolved through bacterial invasion in mammalian cells, antibiotics could provide an alternative approach to target mitochondria, especially in cancers with increased mitochondrial activities. In this study, we investigated the therapeutic potential of bacteriostatic antibiotics in regulating the growth potential of colorectal cancer (CRC) cells, which differ in their metastatic potential and mitochondrial functions.

Methods

A combination of viability, cell migration, and spheroid formation assays was used to measure the effect on metastatic potential. The effect on mitochondrial mechanisms was investigated by measuring mitochondrial DNA copy number by qPCR, biogenesis (by qPCR and immunoblotting), and functions by measuring reactive oxygen species, membrane potential, and ATP using standard methods. In addition, the effect on assembly and activities of respiratory chain (RC) complexes was determined using blue native gel electrophoresis and in-gel assays, respectively). Changes in metastatic and cell death signaling were measured by immunoblotting with specific marker proteins and compared between CRC cells.

Results

Both tigecycline and tetracycline effectively reduced the viability, migration, and spheroid-forming capacity of highly metastatic CRC cells. This increased sensitivity was attributed to reduced mtDNA content, mitochondrial biogenesis, ATP content, membrane potential, and increased oxidative stress. Specifically, complex I assembly and activity were significantly inhibited by these antibiotics in high-metastatic cells. Significant down-regulation in the expression of mitochondrial-mediated survival pathways, such as phospho-AKT, cMYC, phospho-SRC, and phospho-FAK, and upregulation in cell death (apoptosis and autophagy) were observed, which contributed to the enhanced sensitivity of highly metastatic CRC cells toward these antibiotics. In addition, the combined treatment of the CRC chemotherapeutic agent oxaliplatin with tigecycline/tetracycline at physiological concentrations effectively sensitized these cells at early time points.

Conclusion

Altogether, our study reports that bacterial antibiotics, such as tigecycline and tetracycline, target mitochondrial functions specifically mitochondrial complex I architecture and activity and would be useful in combination with cancer chemotherapeutics for high metastatic conditions.