bluuebunny/crossref_metadata_2025 huggingface dataset:
Redefining urban digital twins for the federated data spaces ecosystem: A perspective
Authors: Gil Jorge , Petrova-Antonova Dessislava , Kemp Graham JL
Published: December 2024

Urban Digital Twins (UDTs) promise to facilitate the transition to a smarter planning and decision-making process, but they face many challenges to meet stakeholders’ expectations and to support delivering a better living environment for citizens. Their full potential can only be reached through more flexible sharing and integration of data and data models. From this perspective, we argue that UDTs can be realised in an ecosystem of data spaces that support a federated data architecture. We present the conceptual architecture for UDTs in a federated data spaces ecosystem, describe the different components and layers, and reflect on the UDT mediator role in relation to other actors in the ecosystem. We aim to contribute to the field of UDTs by showing the way forward for their development, connected to the concepts of data spaces and federated database systems, and to the field of data spaces by introducing UDTs as a new component playing a mediator role.
Impact of Tumor Size on Endoluminal Resection of Subepithelial Tumors of the Esophagus
Authors: Hadi Yousaf B. , Kumta Nikhil A.
Published: December 2024

Subepithelial tumors arise from gastrointestinal wall layers outside of the mucosa. These lesions in the esophagus are mostly benign, but some tumors arising from the muscularis propria have malignant potential. Management includes surveillance or resection, which was conventionally performed with surgery; contemporary resection techniques include endoscopic resection or thoracoscopic resection. Increasing data suggests high rates of complete and en-bloc resection with endoscopic approach with a low adverse event profile. Candidacy for endoscopic resection of esophageal subepithelial tumors should be determined based on size, morphology, location, etiology, and a shared decision-making approach with the patient in the context of available endoscopic expertise.
BRAFV600E induces key features of LCH in iPSCs with cell type–specific phenotypes and drug responses
Authors: Abagnale Giulio , Schwentner Raphaela , Ben Soussia-Weiss Philipp , van Midden Wouter , Sturtzel Caterina , Pötschger Ulrike , Rados Magdalena , Taschner-Mandl Sabine , Simonitsch-Klupp Ingrid , Hafemeister Christoph , Halbritter Florian , Distel Martin , Eder Sebastian K. , Hutter Caroline
Published: December 2024

Langerhans cell histiocytosis (LCH) is a clonal hematopoietic disorder defined by tumorous lesions containing CD1a+/CD207+ cells. Two severe complications of LCH are systemic hyperinflammation and progressive neurodegeneration. The scarcity of primary samples and lack of appropriate models limit our mechanistic understanding of LCH pathogenesis and affect patient care. We generated a human in vitro model for LCH using induced pluripotent stem cells (iPSCs) harboring the BRAFV600E mutation, the most common genetic driver of LCH. We show that BRAFV600E/WT iPSCs display myelomonocytic skewing during hematopoiesis and spontaneously differentiate into CD1a+/CD207+ cells that are similar to lesional LCH cells and are derived from a CD14+ progenitor. We show that BRAFV600E modulates the expression of key transcription factors regulating monocytic differentiation and leads to an upregulation of proinflammatory molecules and LCH marker genes early during myeloid differentiation. In vitro drug testing revealed that BRAFV600E-induced transcriptomic changes are reverted upon treatment with mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKis). Importantly, MAPKis do not affect myeloid progenitors but reduce only the mature CD14+ cell population. Furthermore, iPSC-derived neurons (iNeurons) cocultured with BRAFV600E/WT iPSC-derived microglia-like cells, differentiated from iPSC-derived CD34+ progenitors, exhibit signs of neurodegeneration with neuronal damage and release of neurofilament light chain. In summary, the iPSC-based model described here provides a platform to investigate the effects of BRAFV600E in different hematopoietic cell types and provides a tool to compare and identify novel approaches for the treatment of BRAFV600E-driven diseases.
Impact of measurable residual disease clearance kinetics in patients with AML undergoing intensive chemotherapy
Authors: Jen Wei-Ying , Sasaki Koji , Ravandi Farhad , Kadia Tapan M. , Wang Sa A. , Wang Wei , Loghavi Sanam , Daver Naval G. , DiNardo Courtney D. , Issa Ghayas C. , Abbas Hussein A. , Nasnas Cedric , Bataller Alex , Urrutia Samuel , Karrar Omer S. , Pierce Sherry , Kantarjian Hagop M. , Short Nicholas J.
Published: December 2024

The prognostic impact of measurable residual disease (MRD) in acute myeloid leukemia (AML) is unequivocal; however, the optimal time point for achieving undetectable MRD is unclear. We retrospectively studied patients with newly diagnosed (ND) AML who achieved remission with frontline intensive chemotherapy and had MRD assessed by flow cytometry after induction (time point 1 [TP1]) and after cycles 2 or 3 (TP2). Cases were grouped into MRD negative (Neg)/Neg, positive (Pos)/Neg, or Pos/Pos at TP1 and TP2, respectively. Of 1980 patients with ND AML, 277 met the inclusion criteria and were included in this analysis. The median relapse-free survival (RFS) was 73 months, 22 months, and 5 months for the MRD Neg/Neg, Pos/Neg, and Pos/Pos groups, respectively (P < .01). There was a significant difference between the Neg/Neg and Pos/Neg groups (P = .05), suggesting benefit to early MRD negativity. The median overall survival (OS) was 81 months, 40 months, and 9 months, respectively (P < .01), but the difference between Neg/Neg and Pos/Neg was not statistically significant (P = .19). Landmark analysis demonstrated the benefit of stem cell transplant (SCT), particularly in Neg/Neg intermediate-risk AML (median RFS, not reached vs 15 months; P < .01). On multivariable analysis, MRD Pos/Neg was independently associated with a worse RFS than Neg/Neg (hazard ratio, 1.73; 95% confidence interval, 1.09-2.75; P = .02) but not for OS (P = .15). In conclusion, undetectable flow MRD after induction is associated with better RFS than undetectable MRD achieved later during consolidation. SCT benefited patients with intermediate-risk AML, regardless of MRD kinetics.
Sarcopenia in interstitial lung disease
Authors: Sheehy Robert , McCormack Samuel , Fermoyle Caitlin , Corte Tamera
Published: December 2024

Background

Interstitial lung disease (ILD) encompasses a heterogeneous group of chronic lung conditions with considerable variability in prognosis and response to treatment. People with reduced muscle mass and function, known as sarcopenia, have a higher risk of mortality and adverse clinical outcomes both in the general population and in other chronic disease states. The importance of sarcopenia across the spectrum of patients with ILD is not well established.

Objectives

In this narrative review, we explore the prevalence and clinical implications of sarcopenia in patients with ILD, evaluate the optimal methods to diagnose sarcopenia in this patient population and review treatment interventions.

Findings

Almost one third of patients with chronic forms of ILD have evidence of sarcopenia. Sarcopenia is associated with adverse clinical outcomes and increased risk of mortality in select populations with ILD. Screening tests such as the SARC-F (strength, assistance walking, rise from a chair, climb stairs, falls) questionnaire and clinical assessment tools (including grip strength dynamometry) are well validated. Medical imaging modalities, including computed tomography, are hampered by lack of a gold standard and normative values, but have been used in patients with ILD in acute care and research settings. If sarcopenia is identified, multidimensional interventions such as pulmonary rehabilitation are beneficial.

Conclusion

Sarcopenia is common in patients with ILD and is associated with poorer outcomes. Accordingly, if identified, targeted interventions should be considered. Validated diagnostic criteria exist, but the optimal use of medical imaging techniques in this patient cohort remains an area of uncertainty.
Revisiting the follicle-stimulation hormone receptor expression and function in human myometrium and adipose tissue
Authors: Palak Ewelina , Ponikwicka-Tyszko Donata , Pulawska-Moon Kamila , Sztachelska Maria , Milewska Gabriela , Modzelewska Beata , Kleszczewski Tomasz , Koivukoski Maria L. , Bernaczyk Piotr , Hady Hady Razak , Gołaszewski Piotr , Lupinska Aleksandra N. , Kulikowski Marek , Lemancewicz Adam , Huhtaniemi Ilpo T. , Wolczynski Slawomir , Rahman Nafis A.
Published: December 2024

Background

Extragonadal follicle-stimulating hormone receptor (FSHR) expression at low levels has been shown in several normal and tumor tissues, including myometrium and adipose tissue. FSH-FSHR signaling in the myometrium has been suggested to regulate uterine contractile activity and the timing of labor. In contrast, FSH-FSHR has been linked to the activation of brown/beige fat thermogenesis in adipose tissue. The issue of extragonadal FSHR expression and its functionality remains contentious within the scientific community, as contradictory findings necessitate further independent and critical analyses. Hereby, we re-investigated the FSHR expression and its functionality in normal non-pregnant (M-NP) and pregnant (N-P) human myometrium, as well as in human visceral (VAT) and subcutaneous (SCAT) adipose tissue (AT).

Methods

FSHR expression at mRNA (real-time qPCR, RNAscope in situ hybridization) and protein (immunohistochemical staining) levels in adipose tissue, myometrium, and adipocytes were evaluated. Myometrium and adipocytes were treated with recombinant (rh)FSH to study its effects on functional pathways. Myometrium contractile activity was measured using a force transducer with digital output and the DASYLab software unit. Cyclic adenosine monophosphate (cAMP) production by myometrium explants and adipocytes was measured using a cAMP ELISA Kit. The activation of the AKT pathway in myometrium and adipocytes was analyzed by Western blot analysis.

Results

Contrary to previous observations, we found no expression of FSHR at either mRNA or protein levels in M-NP, N-P, VAT, and SCAT. Treatment with recombinant human FSH (rhFSH) showed no effect on cAMP production or phosphorylation of AKT in M-NP, N-P, as well as in VAT and SCAT. rhFSH treatment did not influence contractile activity in M-NP, N-P.

Conclusions

These findings suggest that the FSHR signaling pathway does not regulate myometrial contractility during pregnancy. Additionally, the absence of FSHR expression in both VAT and SCAT implied that FSHR does not play a role in the functional signaling pathways in adipose tissues. In conclusion, our findings contradict earlier data on the involvement of FSH-FSHR signaling in regulating myometrial contractility near term, as well as in adipose tissue function.
Exercise promotes skeletal muscle growth in adolescents via modulating Mettl3-mediated m6A methylation of MyoD in muscle satellite cells
Authors: Feng Shujing , Zhou Hao , Lin Xingzuan , Zhu Siyuan , Chen Huifang , Zhou Han , Wang Ru , Wang Peng , Shao Xiexiang , Wang Jianhua
Published: December 2024

Background

Exercise exerts positive impacts on skeletal muscle health and homeostasis. Emerging evidence suggests that m6A methylation is involved in various physiological processes. However, the impact of exercise on adolescent skeletal muscle growth and the underlying epigenetic mechanisms remain poorly understood.

Methods

The lower-limb skeletal muscles were harvested from exercise and control groups to compare the skeletal muscle growth in adolescents. mRNA sequencing was conducted to explore the mechanisms underlying enhanced skeletal muscle growth following exercise. The effects and mechanisms of Mettl3-mediated m6A methylation on adolescent skeletal muscle growth were investigated using muscle satellite cell (MuSC)-specific Mettl3 knockout (KO) mice. The potential function of MyoD for skeletal muscle growth in adolescents was explored by phenotypes after overexpression and evaluation of in vivo myogenesis. Additionally, the effects of the methyl donor betaine on adolescent skeletal muscle growth were investigated in vitro and in vivo.

Results

Exercise could promote skeletal muscle growth in adolescents. Sequencing data analysis and confirmation assays uncovered that exercise significantly increased Mettl3-mediated m6A methylation and elevated the expression levels of activation marker MyoD in MuSCs. Establishment of MuSC-specific Mettl3 KO mice further demonstrated that Mettl3-mediated m6A methylation in MyoD contributed to skeletal muscle growth during adolescence. Mettl3-mediated m6A methylation regulated MyoD mRNA stability at the posttranscriptional level in MuSCs, with a functional site at 234 bp A. Increased expression of MyoD could contribute to myogenesis of adolescent MuSCs. Furthermore, the methyl donor betaine could enhance MyoD expression, contributing to MuSCs activation and skeletal muscle growth in adolescents by boosting m6A methylation levels.

Conclusions

Exercise promoted skeletal muscle growth in adolescents through facilitating MyoD mRNA stability of MuSCs in a Mettl3-mediated m6A-dependent manner. The methyl donor betaine could be a potential alternative to exercise for promoting adolescent skeletal muscle growth by directly augmenting the global levels of m6A methylation. These findings may provide a theoretical foundation for encouraging daily fitness exercise and ensuring healthy growth in adolescents.
Pheno-Ranker: a toolkit for comparison of phenotypic data stored in GA4GH standards and beyond
Authors: Leist Ivo C. , Rivas-Torrubia María , Alarcón-Riquelme Marta E. , Barturen Guillermo , Consortium PRECISESADS Clinical , Gut Ivo G. , Rueda Manuel
Published: December 2024

Background

Phenotypic data comparison is essential for disease association studies, patient stratification, and genotype–phenotype correlation analysis. To support these efforts, the Global Alliance for Genomics and Health (GA4GH) established Phenopackets v2 and Beacon v2 standards for storing, sharing, and discovering genomic and phenotypic data. These standards provide a consistent framework for organizing biological data, simplifying their transformation into computer-friendly formats. However, matching participants using GA4GH-based formats remains challenging, as current methods are not fully compatible, limiting their effectiveness.

Results

Here, we introduce Pheno-Ranker, an open-source software toolkit for individual-level comparison of phenotypic data. As input, it accepts JSON/YAML data exchange formats from Beacon v2 and Phenopackets v2 data models, as well as any data structure encoded in JSON, YAML, or CSV formats. Internally, the hierarchical data structure is flattened to one dimension and then transformed through one-hot encoding. This allows for efficient pairwise (all-to-all) comparisons within cohorts or for matching of a patient’s profile in cohorts. Users have the flexibility to refine their comparisons by including or excluding terms, applying weights to variables, and obtaining statistical significance through Z-scores and p-values. The output consists of text files, which can be further analyzed using unsupervised learning techniques, such as clustering or multidimensional scaling (MDS), and with graph analytics. Pheno-Ranker’s performance has been validated with simulated and synthetic data, showing its accuracy, robustness, and efficiency across various health data scenarios. A real data use case from the PRECISESADS study highlights its practical utility in clinical research.

Conclusions

Pheno-Ranker is a user-friendly, lightweight software for semantic similarity analysis of phenotypic data in Beacon v2 and Phenopackets v2 formats, extendable to other data types. It enables the comparison of a wide range of variables beyond HPO or OMIM terms while preserving full context. The software is designed as a command-line tool with additional utilities for CSV import, data simulation, summary statistics plotting, and QR code generation. For interactive analysis, it also includes a web-based user interface built with R Shiny. Links to the online documentation, including a Google Colab tutorial, and the tool’s source code are available on the project home page: https://github.com/CNAG-Biomedical-Informatics/pheno-ranker.
Transforming community-based primary health care delivery through comprehensive performance measurement and reporting: examining the influence of context
Authors: Wong Sabrina T. , Thandi Manpreet , Martin-Misener Ruth , Johnston Sharon , Hogg William , Burge Fred
Published: December 2024

Background

Community-based primary health care represents various community-based health care (CBPHC) models that incorporate health promotion and community development to deliver first-contact health services. Learning health systems (LHSs) are essential for improving CBPHC in which feedback from relevant stakeholders is used to continuously improve health systems with the goal of achieving population health and health equity. Performance reporting is one way to present data to clinicians and decision makers to facilitate a process of reflection, participation, and collaboration among partners to improve CBPHC.

Methods

Our objective was to obtain feedback on a regional CBPHC performance portrait through key informant interviews. We used purposive convenience sampling to recruit participants who were clinicians in primary care and/or decision-makers in primary care at a regional level. The performance portrait summarized results of survey questions asked of patients, providers, and primary care organizations. The portrait was organized by the 10 pillars of the Patient’s Medical Home (PMH) model. Interview questions specifically asked about portrait content, formatting, interpretability, utility, and dissemination strategies. Content analysis was used to analyze interview data.

Results

We completed 19 interviews with key informants from the Canadian provinces of Nova Scotia (n = 8), Ontario (n = 6) and British Columbia (n = 5). We coded transcripts into four content areas: (1) Usability as influenced by content and interpretability, (2) Formatting, (3) Utility, and (4) Dissemination. Using data and reporting back to clinicians and decision-makers about how their practices and jurisdictions are performing in primary care in meaningful ways is important. Our results suggest having available methodology notes, including the analysis used to develop any scoring, sampling and sample sizes, and interpretation of the statistics is necessary.

Conclusions

This research was the first to create a comprehensive performance portrait using data driven by factors that are important to primary care partners. We obtained important feedback on the portrait in the context of usability, formatting, utility, and dissemination. This data needs to be used to provide feedback in continuous cycles to evaluate and improve CBPHC models as part of a LHS.
Ethics practices associated with reusing health data: an assessment of patient registries
Authors: van den Akker Olmo R. , Stark Susanne , Strech Daniel
Published: December 2024

Background

As routinely collected patient data have become increasingly accessible over the years, more attention has been directed at the ethics of using such data for research. Patient data is often available to researchers through patient registries that typically collect data of patients with a specific condition. While ethical guidelines for using patient data are presented frequently in the literature, it is currently unknown how patient registries implement the recommendations from these guidelines in practice and how they communicate their practices. In this project, we assessed to what extent a sample of 51 patient registries provides information about a range of ethics practices.

Methods

We searched for patient registries in the resource database of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Our ethics reporting checklist was based on three sources: the Registry Evaluation and Quality Standards Tool (REQueST), the Agency for Healthcare Research and Quality (AHRQ) guide for good registry practices, and a systematic review of the principles and norms related to health data sharing by Kalkman and colleagues. The checklist includes 26 questions about five ethics components: governance, conflicts of interest, informed consent, privacy and data protection, and use-and-access.

Results

We found substantial heterogeneity in the way patient registries provide information about ethics practices. Patient registries often mentioned their governance structure and any potential conflicts of interests but typically did not describe the responsibilities and rights allocated to their funders. Information about informed consent was often provided to patients, but the available documents often lacked relevant information like the benefits and risks of participation. Privacy and data protection and use-and-access policies were typically discussed but not very concretely.

Conclusions

We conclude that registries typically provide information about key ethics practices such as governance, conflicts of interest, informed consent, privacy and data protection, and use-and-access procedures, but this information is often not as detailed as recommended in existing guidelines. The ethics reporting checklist we designed could be helpful for the ethical assessments of patient registries and other types of registries in the future as well as for self-assessment of registries aiming to improve their ethics practices.
Non-invasive MRI of blood-cerebrospinal fluid-barrier function in a mouse model of Alzheimer’s disease: a potential biomarker of early pathology
Authors: Perera Charith , Cruz Renata , Shemesh Noam , Carvalho Tânia , Thomas David L. , Wells Jack , Ianuș Andrada
Published: December 2024

Background

Choroid plexus (CP) or blood-cerebrospinal fluid-barrier (BCSFB) is a unique functional tissue which lines the brain’s fluid-filled ventricles, with a crucial role in CSF production and clearance. BCSFB dysfunction is thought to contribute to toxic protein build-up in neurodegenerative disorders, including Alzheimer’s disease (AD). However, the dynamics of this process remain unknown, mainly due to the paucity of in-vivo methods for assessing CP function.

Methods

We harness recent developments in Arterial Spin Labelling MRI to measure water delivery across the BCSFB as a proxy for CP function, as well as cerebral blood flow (CBF), at different stages of AD in the widely used triple transgenic mouse model (3xTg), with ages between 8 and 32 weeks. We further compared the MRI results with Y-maze behaviour testing, and histologically validated the expected pathological changes, which recapitulate both amyloid and tau deposition.

Results

Total BCSFB-mediated water delivery is significantly higher in 3xTg mice (> 50%) from 8 weeks (preclinical stage), an increase which is not explained by differences in ventricular volumes, while tissue parameters such as CBF and T1 are not different between groups at all ages. Behaviour differences between the groups were observed starting at 20 weeks, especially in terms of locomotion, with 3xTg animals showing a significantly smaller number of arm entries in the Y-maze.

Conclusions

Our work strongly suggests the involvement of CP in the early stages of AD, before the onset of symptoms and behavioural changes, providing a potential biomarker of pathology.
Cognitive behavioral therapy for pediatric obsessive-compulsive disorder delivered via internet videoconferencing: a manualized sensor-assisted feasibility approach
Authors: Klein Carolin S. , Alt Annika K. , Pascher Anja , Kühnhausen Jan , Seizer Lennart , Ilg Winfried , Thierfelder Annika , Primbs Jonas , Menth Michael , Barth Gottfried M. , Gawrilow Caterina , Conzelmann Annette , Renner Tobias J. , Hollmann Karsten
Published: December 2024

Background

Between 1 and 4% of children and adolescents suffer from obsessive-compulsive disorder (OCD) worldwide, but the majority of these young people do not have access to cognitive behavioral therapy (CBT) as a first-line treatment. CBT delivered via online videoconferencing (vCBT) offers a new way to provide young people with therapy, especially in the home environment where symptoms usually occur.

Methods

In this study, we investigated the feasibility of a newly revised vCBT manual, symptom change during treatment, and effects on family life and social functioning. 20 patients with OCD, aged 12–18 years, were treated during 14 weekly sessions while using a multimodal sensor system that assessed their physiological and behavioral responses during therapy. Treatment was delivered in real time via an online videoconferencing platform. Measurements of feasibility, acceptance, and implementation were evaluated descriptively, and clinical measures were assessed with t tests.

Results

The primary results showed that patients and parents perceived the manual-based vCBT as feasible and easy to understand. According to the therapists’ ratings, all treatment modules and the content could be carried out in accordance with the manual. As a secondary outcome, OCD symptoms improved significantly during treatment (p <.001, d = 1.87), revealed by an average decrease of more than half in the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score. As the psychotherapy could be implemented directly in the patients’ home environment, low barriers to participation were reported, and the majority of participants reported improvements in family life after treatment.

Conclusions

In summary, the results of this feasibility study indicated a successful application of manual-based psychotherapy delivered via videoconferencing for pediatric OCD supported by a sensor system. This method should be further investigated in future randomized controlled trials with larger patient samples.

Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT05291611], first submission: 2021-12-10.
Civilian pattern of injuries in armed conflicts – a systematic review
Authors: Chevalley Karl , Zimmerman Jonas , Mittendorf Anton , Sennersten Filippa , Dalman Anton , Frogh Safora , Ringart Theo , Robinson Yohan , Sandström Göran
Published: December 2024

Background

War causes severe suffering and harm to the civilian population. Knowledge about civilian injury patterns constitutes a part of the dimensioned planning and preparedness for medical care and civilian defence in times of war. This systematic review is conducted on request from The Swedish National Board of Health and Welfare and includes civilian injury patterns in modern war.

Methods

The aim of the study is to describe civilian injury patterns in war 1973–2023. We have conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The protocol has been registered 2023-05-06 in PROSPERO (CRD4202321483).

Results

The search resulted in 3455 identified articles. 1226 of those were duplicates. 2229 studies were assessed, and 1817 papers were excluded. 412 papers went through full text assessment resulting in 63 remaining papers. Injuries to the extremities constitutes 50%, followed by head injuries (26%) and injuries to the chest (18%). Notably, 23% of the wounded are children.

Discussion

There is no standardized classification or method to report and describe civilian war injuries and the injury panorama. Variations in how the injuries were reported made synthesis of the results difficult. In the present survey we haven’t investigated mortalities and causes of death. Reliable data from recent wars, such as the ongoing war in Ukraine and Gaza, was missing from the open literature.

Conclusions

The distribution of injuries seems comparable with data from World War II and the conflict in Korea. There is no standardized simple protocol to report civilian injuries in war. Ideally, a protocol should include even the severity impact of the injuries. Knowledge of civilian injury pattern and estimate of the total number of wounded is important to plan the civilian health care capabilities in war time.
Optimizing hexanoic acid biosynthesis in Saccharomyces cerevisiae for the de novo production of olivetolic acid
Authors: Schäfer Kilan J. , Aras Marco , Boles Eckhard , Kayser Oliver
Published: December 2024

Medium chain fatty acids (MCFAs) are valuable platform compounds for the production of biotechnologically relevant chemicals such as biofuels and biochemicals. Two distinct pathways have been implemented in the yeast Saccharomyces cerevisiae for the biosynthetic production of MCFAs: (i) the mutant fatty acid biosynthesis (FAB) pathway in which the fatty acid synthase (FAS) complex is mutated and (ii) a heterologous multispecies-derived reverse β-oxidation (rBOX) pathway. Hexanoic acid has become of great interest as its acyl-CoA ester, hexanoyl-CoA, is required for the biosynthesis of olivetolic acid (OA), a cannabinoid precursor. Due to insufficient endogenous synthesis of hexanoyl-CoA, recombinant microbial systems to date require exogenous supplementation of cultures with hexanoate along with the overexpression of an acyl-CoA ligase to allow cannabinoid biosynthesis. Here, we engineer a recombinant S. cerevisiae strain which was metabolically optimized for the production of hexanoic acid via the FAB and rBOX pathways and we combine both pathways in a single strain to achieve titers of up to 120 mg L−1. Moreover, we demonstrate the biosynthesis of up to 15 mg L−1 OA from glucose using hexanoyl-CoA derived from the rBOX pathway.
High vector competence for chikungunya virus but heavily reduced locomotor activity of Aedes albopictus from Germany at low temperatures
Authors: Lühken Renke , Rauhöft Leif , Pluskota Björn , Lange Unchana , Helms Michelle , Becker Norbert , Schmidt-Chanasit Jonas , Kuhn Carola , Tannich Egbert , Jansen Stephanie , Heitmann Anna
Published: December 2024

Background

The incidence of human infections caused by arthropod-borne viruses, such as the chikungunya virus (CHIKV), has increased globally due to a number of factors, such as climate change and globalization. The exotic mosquito species Aedes albopictus is a significant vector for CHIKV, raising concerns about its transmission potential in temperate regions, including Central Europe. We have therefore investigated the vector competence of Ae. albopictus for CHIKV at constant and fluctuating temperatures between 15 °C and 24 °C to assess the transmission risk in Europe.

Methods

Aedes albopictus mosquitoes were reared and artificially infected with CHIKV. Infection rates and transmission efficiencies (TEs) were determined after 14 days of incubation at constant and fluctuating (± 5 °C) mean temperatures of 15 °C, 18 °C, 21 °C and 24 °C. In addition, mosquito locomotor activity was measured under the same fluctuating temperature conditions. A risk map for CHIKV transmission in Europe was generated combining temperature data and the current distribution of Ae. albopictus.

Results

CHIKV transmission was observed at all tested temperatures. The highest TEs were recorded at fluctuating temperatures of 18 °C (54.3%) and 21 °C (58.6%), while the lowest TE was observed at a constant temperature of 15 °C (5.6%). TEs at fluctuating temperatures of 15 °C and 24 °C were the same (32.5%). Mosquito activity showed a nocturnal unimodal activity pattern with a peak during the start of the scotophase (hour 20). The proportion of active mosquitoes per hour increased with temperature and was nearly zero at 15 °C. The risk map indicated that regions in Southern and Central Europe, including recently invaded areas north of the Alps, have temperatures theoretically allowing CHIKV transmission for at least some days per year.

Conclusions

While CHIKV can be transmitted by Ae. albopictus at 15 °C, the activity of this mosquito is strongly decreased at this temperature, likely reducing the transmission risk. These findings emphasize the importance of considering both vector competence and mosquito activity when assessing the risk of arbovirus transmission in temperate regions. Further studies are needed to validate these laboratory findings under field conditions.

Graphical abstract
SiRCle (Signature Regulatory Clustering) model integration reveals mechanisms of phenotype regulation in renal cancer
Authors: Mora Ariane , Schmidt Christina , Balderson Brad , Frezza Christian , Bodén Mikael
Published: December 2024

Background

Clear cell renal cell carcinoma (ccRCC) tumours develop and progress via complex remodelling of the kidney epigenome, transcriptome, proteome and metabolome. Given the subsequent tumour and inter-patient heterogeneity, drug-based treatments report limited success, calling for multi-omics studies to extract regulatory relationships, and ultimately, to develop targeted therapies. Yet, methods for multi-omics integration to reveal mechanisms of phenotype regulation are lacking.

Methods

Here, we present SiRCle (Signature Regulatory Clustering), a method to integrate DNA methylation, RNA-seq and proteomics data at the gene level by following central dogma of biology, i.e. genetic information proceeds from DNA, to RNA, to protein. To identify regulatory clusters across the different omics layers, we group genes based on the layer where the gene’s dysregulation first occurred. We combine the SiRCle clusters with a variational autoencoder (VAE) to reveal key features from omics’ data for each SiRCle cluster and compare patient subpopulations in a ccRCC and a PanCan cohort.

Results

Applying SiRCle to a ccRCC cohort, we showed that glycolysis is upregulated by DNA hypomethylation, whilst mitochondrial enzymes and respiratory chain complexes are translationally suppressed. Additionally, we identify metabolic enzymes associated with survival along with the possible molecular driver behind the gene’s perturbations. By using the VAE to integrate omics’ data followed by statistical comparisons between tumour stages on the integrated space, we found a stage-dependent downregulation of proximal renal tubule genes, hinting at a loss of cellular identity in cancer cells. We also identified the regulatory layers responsible for their suppression. Lastly, we applied SiRCle to a PanCan cohort and found common signatures across ccRCC and PanCan in addition to the regulatory layer that defines tissue identity.

Conclusions

Our results highlight SiRCle’s ability to reveal mechanisms of phenotype regulation in cancer, both specifically in ccRCC and broadly in a PanCan context. SiRCle ranks genes according to biological features. https://github.com/ArianeMora/SiRCle_multiomics_integration.
Influence of underlying condition and performance of sepsis bundle in very old patients with sepsis: a nationwide cohort study
Authors: Kim Duk Ki , Kim Soyun , Kang Da Hyun , Ju Hyekyeong , Oh Dong Kyu , Lee Su Yeon , Park Mi Hyeon , Lim Chae-Man , Hyon YunKyong , Lee Song I ,   the Korean sepsis Alliance (KSA) investigators, Jeon Kyeongman , Park Sunghoon , Lee Yeon Joo , Hong Sang-Bum , Suh Gee Young , Cho Young-Jae , Ko Ryoung-Eun , Lim Sung Yoon , Heo Jeongwon , Lee Jae-myeong , Kim Kyung Chan , Lee Yeon Joo , Chang Youjin , Jeon Kyeongman , Lee Sang-Min , Hong Suk-Kyung , Cho Woo Hyun , Kwak Sang Hyun , Lee Heung Bum , Ahn Jong-Joon , Seong Gil Myeong , Lee Song I , Park Sunghoon , Park Tai Sun , Lee Su Hwan , Choi Eun Young , Moon Jae Young
Published: December 2024

Background

Sepsis is a life-threatening condition that affects individuals of all ages; however, it presents unique challenges in very old patients due to their complex medical histories and potentially compromised immune systems. This study aimed to investigate the influence of underlying conditions and the performance of sepsis bundle protocols in very old patients with sepsis.

Methods

We conducted a nationwide cohort study of adult patients with sepsis prospectively collected from the Korean Sepsis Alliance Database. Underlying conditions, prognosis, and their association with sepsis bundle compliance in patients with sepsis aged ≥ 80 years were analyzed.

Results

Among the 11,981 patients with sepsis, 3,733 (31.2%) were very old patients aged ≥ 80 years. In-hospital survivors (69.8%) were younger, less likely male, with higher BMI, lower Charlson Comorbidity Index, lower Clinical Frailty Scale, and lower Sequential Organ Failure Assessment (SOFA) scores. The in-hospital survivor group had lower lactate measurement but higher fluid therapy and vasopressor usage within the 1-h bundle. Similar trends were seen in the 3-h and 6-h bundles. Furthermore, in-hospital survivors were more likely to receive appropriate empiric antibiotics within 24 h. In-hospital mortality was associated with age, Clinical Frailty Scale, SOFA score, comorbidities, Life sustaining treatment issue, interventions in the ICU and vasopressor use in the 1-h sepsis bundle.

Conclusions

Addressing underlying conditions and enhancing sepsis bundle adherence is crucial for better outcomes in very old patients with sepsis. Personalized approaches and increased awareness are essential. Further research should explore interventions to optimize sepsis care in this population.
Study on Preparation and Thermophysical Properties of Binary Paraffin Phase Change Concrete
Authors: Jia Zhiwen , Li Dongwei , Wang Zecheng , Wang Zhenhua , Fang Fang
Published: December 2024

The binary phase change paraffin (BP) was prepared using the melt blending method, followed by adsorption and encapsulation to produce the phase change aggregate. Phase change concrete was subsequently prepared using the volumetric replacement method. The study examined the thermal properties of BP, along with the semi-adiabatic temperature rise and thermal conductivity of the phase change concrete at different replacement rates. The results indicate that BP exhibits two plateau regions, with phase change intervals varying according to the mass ratio. The high-temperature phase change interval ranges from 18.3 °C to 47.3 °C, while the low-temperature phase change interval ranges from 0.1 °C to 4.6 °C. When the mass ratio of 48# paraffin to 5# paraffin is 7:3, the peak phase change temperatures are 2.58 °C and 44.52 °C, with corresponding enthalpies of 66.52 J/g and 102.63 J/g, respectively. The addition of phase change aggregate effectively reduces the hydration temperature rise of concrete, slows the rate of temperature increase, and decreases the thermal conductivity. The semi-adiabatic temperature rise curve of the phase change concrete exhibits an "S"-shaped variation over time, with the composite exponential function providing a more accurate representation of this process.
Construction of the porcine genome mobile element variations and investigation of its role in population diversity and gene expression
Authors: Hu Jianchao , Gui Lu , Wu Zhongzi , Huang Lusheng
Published: December 2024

Background

Mobile element variants (MEVs) have a significant and complex impact on genomic diversity and phenotypic traits. However, the quantity, distribution, and relationship with gene expression and complex traits of MEVs in the pig genome remain poorly understood.

Results

We constructed the most comprehensive porcine MEV library based on high-depth whole genome sequencing (WGS) data from 747 pigs across 59 breeds worldwide. This database identified a total of 147,993 polymorphic MEVs, including 121,099 short interspersed nuclear elements (SINEs), 26,053 long interspersed nuclear elements (LINEs), 802 long terminal repeats (LTRs), and 39 other transposons, among which 54% are newly discovered. We found that MEVs are unevenly distributed across the genome and are strongly influenced by negative selection effects. Importantly, we identified 514, 530, and 584 candidate MEVs associated with population differentiation, domestication, and breed formation, respectively. For example, a significantly differentiated MEV is located in the ATRX intron between Asian and European pigs, whereas ATRX is also differentially expressed between Asian and European pigs in muscle tissue. In addition, we identified 4,169 expressed MEVs (eMEVs) significantly associated with gene expression and 6,914 splicing MEVs (sMEVs) associated with gene splicing based on RNA-seq data from 266 porcine liver tissues. These eMEVs and sMEVs explain 6.24% and 9.47%, respectively, of the observed cis-heritability and highlight the important role of MEVs in the regulation of gene expression. Finally, we provide a high-quality SNP–MEV reference haplotype panel to impute MEV genotypes from genome-wide SNPs. Notably, we identified a candidate MEV significantly associated with total teat number, demonstrating the functionality of this reference panel.

Conclusions

The present investigation demonstrated the importance of MEVs in pigs in terms of population diversity, gene expression and phenotypic traits, which may provide useful resources and theoretical support for pig genetics and breeding.
Let’s talk about body neutrality: content analysis of #bodyneutrality on TikTok
Authors: Mancin Paolo , Vall-Roqué Helena , Grey Wesley , Griffiths Scott , Bonell Sarah
Published: December 2024

Background

To date, over 1.3 billion videos with the hashtag #bodyneutrality have been viewed on TikTok. Despite this, little existing literature has unpacked how body neutrality is conceptualised on TikTok. We examined how TikTok creators construct meaning and generate discourse surrounding #bodyneutrality.

Methods

Extending on previous works in the body neutrality space, we conducted a hybrid content/thematic analysis of TikTok videos in three different languages (English, Spanish, and Italian). Initially, 300 videos displaying “#bodyneutrality” were identified on TikTok. The first 178 TikTok videos were analysed, following the principles of data saturation and feasibility.

Results

We developed three themes: (1) The normalisation of diverse bodies, (2) The rejection of appearance as fundamentally important, and (3) Body neutrality is (better than) body positivity.

Conclusions

In line with conceptualisations of body neutrality in existing literature, some content emphasised the importance of devaluing physical appearance. Building on existing definitions, most creators also framed body neutrality as speaking to the fundamental humanness of owning a body and attempted to normalise various body shapes/sizes. Conversely, some content employed #bodyneutrality to promote or examine body positivity principles or to condemn appearance-based stigmatisation. Our study is one of the first to examine how body neutrality is understood and employed by people in the real world.
Training emotional competencies at the workplace: a systematic review and metaanalysis
Authors: Mehler Miriam , Balint Elisabeth , Gralla Maria , Pößnecker Tim , Gast Michael , Hölzer Michael , Kösters Markus , Gündel Harald
Published: December 2024

Recent systematic reviews have shown that emotional competencies can be improved through training. In the workplace, such training has become increasingly popular over the last decade. These programs aim to enhance emotional intelligence, empathy or emotion regulation. This study wants to assess the training effects and potential moderators of these workplace interventions. To our knowledge, this is the first systematic review that focuses on the workplace context and integrates emotional intelligence, empathy, and emotion regulation training interventions. This study has been preregistered with PROSPERO and a protocol has been published before the review was conducted (CRD42021267073). We conducted a systematic literature search using Embase, PsycInfo, PSYNDEX, Web of Science and the Cochrane Central Register of Controlled Trials. The included studies were analyzed in two metaanalyses. In the primary analysis, we analyzed standardized mean changes in emotional competencies before and after the training for 50 included studies, depending on (a) training construct and (b) participants’ profession (teachers, health professionals, managers, and others). To determine the efficacy of the trainings, we conducted a separate metaanalysis of controlled trials only (k = 27). Both metaanalyses yielded moderate overall effect sizes that also persisted more than three months after the training end: (1) SMDpre-post = 0.44 (95% CI [0.29, 0.59]), (2) SMDEG-CG = 0.46 (95% CI [0.30, 0.63]). All professions benefited equally from the interventions and we observed no significant differences in the effectiveness of emotional intelligence, empathy, and emotion regulation trainings. Overall, our results suggest that workplace interventions effectively train emotional competencies, regardless of profession or specific training focus. Limitations are the high heterogeneity and the low methodological quality of the studies analyzed. Our study shows the need for more high-quality studies, like randomized controlled trials. Additionally, companies may consider incorporating emotional competence training into their employee and leadership development programs routinely. This study was preregistered on PROSPERO (CRD42021267073).
Parents, friends, and classmates: reference groups and dropout from vocational education and training in Germany
Authors: Siembab Matthias
Published: December 2024

This study examines the influence of social contexts on the decision to either complete or leave the first vocational education and training (VET) position among young German apprentices—an aspect that has received little attention in dropout research. In particular, the role of three reference groups—parents, friends and classmates at vocational school—in shaping this decision is examined. Using longitudinal data from the German National Educational Panel Study, the analysis addresses two key research questions: (1) Which reference groups are associated with the dropout decision? (2) And how do they influence the decision-making process? For this purpose, the study primarily investigates apprentices’ perceptions of the normative expectations and career ambitions of these groups, and compares the occupational achievements of apprentices and their parents. Two main results are found: (a) Parents and friends have a normative function; apprentices are more likely to complete their VET successfully if they believe that their parents and friends expect them to do so. (b) Both classmates and parents serve a comparative function; if apprentices perceive high career ambitions among their classmates, this may be intimidating and increase the risk of dropping out—in favor of switching to another training occupation. In addition, having parents with a higher occupational status seems to encourage apprentices to pursue a more demanding career path in the case of a change in training occupation. This study supports the notion that a multitude of actors contribute to the success of VET. Therefore, it could be beneficial for career guidance and counseling efforts to extend beyond individual counseling and consider actors who, although indirectly involved in VET, act as important reference groups for apprentices.