bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient demographics, medical factors, treatment modalities and satisfaction at five traditional Chinese medicine practices: A cross-sectional study
Authors: Liu Yingchao , Lyu Xiaoying , Pradhan Saroj K. , Li Yiming , Liu Xingfang , Bauder Ralf , Heggli Tanja , Wang Xiaying , Furian Michael 
Published: December 2024

1AbstractBACKGROUNDTraditional Chinese Medicine (TCM) is increasingly integrated into healthcare and insurance systems, therefore, it is essential to understand its current status and patients’ perspectives.METHODSThis cross-sectional study was conducted from January 1st to December 31st, 2023, across five TCM practices in Switzerland. All patients attending their sixth therapy session were invited to complete an electronically anonymized questionnaire covering patient demographics, treatment experiences, and satisfaction.RESULTSA total of 461 patients participated in the survey, with the majority being female (60.1%) and aged 50 years or older (57.4%). Among them, 54.0% reported multiple health conditions, with 32.9% having musculoskeletal disorders and 31.8% suffering from chronic pain as the main reasons for seeking therapy. Most patients received weekly TCM treatments (91.3%), with 50.7% also undergoing conventional therapies. Of the respondents, 50.0% reported full coverage for their TCM therapy costs. TCM was mainly accessed through personal recommendations (44.5%), and 92.2% experienced wait times under 10 minutes. Acupuncture was the predominant treatment (95.7%), with 35.8% receiving additional dietary advice. Overall satisfaction reached 96.5%, and 99.5% expressed intent to continue TCM. Full compared to no TCM expense coverage was positively associated with treatment satisfaction (odds ratio = 2.42, 95% CI [1.10 to 5.31], p = 0.028), while other medical factors showed no significant impact on satisfaction.CONCLUSIONThis study indicates that women, patients over 50 years, and those with multiple health conditions, especially musculoskeletal and pain conditions, are more likely to seek regular integrated TCM treatment. Patients reported high satisfaction with TCM, and treatment satisfaction was positively associated with full compared to no health insurance coverage. Future research should include more TCM practices and patients to further generalize these findings and precisely assess the impact of insurance coverage on TCM satisfaction to meet patient needs better.
Ancestral aryl sulfatases in the alkaline phosphatase family allow for greater increases in catalytic efficiency than extant variants
Authors: Eenink Bernard , Heberlein Magdalena , Holstein Josephin M. , Lange Andreas , Dilkaute Carina , Kaminski Tomasz S. , Bornberg-Bauer Erich , Jose Joachim , Hollfelder Florian , van Loo Bert 
Published: December 2024

AbstractCharacterizing the dynamics and functional shifts during protein evolution is essential, both for understanding protein evolution and for rationalizing efficient strategies for e.g. enzymes with desired and effective functions.Most proteins organize in families, sets of divergent sequences which share a common ancestor and a have a similar structural fold.We study Aryl sulfatases (ASs), a subfamily of the large and evolutionary old alkaline phosphatase superfamily. Together with their computationally reconstructed putative common ancestors, we expressed and enzymatically characterized these enzymes using micro-fluidics generated high-throughput libraries.We compare the evolvability and robustness of ancestors and four extant ASs which all exhibit catalytic promiscuity towards a range of substrate classes.Sixteen libraries with distinct mutational loads were expressed in individual cells inside micro-droplets.We find that higher mutational loads yielded a longer tail of active variants but fewer total improved variants.The effects of mutational load varied quantitatively between enzymes, meaning in some enzymes a higher, in others a lower mutational load was beneficial, highlighting the importance of testing various mutagenesis regimes.Although ancestors did not display the highest proportion of active variants, they did exhibit the greatest activity increases.We conclude that in ASs the ancestors are not necessarily more promiscuous but the fitness landscape around them is more shallow and thus more amenable to evolutionary optimization.
E-cadherin endocytosis promotes non-canonical EGFR:STAT signalling to induce cell death and inhibit heterochromatinisation
Authors: Ramirez-Moreno Miguel , Quinton Amy , Jacobsen Eleanor , Stempor Przemyslaw A. , Zeidler Martin P. , Bulgakova Natalia A. 
Published: December 2024

SummarySignalling molecules often contribute to several signalling pathways that produce distinct transcriptional outputs and cellular phenotypes. One of the major unanswered questions in cell biology is how multiple activities of signalling molecules are coordinated in space and time in vivo. Here, we focus on the Signal Transducer and Activator of Transcription (STAT) protein as a paradigm of signalling molecules involved in several independent signalling pathways. In addition to the canonical pathways, whereby STAT is phosphorylated and activated by Janus Kinases, STAT is involved in at least two non-canonical pathways. In one pathway, STAT is activated by the Epidermal Growth Factor Receptor (EGFR) promoting apoptosis. In another, it binds the Heterochromatin Protein 1 (HP1) to enhance heterochromatin formation. UsingDrosophilawing discs as an epithelial system, we demonstrate that all three STAT activities coexist in this tissue. We provide evidence that while the canonical STAT signalling is dominant over non-canonical pathways, EGFR:STAT and HP1:STAT pathways compete for the availability of unphosphorylated STAT. We also describe the role of the cell-cell adhesion protein E-cadherin in EGFR:STAT signalling. Both EGFR and STAT colocalise with E-cadherin at cell-cell junctions and on intracellular vesicles. Elevated intracellular E-cadherin promotes EGFR:STAT pathway leading to apoptosis, whereas blocking E-cadherin endocytosis prevents apoptosis induction. Altogether, we propose that E-cadherin endocytosis controls the balance between two non-canonical STAT activities in a potential tumour-suppressive mechanism – junctional disassembly in dysregulated epithelial-to-mesenchymal transitions would shift this balance towards the EGFR:STAT signalling to promote apoptosis.
Oncogenic RAS Induces a Distinctive Form of Non-Canonical Autophagy Mediated by the P38-ULK1-PI4KB Axis
Authors: Wang Xiaojuan , Li Shulin , Lin Shiyin , Han Yaping , Zhan Tong , Huang Zhiying , Wang Juanjuan , Li Ying , Deng Haiteng , Zhang Min , Feng Du , Ge Liang 
Published: December 2024

SUMMARYCancer cells with RAS mutations exhibit enhanced autophagy, essential for their proliferation and survival, making it a potential target for therapeutic intervention. However, the regulatory differences between RAS-induced autophagy and physiological autophagy remain poorly understood, complicating the development of cancer-specific anti-autophagy treatments. In this study, we identified a form of non-canonical autophagy induced by oncogenic KRAS expression, termed RAS-induced non-canonical autophagy via ATG8ylation (RINCAA). RINCAA involves distinct autophagic factors compared to those in starvation-induced autophagy and incorporates non-autophagic components, resulting in the formation of non-canonical autophagosomes with multivesicular/multilaminar structures labeled by ATG8 family proteins (e.g., LC3 and GABARAP). We have designated these structures as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A notable feature of RINCAA is the substitution of the class III PI3K in canonical autophagy for PI4KB. We identified a regulatory P38-ULK1-PI4KB-WIPI2 signaling cascade governing this process, where ULK1 phosphorylation at S317, S479, S556, and S758 activates PI4KB. This activation involves PI4KB phosphorylation at S256 and T263, initiating PI4P production, ATG8ylation, and non-canonical autophagy. Importantly, elevated PI4KB phosphorylation at S256 and T263 was observed in RAS-mutated cancer cells and colorectal cancer specimens. Inhibition of PI4KB S256 and T263 phosphorylation led to a reduction in RINCAA activity and tumor growth in both xenograft and KPC models of pancreatic cancer, suggesting that ULK1-mediated PI4KB-Peptide-1 phosphorylation could represent a promising therapeutic target for RAS-mutated cancers.
I/σIvs{Rmerg, Rmeas, Rpim, CC1/2} for Crystal Diffraction Data Quality Evaluation
Authors: Fu Zheng-Qing , Geisbrecht Brian V. , Bouyain Samuel , Dyda Fred , Chrzas John , Kandavelu Palani , Miller Darcie J. , Wang Bi-Cheng 
Published: December 2024

AbstractX-ray crystal diffraction has provided atomic-level structural information on biological macromolecules. Data quality determines the reliability of structural models. In most cases, multiple data sets are available from different crystals and/or collected with different experimental settings. Reliable metrics are critical to rank and select the data set with the highest quality. Many measures have been created or modified for data quality evaluation. However, some are duplicate in functionality, and some are likely misused due to misunderstanding, which causes confusion or problems, especially at synchrotron beamlines where experiments proceed quickly. In this work, these measures are studied through both theoretical analysis and experimental data with various characteristics, which demonstrated that: 1). {Rmerg, Rmeas, Rpim, CC1/2} all measure the equivalence of reflections, and the low-shell values of these metrics can be used as reliable indicators for correctness (or trueness) of Laue symmetry; 2). High-shell I/σI is a reliable and better indicator to select resolution cutoff while the overall value measures the overall strength of the data.
Comparison of infliximab versus cyclophosphamide on treatment of refractory uveitis of Behcet’s disease: pilot clinical study
Authors: Sadeghi Alireza , Karimimoghadam Arezoo , Davatchi Fereydoun , Shahram Farhad , Mazloomzadeh Saeideh , Behnamghader Azadeh , Jalili Nooshin , Biglari Sajjad , Jourahmad Zahra 
Published: December 2024

AbstractBackgroundTo evaluate the effect of infliximab (IFX), in comparison with cyclophosphamide (CP) on refractory uveitis of BD.MethodsSubjects with uveitis and retinal vasculitis (RV) resistant to conventional treatment were included. Ten patients were divided in the IFX and CP groups. Patients in the IFX group received four courses of 3 mg/kg of IFX, intravenously. Patients in the CP group received four courses of pulse CP of 1000 mg, by the monthly interval. All patients received weekly 25 mg of methotrexate, (or 5 mg/kg of cyclosporine daily), and 3 mg/kg and 1 mg/kg of daily azathioprine and prednisolone, respectively. To evaluate the treatment effects, visual acuity (VA), anterior uveitis (AU), posterior uveitis (PU), and RV were assessed, at the baseline and four months after treatment.ResultsIn ten patients included in this study there were no significant differences in the treatment effects of IFX, compared to the CP regarding VA, PU, AU and RV. RV became inactive after four months of treatment in all five patients in the IFX group versus four patients in the CP group.ConclusionIFX and CP have the same efficacy in the short-term treatment of uveitis in BD. In future investigations, multi-center studies with larger sample sizes are required to investigate the cost-effectiveness of IFX in the treatment of uveitis of BD.HighlightsA new anti-TNF biologic agent, infliximab and cyclophosphamide have the same efficacy in the treatment of uveitis in BD, and since it has less toxicity, it is a superior treatment option.In areas where access to the contemporary treatment is limited and expensive, the use of traditional medication results in an increased quality-adjusted life year (QALY).Multi-center studies with larger sample sizes are required to investigate the cost-effectiveness of infliximab in the treatment of uveitis of BD.
The genetic landscape of kynurenine predicts neurovascular pathology and disrupted white matter integrity in patients with mood disorders
Authors: Bravi Beatrice , Fortanyer-Uyà Lidia , Paolini Marco , Comai Stefano , Poletti Sara , Cristina Lorenzi , Spadini Sara , Serretti Alessandro , Colombo Cristina , Zanardi Raffaella , Benedetti Francesco 
Published: December 2024

AbstractLow-grade systemic inflammation is linked to cardiometabolic diseases and increased cardiovascular risk. Patients with mood disorders, such as Major Depressive Disorder (MDD) and Bipolar Disorder (BD), also show elevated cardiovascular risk and inflammatory markers, suggesting shared biological pathways between mood and cardiometabolic conditions. The kynurenine (KYN) pathway, activated by inflammatory cytokines and involved in neurotransmitter systems linked to mood, provides a promising area to explore inflammatory-related genetic overlaps in these disorders, with increasing interest in the SH2B3 rs3184504 SNP. Imaging markers like white matter hyperintensities (WMHs) and white matter (WM) microstructure alterations are associated with mood and cardiovascular disorders.This study aimed to investigate the genetic load link to KYN levels, such as KYN polygenic risk score (PRS) and its effect on white matter hyperintensities (WMHs), outcomes of presumed vascular suffering, and WM microstructure in a sample of 95 MDD and 80 BD patients.Higher PRS for KYN was associated with increased circulating KYN levels and KYN/TRP ratio. KYN PRS predicted the presence of WMHs. The SH2B3 rs3184504 T variant was associated with increased PRS for KYN and a higher number of WMHs. KYN levels and KYN/TRP ratio were not associated with WMHs, while KYN PRS positively correlated with higher axial (AD) and mean diffusivity (MD), with a nominal significance for radial diffusivity (RD).The findings support a genetic contribution to elevated KYN and WM integrity alterations in mood disorders. PRS for KYN indicates a potential predisposition to inflammatory and vascular dysregulation, and SH2B3 rs3184504 may modulate this risk.
Perceived facilitators and barriers to physical activity, using the COM-B Model for Behavioural Change, in people with chronic pain: a qualitative evaluation of patient and stakeholder perspectives
Authors: Higgins C , Dall PM , Leese C , Adair P , Cameron PA , Inglis SK , Christogianni A , Smith BH , Colvin L 
Published: December 2024

AbstractBackgroundPhysical inactivity is a substantial public health concern and a particularly challenging problem to address. Physical activity is shown to be of therapeutic benefit to those living with chronic pain, but intervention studies have often been unsuccessful in promoting sustainable engagement with physical activity in this population.AimTo develop a more comprehensive understanding of the barriers to engaging with sustainable physical activity and the facilitators that promote this engagement in people with chronic pain.Design & settingThe study design was qualitative, informed by behaviour change theory (the COM-B model), and participants were drawn from two settings. First, 36 adults living with moderate-severe chronic pain were recruited from a specialist NHS pain service. Secondly, 15 stakeholders were recruited to represent a range of healthcare sectors involved in supporting people with chronic pain.MethodOne-to-one semi-structured interviews, informed by the COM-B model, were conducted between May 2020 and October 2021. Interviews were conducted by telephone or using online conferencing software and were transcribedverbatimand anonymised. The Framework Method was used to interpret the data.ResultsThe barriers to sustainable physical activity engagement in people with chronic pain are expansive, and the inclusion of stakeholder perspectives is valuable in developing a more comprehensive understanding of these barriers and also of the facilitators that are successful in promoting sustainable physical activity in this population.ConclusionsThe COM-B model provides a robust theoretical framework for organising and understanding these barriers and facilitators in a way could that inform effective intervention design.
COVID-19 vaccination and short-term mortality risk: a nationwide self-controlled case series study in The Netherlands
Authors: Slurink Isabel AL , de Boer Annemarijn R , Bonten Marc JM , Sturkenboom Miriam CJM , Bruijning-Verhagen PCJL 
Published: December 2024

AbstractExcess mortality during the COVID-19 pandemic partly exceeded COVID-19-related deaths, indicating that other causes may have contributed. We conducted a retrospective data-linkage study including all Dutch inhabitants to investigate the impact of COVID-19 vaccination on excess mortality using a modified self-controlled case series method. We found a 44% lower relative incidence of all-cause deaths in the first three weeks after the primary vaccination compared to more than three weeks after vaccination (IRR 0.56, 95%CI 0.54-0.57). This lower incidence was consistent across vaccine types, doses, genders, age groups, and individuals with or without prior SARS-CoV-2 infection or comorbidities, and for non-COVID-19 related deaths. For booster vaccinations, the relative incidence was similar (IRR 0.49, 95%CI 0.49-0.50). In comparison, we observed a 16-fold higher incidence of all-cause deaths in the three weeks following a registered positive SARS-CoV-2 infection compared to more than three weeks after infection (IRR 16.19, 95%CI 15.78-16.60). A lower relative incidence of short-term deaths following COVID-19 vaccination support that COVID-19 vaccination is not associated with the observed excess mortality.
A pen mark is all you need - Incidental prompt injection attacks on Vision Language Models in real-life histopathology
Authors: Clusmann Jan , Schulz Stefan J. K. , Ferber Dyke , Wiest Isabella C. , Fernandez Aurélie , Eckstein Markus , Lange Fabienne , Reitsam Nic G. , Kellers Franziska , Schmitt Maxime , Neidlinger Peter , Koop Paul-Henry , Schneider Carolin V. , Truhn Daniel , Roth Wilfried , Jesinghaus Moritz , Kather Jakob N. , Foersch Sebastian 
Published: December 2024

AbstractVision-language models (VLMs) can analyze multimodal medical data. However, a significant weakness of VLMs, as we have recently described, is their susceptibility to prompt injection attacks. Here, the model receives conflicting instructions, leading to potentially harmful outputs. In this study, we hypothesized that handwritten labels and watermarks on pathological images could act as inadvertent prompt injections, influencing decision-making in histopathology. We conducted a quantitative study with a total of N = 3888 observations on the state-of-the-art VLMs Claude 3 Opus, Claude 3.5 Sonnet and GPT-4o. We designed various real-world inspired scenarios in which we show that VLMs rely entirely on (false) labels and watermarks if presented with those next to the tissue. All models reached almost perfect accuracies (90 - 100 %) for ground-truth leaking labels and abysmal accuracies (0 - 10 %) for misleading watermarks, despite baseline accuracies between 30-65 % for various multiclass problems. Overall, all VLMs accepted human-provided labels as infallible, even when those inputs contained obvious errors. Furthermore, these effects could not be mitigated by prompt engineering. It is therefore imperative to consider the presence of labels or other influencing features during future evaluation of VLMs in medicine and other fields.
The Impact of Obesity-Related Genetic Variants on NF-κB Signaling in Cardiovascular Disease: A Systematic Review
Authors: Shafi Viqas , Khan Nabeel Ahmad , Siddiqui Ifrah 
Published: December 2024

AbstractObjectiveTo investigate how genetic variations in obesity-related genes (FTO, MC4R, LEP, LEPR, PCSK1, PPARG, BDNF, SIM1, TBC1D1, ADRB3, UCP1, and SH2B1) impact the NF-κB signaling pathway, exploring mechanisms of NF-κB activation, downstream inflammatory responses, and their role in cardiovascular disease (CVD) development in the context of obesity.BackgroundObesity is a leading contributor to chronic diseases, including CVD, driven in part by chronic low-grade inflammation. The NF-κB signaling pathway, a central regulator of inflammatory responses, is implicated in the pathophysiology of obesity and CVD. Genetic variations in obesity-related genes may modulate NF-κB activation and its downstream effects, exacerbating inflammation and cardiovascular risks. Understanding these mechanisms can inform therapeutic strategies to mitigate inflammation and improve health outcomes in individuals with obesity.MethodsA systematic review of the literature was conducted using PUBMED, MEDLINE, and Google Scholar, focusing on genetic variations in the obesity-related genes FTO, MC4R, LEP, LEPR, PCSK1, PPARG, BDNF, SIM1, TBC1D1, ADRB3, UCP1, and SH2B1. Studies examining the effects of these variations on NF-κB activation, inflammatory pathways, and CVD development were included. The search was performed with no date restrictions and followed PRISMA guidelines. Articles were screened for relevance, methodological rigor, and insights into the interplay between genetic factors, inflammation, and cardiovascular pathology. Data extraction focused on key findings linking gene variants to NF-κB signaling and their downstream effects.ResultsGenetic variations in FTO, MC4R, LEP, LEPR, and SH2B1 were found to disrupt insulin and leptin signaling, resulting in enhanced NF-κB activation and chronic inflammation. Variants in PPARG and UCP1 increased oxidative stress, further amplifying NF-κB signaling. These changes promoted endothelial dysfunction, atherosclerosis, and heightened CVD risk. Interactions between these genetic factors created a pro-inflammatory state, exacerbating cardiovascular complications in obese individuals.ConclusionThis study underscores the critical role of genetic variations in obesity-related genes in modulating NF-κB signaling, driving chronic inflammation, and increasing CVD risk. Targeting these pathways may provide therapeutic opportunities to reduce inflammation and improve cardiovascular health in obese populations.