bluuebunny/crossref_metadata_2025 huggingface dataset:
Lighting Matches: On How to Have a Virtuous Sense of Superiority
Authors: Vasalou Sophia
Published: February 2025

Despite apparent tensions with his overall outlook, al-Ghazālī endorses the inclusive view that all of God’s names form a legitimate object of human aspiration. This chapter weighs up his position by investigating his treatment of the divine name mutakabbir. Al-Ghazālī gives different accounts of this name in different works. In the Revival, he accepts its ordinary linguistic meaning and argues that a virtuous sense of superiority is possible for human beings in principle but not in practice, due to their cognitive limitations. In the Beautiful Names, his solution instead lies in providing a reformed account of the meaning of the term.
Nice Theory, Shame about the Practice: Moral Ideals, Psychological Realism, and the Unusual Case of God’s Character
Authors: Vasalou Sophia
Published: February 2025

This chapter takes up a separate challenge posed by the idea of godlikeness, which concerns its practical feasibility. Recent writing on ethics places a strong emphasis on the answerability of moral inquiry to empirical facts about human psychology. Recent literature on exemplars suggests two reasons for scepticism about the practical efficacy of taking God as a moral model. God is too unlike us; and God is too superior. Exemplars who are not sufficiently similar to us in relevant dimensions, and who are excessively superior in the moral dimension, have a negative or neutral motivational effect. A closer consideration of the epistemic channels through which we gain knowledge of God’s character contributes to this scepticism.
The Future of God’s Beautiful Names: On Awe, the Power of Words, and Why Great Exemplars Attract Us
Authors: Vasalou Sophia
Published: February 2025

Set against the survey of intellectual resources provided in Chapter 12, this chapter argues for the need to go beyond such resources and invest in a wide-ranging empirical investigation of how the ideal of godlikeness has been pursued both in historical communities and in present times. This ideal remains active in both scholarly and popular levels of Islamic culture. A study of its social realizations can help enrich current lines of inquiry on character education and exemplars. It can illuminate, among others, questions about moral emotions such as admiration and awe, about the role of moral language in character education, and about how different kinds of narrative practices mediating different forms of exemplarity may support moral learning. The chapter concludes by considering the questions raised by the recurring emphasis on morally outstanding exemplars in a wide variety of cultural traditions and the different explanatory possibilities this phenomenon invites.
Trends in depression in the European population aged 50 years and older by geographic region
Authors: Núñez-Cortés Rodrigo , Calatayud Joaquín , Andersen Lars Louis , Villafañe Jorge Hugo , Suso-Martí Luis , López-Bueno Rubén
Published: February 2025

This study assesses the prevalence and trends of depression in the European population aged 50 years and older between 2004 and 2022 in different geographical regions. We retrieved and pooled data from waves 1,2,4,5,6,7,8, and 9 of the Survey of Health, Ageing and Retirement in Europe (SHARE) conducted between 2004 and 2022. The 12-item EURO-D scale was used as a continuous marker of depression risk. Twenty-eight countries were classified into five geographical regions (Eastern, Western, Southern and Northern Europe, and Israel) as defined by the United Nations. A total of 375 693 observations corresponding to 146 888 participants (weighted mean age 65.8 years [SE=0.2], 54.2% women) were included in the study. In 2022, the overall prevalence of self-reported depression in Europe was 28.3% (95% CI: 27.0-29.7). From 2004 to 2022, the prevalence of self-reported depression in Europe decreased significantly by 5.9% (95% CI= -8.1 to -3.8). In particular, in Southern Europe, the prevalence of depression decreased significantly by 8.8% (95% CI= -12.3 to -5.2). No significant differences were observed in the other geographic regions. These findings highlight the need to develop depression screening and prevention strategies focused on countries with higher prevalence and identified associated factors.
CRIBAR: a fast and flexible sgRNA design tool for CRISPR imaging
Authors: Chen Xiaoli , Rahaman Md Mahfuzur , Naseri Ardalan , Zhang Shaojie
Published: February 2025

Motivation

CRISPR imaging enables the real-time tracking of nucleic acids. Using guide RNAs (gRNAs) to direct fluorescent tags to target regions allows for precise nucleic acid monitoring via microscopy. The design of gRNAs largely affects the efficacy of CRISPR imaging. Currently, available gRNA design tools are developed primarily for gene editing, often producing individual gRNAs that target genes or regulatory elements.

Results

In this study, we introduce CRIBAR, a computational tool developed to systematically design single-guide RNAs (sgRNAs) for CRISPR imaging applications. CRIBAR first generates sgRNA sets optimized to maximize the number of on-target binding sites and then evaluates the potential off-target effect. The results of the in silico experiment show that CRIBAR enables CRISPR imaging in non-repetitive regions.

Availability and implementation

CRIBAR is available as a software package at https://github.com/ucfcbb/CRIBAR and as a web server at http://genome.ucf.edu/CRIBAR.
Prediction of molecular subtypes for endometrial cancer based on hierarchical foundation model
Authors: Cui Haoyu , Guo Qinhao , Xu Jun , Wu Xiaohua , Cai Chengfei , Jiao Yiping , Ming Wenlong , Wen Hao , Wang Xiangxue
Published: February 2025

Motivation

Endometrial cancer is a prevalent gynecological malignancy that requires accurate identification of its molecular subtypes for effective diagnosis and treatment. Four molecular subtypes with different clinical outcomes have been identified: POLE mutation, mismatch repair deficient, p53 abnormal, and no specific molecular profile. However, determining these subtypes typically relies on expensive gene sequencing. To overcome this limitation, we propose a novel method that utilizes hematoxylin and eosin-stained whole slide images to predict endometrial cancer molecular subtypes.

Results

Our approach leverages a hierarchical foundation model as a backbone, fine-tuned from the UNI computational pathology foundation model, to extract tissue embedding from different scales. We have achieved promising results through extensive experimentation on the Fudan University Shanghai Cancer Center cohort (N = 364). Our model demonstrates a macro-average AUROC of 0.879 (95% CI, 0.853–0.904) in a 5-fold cross-validation. Compared to the current state-of-the-art molecular subtypes prediction for endometrial cancer, our method outperforms in terms of predictive accuracy and computational efficiency. Moreover, our method is highly reproducible, allowing for ease of implementation and widespread adoption. This study aims to address the cost and time constraints associated with traditional gene sequencing techniques. By providing a reliable and accessible alternative to gene sequencing, our method has the potential to revolutionize the field of endometrial cancer diagnosis and improve patient outcomes.

Availability

The codes and data used for generating results in this study are available at https://github.com/HaoyuCui/hi-UNI for GitHub and https://doi.org/10.5281/zenodo.14627478 for Zenodo.

Supplementary information

Supplementary data are available at Bioinformatics online.
Effectiveness and safety of methods to prevent bloodstream and other infections and noninfectious complications associated with peripherally inserted central catheters: A systematic review and meta-analysis
Authors: Dobrescu Andreea , Constantin Alexandru Marian , Pinte Larisa , Chapman Andrea , Ratajczak Piotr , Klerings Irma , Emprechtinger Robert , Allegranzi Benedetta , Grayson Michael Lindsay , Toledo Joao Paulo , Gartlehner Gerald , Nussbaumer-Streit Barbara
Published: February 2025

Background

Peripherally inserted central catheters (PICCs) have a 29% complication rate. This systematic review assessed 25 interventions to prevent PICC-associated infectious and noninfectious complications in participants of all ages.

Methods

We searched electronic databases (MEDLINE, Embase, Cochrane Library, WHO Global Index Medicus, CINAHL) and reference lists for randomized (RCTs) and nonrandomized studies published from January 1, 1980–May 8, 2024. We dually selected studies, assessed risk of bias, extracted data, and rated certainty of evidence (COE). We included both single interventions of interest and combinations of at least two (bundle/multimodal). If three or more RCTs existed, we conducted Bayesian random-effects meta-analyses.

Results

Seventy-four studies met our eligibility criteria (60 on individual interventions, 14 on bundle/multimodal), addressing 13 of 25 research questions. The majority were conducted in high-income countries; 36 focused on neonates. Evidence was very uncertain for 11 of the 13 research questions. Evidence with a stronger COE showed that ultrasound-guided catheter insertion reduced phlebitis/thrombophlebitis in adults compared to non-ultrasound-guided insertion (five RCTs; risk ratio [RR] 0.19, 95% credible interval 0.08–0.50); silicone catheters increased phlebitis/thrombophlebitis compared to nonsilicone (one RCT, RR 2.00, 95% confidence interval [95%CI] 1.26–3.17). Bundle interventions decreased local infections (one RCT, RR 0.47, 95%CI 0.31–0.72) and phlebitis/thrombophlebitis in adults (one RCT, RR 0.35, 95%CI 0.22–0.56) compared to routine care.

Conclusions

Ultrasound-guided catheter insertion and nonsilicone catheters effectively prevented PICC complications. The evidence for other comparisons was too uncertain to draw conclusions, highlighting the urgent need for additional studies on prevention and control interventions.
Floral scent emission of Epiphyllum oxypetalum: discovery of its cytosol-localized geraniol biosynthesis
Authors: Zhang Yiyang , Zhang Yuhan , Zhang Andong , Tian Qiurui , Yang Bin , Wei Likun , Wu Wei , Zhu Ting , Zhou Zhiwei , Wang Jiaqi , Liu Zhibin , Tang Wei , Xiao Haijun , Liu Mingchun , Li Tao , Sun Qun
Published: February 2025

Epiphyllum oxypetalum, a renowned ornamental species in Cactaceae, releases attractive fragrance during its infrequent, transient and nocturnal blooms. However, the floral fragrance composition and biosynthesis remain largely unexplored. Employing volatilomics, transcriptomics and biochemistry, we systematically characterized the composition, emission dynamics and biosynthesis of the floral scent of E. oxypetalum. The floral scent composition of E. oxypetalum was highly dynamic. Starting after 20:00 local time, volatile emission increased 200-fold within six hours. At full bloom, geraniol accounted for 72.54% of the total emission, followed by benzyl alcohol (12.96%) and methyl salicylate (3.75%). These scents predominantly originated from petals and sepals. Transcriptomic analysis and inhibition assays using pathway-specific inhibitors revealed that the mevalonate pathway was the precursor source for geraniol biosynthesis. Functionally characterized cytosol localizing geraniol synthase EoTPSa1 was the key enzyme responsible for geraniol biosynthesis. Together, these findings pinpointed a cytosolic biosynthetic route for the major scent volatile geraniol in E. oxypetalum. Our study provides new insights into the emission dynamics and biosynthesis of E. oxypetalum floral scents. In particular, we demonstrated a distinctive mevalonate pathway-based geraniol biosynthetic pathway, which may hold potential for the development of novel perfume products.
Characteristics of Lateral Clavicle Fractures Treated With Coracoclavicular Ligament Repair or Reconstruction in a Military Population
Authors: Panarello Nicholas M , O’Hara Matthew M , Harrington Colin J , Feeley Scott M , McCarthy Conor F , Colantonio Donald F , Dickens Jonathan F , Kilcoyne Kelly G
Published: February 2025

Introduction

Lateral clavicle fractures comprise a minority of all clavicle fractures and are associated with high rates of nonunion when managed nonoperatively. Various fixation methods have been described, including augmentation with coracoclavicular (CC) ligament repair or reconstruction. Outcomes following the surgical treatment of lateral clavicle fractures are limited to small case series and systematic reviews, and the literature within physically demanding populations remains sparse. We sought to describe the characteristics and complications of operative lateral clavicle fractures treated with CC ligament repair or reconstruction within the Military Health System.

Materials and Methods

We queried the U.S. Military Health System Data Repository for patients with a lateral clavicle fracture treated with CC ligament repair or reconstruction between October 2013 and March 2020. We reviewed electronic health records, including patient demographics, radiographs, operative reports, and clinical notes, to assess injury characteristics, surgical constructs, postoperative complications, and functional outcomes.

Results

A total of 40 patients underwent CC ligament repair (n = 20, 50%) or reconstruction (n = 20, 50%) for treatment of lateral clavicle fractures during the study period. Twenty-two (55%) patients underwent surgery within 6 weeks of injury, and 40% (n = 18) required concomitant open reduction and internal fixation. Complications included adhesive capsulitis (n = 3, 7.5%), unplanned return to the operating room (n = 4, 10%), and loss of CC reduction (n = 10, 25%). Twenty-six (65%) patients achieved a full, pain-free range of motion. There was a statistically significant association between postoperative complications and shoulder pain or diminished range of motion (P = .026). Seven of 32 (21.9%) active-duty service members required medical separation from military service. Female sex (P = .04) and distal clavicle plate fixation increase the risk of unplanned return to the operating room (P = .01). Nicotine use was predictive of eventual military separation (P = .004).

Conclusions

In this case, a series of lateral clavicle fractures treated with CC ligament repair or reconstruction, all patients achieved fracture union and the majority of patients regained full, pain-free range of motion. Complications were common and portended a poor functional outcome. At the conclusion of their fracture care, 1 in 5 active-duty patients necessitated medical separation from military service.
Human Single-Cell RNA-Sequencing Data Supports the Hypothesis of X Chromosome Insensitivity but Is Ineffective in Testing the Dosage Compensation Model
Authors: Chen Jiabi , Chen Xiaoshu
Published: February 2025

A controversy in evolutionary genetics is whether active dosage compensation is necessary to resolve the gene dosage imbalance between the X chromosome and autosomes. ScRNA-seq data could provide insight into this issue. However, it's crucial to carefully evaluate whether inherent characteristics of scRNA-seq, such as the sparsity of detected genes, might bias the X:AA expression ratio in mammals. This study evaluated two common strategies for selecting genes in the calculation of X:AA, namely, filter-by-expression and filter-by-fraction, with simulated scRNA-seq and bulk RNA-seq datasets. We found that both strategies produce an inflated X:AA, thus artifactually supporting dosage compensation. Analyzing empirical human Smart-seq2 data, results from the filter-by-expression strategy suggested that X-linked genes were more highly expressed than autosomal genes, a pattern that is neither predicted by dosage compensation nor explained by genes escaping X chromosome inactivation. However, the results of the filter-by-fraction strategy are consistent with the simulation. Furthermore, despite biasing for mean expression levels, we found that scRNA-seq data could be used to detect X-to-autosome expression noise differences as small as 10%, which enabled investigation into the distribution of genes that are more likely insensitive to gene dosage changes. Analysis of the empirical Smart-seq2 data revealed a 10% to 15% increase in expression noise for X chromosomes compared with autosomes and a significant depletion of dosage-sensitive genes on X chromosomes. Overall, these results highlight the need to be cautious when interpreting scRNA-seq data, particularly when comparing the expression of different genes, and provide additional evidence for the hypothesis of X chromosome insensitivity.
Hepatitis E virus Infection in Vietnamese Pregnant Women with Hepatitis B: Prevalence and Clinical Outcomes
Authors: Thi Hong Van Le , Van Tong Hoang , Thanh Thuyet Bui , Lan Anh Bui , Chi Cao Le , Thu Trang Do , Xuan Hoan Nghiem , Xuan Huy Trinh , Thu Hang Ngo , Van Mao Can , Thi Thanh Huyen Tran , Linh Toan Nguyen , Huu Song Le , Bock C -Thomas , Wedemeyer Heiner , Velavan Thirumalaisamy P , Tien Sy Bui
Published: February 2025

Background

Hepatitis E virus (HEV) infection during pregnancy is associated with obstetric complications and adverse maternal and neonatal outcomes. This study aimed to determine the seroprevalence of HEV and RNA positivity in both healthy pregnant women and women co-infected with hepatitis B virus (HBV).

Methods

A cross-sectional study was conducted involving 528 pregnant women (278 with and 250 without HBsAg) in their third trimester. Anti-HEV specific IgG and IgM antibodies were tested using ELISA, while HEV-RNA was detected by nested PCR. The status of anti-HEV antibodies was analysed regarding pregnancy outcomes and the risks of obstetric complications.

Results

The results indicated that 24% (127/528) of participants tested positive for anti-HEV IgG, while 2.5% (13/528) showed detectable anti-HEV IgM. Among HBV-positive women, 26% (55/250) had anti-HEV IgG, comparable to 22% (61/278) in HBV-negative controls. Notably, 28% (140/501) of cord blood samples were positive for anti-HEV IgG. No cases of HEV-RNA were detected. The prevalence of anti-HEV IgG increased with maternal age and was associated with higher infant birth weights. Anti-HEV IgM positivity was associated with an increased risk of neonatal infections (OR=20.6; p=0.05). Among HBsAg-positive women, those with anti-HEV IgG (26%) had higher gestational age at delivery, infant birth weights, but lower platelet counts and prothrombin times (p<0.05).

Conclusions

These findings highlight the endemic nature of HEV in Vietnam and underscore the potential risks of co-infection with HBV during pregnancy, which may lead to adverse obstetric outcomes.
Assessment of immune modulation strategies to enhance survival and integration of human neural progenitor cells in rodent models of spinal cord injury
Authors: Lou Zijian , Post Alex , Nagoshi Narihito , Hong James , Hejrati Nader , Chio Jonathon Chon Teng , Khazaei Mohamad , Fehlings Michael G
Published: February 2025

Regenerative therapies are currently lacking for spinal cord injury (SCI). Neural progenitor cells (NPCs) have emerged as a promising therapeutic approach. To facilitate translation of NPCs into the clinic, studying human NPCs in rodent models is required. The preclinical study of human NPCs in rodent models of SCI necessitates an optimal selection of immunomodulatory strategies, requiring a balance between modulating the immune system and preserving its functionality.
Network expression analysis identifies and experimentally validates the involvement of Fosb in acute kidney injury
Authors: Tang Xiaoyan , Shen Changqiong , Liu Chunqiu , Gao Jianya
Published: February 2025

Acute kidney injury (AKI) is a complex clinical syndrome associated with increased incidence and mortality rates among critically ill patients, often leading to multiple organ dysfunction, which underscores the need to better understand its molecular mechanisms. In this study, common differentially expressed genes (DEGs) between various AKI models and control groups were extracted using the Gene Expression Omnibus (GEO) database, followed by an exploration of potential signaling pathways involved in AKI. Key genes in the development of AKI were identified through Weighted Gene Co‐expression Network Analysis (WGCNA) and protein–protein interaction (PPI) networks, and the expression of hub genes was validated using quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC) and flow cytometry. A total of 1265 DEGs significantly associated with AKI were identified, with GO and KEGG analyses revealing significant enrichment in pathways related to kidney development, muscle regulation, and amino acid biosynthesis. WGCNA further screened AKI‐related modules, identifying 290 DEGs significantly linked to the disease state. PPI network analysis revealed Fosb as a significantly upregulated hub gene in AKI, with experimental validation demonstrating its substantial upregulation in patients with acute tubular necrosis (ATN), HR‐induced HK‐2 cells injury and ischemia–reperfusion injury (IRI) mice. Inhibition of Fosb alleviated hypoxia‐reoxygenation (HR)‐induced apoptosis and inflammation in HK‐2 cells by suppressing the AP‐1 complex (Fosb/C‐Jun) signaling pathway. Therefore, Fosb is significantly upregulated in AKI and associated with inflammation mediated by the AP‐1 signaling pathway, suggesting its potential as a diagnostic biomarker and therapeutic target for AKI.
Prussian blue nanoparticles prevent RANKL‐induced osteoclastogenesis by scavenging ROS and inactivating NF‐κB/MAPK signaling pathways
Authors: Yang Jiancheng , Tang Qinghua , Li Siyu , Yang Lei , Yang Ming , Li Qingmei , Feng Yan , Pan Mingming , Zeng Yuhong
Published: February 2025

The accumulation of intracellular reactive oxygen species (ROS) is widely recognized to stimulate the development of osteoclasts, a crucial factor in the onset of osteoporosis. The ROS scavenging capability of Prussian blue nanoparticles (PBNPs) is exceptional, and they possess excellent biocompatibility. However, the effects of PBNPs on osteoporosis remain unknown. Present study aimed to investigate whether PBNPs could inhibit osteoclast differentiation and prevent ovariectomy (OVX)‐induced bone loss by suppressing ROS. In vitro experiments demonstrated that PBNPs attenuated osteoclastogenesis and downregulated the expression of osteoclast‐related genes. Mechanistically, PBNPs reduce cellular ROS by blocking RANKL‐induced ROS generation and increasing the expression of ROS scavenging enzymes, which in turn block the NF‐κB, ERK, JNK, and p38 pathways, thereby reducing NFATc1 signaling. According to in vivo experimental results, OVX caused a significant rise in ROS in the bone marrow, an increase in osteoclastic number on the bone surface, and substantial bone loss; however, PBNPs significantly reduced ROS and successfully protected OVX‐induced bone damages. In conclusion, this study showed for the first time that PBNPs prevented OVX‐induced bone loss and attenuate osteoclastogenesis, indicating that PBNPs may be a viable alternative therapy for the management of osteoclast‐associated bone disorders.
Intraoperative Cholangiogram Interpretation for Laparoscopic Transcystic Bile Duct Exploration: Is Concurrence Possible?
Authors: Turco Jennifer , Pugliese Matthew , Trivedi Anand , Aldridge Oscar , Webber Laurence , Ballal Mohammed
Published: February 2025

Background:

Laparoscopic transcystic bile duct exploration (LTCBDE) represents a secure and efficacious approach for managing common bile duct (CBD) stones, particularly in patients concurrently undergoing laparoscopic cholecystectomy (LC). The decision to proceed with LTCBDE hinges on real-time assessment of the intraoperative cholangiogram (IOC), which is highly operator-dependent and poorly interpreted. No established criteria exist to guide the evaluation of IOCs for LTCBDE. This study aims to ascertain the concordance among surgeons, experienced in LTCBDE, on critical aspects of IOC interpretation.

Methods:

A retrospective collection of IOC images of 40 patients who underwent LC, IOC, and LTCBDE at a tertiary university hospital between 2017 and 2018 was undertaken. Two hepato-pancreato-biliary (HPB) and 2 acute care surgery (ACS) specialists independently reviewed the images. They were tasked with assessing IOC features hypothesized to influence duct exploration and stone extraction complexity, along with overall suitability for LTCBDE based exclusively on the IOC images. Agreement percentages were calculated and Kappa inter-rater reliability statistics were assessed.

Results:

The overall agreement percentages concerning IOC features ranged between 52.5% and 82.5% with agreements surpassing 75% deemed robust. Maximum agreement was achieved in the interpretation of cystic duct morphology, whether straight or characterized by spiral valves. The concurrence for amenability of LTCBDE also demonstrated substantial accord among surgeons (ACS: 92.5%, HPB: 95%, total: 87.5%). Consistently high agreement was evident within specialty groups.

Conclusions:

Anatomical attributes displayed superior agreement levels, as opposed to variables necessitating measurements. We recommend the development of a structured approach for the interpretation of IOC to facilitate surgical education in LTCBDE.
Safety, Effectiveness, and Participant Satisfaction With Multiple Simultaneous Cryolipolysis Treatments Using a Dual-Applicator Cryolipolysis System
Authors: Bachelor Eric , Moradi Amir , Stevens Grant , Scott-Shemon Deja , Ostrowski Rafael , Madere Tonia , Gamio Sylvia
Published: February 2025

BACKGROUND

Cryolipolysis is a safe, effective, and noninvasive treatment for subcutaneous fat reduction.

OBJECTIVE

Assess safety, effectiveness, and participant satisfaction with multiple simultaneous dual-applicator cryolipolysis treatments on the torso.

MATERIALS AND METHODS

Adult participants received multiple simultaneous treatments to the torso (i.e., flanks, abdomen, back/bra area). Primary effectiveness end point was ≥70% correct identification of baseline versus week 12 post–final treatment photographs by ≥2 of 3 independent reviewers; safety end point was frequency of adverse device effects (ADEs). Secondary end points included fat layer thickness reduction and participant satisfaction/comfort.

RESULTS

Mean participant age (N = 35) was 40.4 years, 77.1% were female, and mean body mass index was 24.9 kg/m2. A mean of 20.8 treatment cycles were received over 2 treatment sessions. The primary effectiveness end point was met; 75% of pretreatment images were correctly identified. Mean reduction in fat layer thickness was 0.33 cm. Most ADEs were mild, with no serious events. Mean overall participant satisfaction with the procedure was 82.8%. Mean maximum pain scores were 2.6 and 4.1 (scale of 10) during treatment sessions 1 and 2, respectively.

CONCLUSION

Multiple simultaneous cryolipolysis treatments on the torso using a dual-applicator system were safe and effective, with high overall participant satisfaction.
Targeting protein hyperSUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma crosstalk
Authors: Olaizola Paula , Olaizola Irene , Lapitz Ainhoa , Val Beatriz , Izquierdo-Sanchez Laura , Fernandez-Barrena Maite G. , O’Rourke Colm J. , Lee-Law Pui Y. , Gradinaru Andreea , Jimenez-Agüero Raul , La Casta Adelaida , Riaño Ioana , Macias Rocio I.R. , Marin Jose J.G. , Martinez-Chantar Maria L. , Avila Matias A. , Aspichueta Patricia , Andersen Jesper B. , Boulter Luke , Bujanda Luis , Rodrigues Pedro M. , Perugorria Maria J. , Banales Jesus M.
Published: February 2025

Background and Rationale:

Cholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target.

Approach and Results:

Analysis of CCA tumors from four patient cohorts and CCA cell lines, revealed increased expression of the SUMOylation machinery genes SAE1 and UBE2I, regardless of the tumor’s molecular profile, resulting in elevated levels of SUMO1-conjugated proteins. Higher SAE1 and UBE2I levels were both indicative of unfavorable clinical outcomes. Deregulated SUMOylated proteins in CCA, mostly linked to cell proliferation, survival, and homeostasis, were identified through immunoprecipitation and mass spectrometry. Genetic (UBE2I-knockdown) and pharmacological (ML792 and SAMe) inhibition of SUMOylation effectively suppressed tumorigenesis in subcutaneous and oncogene-driven CCA models, reducing the presence of cancer-associated fibroblasts (CAFs) and increasing the recruitment of anti-tumor immune cells. In vitro, targeting SUMOylation induced CCA cell death and reduced cell proliferation, colony formation, and spheroid growth. Importantly, ML792 and SAMe did not adversely affect normal human cholangiocytes. Moreover, co-culture of wild-type or UBE2I-knockdown CCA cells with CAFs revealed that depleting SUMOylation in CCA cells impaired CAF cell growth and altered their protein secretome, ultimately disrupting CCA growth through a regulatory feedback loop.

Conclusion:

Aberrant SUMOylation drives CCA progression by enhancing cell survival, proliferation, and shaping the tumor microenvironment. Targeting SUMOylation shows potential in inhibiting CCA growth, representing a promising therapeutic strategy.
Ciliary Neurotrophic Factor Implant in Geographic Atrophy from Age-related Macular Degeneration: A Long-Term Case Study
Authors: Shiromani Sakshi , Leef Donna , Jain Nieraj , Yan Jiong
Published: February 2025

Purpose:

To report a case of thirteen-year long progression of geographic atrophy (GA) from dry age-related macular degeneration (AMD) with ciliary neurotrophic factor (CNTF) implant, NT-501, in one eye, compared to the untreated contralateral eye.

Methods:

Using sequential images from 2012 to 2024, the macular GA and peripapillary atrophy was identified as areas of definitely decreased autofluorescence on fundus autofluorescence (FAF) and clearly delineated areas of hyperreflectivity on near infrared reflectance (NIR-R). Optical coherence tomography B scans confirmed areas of complete retinal pigment epithelium and outer retinal atrophy to support FAF grading.

Results:

A 76-year-old male received the CNTF implant in the right eye in August 2011. Macular GA area on short wavelength FAF exhibited growth from 4.51 mm2 (8/2012) to 14.46 mm2 (6/2020), in the treated right eye, and from 3.2 mm2 to 14.92 mm2 in the untreated left eye. The linearized growth rates were 0.21 mm/y (right) and 0.26 mm/y (left), showing a 16.3% difference. A similar pattern was seen on green laser FAF from 2018 to 2024, with peripapillary atrophy progression rates of 0.2 mm2/y (right) and 1.03 mm2/y (left).

Conclusions:

Notably, the implanted eye, exhibited less progression of macular GA and peripapillary atrophy. While acknowledging the limitations of a single case, we highlight the potential benefits of using the CNTF implant, a one-time surgical procedure, in reducing the treatment burden for atrophic AMD patients. We hope to see further reports from other sites that participated in this compassionate use protocol for NT-501 in atrophic AMD.
Choroidal Synphlebia in a Patient with Central Serous Chorioretinopathy
Authors: Naderi Amirreza , Spaide Richard
Published: February 2025

Purpose:

To describe the choroidal vascular abnormality of conjoined choroidal vessels, synphlebia, in a patient with central serous chorioretinopathy (CSC).

Methods:

A patient initially referred for pigmentary retinal dystrophy later developed central serous retinopathy and underwent a comprehensive examination with multimodal imaging.

Results:

A 30-year-old man had an undiagnosed pigmentary retinopathy and nyctalopia was found to have a DHDDS mutation, confirming a retinitis pigmentosa diagnosis. A year later, he presented with bilateral central serous chorioretinopathy. During the venous phase of indocyanine green angiography individual vessels could not be differentiated in the posterior pole. Swept-source optical coherence tomography revealed an abnormally thick choroid with enormous vascular channels that did not appear to have separation into individual tubular structures. These abnormal vessels nearly occupied the entire thickness of the choroid in the macular region. There was little sign of any intermediate-sized choroidal vessels in the posterior pole. A review of other patients with DHDDS mutation showed no similar choroidal vascular changes.

Conclusion:

Large, conjoined veins, which we termed synphlebia, were seen in an eye with CSC. Loading of the choriocapillaris from these enlarged vascular channels may have contributed to hyperpermeability and formation of serous fluid. Observation of this choroidal vascular pattern suggests that a CSC phenotype may develop through more than one pathway.
Cellulosimicrobium spp. – A novel cause of endogenous endophthalmitis diagnosed on DNA sequencing
Authors: Shettigar Manoj P. , Sheba Esther , Joseph Joveeta , Dave Vivek Pravin
Published: February 2025

Purpose:

To report two cases of Cellulosimicrobium. spp – A novel cause of endogenous endophthalmitis diagnosed on DNA sequencing

Methods:

Our non-comparative retrospective descriptive case series included two clinically diagnosed cases of endogenous endophthalmitis. We noted the clinical presentations, management outcomes, and microbiological workup. The patients underwent pars plana vitrectomy with intravitreal empirical antibiotics and microbiological investigation of the vitreous sample. The vitreous biopsy samples from both cases underwent routine microbiological evaluation, PCR, and DNA sequencing, which played a crucial role in the diagnosis.

Results:

Both cases were of young males aged 12 and 13 years, respectively, who presented with painful diminution in vision and redness. The mode of infection was deemed endogenous, given the spontaneous occurrence of endophthalmitis. Both patients underwent pars plana vitrectomy followed by intravitreal empirical antibiotics injection (Vancomycin and Ceftazidime). Vitreous biopsy demonstrated thick Gram-positive beaded bacilli. DNA sequencing revealed Cellulosimicrobium spp. The organism was found to be multi-drug resistant but was susceptible to Vancomycin. Post vitrectomy, a rhegmatogenous retinal detachment was noted. Both patients underwent silicone oil injections and, over the next month, showed complete resolution of endophthalmitis. Snellen's best-corrected visual acuity in Case 1 remained at counting fingers close to face due to a recurrent retinal detachment, while in Case 2, it improved to 20/50 from baseline.

Conclusion:

Cellulosimicrobium spp. can cause endogenous endophthalmitis, and the infection can be multi-drug-resistant. Organism identification may be elusive using routine smear culture techniques but can be confirmed by DNA sequencing.
Psychometric Properties and Measurement Invariance of the Patient Health Questionnaire 9 in an Italian Coronary Heart Disease Population
Authors: Di Matteo Roberta , Bolgeo Tatiana , Simonelli Niccolò , Dal Molin Alberto , Bassola Barbara , Lusignani Maura , Maconi Antonio , Rasero Laura , Vellone Ercole , Iovino Paolo
Published: February 2025

Background

Depression is common in patients with coronary heart disease (CHD). The 9-item patient health questionnaire (PHQ-9) is an instrument for screening depression. However, evidence on the psychometric properties of the PHQ-9 in Italian populations with CHD is still lacking.

Objective

The objective of this study was to examine the psychometric properties and measurement invariance of the PHQ-9 in a large CHD sample.

Methods

This is a secondary analysis of 3-month follow-up data collected from a multicenter longitudinal study. Patients completed a battery of self-reported instruments that included the PHQ-9 and the generalized anxiety disorder scale-7 (GAD-7). Factorial validity was assessed with confirmatory factor analysis. Convergent validity was tested by inspecting the correlations between the PHQ-9 and GAD-7 scores, and other sociodemographic factors. Internal consistency was investigated with the model-based internal consistency reliability index. Measurement invariance was tested across sex and age (≥65 vs <65 years) with confirmatory multigroup factor analysis.

Results

We enrolled 427 patients (mean age, 64.41 years; 78.9% male; 66.7% married). The confirmatory factor analysis supported a bi-dimensional factor structure with the factors measuring somatic and cognitive symptoms. Convergent validity testing showed significant positive correlations of the PHQ-9 scores with the GAD-7 scores, gender, and perceived financial status. The model-based internal consistency reliability index was adequate at 0.80. Measurement invariance across age was confirmed at the scalar level, whereas invariance across sex was achieved at the metric level.

Conclusion

The PHQ-9 shows adequate psychometric and invariance properties across age groups in patients with CHD. Hence, this instrument can be used in clinical practice and research to assess the severity of depression in patients with CHD and to compare depression scores between younger and older individuals.
Clinicopathologic and Molecular Characterization of Gynecologic Carcinosarcomas With a Mesonephric-Like Carcinomatous Component
Authors: Mendoza Rachelle P. , Tjota Melisa Y. , Choi Donghyuk N. , Chapel David B. , Kolin David L. , Euscher Elizabeth D. , Barroeta Julieta E. , Numan Tricia A. , Xing Deyin , Afkhami Michelle , Bakkar Rania , Lastra Ricardo R.
Published: February 2025

Carcinosarcoma with a mesonephric-like carcinomatous component (MLCS) is a rare subtype of gynecologic malignancy recently described in the literature. This study aims to expand the genomic characterization of MLCS by performing independent molecular analysis of the carcinomatous and sarcomatous components in a series of MLCS. Eight cases of gynecologic MLCS (endometrial, lower uterine segment, and ovarian) were identified and underwent clinicopathologic evaluation. Genomic DNA extraction and next-generation sequencing (NGS) were performed separately from the carcinomatous and sarcomatous components of 4 tumors, while 2 tumors underwent NGS of combined carcinomatous and sarcomatous components. The average age at diagnosis was 65.6 years (range 50 to 83 years). MLCS patients were diagnosed at FIGO stage I (n=3), stage II (n=2), stage III (n=2), and stage IV (n=1). The carcinomatous and sarcomatous components were observed to harbor the same single nucleotide variations. All cases had less than 10 mutations/Mb and were microsatellites stable. All cases (6/6, 100%) harbored KRAS point mutations in codon 12, including the following variants: p.G12D (n=2), p.G12A (n=2), and p.G12V (n=2). Five cases showed additional alterations in ARID1A (case 1), PTEN (case 2), PIK3CA (case 4), SPOP (case 6), TET1 (case 6), BUB1 (case 7), LYN (case 7) and PTPRD (case 7). The presence of both KRAS and PTEN/PIK3CA alterations suggests a combined endometrioid and mesonephric differentiation in MLCS.
Expression of human immunodeficiency virus envelope protein in the human central nervous system
Authors: Agbey Christy , Walton Sofia , Campbell Lee Antony , Nath Avindra , Smith Bryan , Snow Joseph , Wiebold Amanda , Hou Chunyan , Ma Junfeng , Mocchetti Italo ,   the NIH-Neuro-HIV Research Consortium
Published: February 2025

Objective/Design:

The human immunodeficiency virus (HIV) envelope glycoprotein gp120 contributes to neuronal damage that could lead to human immunodeficiency virus-mediated neurocognitive disorder. However, it is debated whether gp120 could promote direct neurotoxicity to synapses because it may not be present in the central nervous system of people living with human immunodeficiency virus (PLWH) on antiretroviral therapy (ART). This study sought to establish whether gp120 is expressed in the human central nervous system in the pre- and post- ART era.

Methods:

We utilized real-time polymerase chain reaction (PCR) to detect the envelope mRNA in postmortem caudate nucleus from pre-ART era. HIV negative samples were used as controls. We then used RNAscope fluorescence multiplex to identify which cells express the envelope mRNA. To determine whether gp120 is present despite ART, we analyzed cerebrospinal fluid (CSF) samples from PLWH on ART using mass spectrometry.

Results:

Using PCR, we detected the envelope mRNA in the caudate nucleus from PLWH with neurocognitive impairment but not in control samples. With RNAscope, we detected the envelope mRNA in microglia and astrocytes in the frontal cortex and caudate nucleus from HIV-positive tissue. With mass spectrometry, we identified a gp120 peptide in the CSF of PLWH on antiretroviral therapy (n = 20) but not in control subjects (n = 7).

Conclusion:

Our data suggest that despite antiretroviral therapy, gp120 is expressed and likely released by infected cells, suggesting that gp120 could be one of the key factors in the neuropathology observed in people living with human immunodeficiency virus.
Comparative Analysis of Dynamic Esthetic Characteristics in Spontaneous Smiles Among Hani and Han Youths in Yunnan Province, China
Authors: Liang Hongrun , Lin Yunhong , Ren Xiaoxue , Fu Wanni , Li Xingxing
Published: February 2025

Objective:

The aim of this study is to examine the dynamic esthetic characteristics of spontaneous smiles in Hani and Han youths in Yunnan Province.

Methods:

Employing a multistage stratified cluster random sampling approach, participants from the Hani and Han ethnic groups in Yunnan Province were recruited. Digital videography was used to capture facial characteristics at both rest and during spontaneous smiles. Subsequently, selected images were analyzed for dynamic esthetic parameters concerning the lips, teeth, and gingiva using image measurement software.

Results:

The study included youths from the Hani (n = 68) and Han (n = 59) ethnic groups in Yunnan Province. During spontaneous smiles, the exposure of maxillary central incisors was more pronounced compared with maxillary lateral incisors and canines in both ethnic groups. Variations in gingival display of central incisors were observed among males in the 2 ethnic groups (P < 0.05). The mobility of the mouth corner’s width was significantly greater in Han males compared with Hani males (P < 0.05). Conversely, the width of the mouth corner during spontaneous smiles was greater in Hani females than in Han females (P < 0.05). Regarding the relationship between the gingival line and the upper lip, the unexposed type was predominant among males of both ethnicities, whereas the parallel type was predominant among females. Parallel and straight smile arcs were commonly observed among participants from both ethnicities.

Conclusion:

The dynamic esthetic characteristics of the lips, teeth, and gingiva exhibit similarities between the youth of Hani and Han ethnicities in Yunnan Province. However, notable differences in certain dynamic smile esthetic traits exist between the sexes.
How Autism Impacts Children’s Working Memory for Faces
Authors: Esfahan Shahrzad M. , Sepahi Narges , Rezayat Ehsan
Published: February 2025

This study investigates how visual working memory (WM) functions in children with Autism Spectrum Disorder (ASD) compared to typically developing (TD) children aged 7 to 12, focusing on their ability to remember faces. The primary goal was to understand the differences in visual WM performance between these two groups and identify the sources of memory recall errors. Findings indicate that children with ASD demonstrated significantly poorer visual WM compared to their TD counterparts, particularly in the precision of memory recall. Despite this difference, both groups exhibited similar rates of random guessing, suggesting that the challenges faced by children with ASD are more about accuracy than guessing strategy. This research sheds light on the specific deficits in visual WM associated with ASD, enhancing our understanding of the cognitive mechanisms at play and highlighting potential areas for targeted interventions to support these children.
Offset analgesia and onset hyperalgesia: A comparison between women with non-suicidal self-injury and healthy women
Authors: Fust Jens , Kastrati Gránit , Bjureberg Johan , Jayaram-Lindström Nitya , Hellner Clara , Kosek Eva , Fransson Peter , Jensen Karin B. , Lalouni Maria
Published: February 2025

Individuals who engage in non-suicidal self-injury (NSSI) exhibit reduced pain sensitivity compared to the general population. It has been argued that this hypoalgesic characteristic may be attributable to hyper-effective pain modulation; however, empirical support for this theory remains inconsistent. The aim of the study was to use a combined offset analgesia (OA) and onset hyperalgesia (OH) protocol to investigate if women with NSSI have a propensity to inhibit nociceptive signals to a higher degree (stronger OA response) and facilitate nociceptive signals to a lesser degree (weaker OH response), compared to a control group. Data was collected from 76 women, 18-35 age (37 with NSSI and 39 healthy controls). The OA and OH protocol was combined with functional magnetic resonance imaging (fMRI). The NSSI group displayed a weaker OH response, compared to the control group. This suggests that women with NSSI do not facilitate nociceptive signals to the same extent as healthy women. However, there were no significant differences between the groups regarding OA. Across all participants, we observed stronger activation in the primary sensory cortex during the OH condition, compared to the control condition. The results offer partial support for the general hypothesis that women with NSSI demonstrate enhanced pain modulation.
ZSeeker: An optimized algorithm for Z-DNA detection in genomic sequences
Authors: Wang Guliang , Mouratidis Ioannis , Provatas Kimonas , Chantzi Nikol , Patsakis Michail , Georgakopoulos-Soares Ilias , Vasquez Karen
Published: February 2025

Z-DNA is an alternative left-handed helical form of DNA with a zigzag-shaped backbone that differs from the right-handed canonical B-DNA helix. Z-DNA has been implicated in various biological processes, including transcription, replication, and DNA repair, and can induce genetic instability. Repetitive sequences of alternating purines and pyrimidines have the potential to adopt Z-DNA structures. ZSeeker is a novel computational tool developed for the accurate detection of potential Z-DNA-forming sequences in genomes, addressing limitations of prior methods. By introducing a novel methodology informed and validated by experimental data, ZSeeker enables the refined detection of potential Z-DNA-forming sequences. Built both as a standalone Python package and as an accessible web interface, ZSeeker allows users to input genomic sequences, adjust detection parameters, and view potential Z-DNA sequence distributions and Z-scores via downloadable visualizations. Our Web Platform provides a no-code solution for Z-DNA identification, with a focus on accessibility, user-friendliness, speed and customizability. By providing efficient, high-throughput analysis and enhanced detection accuracy, ZSeeker has the potential to support significant advancements in understanding the roles of Z-DNA in normal cellular functions, genetic instability, and its implications in human diseases.

Availability

ZSeeker is released as a Python package under the GPL license as a multi-platform application and is available at:https://github.com/Georgakopoulos-Soares-lab/ZSeeker. A web-interface of ZSeeker is publicly available athttps://zseeker.netlify.app/.