julilili42/papers huggingface dataset:
p21-activated kinases (PAKs) regulate FGF1/PDE4D antilipolytic pathway and insulin resistance in adipocytes
2025-07-15

Increasing evidence suggests that adipose tissue plays a key role in the development, progression, and treatment of the globally epidemic disease type 2 diabetes (T2D). For example, adipose tissue dysfunction, lipotoxicity, and insulin resistance (IR) are major contributors and targets for the treatment of T2D. We previously identified the Fibroblast growth factor 1 (FGF1)/Phosphodiesterase 4D (PDE4D) pathway, which lowers plasma glucose concentration by suppressing lipolysis in adipose tissue and ultimately regulating hepatic glucose production in obese insulin-resistant mice. While phosphorylation of PDE4D is critical for its activity, the upstream signaling mechanisms remain unclear. In this study, we identified p21-activated kinases (PAKs) as regulator of PDE4D phosphorylation and suppression of lipolysis by FGF1. Inhibition of PAK-induced cAMP accumulation prevented antilipolytic function of FGF1, and reversed suppression of lipolysis caused by PDE4D overexpression, linking PAKs to the regulation of cAMP by PDE4D in murine adipocytes in vitro. Chronic inhibition of PAKs decreased lipid accumulation in both mouse and human adipocyte cultures, lowered expression of adipogenic markers, and induced IR, suggesting a previously unidentified role of PAKs in adipocyte function and differentiation. We conclude that PAKs play a crucial role in regulating the FGF1/PDE4D antilipolytic pathway, adipogenesis and IR, thereby highlighting their potential as therapeutic targets for T2D.
Systemic Sclerosis in Women—Impact on Sexuality, Fertility, Pregnancy, and Menopause
2025-07-15

Background: Systemic sclerosis is a systemic autoimmune disease that also impacts women’s health in very different ways. Methods: This review summarises the most important data on sexuality, fertility, pregnancy, and menopause from the last 10 years. Findings: We identified nine articles with data on sexuality and a prevalence of sexual dysfunction varying between 46 and 90%. Fertility was examined in six studies, with evidence for a negative influence at least on ovarian reserve. With regard to menopause, only three studies are mentioned that show an increased risk for premature menopause in SSc women. Although pregnancies are rare in SSc women after disease onset, there is growing evidence that pregnancies are feasible but go along with a higher maternal and foetal risk compared to healthy controls. Interpretation: SSc is dominated by female gender, but aspects of women’s health influenced by the disease are still often ignored. The treating physician should be aware of the mostly negative impact on sexuality, fertility, and pregnancy and address these topics with the patients to adapt treatment and follow-up examinations to the patients’ complaints and life situation.
Constructed growth charts and nutrition for pontocerebellar hypoplasia type 2A
2025-07-15

Abstract Aim To calculate growth charts for pontocerebellar hypoplasia (PCH) type 2A (PCH2A) and compare them to German reference charts, especially with regard to nutritional aspects. Method Data were gathered from a cohort of patients with genetically confirmed PCH2A, who were predominantly recruited through the German PCH patient network (65 patients [33 female, 32 male] at a mean age of 8 years 7 months). We collected data retrospectively using a parent questionnaire, and from medical records (December 2020–September 2022). Disease‐specific growth charts were prepared from predominantly longitudinal data using the gamlss package implemented in R. Sex‐disaggregated growth charts for PCH2A were compared to German reference data from the Kinder‐ und Jugendgesundheitssurvey (German Health Interview and Examination Survey for Children and Adolescents). Results The height and weight of participants with PCH2A were within the reference range at birth. Mean height was significantly lower at 6 months of age, weight at 3 months, and body mass index at 4 months. These deviations were also mostly significant later on. Head circumference in individuals with PCH2A was significantly below average at birth; all participants showed severe and progressive microcephaly in the further course. Caloric intake was within or above reference values. Interpretation Participants with PCH2A exhibited progressive microcephaly and frequently failed to thrive. Disease‐specific growth charts are a helpful tool to monitor those with PCH2A.
Non-antibiotics disrupt colonization resistance against enteropathogens
2025-07-16

Abstract Non-antibiotic drugs can alter the composition of the gut microbiome 1 , but they have largely unknown implications for human health 2 . Here we examined how non-antibiotics affect the ability of gut commensals to resist colonization by enteropathogens 3 . We also developed an in vitro assay to assess enteropathogen growth in drug-perturbed microbial communities. Pathogenic Gammaproteobacteria were more resistant to non-antibiotics than commensals and their post-treatment expansion was potentiated. For 28% of the 53 drugs tested, the growth of Salmonella enterica subsp. enterica serovar Typhimurium. ( S . Tm) in synthetic and human stool-derived communities was increased, and similar effects were observed for other enteropathogens. Non-antibiotics promoted pathogen proliferation by inhibiting the growth of commensals, altering microbial interactions and enhancing the ability of S . Tm to exploit metabolic niches. Drugs that promoted pathogen expansion in vitro increased the intestinal S . Tm load in mice. For the antihistamine terfenadine, drug-induced disruption of colonization resistance accelerated disease onset and increased inflammation caused by S . Tm. Our findings identify non-antibiotics as previously overlooked risk factors that may contribute to the development of enteric infections.
Much higher covariation with foveation timing by superior colliculus than primary visual cortical neuronal activity
2025-07-16

Abstract The superior colliculus (SC) is a potent driver for orienting movements, but it also possesses robust, short-latency visual responses. Even though such responses largely derive from direct primary visual cortical (V1) input, their relationship to V1 activity has never been analyzed with the same experimental subjects and stimuli. Here, we revisited pioneering observations that trial-by-trial variability in either the SC or V1 may predict variability in eye movement timing. We found that V1 covariation with behavioral variability was virtually non-existent in comparison to the SC, whether with respect to visual response onset latency, visual response strength, or pre-stimulus state. By far, the largest predictor of behavioral variability was visual response strength in SC visual-motor neurons. These results suggest that the SC reformats its inputs for exploitation of the SC’s proximity to the motor periphery; V1 aids in jumpstarting the sensing process, but the SC much more directly supports visually-driven orienting.
AAV8-based gene replacement therapy for hereditary spastic paraplegia type 5
2025-07-16

Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessive neurological disorder caused by mutations in the CYP7B1 gene, which encodes cholesterol 7α-hydroxylase, an essential enzyme in cholesterol metabolism. These mutations lead to elevated levels of 25- and 27-hydroxycholesterol, oxysterols known to be neurotoxic and blood-brain-barrier permeable. Their accumulation contributes significantly to SPG5 pathogenesis, resulting in spastic gait disturbance and severely impaired quality of life. Using a Cyp7b1<sup>-/-</sup> mouse model that mirrors the metabolic phenotype of SPG5, we developed a gene therapy approach to correct oxysterol imbalance. We designed an AAV8-TTR-hCYP7B1 vector to deliver the CYP7B1 gene specifically to the liver. Following intravenous administration, oxysterol levels in blood and liver were rapidly normalized, even at low doses (1E10), with no observed toxicity at the highest tested dose (1E11). Despite these promising peripheral results, oxysterol levels in the brain, particularly 27-hydroxycholesterol, remained only partially corrected six weeks post-treatment. Our findings suggest that while liver-targeted gene therapy is effective at restoring peripheral cholesterol metabolism, a successful therapeutic strategy for SPG5 must also address central nervous system involvement. We conclude that successful treatment of SPG5 would require a novel gene therapeutic approach that also targets the CNS.
Risk for non-sentinel metastases in the contralateral groin in patients with a unilateral positive sentinel lymph node in primary vulvar cancer- a subgroup analysis of the AGO-VOP.2 QS Vulva Study
2025-07-16

In this large multicenter retrospective study the risk of contralateral groin recurrence was low (3,1 %). Therefore, morbidity should be carefully balanced against oncologic safety and omission of contralateral LAE should be considered.
XBB.1.5 COVID-19 mRNA Vaccines Induce Inadequate Mucosal Immunity in Patients with Inflammatory Bowel Disease
2025-07-16

Background: Mucosal immunity plays a pivotal role in preventing infections with SARS-CoV-2. While COVID-19 mRNA vaccines induce robust systemic immune responses in patients with inflammatory bowel disease (IBD), little is known about their efficacy in the mucosal immune compartment. In this sub-investigation of the ongoing STAR-SIGN study, we present the first analysis of mucosal immunity elicited by XBB.1.5 mRNA vaccines in immunocompromised patients with IBD. Methods: IgG and IgA antibodies targeting the receptor-binding domain of the SARS-CoV-2 JN.1 variant were quantified longitudinally in the saliva of IBD patients using the multiplex immunoassay MultiCoV-Ab. Antibody levels were quantified before and 2–4 weeks after vaccination with XBB.1.5 mRNA vaccines. All patients previously received three doses with original COVID-19 vaccines. Results: Mucosal IgG antibodies were readily induced by XBB.1.5 mRNA vaccines (p = 0.0013 comparing pre- and post-vaccination levels). However, mucosal IgA levels were comparable before and after vaccination (p = 0.8233). Consequently, mucosal IgG and IgA antibody levels correlated only moderately before and after immunization (pre-vaccination: r = 0.5294; p = 0.0239; post-vaccination: r = 0.4863; p = 0.0407). Contrary to a previous report in healthy individuals, vaccination did not induce serum IgA in patients with IBD (p = 0.5841 comparing pre- and post-vaccination levels). These data suggest that COVID-19 mRNA vaccines fail to elicit mucosal IgA in patients with IBD. Conclusions: Since mucosal IgA plays a pivotal role in infection control, the lack of IgA induction indicates that patients lack sufficient protection against SARS-CoV-2 infections which warrants the development of mucosal COVID-19 vaccines.
Altered thymic niche synergistically drives the massive proliferation of malignant thymocytes
2025-07-16

Abstract The discovery of genetic alterations in patient samples over the last decades has reinforced a cell-autonomous view of proliferative expansion during T- cell acute lymphoblastic leukemia (T-ALL) development in the thymus. However, the potential contribution of non-cell-autonomous factors, particularly the impact of thymic epithelial cells (TECs) within the thymic niche during the initiation phase, remains unexplored. In this study, we combine a cell-based computational model of the thymus with complementary in vivo experiments in medaka (Oryzias latipes) to systematically analyze the impact of 12 cell-autonomous and non- autonomous factors, individually and in combination, on the proliferation of normal and malignant thymocytes carrying interleukin-7 receptor (IL7R) gain-of-function mutations or elevated IL7R levels, as observed in T-ALL patients. By simulating over 1500 scenarios, we show that while a dense TEC network favored the proliferation of normal thymocytes, it inhibited the proliferation of malignant lineages, which achieved their maximal proliferative capacity when TECs were sparsely distributed. Our in silico model further predicts that specific mutations could accelerate proliferative expansion within a few days. This prediction was experimentally validated, revealing the rapid onset of thymic lymphoma and systemic infiltration of malignant T-cells within just 8 days of embryonic development. These findings demonstrate that synergistic interaction between oncogenic alterations and modifications in the thymic niche can significantly accelerate disease progression. Our results also suggest that negative feedback from the proliferative state suppresses thymocyte differentiation. Overall, this multidisciplinary work reveals the critical role of TEC-thymocyte interactions in both the initiation and progression of T-ALL, highlighting the importance of the thymic microenvironment in early leukemogenesis.
Marker-independent imaging reveals a correlation of fibrotic and epigenetic alterations in endometriosis
2025-07-16

Abstract Introduction Endometriosis describes the presence of endometrial glands outside of the uterus and can cause various symptoms such as chronic pelvic pain, hypermenorrhea and infertility. These complications pose an extreme burden on the patients, especially as up to date, the average time until diagnosis can consume several years and requires invasive laparoscopy. Objectives The aim of this study is to molecularly characterize endometrium and endometriosis using marker-independent Raman microspectroscopy to identify potential biomarkers and validate its diagnostic potential. Methods After histopathological characterization of tissue sections of human endometrium and endometriosis, Raman microspectroscopy was performed on the gland region. Multivariate analysis of the hyperspectral maps was used to localize major subcellular structures and further decipher their molecular composition. Samples from different anatomical regions and throughout all menstrual cycle phases were analyzed. Results Raman imaging enabled label-free visualization of tissue morphology and submolecular tissue characterization. Distinct differences between endometrium and endometriosis were found for collagen type I and nuclear signatures. Spectral deconvolution allowed identification of a Raman biomarker indicative of fibrotic changes in endometriosis samples. Additionally, a significant increase in epigenetic 5mC foci and an increased signal intensity relevant for methylations was detected in nuclei of endometriosis. Furthermore, a neural network-based classification of Raman data resulted in high accuracies in discriminating endometrial and peritoneal tissue from endometriosis. Conclusion The non-destructive approach by hyperspectral Raman imaging enabled for molecular sensitive characterization of endometriotic lesions which could not only be an asset in complementing histopathological tissue evaluation but combined with data-driven classification models support in situ tissue diagnosis.
Open Reduction of Paediatric Supracondylar Humerus Fractures has No Negative Impact on Long-term Functional Outcome and Quality of Life Compared to Closed Reduction
2025-07-16

Abstract The aim of the study was to compare closed and open reduction of displaced paediatric supracondylar humerus fractures with regard to long-term functional outcome and quality of life. In this retrospective study, 30 patients were examined with a displaced supracondylar humerus fracture (14 boys and 16 girls with a median age of 7 years [5–12 years]). The right elbow was affected in 8 cases (27%) and the left elbow in 22 cases (73%). According to the Gartland/Wilkins classification, there were 3× type IIA (10%), 8 × type IIB (27%), 18 × type III (60%) fractures (missing data n = 1 [3%]). All fractures were fixed with a crossed K-wire osteosynthesis. In the 1st group (n = 12), the fractures were reduced closed. In the 2nd group (n = 18), an open reduction was performed. The Quick Disabilities of the Arm, Shoulder and Hand Score (Quick-DASH) and the Paediatric Quality of Life Score (PedsQL) were recorded as outcome parameters after a mean follow-up of 53 months. The two groups were compared in terms of patient- and treatment-related factors and outcome parameters. The proportion of right elbow fractures was significantly higher in group 1 than in group 2 (50% vs. 11%). In group 2, the proportion of more severely displaced fractures was significantly higher than in group 1 (Gartland/Wilkins type III: 98% vs. 17%) and the median operating time was significantly longer (93 min vs. 26 min). There were no significant differences between the two groups in the Quick-DASH (0 [0–39] vs. 0 [0–11], p = 0.219), in the additional module “Sports and Music” of the Quick-DASH (0 [0–37.5], missing data n = 2, vs. 0 [0–50], p = 0.284) and in the PedsQL (95 [63–100] vs. 96 [86–100], p = 0.328). Open reduction of displaced paediatric supracondylar humerus fractures does not lead to a reduction in long-term functional outcome and quality of life compared to closed reduction.
Predicting Developmental Norms from Baseline Cortical Thickness in Longitudinal Studies
2025-07-16

Abstract Normative models have gained popularity in computational psychiatry for studying individual-level differences relative to population norms in biological data such as brain imaging, where measures like cortical thickness are typically predicted from variables such as age and sex. Nearly all published models to date are based on cross-sectional data, limiting their ability to predict longitudinal change. Here, we used longitudinal brain data from the Adolescent Brain Cognitive Development (ABCD) study, comprising cortical thickness measures from 180 regions per hemisphere in youths at baseline (N=6179; 47% females), 2-year (N=6179; 47% females), and 4-year (N=805; 45% females) follow-up. A training set was established from baseline and 2-year follow-up data (N=5374; 47% females), while data from individuals with all three time points available served as an independent test set (N=805; 45% females). We developed sex-specific Baseline-Integrated Norms (B-Norms) that predict brain region thickness at follow-up based on baseline thickness, baseline age, and follow-up age, and compared them to sex-specific standard Cross-Sectional Norms (C-Norms) based on age alone. Out-of-sample testing in 2-year and 4-year follow-up data showed that B-Norms consistently provided better fits than C-Norms for nearly all cortical regions. Explained variance was higher in B-Norms than in C-Norms. We found no significant differences between time points (p = 0.45). Repeated measures ANOVA revealed differences in higher-order moments (e.g., skewness and kurtosis) for both models; for example, skewness varied by model, sex, time point, and their interactions. While improved fit alone does not necessarily indicate a superior normative model - since normative models aim to capture population variance rather than simply optimize fit - we demonstrated that four regions were associated with pubertal changes in B-Norms but not in C-Norms, suggesting enhanced sensitivity of B-Norms to developmental processes. Together, our findings highlight the potential of B-Norms for capturing normative variation in longitudinal structural brain change.
PhyloFusion—Fast and Easy Fusion of Rooted Phylogenetic Trees into Rooted Phylogenetic Networks
2025-07-17

Abstract Unrooted phylogenetic networks are commonly used to represent evolutionary data in the presence of incompatibilities. Although rooted phylogenetic networks offer a more explicit framework for depicting evolutionary histories involving reticulate events, they are reported less frequently, probably due to a lack of tools that are as easily applicable as those for unrooted networks. Here, we introduce PhyloFusion, a fast and user-friendly method for constructing rooted phylogenetic networks from sets of rooted phylogenetic trees. The resulting networks have the tree-child property. The algorithm accommodates trees with unresolved nodes—often resulting from the contraction of low-support edges—as well as some degree of missing taxa. We demonstrate its application to the analysis of functionally related gene groups and show that it can efficiently handle data sets comprising tens of trees or hundreds of taxa. An open source implementation of PhyloFusion is available as part of the SplitsTree app: https://www.github.com/husonlab/splitstree6. All data available here: https://doi.org/10.5061/dryad.k3j9kd5h5
New insights from the application of ZooMS to Late Pleistocene fauna from Grotta di Castelcivita, southern Italy
2025-07-17

Abstract The Middle to Upper Paleolithic cave site of Grotta di Castelcivita (Campania, Southern Italy) contains a key archaeological sequence exhibiting Late Mousterian occupation followed by the Uluzzian techno-complex and an Aurignacian sequence (Protoaurignacian and Early Aurignacian). Abundant faunal remains are found throughout the sequence with variations in taxa present in each period. Previous studies of the morphologically identifiable faunal remains have provided valuable information on species abundance and diversity to reconstruct subsistence behaviour. However, like in many Pleistocene sequences, much of the faunal assemblage is fragmented and unidentifiable. Here we focus on these unidentified fragmentary bones to add greater dimension to the observed patterns. The application of collagen peptide mass fingerprinting (or Zooarchaeology by Mass Spectrometry; ZooMS) on 1263 unidentified bones revealed distinct changes in ZooMS NISP values in the Uluzzian and Protoaurignacian periods where equids and bovids nearly doubled in quantity compared to the original morphologically identified macrofaunal assemblage. New ZooMS identifications of rhinoceros, bear, and canids were made in layers deeper than previous recorded zooarchaeological analyses, extending the presence of these taxa at the site. The unexpectedly high level of collagen preservation in the bones from the cave confirms the potential for further applications of biomolecular approaches to Pleistocene bones from southern Italy.
Online cognitive stimulation intervention (CSI): A novel approach to improve cognitive functions in healthy older adults.
2025-07-17

Cognitive interventions demonstrate promising evidence for minimizing cognitive decline in older adults yet are often criticized for their lack of ecological validity. We designed a real-life intervention using mobile-based shopping applications over 22 weeks and examined its effects on cognitive function. We recruited 102 healthy Malaysian older adults (<i>M</i><sub>age</sub> = 66.18, <i>SD</i> = 4.95) who were randomly assigned to three conditions: experimental, active control, and passive control. The first two groups had weekly sessions but not the latter. The experimental group completed tasks designed to assess inhibition and working memory-updating using online shopping applications (trained applications) with varying difficulty levels, whereas active control participants freely interacted with the same applications without any training instructions. All groups completed assessment sessions in the baseline, posttest, and a 1-month follow-up, including noncomputerized versions of Stroop, Digit Span, and the Paced Auditory Serial Addition Test, and an untrained application (Tripadvisor) measuring inhibition and working memory-updating. Data were analyzed using Bayesian analysis of variance and multivariate multiple regression. Results showed that the experimental group performed better in the Paced Auditory Serial Addition Test-3 s compared to the passive control, suggesting training gains in working memory-updating. The experimental group performed better in inhibition and working memory-updating in the untrained application compared to both control groups, indicating a near transfer effect. In summary, our findings provide evidence that cognitive stimulation by tasks using online shopping activities on mobile phones is beneficial for older adults' cognitive function. (PsycInfo Database Record (c) 2025 APA, all rights reserved).