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464 papers

Pre-TIPS Liver and Spleen Volumetry Are Not Associated With Liver-Related Outcomes After TIPS Placement for Refractory Ascites.

Bedoya JU et al. · Jul 1, 2026

Background & aims Transjugular intrahepatic portosystemic shunt (TIPS) improves survival in refractory ascites. A careful patient's selection is mandatory as TIPS can lead to complications. Liver volumetry is predictive of outcomes before hepatic surgery, but data on its role before TIPS placement are scarce. We aimed to evaluate whether liver and spleen volume measurements are associated with prognosis after TIPS placement in patients with ascites. Methods We analysed data from three French centers, treated with TIPS between 2017 and February 2022. Inclusion criteria encompassed a TIPS placement for refractory or recurrent ascites and availability of cross-sectional imaging. Exclusion criteria included non-cirrhotic portal hypertension, other indications for TIPS, hepatocellular carcinoma beyond Milan criteria, and extrahepatic malignancy. Liver and spleen volumes were measured using pre-TIPS CT or MRI scans. The primary endpoint was 1-year transplant-free survival (TFS). Secondary endpoints were overt hepatic encephalopathy (HE), recurrence of ascites, acute variceal bleeding, and jaundice. Results The 160 patients were included (median age 60 years, male gender 83.8%, alcohol-related cirrhosis 58.8%, with active alcohol consumption in 25.6%, Child-Pugh B cirrhosis in 81.2%, median MELD score was 12). The 1-year TFS was 60.1%. Multivariate analysis identified serum creatinine (HR = 1.01 95% CI [1.00-1.01], p = 0.04), total bilirubin (HR = 1.02 95% CI [1.02-1.04], p = 0.004), and portal pressure gradient (HR = 1.09 95% CI [1.01-1.18], p = 0.03) as independent factors associated with TFS. Neither liver-to-spleen volume ratios (LSVR) (p = 0.36) nor liver volume index (p = 0.92) were significantly associated with death or LT. Overall, 38.1% of patients developed overt HE after TIPS, with lower platelet count (HR = 1.01 95% CI [1.00-1.01], p = 0.04) emerging as an independent predictor. No radiological characteristics were associated with the recurrence of ascites. Conclusions In this multicenter study, liver and spleen volumes were not associated with transplant-free survival or liver-related outcomes in patients undergoing TIPS for ascites. These findings suggest that liver volumetry should not be a determining factor in patient selection for TIPS placement.

Medicine

Validation of a Pregnancy-Associated Glycoprotein-Based Lateral Flow Assay for Early Pregnancy Detection in Goats.

Kara MC et al. · Jul 1, 2026

Background The significant cross-reactivity between bovine, ovine, and caprine pregnancy-associated glycoproteins (PAGs) enables the adaptation of bovine-specific diagnostics for use in other ruminants; consequently, the Alertys OnFarm Pregnancy Test (AOFPT)-a blood-based lateral flow assay-provides a rapid and practical solution for pregnancy detection directly at the animal's head under field conditions. Objectives This study evaluated to assess and validate the performance of AOFPT in goats at days 21 and 28 post-mating, by comparing the results with serum progesterone (P4) analysis and using transabdominal ultrasonography (TAUS) as the gold standard. Methods The study involved 85 Kilis goats, five months post-partum. Estrus was synchronized using an 11-day progestagen device, d-cloprostenol, and PMSG. Whole blood and serum samples were collected on Days 21 and 28 post-mating. AOFPT was performed on-farm immediately after collection. For validation, serum progesterone concentrations were measured via electrochemiluminescence immunoassay, and TAUS was performed on Days 35 and 42, with Day 42 findings serving as the gold standard. Results Results indicated that on Day 21, AOFPT sensitivity, specificity, positive predictive value, and negative predictive value were 79.4%, 93.8%, 98.2%, and 51.7%, respectively. By Day 28, these metrics reached 100%, 81.3%, 95.8%, and 100%. Statistical agreement between AOFPT and the reference method was K = 0.55 (82.14%) on Day 21 and K = 0.87 (96.43%) on Day 28 (p Conclusions AOFPT demonstrated accuracy and reliability closely matching P4 measurements and the reference method. This test provides a practical tool for early on-farm pregnancy diagnosis in goats, potentially enhancing reproductive management and productivity in dairy goat farms and large herds.

Agricultural and Biological Sciences

Circadian-Related Serotonin/Melatonin Level Modulates Cisplatin Ototoxicity Susceptibility Depended on NOS3-NO Pathway.

Qiu S et al. · Jul 1, 2026

Hearing impairment is attributed to factors such as age, genetic predisposition, and environmental influences, among which environmental factors are considered modifiable. Among various environmental factors, the role of poor lifestyle habits is particularly critical, yet the specific mechanisms by which they contribute to hearing damage remain unclear. This study reveals that dysregulated hormone levels due to disrupted light exposure may significantly increase susceptibility to sensorineural hearing loss. In mice, circadian rhythm disruption was found to reduce melatonin and elevate serotonin levels in the inner ear, thereby increasing vulnerability to cisplatin-induced ototoxicity. In both in vivo and in vitro cisplatin-treatment models, we showed that combined treatment with melatonin protected hearing, reduced inner ear cell death, and preserved synaptic connections, whereas serotonin co-administration exacerbated the damage. Using small molecule-protein interaction prediction, we identified NOS3 as a potential target of both melatonin and serotonin, through which they appear to regulate the NO signaling pathway and influence hair cell ferroptosis. Finally, exogenous supplementation of NOS3 in cochlear tissues effectively mitigated cisplatin-induced hair cell damage, even under conditions of circadian rhythm disruption. These findings indicate that the melatonin/serotonin balance modulates susceptibility to sensorineural hearing loss via the NOS3-NO signaling pathway.

Neuroscience

Post-TIPS Dynamics of von Willebrand Factor for Risk Stratification After TIPS Placement.

Hintersteininger M et al. · Jul 1, 2026

Background & aims Transjugular intrahepatic portosystemic shunt (TIPS) placement is used to treat complications of portal hypertension. This study aimed to evaluate the prognostic value of von Willebrand factor antigen (VWF) dynamics following TIPS placement. Methods Patients with TIPS placement at the Medical University of Vienna (2018-2025) and University Medical Center Mainz (2022-2025) with available VWF at baseline (BL) were included. Patients from both cohorts with available VWF after 3 months (M3) were included in the combined longitudinal cohort (CLC). Meaningful VWF decrease (VWF-Response) was defined as a relative VWF change (ΔVWF) of at least -5% at M3. Patients were stratified by presence of VWF-Response and interleukin-6 decrease (IL6-Response) into three groups: both (R2), either/or (R1), and neither (R0). Results Overall, 113 and 86 patients were included in the Vienna and Mainz cohorts, respectively. BL VWF was not associated with mortality in both cohorts. 118 patients constituted the CLC, which showed median BL VWF of 313.0% that decreased to 262.0% at M3 (p = 0.007). Fifty-three patients (44.9%) achieved VWF-Response. Both, VWF change (ΔVWF; asHR: 2.75; 95% CI: 1.07-7.11; p = 0.037) and VWF-Response (asHR: 0.24; 95% CI: 0.09-0.61; p = 0.003) were independently associated with survival. According to VWF and IL6 responses, patients were stratified as low-risk (R2), versus intermediate-risk (R1) versus high-risk (R0) with a cumulative incidence of death at 2 years of follow-up of R2: 10.6% versus R1: 23.1% versus R0: 46.7%, respectively. Conclusion After TIPS placement, VWF-Response identifies patients with a favourable prognosis and can be combined with IL6-Response for risk stratification regarding mortality.

Medicine

Plasma Aryl Hydrocarbon Receptor Agonist Activity Is Associated With Inflammation and Metabolic Dysregulation in Obesity: A Cross-Sectional Study.

Bahman F et al. · Jul 1, 2026

Background The aryl hydrocarbon receptor (AhR) is linked to inflammation, but its plasma agonist activity and association with metabolic and inflammatory markers in obesity remain unclear. This cross-sectional study aimed to determine the level of plasma AhR agonistic activity and its association with systemic inflammation and metabolic dysregulation in obesity. Methods Plasma samples were collected from 80 non-diabetic (39-obese, 23-overweight, and 18-normal/healthy weight) individuals. AhR agonist activity was assessed using a cell-based luciferase reporter assay. Plasma AhR was quantified by ELISA. Inflammatory markers were assessed using a multiplex Luminex platform. Results Our findings indicate that plasma AhR agonist activity is elevated in obese (92.77 ± 4.002 fold activation) compared with normal/healthy weight (51.39 ± 2.335) and overweight participants (67.54 ± 5.24 fold activation). Moreover, the AhR protein was also elevated in obese (94.88 ± 7.62 pg/ml) compared to normal/healthy weight (65.88 ± 6.78 pg/ml) and overweight participants (67.54 ± 5.24 pg/ml), which was positively correlated with AhR activity (r = 0.441, p Conclusions Our findings demonstrate that elevated plasma AhR agonist activity is associated with obesity, systemic inflammation, and metabolic dysregulation. These results highlight AhR activity as a biomarker of interest and support further studies to clarify its mechanistic role and potential clinical relevance in metabolic disorders.

Environmental Science

Clustering Properties of Neuronal Ryanodine Receptor 2 and Remodeling in the APP/PS1 Mouse Model of Alzheimer's Disease.

Munro ML et al. · Jul 1, 2026

Aim The ryanodine receptor (RyR2) is an intracellular Ca 2+ release channel which mediates numerous cellular functions across different tissues. Dysregulation of RyR2 channel activity leads to pathological Ca 2+ release, which often underlies disrupted cellular signaling in disease states. In the heart, RyR2 channels forms discrete clusters and calcium release units (CRUs) which control channel activity. These structures demonstrate nanoscale remodeling in disease states associated with pathological Ca 2+ release activity in the heart. Hence, these nanoscale structures are critical in regulating Ca 2+ release in health and disease. RyR2 is also expressed in brain; however, whether analogous clusters and CRUs form in neurons remains unexplored. Methods Using super-resolution imaging, we assessed RyR2 organization in CA1 pyramidal neurons of wild-type mice. Furthermore, we used the APP/PS1 mouse model of Alzheimer's disease (AD) to assess whether there is nanoscale remodeling of RyR2 in a setting associated with pathological Ca 2+ release in neurons. Results Here, we provide the first identification and detailed characterization of RyR2 clusters in central nervous system neurons, which are comparable to those reported in the heart. Moreover, we observed a decrease in RyR2 cluster size and reduced CRU organization in AD mice at an age associated with high plaque burden and cognitive deficits. This remodeling is analogous to that reported in pathological states in the heart. Conclusion Together, these findings implicate the nanoscale remodeling of RyR2 clusters and CRUs as a novel mechanism underlying Ca 2+ channel dysregulation and neuronal dysfunction in AD.

Biochemistry, Genetics and Molecular Biology

Clinicopathological and molecular characterization of HPV-associated cervical poorly cohesive carcinoma: a rare aggressive entity.

Liu W et al. · Jul 1, 2026

Primary signet-ring cell carcinoma and poorly differentiated adenocarcinoma with poorly cohesive morphology in the cervix are rare conditions, and their clinicopathological features remain poorly described. This study defines primary cervical poorly differentiated adenocarcinomas meeting the diagnostic criteria for poorly cohesive carcinoma as outlined in the 2019 WHO Classification of Digestive System Tumors as 'HPV-associated cervical poorly cohesive carcinomas' (HPV-associated CPCC) and describe their clinicopathological and molecular features. Sixteen HPV-associated CPCC cases were analyzed and classified into three histological subtypes: signet-ring cell carcinoma (n = 4), not otherwise specified (n = 6), and mixed types (n = 6). All patients were Chinese (median age: 46 years; range: 30-66). Vaginal bleeding was the primary presenting symptom (100.0%). High-risk human papillomavirus (HPV) was identified in all tumors, with HPV-18 as the predominant genotype (n = 13), HPV-16 in two cases, and a single case exhibiting concurrent infection with HPV-16, -18, and -58. Overall, 56.3% presented with advanced-stage disease (International Federation of Gynecology and Obstetrics [FIGO] IIIB-IVB), frequently involving regional lymph nodes (56.3%) and distant sites (18.8%). Histopathological examination revealed diffuse stromal infiltration (100%), lymphovascular invasion (75.0%), necrosis (75.0%), and desmoplasia. Immunohistochemically, all cases showed p16 block positivity. Variable expression of antibody-drug conjugate targets was observed, with HER2-low expression (33.3%), and positive staining for Trop-2 (85.7%), nectin-4 (42.9%), and tissue factor (92.3%). During follow-up, disease-specific mortality was 50.0%. The 3-year overall survival rate was 56.3%, which was significantly lower in advanced-stage disease (45.0%) than in early-stage disease (75.0%). Whole-exome sequencing revealed low tumor mutational burden (median 1.28 Muts/Mb), recurrent mutations in AK1, ARHGAP39, KRT24, MICAL3, SLC6A9 (27.3%), KRAS, and KMT2C (18.2%), alongside MUC2 copy gain (63.6%) and bidirectional Y_RNA alterations (gain 54.5%/loss 45.5%). Collectively, HPV-associated CPCC represents a distinct and aggressive subtype characterized by distinctive histopathological features, a predominant association with HPV18, frequent presentation at advanced stages, and marked molecular and biomarker heterogeneity.

Medicine

A Ten-Country Study on Public Perceptions of 5G EMF Emissions: Who Feels Exposed, and Why?

Link SC et al. · Jul 1, 2026

Formal risk assessment considers characteristics such as proximity, dose, and vulnerability. However, public risk perception may also be influenced by other-possibly less relevant-factors such as visibility and novelty. The introduction of 5G and its associated infrastructure and radiofrequency electromagnetic fields (RF-EMF) may therefore change perceptions of RF-EMF from mobile communications in general. To explore this, we conducted an online survey in 10 European countries (n = 10,358) using a picture-based approach. Respondents perceived daily RF-EMF exposures as moderate but expected them to increase with 5G. A mobile phone at the ear was generally associated with higher perceived exposure than multiple base stations. Overall, distance to the RF-EMF source most strongly influenced perceived exposure, followed by the number of sources. 5G reception was linked to higher exposure perception than 4G or Wi-Fi reception. These patterns were consistent across most countries. We conclude that when assessing RF-EMF exposure, people rely on heuristics (e.g., more sources imply more exposure) that often guide them correctly. Understanding when and why people feel particularly exposed can help develop more effective communication about true levels of exposure and risk.

Biochemistry, Genetics and Molecular Biology

Diacylglycerol enantiomer selectivity of diacylglycerol acyltransferases highlights metabolic specialization in triacylglycerol synthesis across the tree of life.

Parchuri P et al. · Jul 1, 2026

Triacylglycerols are the major energy storage lipids in plants, animals, and microorganisms, and are predominantly produced by acyl-CoA:diacylglycerol (DAG) acyltransferases (DGATs). Two enantiomers of the DAG substrate, sn-1,2 and sn-2,3, can be produced by different biological mechanisms; however, little is known about which species produce each enantiomer, the selectivity of DGAT isoforms for either enantiomer, or whether DGAT enantiomer selectivity varies across organisms. Here, DAG enantiomer selectivity of DGAT1 and DGAT2 was measured from eight seed plants, two mammals, one oleaginous yeast, and one photosynthetic microalga using enantiomer-specific in vitro DGAT assays. Across most plants, DGAT1 favored sn-1,2-DAG, whereas DGAT2 preferentially utilized sn-2,3-DAG. However, there were several exceptions. Mammalian DGAT1, DGAT2, and microbial DGAT1s efficiently used both DAG enantiomers, while microbial DGAT2s had unique selectivity. The selectivity of several DGATs for combined acyl-CoA and DAG enantiomer molecular species were also evaluated for biotechnical applications. Therefore, DGAT DAG enantiomer selectivity is common yet strongly dependent on lineage and isoform and likely shaped in part by species-specific metabolic context of triacylglycerol synthesis, turnover, and remodeling. This work expands our understanding of DGAT function and establishes a foundation for leveraging enantiomer-selective acyltransferases in metabolic engineering of tailored lipid products.

Biochemistry, Genetics and Molecular Biology

Formulation of Peptide-Based Nanoparticles Using a Microfluidic Device.

Hammoum T et al. · Jul 1, 2026

Peptide-based nanoparticles (PBN) have emerged as a promising alternative to lipid nanoparticles (LNP) for nucleic acid delivery and efficient cellular uptake. In this study, we evaluated the formulation of WRAP5 (W- and R-rich amphipathic peptide 5)-based PBN using a microfluidic device and assessed the impact of key process parameters, flow rate ratio (FRR), total flow rate (TFR), and mixing channel design, on nanoparticle characteristics. Across 72 formulations encapsulating small interfering RNA (siRNA) or plasmid DNA (pDNA), dynamic light scattering revealed consistent mean sizes ranging from 50 to 70 nm, with a low polydispersity index (PdI < 0.22), independent of FRR, TFR, or mixer type. Stability studies demonstrated that siRNA-loaded PBN exhibited moderate size increases during storage at 4°C, whereas pDNA-loaded PBN remained highly stable for up to 70 days. Biological assays confirmed robust activity: WRAP5:siRNA PBN achieved approximately 50% CDK4 silencing in GIST-T1 cells, and WRAP5:pDNA PBN mediated efficient mCHERRY expression in HeLa cells, regardless of formulation method or storage duration. These findings highlight the robustness and scalability of WRAP5-based PBN, contrasting with LNP systems that require stringent control of FRR and TFR, and partially underscore their potential for nucleic acid delivery applications.

Biochemistry, Genetics and Molecular Biology