Browse Articles

Loss of ICOSL expression in the progression to cervical carcinoma

Human papillomavirus (HPV)–related lesions contain types with benign outcomes and those with a risk of progression to cancer. We addressed the role of immune surveillance in 76 cervical biopsies (normal = 23, HPV+ benign = 16, HPV+ precancer = 37) by studying the infiltration of cytotoxic T cells and the expression of the immune modulators PDL1, ICOSL, and miR-155 and compared the data to 101 cervical squamous cell carcinomas. In the normal cervix, ICOSL expression was restricted to the endocervical epithelia whereas neither miR-155 nor PDL1 were detected. MiR-155 was up-regulated in both the benign (88%) and precancerous (92%) HPV squamous intraepithelial lesions (SIL) and colocalized to cells in the upper part of the lesion that is the area with productive viral infection. Both PDL1 (95%) and ICOSL (89%) were only evident in the precancerous SIL and each localized to squamous cells in the basal aspect that lacked replicating virus. In both microinvasive and invasive cervical squamous cell cancer miR-155 expression remained high (83%) as did PDL1 expression (80%) but ICOSL detection was reduced to 17%. Infiltration by CD8+ T cells was intense in the invasive lesions and these cells were mostly inactive as determined by the lack of granzyme B colocalization. It is concluded that miR-155 expression is a marker of HPV infection in both benign and precancerous lesions, whereas the approximately 10% of the latter lesions that progress to cancer gain PDL1 and lose ICOSL expression, which are important factors in avoiding immune surveillance.

A potential age-independent MASLD-related liver fibrosis index based on metabolic profiling

Integrated comparative analysis of T-staging of laryngeal carcinoma on parallel versus non-parallel vocal cord CT planes with its potential treatment pitfalls

Accurate CT staging plays a crucial role in guiding effective management of laryngeal carcinoma, as endoscopic assessment alone may not provide a comprehensive evaluation of tumor spread. Consequences of non-compliance to parallel vocal cord plane for tumors remained unexplored in existing literature. We aimed to compare T-staging parameters of laryngeal carcinoma on CT neck in non-parallel and parallel to vocal cord axial planes and analyse degree of discrepancy between them. We retrospectively studied 34 larynges with squamous cell carcinoma on non-parallel plane① and parallel to vocal cord plane② axial CT scan. Quantitative (anteroposterior AP, transverse Tr, anterior commissure ACom) and qualitative (site, intralaryngeal and extralaryngeal extension) T-staging variables were interpreted in both planes and differences between them were registered. Kappa analysis was employed to get level of disagreement between tumor reporting of each plane. There was minimal to worse agreement between T-staging in these planes (k = −0.059 to 0.353). Difference between means of ACom was significant, but not AP and Tr dimensions. Categorical variables in plane② showed majority of glottic origin (70.5%) and T1a (38.2%) stage, while plane① had subglottic (52.9%) and T2 (41.1%). Overall plane① showed 41.1% altered staging (mostly T1,T2), out of which 71.2% were upstaged. Rest unaffected larynges (28.8%, n = 20) showed either change in origin (41.2%) or ACom involvement (58.8%). Consequently, 73.5% (n = 25) patients in plane ① manifested at least one change, so can jeopardise targeted management. Results established that non-adherence to reporting on parallel CT larynx can result in significant variability in principal qualitative and quantitative T-stage tumor parameters, hence imperiling patients to over or undertreatment.

CryoEM structure of ALK2:BMP6 reveals distinct mechanism that allow ALK2 to interact with both BMP and activin ligands

Ligands in the transforming growth factor β (TGF-β) family [activins, Bone Morphogenetic Proteins (BMPs), and TGF-βs] signal by bringing together two type I and two type II receptors. Activin receptor-like kinase-2 (ALK2) is the only type I receptor among the seven TGF-β type I receptors that interacts with both activin and BMP ligands. With BMPs, ALK2 acts as a signaling receptor to activate small mothers against decapentaplegic 1 (SMAD1)/5/8 signaling. Alternatively, with activins, such as Activin A (ActA), ALK2 forms nonsignaling complexes that negatively regulate ALK2 and ActA signaling. To gain insight into how ALK2 interacts with two distinct classes of ligands, we resolved the cryoelectron microscopy structure of ALK2 in complex with the type II receptor, ActRIIB, and the ligand, BMP6, in parallel with the corresponding structure with ALK3 for direct comparison. These structures demonstrate that ALK2 and ALK3 utilize different mechanisms to interact with BMP6 at the wrist interface, with ALK2 relying on BMP6 glycosylation and ALK3 relying on a salt bridge. Modeling of ALK2:ActA reveals that binding relies on ActA’s fingertip region, mirroring the interaction of ActA with its other receptor, ALK4. Our results demonstrate that ALK2 is a “hybrid” receptor that incorporates features of BMP type I receptors such as ALK3 at the wrist interface and an activin type I receptor such as ALK4 at the fingertip.

Evaluating the ability of large Language models to predict human social decisions

Mechanism of Huanglian Wendan Decoction in ameliorating non-alcoholic fatty liver disease via modulating gut microbiota-mediated metabolic reprogramming and activating the LKB1/AMPK pathway

Background Huanglian Wendan Decoction (HLWDD), a classical traditional Chinese medicine (TCM) formula, has shown therapeutic promise in treating metabolic disorders. However, its underlying mechanisms against non-alcoholic fatty liver disease (NAFLD) remain unclear. Objective This study aimed to elucidate the pharmacological mechanisms by which HLWDD ameliorates NAFLD, focusing on its impact on lipid metabolism, gut microbiota, and amino acid regulation. Methods A NAFLD rat model was established by administering a high-sugar, high-fat, high-salt diet for 20 weeks. The core components of HLWDD were identified and quantified using UPLC-Q-TOF-MS/MS and HPLC, and further validated via network pharmacology and molecular docking. Therapeutic efficacy was assessed through analysis of body weight, serum lipid profiles, inflammatory cytokines, hepatic histology, and protein expression. Gut microbiota composition and liver-intestine metabolite profiles were evaluated using metagenomic sequencing and LC-MS/MS. Results Seven key constituents, including quercetin and berberine, were quantified (15.11–164.37 μg/mL) and shown to interact with lipid metabolism targets such as liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor alpha (PPARα), and carnitine palmitoyltransferase 1A (CPT1A). HLWDD treatment significantly reduced body weight, hepatic lipid accumulation, and serum levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol. Proinflammatory cytokines (IL-6, IL-1β, TNF-α) were notably suppressed. Mechanistically, HLWDD activated the LKB1/AMPK signaling pathway and modulated aspartic acid metabolism in association with increased abundance of Akkermansia in the gut. Metabolomic analysis identified 13 differential metabolites, with aspartic acid showing strong correlations with Akkermansia and LKB1/AMPK activity. Conclusion HLWDD exerts its anti-NAFLD effects by enhancing Akkermansia-mediated aspartate metabolism, thereby activating the LKB1/AMPK axis and promoting lipid oxidation via CPT1A and PPARα. This study provides new mechanistic insight into the gut–liver axis in NAFLD and highlights HLWDD as a multi-targeted therapeutic approach for restoring metabolic balance.

Cohort mortality forecasts indicate signs of deceleration in life expectancy gains

The fast-paced improvements in mortality in high-income countries since the early 1900s have led to a sustained increase in life expectancy. However, whether this linear trend will continue or life expectancy gains will decelerate in the near future remains unclear. To answer this question, we apply multiple established and recently developed mortality forecasting methods to estimate cohort life expectancy for individuals born between 1939 and 2000 in 23 high-income countries. Across all forecasting methods, our results robustly and consistently indicate a deceleration in cohort life expectancy. The previously observed pace of improvement, 0.46 y per cohort, declines by 37% to 52%, depending on the method used. Robustness checks suggest that these findings are unlikely to be solely due to downward bias in cohort life expectancy forecasts. Furthermore, an age-decomposition analysis indicates that this deceleration is primarily driven by a slower pace of mortality improvement at very young ages. Over half of the total deceleration is attributable to mortality trends under age 5, while more than two-thirds is explained by mortality trends under age 20. This pattern had already emerged in the observed data for the cohorts included in our analysis. Thus, even if these estimates turned out to be overly pessimistic, it is unlikely that the deceleration will reverse in the near future.

Perceived risk of cardiovascular diseases and its determinants in Hookah users in Southwest of Iran

Efficacy of Pulsatilla saponin B4 for treatment dairy cows affected with clinical mastitis

In order to explore the therapeutic effect of natural compound Pulsatilla saponin B4 (PSB4) on clinical mastitis (CM) in dairy cows, 40 dairy cows with CM and 20 healthy dairy cows were selected as experimental samples in a large dairy farm. The CM cows were randomly divided into two groups (20 cows in each group), namely the PSB4 group treated with PSB4 neck intramuscular injection and the positive drug (PC) group treated with ceftiofur sodium neck intramuscular injection as a positive control. Another 20 healthy dairy cows were neck intramuscular injected with the same amount of normal saline to serve as a normal control (NC) group. The treatment duration was 7 days. The body temperature and milk yield of all cows were recorded on days 0, 4 and 7, while blood and milk samples were collected for the determination of relevant laboratory indicators, including somatic cell count (SCC), pathogenic microorganisms, immune factors, cytokines, antioxidant indexes, hematological and biochemical indexes. The results showed that PSB4 effectively restored the body temperature of diseased cattle, reduced SCC, significantly increased milk yield, effectively inhibited pathogenic bacteria, and significantly restored the levels of serum C-reactive protein (CRP), interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α); immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM); total antioxidant capacity (T-AOC), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and other indicators. In addition, some indicators of blood routine and blood biochemistry also returned to normal levels. In summary, PSB4 has a significant therapeutic effect on CM in dairy cows, and has a similar effect to the positive drug, which can provide a new strategy for reducing the use of antibiotics in dairy cattle farms.

Community detection for directed networks revisited using bimodularity

Community structure is a key feature omnipresent in real-world network data. Plethora of methods have been proposed to reveal subsets of densely interconnected nodes using criteria such as the modularity index. These approaches have been successful for undirected graphs but directed edge information has not yet been dealt with in a satisfactory way. Here, we revisit the concept of directed communities as a mapping between sending and receiving communities. This translates into a definition that we term bimodularity. Using convex relaxation, bimodularity can be optimized with the singular value decomposition of the directed modularity matrix. Subsequently, we propose an edge-based clustering approach to reveal the directed communities including their mappings. The feasibility of the framework is illustrated on a synthetic model and further applied to the neuronal wiring diagram of the Caenorhabditis elegans , for which it yields meaningful feedforward loops of the head and body motion systems. This framework sets the ground for the understanding and detection of community structures in directed networks.

Correction: Variations in wetland soil labile organic carbon fractions and microbial characteristics along urban–rural gradients in Shenyang city

The relationship between artistic skills and academic engagement among artistically gifted non-specialist university students

Background This study aimed to investigate the level of artistic skills and academic engagement among artistically gifted non-specialist students at Prince Sattam bin Abdulaziz University, Saudi Arabia. It also attempted to identify the relationship between students’ artistic skills and academic engagement. The study followed a mixed methods design where both quantitative and qualitative data was collected and analyzed. The participating students (102 students enrolled in the university’s Gifted Care Unit) completed an author-developed questionnaire probing their artistic skills (cognitive, performance, and emotional) and academic engagement (vigor, dedication, and absorption). In addition to its 30 Likert scale items, the questionnaire had an open-ended question about ways to promote artistic skills from the perspective of the students. Furthermore, the author electronically interviewed 14 members of the Gifted Care Unit and got them to respond to the same open-ended question in the students’ questionnaire, i.e., what are your suggestions for promoting students’ artistic skills. The quantitative data analysis via descriptive statistics revealed that the students had high artistic skills and academic engagement. Pearson correlations revealed a significant positive relationship between artistic skills and academic engagement. Standard regression analysis produced a significant model where artistic skills explained 11% of variance in students’ academic engagement. Of the individual dimensions of artistic skills, only performance skills explained 13% of students’ academic engagement. The analysis of students’ and members’ responses to the open-ended question revealed some shared themes, e.g., the students’ need for more specialized training, contact with professional experiences, support from significant others, and creativity-stimulating competitiveness.. A number of implications are offered. Conclusion The important finding in this study is that ASs, especially performance skills, contribute to students’ AE. This makes it important for specialized entities like the Gifted Care Unit to exert more efforts to identify artistically gifted students in all university programs. These efforts can identify students who are aware of their artistic skills and students who have artistic skills but are unaware of them. The art culture should be spread all over the university to attract more students to join the Gifted Care Unit. The artistically gifted students should be provided with specialized training, contact with outside sources of artistic experience, an art-nurturing environment, incentives to be more creative, and support, especially spiritual support.

G-quadruplexes as a source of vulnerability in BRCA2 <i>-</i> deficient granule cell progenitors and medulloblastoma

Biallelic pathogenic variants in the essential DNA repair gene BRCA2 cause Fanconi anemia complementation group D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under Sonic Hedgehog (SHH) activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 Δex3-4 ;Trp53 −/− animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping putative G-quadruplexes (G4s). Brca2 -deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary medulloblastoma tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2-deficient medulloblastomas.

Understanding farmer’s knowledge, attitudes, and practices towards adopting livestock interventions for food and nutrition security in Bangladesh using latent class analysis

Citizen science reveals alarming update on the invasion of the Asian mantleslug Meghimatium pictum in Brazil

The Asian mantleslug Meghimatium pictum is an exotic species introduced to Brazil in the late 1990s, but only formally reported in 2011. Since then, it has been deemed an agricultural pest and given the status of an invasive species; furthermore, it has been confirmed as an intermediate host for the nematode Angiostrongylus costaricensis in Brazil. Despite its potential for impacts, no additional studies on the status of its invasion have been conducted since the initial report. In this study, we used the citizen science platform iNaturalist to analyse the current distribution of M. pictum in Brazil, while also using genetic barcode data to understand the relationships between Brazilian and Asian populations and applying a species distribution model to investigate the suitable range for its distribution in Brazil. Our survey has recovered a total of 520 new records of this species in Brazil, confirming its spread to four additional states since its original report. Currently, M. pictum is recorded in the Distrito Federal and the states of Minas Gerais, Espírito Santo, Rio de Janeiro, São Paulo, Paraná, Santa Catarina, and Rio Grande do Sul. Our phylogenetic analysis suggests a close relationship between M. pictum populations in South America and those from Okinawa, Taiwan, and Guangzhou (mainland China), the latter being the most likely point of origin for the South American populations. Our species distribution model supports the idea that, in Brazil, the species is largely restricted to subtropical areas belonging to the Atlantic Forest ecoregion, while also showing suitable areas where the species has not been recorded yet and might become established in the near future. The implications of these findings are discussed, highlighting the recent surge in records and the usefulness of iNaturalist as a tool to monitor invasive species in the country.

Substantial reductions in black carbon from both fossil fuels and biomass burning during China’s Clean Air Action

Black carbon (BC) aerosols exacerbate air pollution and climate warming, but their climatic impacts and sources are poorly constrained by bottom–up emission inventories (EIs). China’s Clean Air Action (CAA), which was launched in 2013, provides an excellent opportunity for investigating interannual variations in source contributions and validate the accuracy of EIs. Here, we present an 11-y (2008–2018) record of the BC concentration and its source-diagnostic radiocarbon ( 14 C) and stable carbon isotope ( 13 C) signatures at a receptor site in the Pearl River Delta (PRD) region, South China. The results revealed that the implementation of the CAA (2014–2018) led to a 41% reduction in the BC concentration compared with that in the preaction period (2008–2013). There is a large and systemic discrepancy over the whole period in the contribution of biomass burning to BC in South China between predictions from technology-based EIs (4 to 9%) and these source-diagnostic dual-isotopic fingerprints of actual ambient aerosols (21 to 32%). Observational constraints by source-diagnostic δ 13 C/Δ 14 C isotope measurements revealed that the reduction in biomass burning contributed 22% to the decrease in BC associated with the CAA, whereas predictions from EIs assigned a much smaller fraction. These results emphasize the need for observation-based source diagnostics of changing BC emission sources. Detailed source apportionment using independent δ 13 C/Δ 14 C isotope methodology is crucial for refining air pollution control strategies and improving the accuracy of models used for assessing the air quality and climate effects of BC in China and elsewhere.

Optically-driven organic nano-step actuator for reconfigurable photonic circuits

Nonlocal complex short pulse equation in $${\mathcal{P}\mathcal{T}}$$-symmetry like symmetry breaking, breather–grammian interactions and soliton solutions

Rupture risk assessment for AComA aneurysms with morphological, hemodynamic and structural mechanical analysis

Introduction The Anterior Communicating Artery complex (AComA) is one of the most common intracranial aneurysms locations. Accurate rupture risk assessment in patients with cerebral aneurysms is essential for optimizing treatment decisions. Computational fluid dynamics has significantly advanced insight into aneurysmal hemodynamics. Many studies concentrate predominantly on blood flow patterns, frequently neglecting the biomechanical properties of the aneurysm wall. Fluid-structure interaction analysis combines hemodynamic behavior with wall mechanics, potentially facilitating a more thorough evaluation of rupture risk assessment. Methods In this study, we employed advanced techniques to investigate several single and composite parameters to predict the rupture risk of AComA aneurysms in a cohort of 150 patients treated at the Kepler University Hospital in Linz, Austria. For this reason, clinical, morphological, hemodynamic, and structural mechanical parameters were assessed. Results A subsequent workflow analysis, consisting of comparative analysis, collinearity analysis, predictive modeling, composite parameter, performance evaluation, and internal threshold validation, revealed the Gaussian curvature GLN (AUC = 0.91) with a sensitivity of 0.93 and specificity of 0.83 as a best-performing single parameter for aneurysm rupture prediction. Composite parameters like WGD (combination of wall shear stress, Gaussian curvature, and wall displacement) achieved an AUC of 0.89, and WG (combination of wall shear stress and Gaussian curvature) an AUC of 0.88. An internal validation with 25 independent ruptured aneurysms was performed, and the previous results were confirmed with very high sensitivity values of 0.92 for GLN. Conclusion Our findings indicate that the investigated morphological, hemodynamic, and structural, mechanical parameters could provide a potential tool for evaluating rupture risk for AComA aneurysms. The single morphological parameter GLN offers, followed by composite parameters WGD and WG, excellent prediction power for the aneurysm rupture state, as confirmed by internal validation. Further studies are warranted to evaluate the prospective clinical application of these parameters.

Quantum relaxometry for detecting biomolecular interactions with single NV centers

The investigation of biomolecular interactions at the single-molecule level has emerged as a pivotal research area in life science, particularly through optical, mechanical, and electrochemical approaches. Spins existing widely in biological systems offer a unique degree of freedom for detecting such interactions. However, most previous studies have been largely confined to ensemble-level detection in the spin degree. Here, we developed a molecular interaction analysis method approaching single-molecule level based on relaxometry using the quantum sensor, nitrogen-vacancy (NV) center in diamond. Experiments utilized an optimized diamond surface functionalized with a polyethylenimine nanogel layer, achieving ∼ 10 nm average protein distance and mitigating interfacial steric hindrance. Then we measured the strong interaction between streptavidin and spin-labeled biotin complexes, as well as the weak interaction between bovine serum albumin and biotin complexes, at both the micrometer scale and nanoscale. For the micrometer-scale measurements using ensemble NV centers, we reexamined the often-neglected fast relaxation component and proposed a relaxation rate evaluation method, substantially enhancing the measurement sensitivity. Furthermore, we achieved nanoscale detection approaching single-molecule level using single NV centers. This methodology holds promise for applications in molecular screening, identification, and kinetic studies at the single-molecule level, offering critical insights into molecular function and activity mechanisms.