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Cotranslational assembly directs the biogenesis of the m <sup>6</sup> A methyltransferase complex
The chemical modification N 6 -methyladenosine (m 6 A) is catalyzed by the m 6 A methyltransferase complex (MTC) comprising METTL3 and METTL14 in the nucleus. Structural evidence reveals that METTL3 primarily functions as the catalytic core, while METTL14 serves as an RNA-binding scaffold. However, the mechanism directing the complex assembly in vivo remains enigmatic. Here, we demonstrate that MTC is formed by a cotranslational mechanism in which nascent METTL3 interacts with METTL14 polypeptide chain exposed from the ribosome exit tunnel. The methyltransferase domains in the subunits determine the specificity of their cotranslational interaction. In contrast, WTAP, the regulatory subunit of MTC, is recruited to the complex posttranslationally. We further identify CCT4, the key subunit of cytosolic chaperonin TCP-1, as an essential facilitator of the endogenous MTC assembly process. Depletion of CCT4 results in dramatic reduction of METTL3–METTL14 heterodimer formation. Remarkably, we engineer a cell-permeable peptide M14P1, which could disrupt cotranslational assembly of MTC, thereby impairing m 6 A deposition and significantly attenuating the proliferation of acute myeloid leukemia (AML) cells and promoting apoptosis. Collectively, our findings unravel intrinsic mechanisms governing the in vivo assembly of MTC, and provide a potential therapeutic strategy to disrupt oncogenic m 6 A pathways and impede AML progression.
Influence of partial or total substitution of wheat flour and sunflower oil with Sacha inchi (Plukenetia volubilis L.) flour and oil on the quality and nutritional properties of cookies
Background The increasing demand for healthier and more sustainable foods has driven the reformulation of bakery products using alternative ingredients. Sacha inchi ( Plukenetia volubilis L.), an Amazonian oilseed rich in proteins, unsaturated fatty acids, and bioactive compounds, represents a promising resource to enhance the nutritional and functional quality of baked goods while valorizing agro-industrial by-products. Methodology This study investigated the effects of partially or totally replacing wheat flour and sunflower oil with defatted Sacha inchi oilcake flour and Sacha inchi oil on the nutritional, physicochemical, and functional properties of cookies. Nine formulations were developed, including a control and eight experimental variants. Proximate composition, mineral content, lipid profile, total polyphenols, antioxidant activity (FRAP and DPPH assays), texture, geometry, and color parameters were evaluated. Results Cookies containing Sacha inchi flour showed significant increases in protein (up to 19.65%), fat, fiber (6-fold higher), ash, and energy, with a reduction in carbohydrates. Mineral content increased markedly for calcium (10.8-fold), magnesium (10.2-fold), potassium (3-fold), phosphorus (5.4-fold), and zinc (4.6-fold), while iron decreased by 25%. Lipid profiling revealed a higher proportion of polyunsaturated fatty acids, particularly α-linolenic acid (omega-3), and lower saturated fats in cookies containing Sacha inchi oil. The incorporation of Sacha inchi ingredients also increased total polyphenols (up to 1.46-fold) and antioxidant activity (up to 1.99-fold). Texture analysis showed that Sacha inchi flour reduced hardness (up to 5.8 times softer than control), whereas Sacha inchi oil increased firmness (up to 2.4 times). Full replacement of sunflower oil increased cookie diameter and spread ratio, while Sacha inchi flour reduced diameter and increased thickness. Color parameters were also affected, reflecting compositional and Maillard-related changes during baking. Conclusions Replacing wheat flour and sunflower oil with Sacha inchi flour and oil enhanced the nutritional profile, fatty acid composition, and antioxidant capacity of cookies, while modulating their texture and geometry. These findings demonstrate the technological feasibility of using Sacha inchi derivatives as functional ingredients in bakery products, supporting the development of sustainable, health-oriented foods and promoting the valorization of Amazonian crops and by-products.
High prevalence of tomato brown rugose fruit virus in domestic wastewater as a potential viral indicator for treatment systems
Polymer conformational entropy as the driver of complex coacervation
Understanding the mechanisms leading to complex coacervation is a fundamental challenge in biomolecular sciences. Here, we explored the condensation transition and pretransitional behavior of an archetypal system consisting of polyuridylic acid chains (PolyU) and short cationic peptides in buffered aqueous solutions. By combining static and dynamic light scattering with confocal microscopy, we determined the location of the transition and the partitioning of PolyU and peptides between the coexisting phases as a function of the total peptides/PolyU ratio. We find that upon adding peptides in the system, the size of PolyU coils in the single-phase region is progressively reduced by peptide-mediated intrachain bonds. Such conformational constraints become less severe in the dense phase, where part of the bonds become interchain as indicated by the sticky-reptation-type kinetics observed by dynamic light scattering. We propose a phenomenological model in which we include the loss in PolyU conformational entropy induced by peptide decoration and show that this quantity is large enough to be the main driver of the condensation transition. The model well reproduces the observed molecular partitioning between phases. We argue that the role of coil conformational relaxation, here demonstrated for a specific system, might be of general relevance in complex coacervation.
Impact of improved stove intervention on infant acute respiratory infections: Results from a randomized trial in Northwest Ethiopia
Background Globally, millions of young children affected by acute respiratory infections every year, which is the leading cause of death and serious illness among children. Though strategies, including promoting improved stoves, have been implemented to combat this public health challenge, the effectiveness of local improved stoves introduced during pregnancy in reducing household air pollution and related respiratory illnesses remains limited. Method Following the main trial randomization, 343 infants born to mothers in the study groups were followed for six months, with assessments of acute respiratory infections (ARI) occurring every two months. The stove intervention’s impact was evaluated by comparing the acute respiratory infection incidence rate between the intervention and control groups. Respiratory illnesses were assessed using Integrated Management of Childhood Illness (IMCI) guidelines. The incidence rate ratio (IRR) was estimated using a marginal Poisson model fitted via Generalized Estimating Equations (GEE). Result During the six-month follow-up period, a total of 43 infants (18 intervention, 25 control) experienced at least one acute respiratory infection (ARI) episode, resulting in a cumulative incidence of 12% (95% CI: 10, 14%). Although the intervention group consistently showed a reduction in ARI incidence rates compared to the control group (a 20% reduction), the adjusted Incidence Rate Ratio (IRR = 0.81; 95%CI: 0.56, 1.16; P = 0.252) was not statistically significant. A non-significant trend toward benefit was noted overall, with the subgroup analyses suggesting promising, non-significant reductions primarily among female infants and infants from larger families. Conclusion The overall study did not find a statistically significant protective effect of the intervention stoves on ARI incidence. However, the observed non-significant trend suggests a potential protective effect. Further research with larger sample sizes and longer follow-up periods is warranted to confirm this potential benefit. Trial registration The main trial was registered at the Pan African Clinical Trial Registry website under the code PACTR202111534227089, ( https://pactr.samrc.ac.za/ (Identifier) on the registration date of (11/11/2021).
Online 1-session Empowered Relief in Marfan syndrome and related diseases: a single-arm feasibility and pilot efficacy study
Combinatorial treatment of glioblastoma with temozolomide (TMZ) plus 5-ethynyl-2′-deoxyuridine (EdU)
Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with incidence peaking in later life. It is commonly treated with surgery followed by administration of ionizing radiation and the DNA-alkylating agent temozolomide (TMZ). Even though this regimen confers some progression-free survival, there is essentially no cure with the median survival with the standard of care being about 12 mo. Currently, several alternative approaches are being developed to improve upon this outcome. We have already shown EdU alone effectively treats GBM, and we now study the efficacy of TMZ+EdU combination therapy. TMZ+EdU significantly improves antitumor efficacy compared to either single-agent therapy against GBM cell lines in vitro, against three different orthotopic GBM xenograft models, and against passage-zero GBM patient tumor tissues engrafted within an organotypic brain slice culture-based platform. Together, our results suggest that EdU could be effective alongside standard-of-care TMZ in patients with GBM.
Including patient experiences from online sources in guidelines: A natural language processing study on scabies
Objective Including patients’ experience-based knowledge in the development of clinical and public health guidelines has been shown to enhance the quality, relevance, and applicability of guidelines. However, the meaningful and methodologically sound inclusion of patient experiences remains a challenge. This study aimed to showcase the potential of NLP methods as an innovative tool for guideline development to gain insights into patients’ experiential knowledge and to incorporate this into the guideline development process. Methods For the revision of the Dutch public health guideline for scabies, we analyzed patients’ experiences with scabies infestation shared on “dokter.nl”, the Netherlands’ largest online health community, between December 4, 2014, and May 19, 2023. Structural topic modelling was performed to discern thematic clusters from these patient experiences. Results We obtained 5781 unique posts on scabies and identified 13 major themes raised in forum conversations. The most prevalent themes revolved around community support (11.2%), uncertainty about treatment plans (11.1%) and coping with itching (11%). Recognizing scabies, alternative remedies, and decontamination measures were also issues frequently raised. The analysis highlighted the burden of disease and treatment—particularly the psychosocial burden—associated with scabies. This offered guideline developers an unprecedented insight into patients’ experiences resulting in alterations to the Dutch public health guideline for scabies. Conclusion Previous studies have highlighted the benefits of the integration of experiential knowledge for guideline development. Our study provides a novel method to make this type of knowledge accessible and usable for medical guideline development, without additionally burdening patients.
Modeling runoff, sediment yield and conservation measures using SWAT in Ajima catchment, Upper Blue Nile Basin, Ethiopia
Controlled dynamic remodeling of the spliceosome active site enables the first step of splicing
Recent cryoelectron microscopy data have revealed significant conformational rearrangements of the megadalton spliceosome structure during splicing, an essential catalytic process for maturing most human transcripts. However, the molecular trigger of these structural rearrangements for splicing catalysis remains unclear at the atomic level. Here, by analyzing a consistent dataset of multicomponent spliceosome structures, we identified a minimal set of positively charged residues whose dynamic action remodels the spliceosome active site during the first step of splicing. Through equilibrium and enhanced sampling molecular dynamics simulations of multiple splicing intermediates (>2M atoms), we uncover how these residues dynamically operate in coordination with the transient, temporally ordered binding of key spliceosomal proteins (Prp11, Prp8, and Yju2) at the spliceosome core. Our findings reveal a molecular mechanism that ensures precise and timely spliceosome activation, opening promising directions to probe splicing regulation and potentially target its dysfunction in diseases, with broad implications for drug discovery and medicine.
Emphasizing the role of oxidative stress and Sirt-1/Nrf2 and TLR-4/NF-κB in Tamarix aphylla mediated neuroprotective potential in rotenone-induced Parkinson’s disease: In silico and in vivo study
Parkinson’s disease (PD) presents as a progressive deterioration of dopaminergic neurons, a process closely associated with increased oxidative damage due to accumulated reactive oxygen species, leading to weakened antioxidant defenses and ultimately neuronal dysfunction. Currently, no definitive approach exists to counteract the degeneration of dopaminergic neurons in PD. The use of Tamarix aphylla as a protective agent against Parkinson’s disease is not well studied yet. In this study, a rotenone-induced rodent model was utilized to examine the neuroprotective potential of T. aphylla extract. The chemical composition of T. aphylla leaves was analyzed through LC-HR-ESI-MS profiling, identifying 13 metabolites from various chemical categories. Furthermore, the research incorporated the STRING database and Cytoscape software to perform a protein-protein interaction (PPI) analysis, pinpointing essential hub proteins involved in neuroprotection and inflammation in PD. Molecular docking and a 150 ns molecular dynamics simulation were performed to assess the interaction of plant-derived compounds with the Sirt-1 catalytic domain. Compound 12 , one of the bioactive compounds found in T. aphylla , exhibited strong binding affinity and stability throughout the 150 ns simulation, highlighting its role as a neuroprotective agent. This study underscores the fusion of computational and experimental techniques to investigate natural neuroprotective compounds, providing potential therapeutic strategies for PD treatment by influencing key pathways linked to oxidative damage and neuroinflammation.
Ameliorative effects of tallow and olive oil on hyperlipidemia-induced atherogenesis in male albino rats
Correction for Xiao et al., The modern pattern of insect herbivory predates the advent of angiosperms by 60 My
Mortality and comorbidities among teaching professionals: A cross-sectional study in Colombia
Background Teachers play a critical role in social and economic development, yet evidence on their health outcomes in Latin America remains scarce. In Colombia, teachers are generally classified in occupational risk level 1, a category considered to have minimal hazards. This study aimed to describe and compare mortality and comorbidities among teachers and non-teachers in the same risk category, and to explore differences across educational levels within the teaching profession. Methods We conducted a retrospective cohort study using four linked national administrative databases in 2017. Adults affiliated to the contributory health insurance scheme and classified under occupational risk level 1 were included. Teachers were identified and stratified by educational level. Outcomes included one-year all-cause mortality and prevalence of mental health and hearing disorders. Multivariable logistic regression models adjusted for sociodemographic and clinical covariates were used to estimate associations. Results A total of 4,256,719 individuals were included, of whom 353,985 (8.3%) were teachers. Teachers were older (mean age 40.1 vs 36.4 years) and more frequently female (69% vs 60%) than non-teachers. The one-year mortality proportion was higher among teachers (0.14%) than non-teachers (0.11%). After adjustment, teaching was associated with a 15% higher risk of mortality (OR: 1.15, 95% CI: 1.03–1.28). No significant associations were found for mental health (OR: 0.98, 95% CI: 0.96–1.01) or hearing disorders (OR: 0.97, 95% CI: 0.92–1.02). Subgroup analyses showed the highest mortality proportions among teachers in technical and technological education. Conclusions Despite being classified in the lowest occupational risk level, private-sector teachers in Colombia exhibited higher mortality compared with other workers in the same group. Differences in mental health and hearing disorders were not significant. These findings highlight the need to strengthen surveillance, prevention, and protection strategies tailored to teachers, recognizing them as a priority population within occupational health and education policies.
Structural damage analysis using finite element model updating enhanced by response surface methodology
Life without sex: Lack of desire or traumatic retire?
Digital finance and climate risk information disclosure
Under the dual drivers of China’s “Dual Carbon” goals (carbon peaking and carbon neutrality) and the digital technology revolution, the strategic value of corporate climate risk information disclosure has become increasingly prominent. Against this backdrop, this paper systematically explores the relationship between digital finance development and corporate climate risk disclosure using a sample of Chinese A-share listed firms. The research demonstrates that digital finance development significantly promotes corporate climate risk disclosure, a conclusion that remains valid after multiple robustness tests. The study also reveals that digital finance drives climate risk disclosure through alleviating financing constraints, strengthening environmental responsibility, and enhancing reputational incentives. Further analysis indicates that institutional pressure positively moderates the relationship between digital finance and corporate climate risk disclosure; moreover, the impact of digital finance on corporate climate risk disclosure exhibits significant heterogeneity depending on regional factors (rule of law environments and the supply level of digital economy policies), and corporate characteristics (top management backgrounds, lifecycle stages, and equity nature). These findings provide theoretical references and empirical support for balancing digital finance innovation and climate risk governance.
Correction: Construction and application of copula-based trivariate standardized river disconnection index for seasonal rivers in arid and semi-arid areas
Glycosylation of GETV E2 promotes pathogenesis in animal models
Getah virus (GETV) is a mosquito-borne alphavirus. It has posed a threat to various livestock and humans during decades of evolution and spread. However, the viral determinants and mechanisms underlying enhanced virulence remain largely unknown. In this study, we identified E2-N262 glycosylation in GETV as an evolutionary adaptation that promotes receptor binding, innate immune evasion, and virulence. Using reverse genetics technology, we generated recombinant GETV strains―rSD2206 WT and the N262D substitution. In vitro, rSD2206 WT formed larger plaques and replicated more efficiently across multiple cell lines. Despite exhibiting enhanced pathogenicity, higher replication efficiency, and a weaker induction of host antiviral responses compared to the N262D virus in both mouse and suckling pig models, the rSD2206 WT virus retained immunogenicity. Mechanistically, we found that rSD2206 WT increased virion attachment and entry into host cells by enhancing binding affinity to both HS (a GETV attachment factor) and LDLR (a GETV receptor). In addition, the rSD2206 WT strain can evade the host’s antiviral response by interrupting the activation of interferon regulatory factor 3. Structural analysis revealed a significant reduction in binding free energy for rSD2206 WT. This reduction resulted in conformational changes within the E2 protein, which in turn enhanced its stability and subsequently strengthening its receptor-binding capacity. Ultimately, compared to N262D, rSD2206 WT exhibited increased replication in cells overexpressing LDLR, but significantly reduced replication in LDLR −/− mice. These results highlight the critical importance of proactive surveillance of GETV molecular evolution to prevent future outbreaks, which could provide the foundation for the development of attenuated vaccines.