Search Results (95)

Retrieval-Augmented Generation (RAG) offers a promising strategy to harness large language models (LLMs) for delivering up-to-date, accurate clinical guidance while reducing physicians’ cognitive burden, yet its effectiveness hinges on query clarity and structure. We propose an adaptive Self-Query Retrieval (SQR) framework that integrates three refinement modules—PICOT (Population, Intervention, Comparison, Outcome, Time), SPICE (Setting, Population, Intervention, Comparison, Evaluation), and Iterative Query Refinement (IQR)—to automatically restructure and iteratively enhance clinical questions until they meet predefined retrieval-quality thresholds. Implemented on Gemini-1.0 Pro, we benchmarked SQR using thirty postoperative rhinoplasty queries, evaluating responses for accuracy and relevance on a three-point Likert scale and for retrieval quality via precision, recall, and F1 score; statistical significance was assessed by one-way ANOVA with Tukey post-hoc testing. The full SQR pipeline achieved 87% accuracy (Likert 2.4 ± 0.7) and 100% relevance (Likert 3.0 ± 0.0), significantly outperforming a non-refined RAG baseline (50% accuracy, 80% relevance; p < 0.01 and p = 0.03). Precision, recall, and F1 rose from 0.17, 0.39 and 0.24 to 0.53, 1.00, and 0.70, respectively, while PICOT-only and SPICE-only variants yielded intermediate improvements. These findings demonstrate that automated structuring and iterative enhancement of queries via SQR substantially elevate LLM-based clinical decision support, and its model-agnostic architecture enables rapid adaptation across specialties, data sources, and LLM platforms. Full article

The rapid evolution of SARS-CoV-2 has underscored the need for a detailed understanding of antibody binding mechanisms to combat immune evasion by emerging variants. In this study, we investigated the interactions between Class I neutralizing antibodies—BD55-1205, BD-604, OMI-42, P5S-1H1, and P5S-2B10—and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein using multiscale modeling, which combined molecular simulations with the ensemble-based mutational scanning of the binding interfaces and binding free energy computations. A central theme emerging from this work is that the unique binding strength and resilience to immune escape of the BD55-1205 antibody are determined by leveraging a broad epitope footprint and distributed hotspot architecture, additionally supported by backbone-mediated specific interactions, which are less sensitive to amino acid substitutions and together enable exceptional tolerance to mutational escape. In contrast, BD-604 and OMI-42 exhibit localized binding modes with strong dependence on side-chain interactions, rendering them particularly vulnerable to escape mutations at K417N, L455M, F456L and A475V. Similarly, P5S-1H1 and P5S-2B10 display intermediate behavior—effective in some contexts but increasingly susceptible to antigenic drift due to narrower epitope coverage and concentrated hotspots. Our computational predictions show strong agreement with experimental deep mutational scanning data, validating the accuracy of the models and reinforcing the value of binding hotspot mapping in predicting antibody vulnerability. This work highlights that neutralization breadth and durability are not solely dictated by epitope location, but also by how binding energy is distributed across the interface. The results provide atomistic insight into mechanisms driving resilience to immune escape for broadly neutralizing antibodies targeting the ACE2 binding interface—which stems from cumulative effects of structural diversity in binding contacts, redundancy in interaction patterns and reduced vulnerability to mutation-prone positions. Full article

Cardiomyopathies represent a heterogeneous group of myocardial disorders, traditionally classified by phenotype into hypertrophic, dilated, and arrhythmogenic. Historically, these conditions have been attributed to high-penetrance rare variants in key structural genes, consistent with a classical Mendelian pattern of inheritance. However, emerging evidence suggests that this model does not fully capture the full spectrum and complexity of disease expression. Many patients do not harbor identifiable pathogenic variants, while others carrying well-known disease-causing variants remain unaffected. This highlights the role of incomplete penetrance, likely modulated by additional genetic modifiers. Recent advances in genomics have revealed a broader view of the genetic basis of cardiomyopathies, introducing new players such as common genetic variants identified as risk alleles, as well as intermediate-effect variants. This continuum of genetic risk, reflecting an overall genetic influence, interacts further with environmental and lifestyle factors, likely contributing together to the observed variability in clinical presentation. This model offers a more realistic framework for understanding genetic inheritance and helps provide a clearer picture of disease expression and penetrance. This review explores the evolving genetic architecture of cardiomyopathies, spanning from a monogenic foundation to intermediate-risk variants and complex polygenic contribution. Recognizing this continuum is essential for enhancing diagnostic accuracy, guiding family screening strategies, and enabling personalized patient management. Full article

Complex antimony pyrochlores Bi_2.7M_0.46Ni_0.70Sb₂O_10+Δ (M = Zn, Mg) were synthesized from oxide precursors, using the solid-state reaction method. For each composition variant, the pyrochlore phase formation process was studied during solid-state synthesis in the range of 500–1050 °C. The influence of zinc and magnesium on the phase formation process was established. The interaction of oxide precursors occurs at a temperature of 600 °C and higher, resulting in the formation of bismuth stibate (Bi₃SbO₇) as a binary impurity phase. Oxide precursors, including bismuth(III) and antimony(III,V) oxides, are fixed in the samples up to 750 °C, at which point the intermediate cubic phase Bi₃M_2/3Sb_7/3O₁₁ (sp. gr. Pn-3, M = Zn, Ni) is formed in the zinc system. Interacting with transition element oxides, it is transformed into pyrochlore. An intermediate phase with the Bi_4.66Ca_1.09VO_10.5 structure (sp. gr. Pnnm) was found in the magnesium system. The unit cell parameter of pyrochlore for two samples has a minimum value at 800 °C, which is associated with the onset of high-temperature synthesis of pyrochlore. The synthesis of phase-pure pyrochlores is confirmed by high-resolution Raman spectroscopy. The data interpretation showed that the cations in Ni/Zn pyrochlore are more likely to be incorporated into bismuth positions than in Ni/Mg pyrochlore. The nickel–magnesium pyrochlore is characterized by a low-porosity microstructure, with grain sizes of up to 3 μm, according to SEM data. Zinc oxide has a sintering effect on ceramics. Therefore, the grain size in ceramics is large and varies from 2 to 7 μm. Full article

For a highly beneficial mutation A at locus 1 spreading in a very large population, we have analyzed the scenario that at a closely linked locus 2 a second beneficial mutant B arises before A has fixed. Under the assumptions that the fitness of B is greater than that of A and that A- and B-carrying chromosomes can recombine at some rate $r$, recombinants AB may form and eventually fix. We present explicit formulas for the fixation time of AB under additive fitness of the mutants as a function of the frequency $X_2\left(0\right)$ of A at the time when B is introduced. Our analysis suggests that the effect of interference between the beneficial mutations is most pronounced for small values of $X_2\left(0\right)<0.1.$ Furthermore, we identify a threshold value for $r$, above which recombination speeds up fixation. Using published simulation data, we also describe the genomic footprint of competing beneficial mutations. At neutral sites between the two linked selected loci, an excess of intermediate-frequency variants may occur when interference is strong, i.e.,$X_2\left(0\right)$ small. Finally, we discuss under which circumstances this scenario may be encountered in real sequences from recombining genomic regions. Full article

The integration of new technologies in Industry 4.0 has modernised agriculture, fostering the concept of smart agriculture (Agriculture 4.0). Higher education institutions are incorporating digital technologies into agricultural curricula, equipping students in agriculture, agronomy, and engineering with essential skills. The implementation of targeted STEM activities has the potential to enhance the teaching of Agriculture 4.0 through the utilisation of practical applications that stimulate student interest, thereby facilitating more accessible and effective teaching. In this context, this study presents a system comprising retrofitted real-scale components that facilitate the understanding of digital technologies and automations in agriculture. The specific system utilises a typical centrifugal electric pump and a water tank and adds logic to it, so that its flow follows various user-defined setpoints, given and monitored via a smartphone application, despite the in-purpose disturbances invoked via intermediating valves. This setup aims for students to gain familiarity with concepts such as closed-loop systems and PID controllers. Going further, fertile ground is provided for experimentation on the efficiency of the PID controller via testing different algorithmic variants incorporating non-linear methods as well. Feedback collected from the participating students via a corresponding survey highlights the importance of integrating similar hands-on interdisciplinary activities into university curricula to foster engineering education. Full article

Rice (Oryza sativa L.) is essential for global food security and sustains billions worldwide, emphasizing the need to improve production and quality. One key challenge in rice breeding is the inheritance and environmental sensitivity of amylose content, a starch component that influences the texture, water absorption, and firmness after cooking, which are crucial for market acceptance. While international markets prefer low-amylose varieties for their softness, intermediate- and high-amylose varieties are favored in Latin America for their firmness. The objective of this study was to develop a molecular quality assessment methodology that, combined with morphological and culinary evaluations, helps in the selection of rice varieties during the breeding process. First, ten Ecuadorian rice materials were evaluated for milling and culinary quality characteristics, revealing significant grain size, sterility, milling yield, cooking time, and texture variations. Amylose content (AC) is genetically regulated by the waxy gene and its allelic variants, affecting granule-bound starch synthase (GBSS) enzyme expression. Secondly, to classify rice varieties molecularly based on AC, the testing ten genotypes plus nine control varieties were analyzed using microsatellite (SSR) markers. The waxy molecular marker, combined with metaphor agarose gel electrophoresis (MAGE), proved effective for early-stage AC analysis, reducing variety selection costs and improving breeding efficiency. Additionally, a restriction enzyme protocol assay facilitated variety differentiation by selectively cleaving the waxy gene sequence at a specific single-nucleotide polymorphism (SNP) site, allowing for precise AC genetic classification. By integrating molecular techniques with traditional assessments, this study reveals that using marker-assisted selection in breeding programs, as well as supporting the identification and development of high-quality local rice varieties to meet market demands, improves production efficiency and optimizes the assessment of developing varieties under diverse environmental conditions. Full article

Background: Epidemiological studies suggest lung cancer results from the combined effects of smoking and genetic susceptibility. The clinical application of polygenic risk scores (PRSs), derived from combining the results from multiple germline genetic variants, have not yet been explored in a lung cancer screening cohort. Methods: This was a post hoc analysis of 9191 non-Hispanic white subjects from the National Lung Screening Trial (NLST), a sub-study of high-risk smokers randomised to annual computed tomography (CT) or chest X-ray (CXR) and followed for 6.4 years (mean). This study’s primary aim was to examine the relationship between a composite polygenic risk score (PRS) calculated from 12 validated risk genotypes and developing or dying from lung cancer during screening. Validation was undertaken in the UK Biobank of unscreened ever-smokers (N = 167,796) followed for 10 years (median). Results: In this prospective study, we found our PRS correlated with lung cancer incidence (p < 0.0001) and mortality (p = 0.004). In an adjusted multivariable logistic regression analysis, PRS was independently associated with lung cancer death (p = 0.0027). Screening participants with intermediate and high PRS scores had a higher lung cancer mortality, relative to those with a low PRS score (rate ratios = 1.73 (95%CI 1.14–2.64, p = 0.010) and 1.89 (95%CI 1.28–2.78, p = 0.009), respectively). This was despite comparable baseline demographics (including lung function) and comparable lung cancer characteristics. The PRS’s association with lung cancer mortality was validated in an unscreened cohort from the UK Biobank (p = 0.002). Conclusions: In this biomarker-based cohort study, an elevated PRS was independently associated with dying from lung cancer in both screening and non-screening cohorts. Full article

Patients hospitalized due to coronavirus disease 2019 (COVID-19) usually present with severe or critical intensity of symptoms, accompanied by a marked systemic inflammatory response. Classical inflammatory biomarkers, C-reactive protein (CRP), albumin, and red blood cell distribution width (RDW) have previously been reported to be prognostic in hospitalized COVID-19 patients. We performed a retrospective analysis of two large cohorts (2305 and 2328 patients, respectively) of consecutive hospitalized COVID-19 patients with mostly severe and critical symptoms admitted to the tertiary referral center to develop and validate a prognostic score for 30-day mortality based on CRP-to-Albumin-Ratio (CAR), RDW, and age (termed CARRA-VID score). We identified 6 prognostic categories: very low, low, intermediate-1, intermediate-2, high, and very high risk, with corresponding 30-day mortality rates of 2.7%, 10.7%, 30.9%, 47.1%, 61.9%, and 89.7%, respectively. Effective risk stratification was validated in an independent cohort of patients and remained independent of the World Health Organization-defined disease severity and other commonly utilized risk scores. Additional analyses evaluated the score across different time periods dominated by distinct viral variants. We also present a simplified 3-tiered version of the score. A Microsoft Excel Workbook containing the score calculator is provided. Full article

Fluorinated pyrethroids, such as cyfluthrin and cyhalothrin, are more effective insecticides due to their enhanced stability and lipophilicity. However, they pose greater risks to non-target organisms. Their persistence in the environment and accumulation in tissues can lead to increased toxicity and ecological concerns. This study investigates the biodegradation of the fluorinated pyrethroids β-cyfluthrin (BCF) and λ-cyhalothrin (LCH) using a newly isolated Bacillus sp. MFK14 from a garden soil microbial consortium. Initial screening using ¹⁹F NMR analysis showed that the microbial consortium degraded both pyrethroids, leading to the isolation of Bacillus sp. MFK14. Subsequent GC-MS analysis revealed various degradation intermediates in both pyrethroids after incubation with Bacillus sp. MFK14. Notably, Bacillus sp. MFK14 completely degraded β-cyfluthrin and λ-cyhalothrin within 48 h at 30 °C. Fluoride ions from β-cyfluthrin and trifluoroacetic acid (TFA) from λ-cyhalothrin were detected as the end-products by ¹⁹F NMR analysis of the aqueous fraction. The pathway of the degradation was proposed for both the pyrethroids indicating shared biodegradation pathways despite different fluorinations. Inhibition studies with 1-ABT suggested the involvement of bacterial cytochrome P450 (CYP) enzymes in their biodegradation. The CYPome of Bacillus sp. MFK14 includes 23 CYP variants that showed significant sequence similarity to known bacterial CYPs, suggesting potential roles in pyrethroid biodegradation and environmental persistence. These findings highlight the potential for bioremediation of fluorinated pesticides, offering an environmentally sustainable approach to mitigate their ecological impact. Full article

Smith–Lemli–Opitz syndrome (SLOS) is a developmental disability arising from bi-allelic pathogenic variants in the 7-dehydrocholestrol reductase (DHCR7) enzyme and the accumulation of 7-dehydrocholesterol (7-DHC). 7-DHC spontaneously oxidizes and gives rise to cytotoxic oxysterols. Our recent high-throughput screening on Dhcr7-deficient Neuro2a cells identified hydroxyzine (HYZ) as a medication that could counteract the high levels of 7-DHC. We assessed the effects of HYZ in Dhcr7-deficient Neuro2a cells, neuronal cultures and glial cultures from Dhcr7^T93M/T93M transgenic mice, and human dermal fibroblasts from patients with SLOS. LC-MS/MS biochemical analyses revealed a strong modulatory effect of HYZ on post-lanosterol biosynthesis across all four SLOS models. However, the HYZ-induced biochemical changes were complex, dose-dependent, and variable across the four SLOS models. Dhcr7-deficient Neuro2a cells showed decreased 7-DHC, 8-dehydrocholesterol (8-DHC), and desmosterol (DES) levels (all p < 0.01), while neuronal and glial cultures from Dhcr7^T93M/T93M transgenic mice reported 8 significantly altered analytes (all p < 0.001). Human dermal fibroblast from patients with SLOS reacted to HYZ exposure with significantly decreased 7-DHC, 7-dehydrodesmosterol (7-DHD), and dihydrolanosterol (DHL) levels (p < 0.001), coupled with elevation in zymosterol (ZYM), zymostenol (ZYME), and 8-DHC (p < 0.001). Further evaluations are required to determine if the potentially beneficial effects of decreased 7-DHC, 7-DHD and DHL levels in SLOS models and patient biomaterials are counteracted by the rise in other post-lanosterol intermediates. Full article

The Saccharomyces cerevisiae chromosomal architectural protein Hmo1 is categorized as an HMGB protein, as it contains two HMGB motifs that bind DNA in a structure-specific manner. However, Hmo1 has a basic C-terminal domain (CTD) that promotes DNA bending instead of an acidic one found in a canonical HMGB protein. Hmo1 has diverse functions in genome maintenance and gene regulation. It is implicated in DNA damage tolerance (DDT) that enables DNA replication to bypass lesions on the template. Hmo1 is believed to direct DNA lesions to the error-free template switching (TS) pathway of DDT and to aid in the formation of the key TS intermediate sister chromatid junction (SCJ), but the underlying mechanisms have yet to be resolved. In this work, we used genetic and molecular biology approaches to further investigate the role of Hmo1 in DDT. We found extensive functional interactions of Hmo1 with components of the genome integrity network in cellular response to the genotoxin methyl methanesulfonate (MMS), implicating Hmo1 in the execution or regulation of homology-directed DNA repair, replication-coupled chromatin assembly, and the DNA damage checkpoint. Notably, our data pointed to a role for Hmo1 in directing SCJ to the nuclease-mediated resolution pathway instead of the helicase/topoisomerase mediated dissolution pathway for processing/removal. They also suggested that Hmo1 modulates both the recycling of parental histones and the deposition of newly synthesized histones on nascent DNA at the replication fork to ensure proper chromatin formation. We found evidence that Hmo1 counteracts the function of histone H2A variant H2A.Z (Htz1 in yeast) in DDT possibly due to their opposing effects on DNA resection. We showed that Hmo1 promotes DNA negative supercoiling as a proxy of chromatin structure and MMS-induced DNA damage checkpoint signaling, which is independent of the CTD of Hmo1. Moreover, we obtained evidence indicating that whether the CTD of Hmo1 contributes to its function in DDT is dependent on the host’s genetic background. Taken together, our findings demonstrated that Hmo1 can contribute to, or regulate, multiple processes of DDT via different mechanisms. Full article

It was previously reported that tyrosine 97 (Y97) of cytochrome c is phosphorylated in cow heart tissue under physiological conditions. Y97 phosphorylation was shown to partially inhibit respiration in vitro in the reaction with purified cytochrome c oxidase. Here, we use phosphomimetic Y97E Cytc to further characterize the functional effects of this modification both in vitro and in cell culture models. In vitro, phosphomimetic Y97E Cytc showed lower activity in the reaction with purified cow heart cytochrome c oxidase (COX), decreased caspase-3 activity, and reduced rate of reduction. Additionally, the phosphomimetic Y97E Cytc tended to be resistant to heme degradation and showed an increased rate of oxidation. Intact mouse Cytc double knockout fibroblasts were transfected with plasmids coding for phosphomimetic Y97E Cytc and other variants. Compared to cells expressing wild-type Cytc, the cells expressing phosphomimetic Y97E Cytc showed reduced respiration, mitochondrial membrane potential, and reactive oxygen species production, and protection from apoptosis. In an oxygen–glucose deprivation/reoxygenation cell culture model of ischemia/reperfusion injury, mitochondrial membrane potential and reactive oxygen species production were decreased. These data show that Cytc phosphorylation controls the overall flux through the electron transport chain by maintaining optimal intermediate ΔΨm potentials for efficient ATP production while minimizing reactive oxygen species production, thus protecting the cell from apoptosis. Full article

Background/Objectives: Pregabalin is a useful therapeutic option for patients with anxiety or neuropathic pain. Genetic variants in certain genes encoding for transporters related to absorption and distribution could have an impact on the efficacy and safety of the drug. Furthermore, extreme phenotypes in metabolic enzymes could alter pregabalin-limited metabolism. Methods: In this study, we included 24 healthy volunteers participating in a bioequivalence clinical trial and administered pregabalin 300 mg orally; 23 subjects were genotyped for 114 variants in 31 candidate genes, and we explored their impact on pregabalin pharmacokinetics and safety. Results: The uncorrected mean (±SD) of AUC_∞ and C_max were 61,097 ± 14,762 ng*h/mL and 7802 ± 1659 ng/mL, respectively, which were significantly higher in females than in males (p = 0.002 and p = 0.001, respectively), with no differences in dose/weight (DW)- corrected exposure metrics. NAT2 slow acetylators (SAs) showed a 16–18% increase in exposure compared to intermediate (IAs) and normal (NAs) acetylators; NAT2 SAs exhibited a 25% higher t_1/2 as compared with NAT2 IAs and 58% higher compared to NAT2 NAs. In contrast, neither the NAT2 phenotype nor other genetic variants were related to pregabalin adverse drug reaction (ADR) occurrence. On the contrary, sex and sex-related exposure differences (i.e., females and their higher exposure compared to males) were the main predictors of ADR occurrence. Conclusions: Our findings suggest that NAT2 could be partially responsible for the minor proportion of pregabalin metabolism, but the effect of NAT2 phenotype does not seem clinically relevant. Therefore, pharmacogenetic biomarkers appear to play a restrained role in pregabalin pharmacotherapy. Full article

Composting is a key component of sustainable development strategies, as it supports ecological waste management, minimises the impact of human activities on the environment, and promotes the efficient use of natural resources. Reducing the generation of additional waste—as “recirculation” of composted waste—is also an important indicator of sustainability processes. The intermediate fraction (IF) is the material within the 10 mm to 60–90 mm range. It can be incorporated into composting materials to enhance the composting process. Maintaining an appropriate proportion of this fraction in the compost mixture is crucial for its practical use. This research examined the impact of adding the IF to composting on reducing the release of odorous substances. Additionally, it aimed to optimise the composting process by effectively managing the fraction. Optimisation sought to achieve high-quality compost, minimise odour emissions, and enhance the overall efficiency of the process. The study enabled the selection of the optimal variant—adding 9% of IF with inoculum—considering both ammonia emissions and odour impact. This variant yielded 13% less ammonia and 37% less odour than the variant without additives. This included identifying the intermediate fraction’s ideal proportion and adding pre-composted waste to compost piles. Full article