Search Results (4,403)

Background: Multiple Myeloma (MM) is a malignant plasma cell dyscrasia that progresses through the consecutive asymptomatic, often undiagnosed, precancerous stages of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Asymptomatic Multiple Myeloma (SMM). MM is characterized by low survival rates, severe complications and drug resistance; therefore, understanding the molecular mechanisms of progression is crucial. This study aims to detect genetic mutations, both germline and somatic, that contribute to disease progression and drive tumorigenesis at the final stage of MM, using samples from patients presenting MGUS or SMM, and newly diagnosed MM patients. Methods: Mutations were identified through a fully computational pipeline, implemented in a Linux and RStudio environment, applied to each patient sequence, obtained through single-cell RNA-sequencing (scRNA-seq), separately. Structural and functional mutation types were identified by stage, along with the affected genes. The analysis included quality control, removal of the Unique Molecular Identifiers (UMIs), trimming, genome mapping and result visualization. Results: The findings revealed frequent germline and somatic mutations, with distinct structural and functional patterns across disease stages. Mutations in key genes were identified, pointing to molecules that may play a central role in carcinogenesis and disease progression. Notable examples include the HLA-A, HLA-B and HLA-C genes, as well as the KIF, EP400 and KDM gene families, with the first four already confirmed. Comparative analysis between the stages highlighted molecular transition events from one stage to another. Emphasis was given to novel genes discovered in newly diagnosed MM patients, that might contribute to the tumorigenesis that takes place. Conclusions: This study contributes to the understanding of the genetic basis of plasma cell dyscrasias and the transition events between the stages, offering insights that could aid in early detection and diagnosis, guide the development of personalized therapeutic strategies, and improve the understanding of mechanisms responsible for resistance to existing therapies. Full article

Biochar (BC), derived from wood biomass through pyrolysis, exhibits properties that make it a promising additive in mortars for sustainable construction. This study investigated the influence of biochar produced at three pyrolysis temperatures (450 °C, 550 °C, and 700 °C) on the performance of cementitious adhesive mortars. The evaluation encompassed physicochemical characterization, mechanical and adhesive strength, volatile organic compound (VOC) emissions, leachability of contaminants, and a life-cycle assessment (LCA). The results demonstrate that biochar obtained at 700 °C has the highest carbon content, an alkaline pH, and increased porosity. In contrast, biochar produced at 450 °C exhibits better sorption capacity and a higher concentration of functional groups. Incorporating 1–5% BC (produced at any temperature) improves mortar performance; however, higher doses negatively affect adhesion to expanded polystyrene board (EPS) and concrete. Emissions of VOCs and leachable metals largely remained within environmental threshold values, with only isolated instances of exceedance. The LCA revealed that substituting mineral fillers with biochar could reduce the carbon footprint by up to 35% compared to the reference formulation. These findings confirm biochar’s potential as a safe and environmentally beneficial component in low-emission construction materials, aligning with the principles of the circular economy and climate-neutral goals. Full article

The generalized Pareto distribution is frequently used for modeling extreme values above an appropriate threshold level. Since the process of determining the appropriate threshold value is difficult, a mixture of extreme value models rises to prominence. In this study, mixture extreme value models based on exponentiated Pareto distribution are proposed. The Weibull, gamma, and log-normal models are used as bulk densities. The parameter estimates of the proposed models are obtained using the maximum likelihood approach. Two different approaches based on maximization of the log-likelihood and Kolmogorov–Smirnov p-value are used to determine the appropriate threshold value. The effectiveness of these methods is compared using simulation studies. The proposed models are compared with other mixture models through an application study on earthquake data. The GammaEP web application is developed to ensure the reproducibility of the results and the usability of the proposed model. Full article

Background/Objectives: The global increase in multidrug-resistant (MDR) bacterial infections underscores the urgent need for effective and sustainable antimicrobial alternatives. This study investigates the antimicrobial activity of exometabolite-based formulations (ExAFs), derived from the cell-free supernatants (CFS) of native lactic acid bacteria (LAB) applied individually or in combination thereof, against MDR-Escherichia coli strain L1PEag1. Methods: Fourteen ExAFs were screened for inhibitory activity using time–kill assays, and structural damage to bacterial cells was assessed via scanning and transmission electron microscopy (SEM/TEM). The most potent formulation was further characterized by liquid chromatography–tandem mass spectrometry (LC–MS/MS) employing a Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectra (SWATH) approach for untargeted metabolite profiling. Results: Among the tested formulations, E10, comprising CFS from Weissella cibaria UTNGt21O, exhibited the strongest inhibitory activity (zone of inhibition: 17.12 ± 0.22 mm), followed by E1 (CFS from Lactiplantibacillus plantarum Gt28L and Lactiplantibacillus plantarum Gt2, 3:1 v/v) and E2 (Gt28L CFS + EPS from Gt2, 3:1 v/v). Time–kill assays demonstrated rapid, dose-dependent bactericidal activity: E1 and E10 achieved >98% reduction in viable counts within 2–3 h, at 1× MIC, while E2 sustained 98.24% inhibition over 18 h, at 0.25× MIC. SEM and TEM revealed pronounced ultrastructural damage, including membrane disruption, cytoplasmic condensation, and intracellular disintegration, consistent with a membrane-targeting mode of action. Metabolomic profiling of E10 identified 22 bioactive metabolites, including lincomycin, the proline-rich peptide Val–Leu–Pro–Val–Pro–Gln, multiple flavonoids, and loperamide. Several compounds shared structural similarity with ribosomally synthesized and post-translationally modified peptides (RiPPs), including lanthipeptides and lassopeptides, suggesting a multifaceted antimicrobial mechanism. Conclusions: These findings position ExAFs, particularly E10, as promising, peptide-rich, bio-based antimicrobial candidates for food safety or therapeutic applications. The co-occurrence of RiPP analogs and secondary metabolites in the formulation suggests the potential for complementary or multi-modal bactericidal effects, positioning these compounds as promising eco-friendly alternatives for combating MDR pathogens. Full article

Microbial reduction in hexavalent chromium (Cr(VI)) is a well characterized bioremediation strategy, yet the mechanistic diversity among bacterial taxa necessitates detailed investigations into strain-specific pathways. Here, we report the isolation and characterization of Bacillus safensis BSF-4, a halophilic bacterium derived from saline-alkali soil, which demonstrates efficient Cr(VI) reduction capacity. Physiological assays showed that BSF-4 achieved 89.15% reduction of 20 mg/L Cr(VI) within 72 h, with Cr(III) identified as the primary extracellular end product. Resting cell assays and subcellular fractionation analyses confirmed that Cr(VI) reduction predominantly occurs in the extracellular milieu. X-ray photoelectron spectroscopy (XPS) further revealed soluble Cr(III) complexed with extracellular polymeric substances (EPS). Transcriptomic profiling indicated upregulation of membrane-associated transport systems (facilitating Cr(VI) exclusion) and quorum sensing (QS) pathways (mediating adaptive stress responses). These findings highlight a dual mechanism: (1) extracellular enzymatic reduction mediated by EPS-bound redox proteins, and (2) intracellular detoxification via QS-regulated defense pathways. Collectively, Bacillus safensis BSF-4 exhibits robust Cr(VI) reduction capacity under saline conditions, positioning it as a promising candidate for bioremediation of Cr(VI)-contaminated saline soils and aquatic ecosystems. Full article

Background/Objectives: Breast cancer is the most commonly diagnosed cancer worldwide, with high rates of distant metastasis. While circulating tumor cells (CTCs) are the disseminatory units of metastasis and are indicative of a poor prognosis, CTC heterogeneity within individual patients, among breast cancer subtypes, and between primary and metastatic tumors within a patient obscures the relationship between CTCs and disease progression. EpCAM, its homolog Trop2, and a pan-Cytokeratin marker were evaluated to determine their contributions to CTC presence and clustering over the study period. We conducted a systematic longitudinal analysis of 51 breast cancer patients during the course of their treatment to deepen our understanding of CTC contributions to breast cancer progression. Methods: 272 total blood samples from 51 metastatic breast cancer (mBC) patients were included in the study. Patients received diverse treatment schedules based on discretion of the practicing oncologist. Patients were monitored from July 2020 to March 2023, with blood samples collected at scheduled care appointments. Nucleated cells were isolated, imaged, and analyzed using Rarecyte^® technology, and statistical analysis was performed in R using the lmerTest and lme4 packages, as well as in Graphpad Prism version 10.4.1. Results: Both classical CTCs (DAPI+, EpCAM+, CK+, CD45– cells) and Trop2+ CTCs were detected in the blood of breast cancer patients. A high degree of correlation was found between CTC biomarkers, and CTC expression of EpCAM, Trop2, and the presence of CD45+ cells, all predicted cluster size, while Pan-CK did not. Furthermore, while analyses of biomarkers by receptor status revealed no significant differences among HR+, HER2+, and TNBC patients, longitudinal analysis found evidence for discrete trajectories of EpCAM, Trop2, and clustering between HR+ and HER2+ cancers after diagnosis of metastasis. Conclusions: Correlation and longitudinal analysis revealed that EpCAM+, Trop2+, and CD45+ cells were predictive of CTC cluster presence and size, and highlighted distinct trajectories of biomarker change over time between HR+ and HER2+ cancers following metastatic diagnosis. Full article

In this study, we developed a combination strategy of bioenzymes and sophorolipid (SL) co-pretreatment to enhance volatile fatty acids (VFAs) in co-fermentation of waste activated sludge (WAS) and rubberwood hydrolysates (RWHs). Among all the pretreatments, SL and laccase co-pretreatment markedly increased soluble bioavailable substrates (carbohydrates and proteins) by inducing EPS catabolism and WAS disintegration, and obtained the highest VFAs yield of 7049.43 mg/L. The proportion of VFA composition can be controlled by modifying the types and amounts of added bioenzymes. Under SL and laccase co-pretreatment conditions, RWHs were more efficiently converted into VFAs due to the higher activity of WAS, resulting in lower cellulose (3.41%) and lignin (0.66%) content in the fermentation broth. Compared with other pretreatments, SL and laccase co-pretreatment enhanced the enrichment of the functional microorganisms, including anaerobic fermentation bacteria (Firmicutes, Bacteroidota, and Proteobacteria) and reducing bacteria (Acinerobacter and Ahniella). Therefore, the combination pretreatments might be a promising solution for strengthening VFA accumulation in the WAS and RWH co-fermentation. Full article

For the pulsed data streams emitted by multiple signal sources that generate aliasing, traditional density clustering algorithms have the problems of poor clustering effect, heavy reliance on manual experience to set the parameters, and the need to carry out density clustering every time new data are input, resulting in a huge amount of computation. Therefore, an online density clustering algorithm based on the improved golden sine whale optimization is proposed. First, by adding new parameters to the density clustering algorithm, the neighborhood is changed from a single parameter Eps to a joint decision of the parameters Eps and $\theta$, which avoids cross-cluster expansion by more flexibly delimiting the neighborhood range. The improved golden sine whale optimization algorithm is then used to obtain the optimal parameter solution of the DBSCAN algorithm. Finally, the idea of flow clustering is introduced to determine whether a pulse belongs to a valid library, an outlier library, or an inactive library by comparing the distance between the input pulse and each cluster center, effectively reducing the number of pulses required for analysis. The experiment proves that the algorithm improves the sorting accuracy by 57.7% compared to the DBSCAN algorithm and 37.8% compared to the WOA-DBSCAN algorithm. Full article

Background: Despite significant advancements in HIV prevention, Africa continues to bear a disproportionately high burden of new infections. Pre-exposure prophylaxis (PrEP) has demonstrated over 90% efficacy in preventing HIV acquisition when taken consistently; however, its implementation and uptake across African countries remain suboptimal. Objective: This scoping review aims to systematically map existing literature on PrEP uptake and implementation in Africa, identify key barriers and facilitators influencing access and adherence, examine targeted population groups, and explore policy and programmatic approaches to PrEP delivery across diverse African contexts. Methods: The review will follow the methodological framework proposed by Arksey and O’Malley, refined by Levac et al., and will include comprehensive searches of electronic databases, grey literature, and official reports. Data will be thematically synthesized to identify research trends, gaps, and contextual variations. Expected Outcomes: The findings will provide a comprehensive overview of the current landscape of PrEP implementation in Africa, highlighting research trends, contextual variations across countries, and gaps in service delivery and policy frameworks. This will inform future implementation strategies, guide evidence-based approaches to enhance PrEP uptake, and support policymaking to scale up effective interventions across diverse African settings, ultimately contributing to HIV prevention efforts on the continent. Full article

Distention of the urinary bladder wall during filling stretches the urothelium and induces the release of chemical mediators, including adenosine 5′-triphosphate (ATP) and prostaglandins (PGs), that transmit signals between cells within the bladder wall. The urothelium also releases soluble nucleotidases (s-NTDs) that control the availability of ATP and its metabolites at receptor sites in umbrella cells and cells deeper in the bladder wall, as well as in the urine. This study investigated whether PGs regulate the intravesical breakdown of ATP by s-NTDs. Using a murine decentralized mucosa-only bladder model and an HPLC technology with fluorescence detection, we evaluated the decrease in ATP and increase in ADP, AMP, and adenosine (ADO) in intraluminal solutions (ILS) collected at the end of physiological bladder filling. PGD₂, PGE₂, and PGI₂, but not PGF_2α, inhibited the conversion of AMP (produced from ATP) to ADO, likely due to a suppressed intravesical release of s-AMPases. The effects of exogenous PGD₂, PGE₂, and PGI₂ were mediated by DP1/DP2, EP2, and IP prostanoid receptors, respectively. Activation of either DP1 or DP2 receptors by endogenous PGD₂ also led to AMP increase and ADO decrease in ILS-containing ATP substrate. Finally, PGs produced by either COX-1 or COX-2 inhibited the hydrolysis of AMP to ADO. Together, these observations suggest that (1) endogenous PGs (chiefly PGD₂, and to lesser degree PGE₂ and PGI₂) allow release of s-NTDs like s-ATPases and s-ADPases but impede the formation of ADO from intravesical ATP by inhibiting the release of s-NTDs/s-AMPases; (2) it is possible that high concentrations of PGD₂, PGE₂ and PGI₂, as anticipated in inflammation or bladder pain syndrome, delay the ADO production and prolong the action of excitatory purine mediators; and (3) either COX-1 and COX-2 are constitutively expressed in the mouse bladder mucosa or COX-2 is induced by distention of the urothelium during bladder filling. Full article

The use of thermal insulation material in building envelopes is closely related to economic benefits, energy-savings, and carbon reduction of buildings. The construction forms of different components in building envelopes have an important influence on the optimization design of thermal insulation in building envelopes. In this study, an integrated optimization approach is proposed to search for the best solution of thermal insulation in external walls and the optimal combination scheme of different construction forms of envelope components in granaries. The integrated optimization approach consists of an orthogonal experimental design (OEDM) method-based determination module of an optimal combination scheme of different construction forms of components, an assessment model-based quantitative analysis module, and an integrated assessment indicator-based selection module of the best solution of external wall insulation. Firstly, the OEDM method is used to determine the optimal combination scheme of different construction forms of the foundation wall of an external wall, thermal insulation material, external window, roof, and floors in buildings. Secondly, integrated economic, energy, and carbon analysis models are developed to analyze comprehensive performance of external wall insulation. Finally, an integrated assessment indicator consisting of an energy balanced index, a carbon balanced index, and weight coefficients is presented to determine the best solution of external wall insulation. The applications of this optimization approach in different ecological grain storage zones in China demonstrated that the outdoor air temperature characteristics could affect the comprehensive performance of external wall insulation in granaries, significantly. The best solution of external wall insulation in granaries in Turpan city, Daqing city, Kaifeng city, Changsha city, Anshun city, and Danzhou city was expanded polystyrene insulation (EPS) with a layer thickness of 0.078 m, 0.048 m, 0.083 m, 0.089 m, 0.062 m, and 0.131 m, respectively. The greatest difference in the lowest entire construction cost and the lowest carbon emission of external wall insulation among different typical climate regions in China was 12.987 USD/m² and 6.3 kgCO2e/m², respectively. Full article

Extended-reach drilling (ERD) offers substantial economic and operational benefits by accessing extensive reservoir sections with fewer surface facilities, yet poses significant frictional challenges due to complex wellbore geometries and extreme operating conditions. This study introduces a multi-interface lubrication evaluation framework. It systematically assesses oil-based drilling fluids (OBDFs) across three downhole contact scenarios: metal–rock, metal–mud cake, and metal–metal interfaces under HTHP conditions. We developed a quantitative, normalized scoring system. Benchmarked against distilled water (score 0) and W1-110 mineral oil (score 100), it integrates frictional data from various tests into a unified metric for lubricant comparison. Three candidate lubricants—PF-LUBE EP, PF-LUBE OB, and CX-300—were evaluated at varying dosages, lithologies, and applied loads. Results show that at 2 wt%, PF-LUBE EP achieved the most consistent performance, reducing friction coefficients by 36.8% (metal–rock), 27.5% (metal–mud cake), and 32.5% (metal–metal), with a normalized average score of 155.39, outperforming PF-LUBE OB and CX-300 by 12.5% and 18.3%, respectively. Its superior performance is attributed to a bionic dual-layer film formed by organophosphorus anchoring and alkyl slip layers, enabling self-healing and stability under cyclic loading and HTHP environments. PF-LUBE OB and CX-300 also demonstrated friction reduction but with lower normalized scores (138.06 and 131.27), reflecting less stability across varied conditions. The proposed framework bridges the gap between laboratory testing and field-scale application by capturing multi-interface behaviors, enabling objective lubricant selection and dosage optimization for complex ERD operations. These findings not only validate PF-LUBE EP as a robust additive but also establish a scalable methodology for the development and optimization of next-generation OBDF formulations aimed at reducing torque, drag, and equipment wear in challenging drilling environments. Full article

Expandable polystyrene (EPS) nozzle covers can be used to replace traditional metal nozzle covers due to their excellent mechanical properties, as well as being lightweight and ablatable. As an important part of the solid rocket motor, the nozzle cover needs to be designed according to the requirements of the overall system. This study lays a theoretical foundation for the engineering design and performance optimization of the EPS nozzle cover. In this paper, the method of combining test research and numerical simulation is used to explore the pressure bearing capacity of EPS nozzle covers with different thicknesses under linear load. Firstly, the quasi-static tensile, compression and shear tests of EPS materials were carried out by universal testing machine, and the key parameters such as stress-strain curve, elastic modulus and yield strength were obtained; Based on the experimental data, the constitutive model of EPS material with respect to density is fitted and modified; The VUMAT subroutine of the material was written in Fortran language, and the mechanical properties of the nozzle cover with different material model distribution schemes and different thicknesses were explored by ABAQUS finite element numerical simulation technology. The results indicate that the EPS nozzle cover design based on the two material model allocation schemes better aligns with practical conditions; when the end thickness of the EPS nozzle cover exceeds 3 mm, the opening pressure formula for the cover based on the pure shear theory of thin-walled circular plates becomes inapplicable; the EPS nozzle cover exhibits excellent pressure-bearing capacity and performance, with its pressure-bearing capacity showing a positive correlation with its end thickness, and an EPS nozzle cover with a 9 mm end thickness can withstand a pressure of 7.58 MPa (under internal pressure conditions); the pressure-bearing capacity of the EPS nozzle cover under internal pressure conditions is higher than under external pressure conditions, and when the end pressure-bearing surface thickness increases to 9 mm, the internal pressure-bearing capacity is 3.13 MPa higher than under external pressure conditions. Full article

Glucagon-like peptide 1 (GLP-1), a hormone derived from the proglucagon gene, regulates various physiological processes; however, its impact on pregnancy outcomes remains poorly understood. Assessing the effects of GLP-1 on neonates is vital as GLP-1 is increasingly administered during pregnancy. This study evaluates the effect of GLP-1 exposure on maternal complications and neonatal defects in mice. Pregnant female A/J mice received subcutaneous injections of recombinant GLP-1 (rGLP-1; 1000 nmol/kg) on embryonic day 1 (EP, early pregnancy) or day 15 (E15, late pregnancy). Maternal and neonatal body weights, morphology, and mortality were recorded, and mRNA sequencing was conducted to analyze gene expression in neonatal tissues. Maternal body weight decreased following rGLP-1 exposure, and pups born to both the early and late exposure groups experienced significant weight loss. Pups in the late exposure group exhibited uniform skin detachment and a dramatically higher mortality rate than those born to the early exposure group. Further, RT-PCR analysis confirms the significantly increased expression of selected genes in the skin and associated pathogenesis. RNA sequencing of pups’ skin, brain, lung, and liver tissues from the late exposure group showed altered gene expression. Since maternal weight loss, increased neonatal mortality, and altered gene expression have been observed, GLP-1 receptor agonists (GLP-1RAs) should be avoided during pregnancy. Full article

Global warming and rapid urban industrialization are profoundly transforming land-use patterns and carbon storage capacity in terrestrial ecosystems. A rigorous analysis of spatiotemporal variations in regional land-use changes and carbon storage dynamics provides critical insights for sustainable land-use planning and ecological security, particularly within the context of achieving carbon peaking and carbon neutrality targets. In this study, the PLUS-InVEST model was coupled with climate change and policy constraints to construct six future scenarios. We analyzed the characteristics of land-use evolution and the spatial and temporal changes in carbon storage in the Sanjiangyuan region from 2000 to 2020. We also predicted the potential impacts of land-use shift on carbon storage. The results show the following: (1) Land-use transitions exerted significant impacts on carbon stock. The Sanjiangyuan region experienced a net carbon stock reduction of 9.9 × 10⁶ t during 2000–2020, with the most pronounced decline (6.1 × 10⁶ t) occurring between 2000 and 2010. (2) Under the same climate scenario, the natural development (ND) scenario exhibited decreasing carbon reserves relative to 2020 baseline levels. Notably, land-use planning scenarios demonstrated spatially heterogeneous impacts, with the ecological protection (EP) scenario consistently maintaining higher carbon stocks compared to the ND scenario. (3) Multivariate driver interactions exerted stronger control over spatial carbon storage patterns than any individual factor. These findings inform targeted land-use management strategies to enhance regional carbon sequestration capacity, promote sustainable development, and support China’s carbon peaking and neutrality objectives. Full article