Nanomedicines have emerged as a potent anti-tumor strategy with tremendous progress. However, complex structure of integrating different or even opposing nanoproperties into one nanomedicine to improve overall delivery efficiency after intravenous injection hampers clinical translation. Cell membrane-coated biomimetic nanomedicines (CMC-BNs) have been considered as rationally designed next-generation nanomedicines with high therapeutic efficacy, among which blood cell-derived cellular nanosponges (CTI-005) and immunotherapeutic nanomedicines (CE120) have already completed investigational new drug (IND) applications for clinical trials. Whereas, we are conscious of many challenges that need to be addressed before CMC-BNs can move from laboratory studies to clinical applications in solid tumor theranostics, especially the limited intrinsic targeting ability that leads to insufficient tumor penetration and cellular internalization. To overcome the Achilles’ heel, we comprehensively summarize the current state-of-the-art in active targeting strategies, rational design and potential applications, aiming to figure out the potential future directions and provide insights for CMC-BNs clinical translation.

In spite of significant efforts to investigate the ability of hydrogenated and fluorinated graphene to conduct heat, little research has focused particularly upon their other thermal properties, such as thermal contraction and heat capacity, which have implications for the development of thermal nanotechnology. In an attempt to determine these thermal properties, a few experiments have been carried out, with rather conflicting results. In the present study, calculations were performed using molecular dynamics to investigate the thermal properties of graphane and fluorographene and especially the phenomena involved. The thermal expansion coefficients and heat capacities of the two-dimensional materials were determined at different temperatures. The results indicated that graphane is thermally contracted more significantly than graphene. The calculated molar heat capacity at constant volume is about 25.00 J/(mol·K) for graphene and about 29.26 J/(mol·K) for graphane. The specific heat capacity of fluorographene is always lower than that of graphane. A negative relationship does exist between the binding energy and the temperature.Keywords: Carbon materials; Material properties; Thermal contraction; Structural configurations; Molecular dynamics; Thermal phenomena

Triboelectric nanogenerators (TENGs) are emerging as new technologies to harvest electrical power from mechanical energy. With the distinctive working mechanism of triboelectric nanogenerators, they attract particular interest in healthcare monitoring, wearable electronics, and deformable energy harvesting, which raise the requirement for highly conformable devices with substantial energy outputs. Here, a simple, low-cost strategy for fabricating stretchable triboelectric nanogenerators with ultra-high electrical output is developed. The TENG is prepared using PTFE micron particles (PP-TENG), contributing a different electrostatic induction process compared to TENG based on dielectric films, which was associated with the dynamics of particle motions in PP-TENG. The generator achieved an impressive voltage output at 1000 V with current of 25 µA over a contact area of 40×20 mm2. Additionally, the TENG exhibits excellent durability with a stretching strain of 500%, and the electrical output performance does not show any significant degradation even after 3000 cycles at a strain of 400%. The unique design of the device provides high conformability and can be used as a self-powered sensor for human motion detections.

Background This study assessed the risk of Drug reaction with eosinophilia and systemic symptoms (DRESS) associated with various glycopeptide antibiotic treatments, including vancomycin and linezolid. Methods Disproportionality and Bayesian analyses were conducted on data spanning from the first quarter of 2006 to the first quarter of 2023, extracted from the Food and Drug Administration Adverse Event Reporting System, to delineate the signal discrepancies associated with glycopeptide antibiotic-induced DRESS. Results In the studied cohort, a total of 11,155,106 cases were identified, with the majority of affected individuals falling within the 18 to 44 age range. DRESS syndrome was most frequently reported in association with vancomycin and linezolid treatments. Disproportionality and Bayesian analyses revealed a strong association between vancomycin and the occurrence of DRESS. An intraclass correlation analysis comparing vancomycin and linezolid in relation to DRESS syndrome yielded a ranking with vancomycin demonstrating a higher Reporting Odds Ratio (ROR=54.21; 95% Confidence Interval [CI]: 50.00–58.78) than linezolid (ROR=4.04; 95% CI: 2.97–5.49). Additionally, the outcomes of DRESS syndrome induced by vancomycin and linezolid were observed to differ. Conclusions Utilizing data from the Food and Drug Administration Adverse Event Reporting System database, it was determined that vancomycin exhibits a significant association with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Furthermore, among the glycopeptide antibiotics, vancomycin and linezolid were identified as having the highest risk of inducing DRESS syndrome. However, due to potential indication bias, additional clinical research is imperative to ascertain the safety profile of glycopeptide antibiotics conclusively.

Since soil organic nitrogen (N) accounts for over 90% of total soil N, it is a vital indicator of soil fertility. However, there remains an insufficient understanding of the impacts of changes in vegetation restoration maturity on soil ON. Therefore, this study examined arable land and restored grassland, shrub-grassland, shrub, and woodland of 5 a, 15 a, 20 a, and 40 a restoration maturity, respectively to characterize changes in soil ON fractions in the 0–40 cm soil layer and how these changes are regulated by environmental factors. Large changes in soil ON fractions were observed in the 0–40 cm soil stratum of 15-a grassland. TAN, AMN, ASN, AAN, and TUN exceeded those in control (CK) by 26.70%, 22.80%, 26.08%, 31.50% and 28.77%, respectively. AIN of 20-a shrub and 15-a scrub grassland exceeded those of cultivated land by 19.8% and 5.66%, respectively. AIN of 15-a grassland exceeded other vegetation restoration maturities and facilitated soil N accumulation. The rank of the ON components according to proportion was AIN> TUN > AMN > AAN > ASN. AN, TN and SOC had the greatest effects on ON fractions of the soil, whereas powder and pH had no impacts. The results suggest that vegetation restoration can increase the ON content and N sequestration function. The results of this study can act as a scientific reference for soil quality restoration.

A document by Layla Sorkatti. Click on the document to view its contents.

To develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness of fit (GOF) plots and visual-predictive checks (VPC) confirmed acceptable description of the data. The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections for 100 mg and 75 mg.

Youth engage in various forms of aggression both in-person and online, and myriad past studies have explored the antecedents and adverse consequences of these malicious behaviors. The general assumption posits that cyberaggressive acts are compounded by the interplay of different personal, relational, and contextual factors. Therefore the present study assessed the co-occurrence of educational difficulties and different paths of online aggression in middle school students. 959 culturally diverse adolescents from Turkey and Poland, aged 10 to 15 years old were surveyed in a cross-sectional study design in 2022 year. The CATQ scale for assessing Cyberaggression Types, the ESSBS for measuring school burnout, and the 1-item on current school stress as an indicator of school stress management skills were used to measure adolescent characteristics. Latent profile analysis was used to identify profiles of individuals according to involvement in different forms of cyberaggression. Three profiles were observed: low-cyberaggressive adolescents; (2) impulsive cyberperpetrators (n=70); and (3) moderately controlled online aggressive adolescents (n=162). Students from Poland, who reported high levels of exhaustion due to school duties, high burnout due to parental pressure, and loss of interest in school activities had increased odds of being in the Profile with the highest scores in the CATQ scale when compared to the other two profiles. This study confirmed the need for school-based intervention programs to address cyberspace malicious acts using a whole-school and family approach as well as improving intrapersonal skills. The findings also highlight the importance of including an ecological perspective for assessing comprehensive prevention efforts.

A document by Lingyu Fu. Click on the document to view its contents.

In this contribution we present tritium-3He (3H-3He) apparent ages and hydrographic data from 21 expeditions spanning 27 years of Arctic Ocean section work (1987 to 2013) to estimate flow paths and spreading velocities of the Atlantic Waters (AW) circulation on a pan-Arctic scale. Tracer data independently reveal and add a time dimension to the well-organized boundary current that cyclonically flows along the continental slope and add insights into the other circulation branches of the Atlantic layer, hypothesized to be guided by deep topography (Rudels, et al., 1994). Mean spreading velocities differ between the individual branches of the overall circulation pattern. The velocity of the boundary current, as derived from tracer measurements, is approximately 0.8 to 1.5 cm s-1, with no significant difference between the upper and lower Atlantic Water layer. The tritium-3He tracer data show that within the limits of our method the current flow system has been stable over the study period.

Introduction: Heart failure (HF) and type 2 diabetes mellitus (DM2) are global health problems that often lead to muscle atrophy. These conditions are associated with increased autophagy and apoptosis in the muscle cells, resulting in decreased muscle mass. Materials and methods: Male rats were assigned to one of four groups: control (CT), HF+DM (disease model), exercise+HF+DM (EX+HF+DM), and EX+HF+DM+photobiomodulation (EX+HF+DM+PBM). To induce DM2, we administered streptozotocin (0.25 ml/kg, i.p.). HF was induced by coronary ligation. One week post-induction, an eight-week aerobic exercise and PBM protocol was initiated. Western blot analysis was used to measure the expression of apoptosis-related proteins and autophagy. Results: The EX+HF+DM+PBM group showed a substantial increase in Nrf2, p-AKT, and LC3-I levels compared to the HF+DM group. Conclusion: These findings suggest that physical exercise combined with PBM can upregulate proteins that promote myocyte survival in rats with HF and DM2.

Background. Recalcitrant frontal sinusitis in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have a negative impact on quality of life due to frontal pain and a high risk of sinus occlusion, thus necessitating repeated courses of antibiotics, systemic corticosteroids, and multiple surgeries. Objective. The aim of this study was to investigate if the use of biologics can improve symptoms including facial pain and reduce use of rescue treatments in patients with severe uncontrolled CRSwNP and concomitant recurrent frontal sinusitis. Materials and Methods. This is a real-life, observational, no-profit case series. Between November 2022 and December 2023, we enrolled cohort of 10 patients with severe uncontrolled CRSwNP and concomitant recurrent frontal sinusitis associated to invalidating facial pain measured by MIDAS score and that were treated with dupilumab 300 mg every 2 week and followed for at least 12 months. Results. the mean MIDAS score decreased from 45.6±10.7 at baseline to 1.3±2.3 at 6 months (p<0.05). The same trend was observed for VAS craniofacial pain: from 7.3±1.6 at baseline to 1.2±1.5 at 6 months (p<0.05). The use of systemic corticosteroids and analgesics was significantly reduced. No patient needed oral corticosteroids during treatment with dupilumab (p<0.05), and the use of analgesics decreased from 9.6±3.1 mean brief cycles of NSAIDs at baseline to 0.6±1.3 at 1 year of follow-up (p<0.05). Discussion. Our results demonstrated that use of an anti-type-2 inflammatory pathway biologic can improve symptom control including recurrent craniofacial pain and reduce the need for rescue medical treatments in patients with severe uncontrolled CRSwNP and concomitant recurrent frontal sinusitis.

This paper presents a theoretical inquiry into the domain of artificial intelligence (AI). It investigates a multicameral system, which is a popular scheme in state governance. It investigates the system’s applicability to produce failsafe AI alignment. Decision making by parliaments is often structured as a bicameral system, enabling control of those socio-economic systems, which complexity exceeds complexity of the decision makers. This feature is of interest for the AI-systems that are operating beyond Artificial General Intelligence threshold. The paper answers the question, if AI were organized according to the multicameral governance principle, how far can it be benign. The analysis also elucidates the decision making limits in social systems. The paper hints, if a bicameral parliament were as objective as AI, how complex tasks could be entrusted before the legislative body utterly commits a treason against the constituency. This paper presents a formal information system architecture that mimics the multicameral system. A sobriquet for the architecture is Serial Comptroller Network (SCN). It implements a human-assisted, uninterpretable alignment approach. The discussion focuses on a minimalistic solution within the architectural formalism. An assessment for its digital potential, utility, deficiencies and further improvement options are presented to advance AI research, as well as to aid decision making sophistication in structured socio-economic entities.

Context: Scientific research, increasingly reliant on data and computational analysis, confronts the challenge of integrating collaboration and data sharing across disciplines. Collaborative frameworks that support decentralized decision-making and knowledge-sharing are essential, yet integrating them into computational environments presents technical challenges, such as decentralized identity, user-centered policy-making, flexible asset management, automated provenance, and distributed collaborative workflow management. Solution: This study introduces a conceptual framework and its prototype implementation called Decentralized Virtual Research Environment (D-VRE). This approach enhances seamless, trusted data sharing and collaboration within research lifecycles. It incorporates custom sharing policies, secure asset management, collaborative workflows, and research activity tracking, all without centralized oversight. Evaluation: Demonstrated through a real-world case study in the CLARIFY project, the prototype of the decentralized virtual research environment proved effective in enabling advanced data sharing and collaborative scenarios, showcasing its adaptability in scientific research. Results: Integrated into JupyterLab, D-VRE supports custom collaboration agreements and smart contract-based automated execution on the Ethereum blockchain. This ensures secure, verifiable transactions and promotes trust and reliability in shared research findings. Contribution: D-VRE addresses barriers to scientific research collaboration and data sharing, offering a scalable and adaptable decentralized model. This model promotes a more inclusive, efficient, and trustworthy research ecosystem, paving the way for future advancements in virtual research environments.

Genetic analyses of host-specific parasites can elucidate the evolutionary histories and biological features of their hosts. Here, we used population-genomic analyses of ectoparasitic seal lice (Echinophthirius horridus) to shed light on the postglacial history of seals in the Arctic Ocean and the Baltic Sea region. One key question was the enigmatic origin of relict landlocked ringed seal populations in lakes Saimaa and Ladoga in northern Europe. We found that that lice of four postglacially diverged subspecies of the ringed seal (Pusa hispida) and Baltic gray seal (Halichoerus grypus), like their hosts, form genetically differentiated entities. Using coalescent-based demographic inference, we show that the sequence of divergences of the louse populations is consistent with the geological history of lake formation. In addition, local effective population sizes of the lice are generally proportional to the census sizes of their respective seal host populations. Genome-based reconstructions of long-term effective population sizes revealed clear differences among louse populations associated with gray vs. ringed seals, with apparent links to Pleistocene and Holocene climatic variation as well as to the isolation histories of ringed seal subspecies. Interestingly, our analyses also revealed ancient gene flow between the lice of Baltic gray and ringed seals, suggesting that the distributions of Baltic seals overlapped to a greater extent in the past than is the case today. Taken together, our results demonstrate how genomic information from specialized parasites with higher mutation and substitution rates than their hosts can potentially illuminate finer scale population genetic patterns than similar data from their hosts.

A document by Juan Añon-Hidalgo. Click on the document to view its contents.

Protein cis-regulatory elements (CREs) are regions that modulate the activity of a protein through intramolecular interactions. Kinases, pivotal enzymes in numerous biological processes, often undergo regulatory control via inhibitory interactions in cis. This study delves into the mechanisms of cis regulation in kinases mediated by CREs, employing a combined structural and sequence analysis. To accomplish this, we curated an extensive dataset of kinases featuring annotated CREs, organized into homolog families through multiple sequence alignments. Key molecular attributes, including disorder and secondary structure content, active and ATP-binding sites, post-translational modifications, and disease-associated mutations, were systematically mapped onto all sequences. Additionally, we explored the potential for conformational changes between active and inactive states. Finally, we explored the presence of these kinases within membraneless organelles and elucidated their functional roles therein. CREs display a continuum of structures, ranging from short disordered stretches to fully folded domains. The adaptability demonstrated by CREs in achieving the common goal of kinase inhibition spans from direct autoinhibitory interaction with the active site within the kinase domain, to CREs binding to an alternative site, inducing allosteric regulation revealing distinct types of inhibitory mechanisms, which we exemplify by archetypical representative systems. While this study provides a systematic approach to comprehend kinase CREs, further experimental investigations are imperative to unravel the complexity within distinct kinase families. The insights gleaned from this research lay the foundation for future studies aiming to decipher the molecular basis of kinase dysregulation, and explore potential therapeutic interventions.

The RETERO project develops new methods to Reduce, Replace and Refine (3R-principle) animal experiments for assessing the risk of harm to fish when passing through turbines or pumps. Since behavior of fish influences the mortality risk during turbine and pump passages, knowledge about species-specific behavior and its triggers are necessary. A primary objective of the RETERO project is the study of fish behavior in hydraulic conditions similar to turbine and pump intakes. Therefore, an experimental conduit was constructed at the Hubert-Engels Laboratory of Technische Universität Dresden (Germany) specifically for the RETERO project’s study on fish behavior, equipped with a 3D camera infrared tracking system. The conduit was designed to model hydraulic conditions typical for turbine and pump intakes. In the experimental setup the effects of flow velocities exceeding the maximum swim speed of fish, as well as spatial velocity gradients and illumination conditions, on the fish behavior are studied. The data from studies involving brown trout ( Salmo trutta) allow for an analysis of how these fish react to flow accelerations and velocities surpassing their sprint speed, using quantitative metrics for movement and activity. An initial evaluation of these experiments highlights the potential of this approach for further research.

In this paper, we present a new cutting plane method, a variant of Kelley’s cutting plane method. Since the new algorithm, termed a globally cutting hyperplanes algorithm, can solve a nonlinear optimization program we are motivated in this work to present the theory and illustrations. Earlier, authors have reported another variant of Kelley’s cutting plane method termed a sharp-cut algorithm. The new algorithm too is based on successive linear programming principle and has a convergence rate at par with the sharp-cut algorithm. The new algorithm was also able to find multiple optimum solutions by varying a parameter in the algorithm. Two test examples are solved using the algorithm. We then solve a two-point boundary value problem using the new algorithm for the first time. A challenging nonlinear optimization problem from Hock and Schittkowsky (1981) is solved next. Lastly, an application example of profit maximization of an alkylation plant is presented.

Amyloidosis are a group of diseases in which soluble proteins aggregate and deposit in fibrillar conformation extracellularly in tissues. The effectiveness of therapeutic strategies depends on the specific protein involved, being crucial to accurately determine its nature. Moreover, following the diagnosis, the search for the mutation within relatives allows the clinical advice. Here we report the precise diagnosis and explored the possible reasons of the structural pathogenicity. Whole exome sequencing and GATK calling pipeline were leveraged to characterize the protein variant present in a patient with kidney failure. Bioinformatics strategies were applied to suggest potential explanations of the variants aggregation. Our pipeline allowed the identification of a single point variant of fibrinogen Aα chain, which opened the possibility of curative transplantation. I n silico structural analysis, suggested that the pathogenicity of the variant may be attributed to a heightened susceptibility to yield a peptide prone to deposit as an oligomer with a β-sheet structure. Exploiting the comprehensive coverage of whole genome sequencing we managed to fill a vacant stage in the diagnosis of hereditary amyloidosis and to stimulate the advancement in biomedicine.

In the realm of agribusiness, transformative shifts are underway, propelled by the growing demands and expanding scales of grain production. This evolution calls for a critical reevaluation of the existing paradigms in coffee production and marketing paradigms, with a specific focus on integrating Artificial Intelligence (AI). This work aims to review, synthesize, and summarize the available data regarding how Machine Learning (ML) has been used to detect and classify characteristics in coffee beans and leaves. For this purpose, a comprehensive literature review of the most significant research contributions describing the application of AI for advanced classification techniques in coffee agriculture has been carried out. Our analysis suggests that implementing AI technologies allows the classification of coffee, encompassing various attributes such as maturity, roast intensity, disease identification, flavor profiles, and overall quality. More largely, this technological advancement holds the potential to revolutionize coffee farming by providing producers and agricultural specialists with sophisticated tools to enhance production efficiency, minimize costs, and improve the accuracy and confidence of their decision-making processes.

Background: It is necessary to evaluate the parental ability to achieve nutritional adequacy while avoiding allergens for children with food allergies (FA), yet this area is currently understudies. Our study aimed to develop and validate the Parental Self-Efficacy Scale for Dietary Management of Children with Food Allergies (PSED-FA). Methods: PSED-FA was developed through a literature review and semi-structured interviews, refined by a panel of five allergists and five dietitians, and validated using responses from caregivers of children with FA. The construction of the tool involved exploratory factor analysis (EFA), confirmatory factor analysis for model fit, and evaluation of internal consistency using Cronbach’s alpha. Convergent and divergent validity were assessed using the average variance extracted (AVE), maximum shared variance (MSV), and average shared variance (ASV). Results: Participants included nine focus interview groups, with 114 individuals in the validation group. Egg whites (55.2 %), tree nuts (35.2%), and peanuts (22.8%) were the most common allergens. The EFA identified three factors: preparing allergen-free meals, knowledge of nutrition management, and management of food restrictions. The goodness of fit of our model met all the criteria. The tool showed high internal consistency (overall Cronbach’s alpha: 0.902) and met the criteria for both convergent (AVE >0.5) and divergent validity (AVE >MSV and ASV). Conclusion: This study validated a reliable and effective tool for assessing parental self-efficacy in managing the dietary needs of children with FA. This tool can aid health professionals in evaluating parental confidence and identifying areas for improving dietary management in children with FA.

In this paper, we use a stochastic partial differential equation (SPDE) as a model for the density of a population under the influence of random external forces/stimuli given by the environment. We study statistical properties for two crucial parameters of the SPDE that describe the dynamic of the system. To do that we use the Galerkin projection to transform the problem, passing from the SPDE to a system of independent SDEs; in this manner, we are able to find the Maximum likelihood estimator of the parameters. We validate the method by using simulations of the SDEs. We prove consistency and asymptotic normality of the estimators; the latter is showed using the Malliavin-Stein method. We illustrate our results with numerical experiments.

Background: Mast cells are the major effector cells that mediate IgE-dependent allergic reactions via high-affinity IgE receptors. We sought to use integrated network analysis to identify genomic biomarkers associated with high response in IgE-mediated activation of primary human mast cells. Methods: Primary human mast cell cultures derived from a cohort of 262 normal donors were categorized into High, Average and Low responder groups according to their activation response profiles. Microarray analysis followed by qPCR was used to identify genes that were differentially expressed in different responder cultures in their baseline conditions. The data were analyzed by constructing personalized perturbed profile (PEEP). Results: Data derived from qPCR validation of 8 selected genes that exhibited differential expression in the High responder group showed extensive heterogeneity. For upregulated genes, construction of PEEP for each individual sample of all 3 responder groups revealed that High responders exhibited higher percentage of “perturbed” samples whose PEEP values lied outside the normal range of expression. Moreover, the integration of PEEP of 4 selected upregulated genes into distinct sets of combinatorial profiles demonstrated that the specific pattern of upregulated expression of these 4 genes, in a tandem combination, was observed exclusively among the High responders. Conclusion: PEEP analysis was used to integrate the PEEP of a set of signature genes to construct a distinct combinatorial gene expression pattern for each individual sample. Such combinatorial approach was useful in identifying a set of genomic biomarkers that are associated with high degranulation response in human mast cell cultures derived from the blood of a cohort of normal donors.