In recent decades, porous scaffolds for bone tissue engineering (BTE) have gained significant attention. Considerable research efforts have been dedicated to investigating the impact of scaffold pore size on a diverse array of biological processes, including cell-scaffold interactions, substance transportation, and vascularization. However, the multi-scale hierarchical porosity, a key structural characteristic of natural bone, has rarely been replicated in BTE scaffolds due to the challenges of controlling the scaffold structure across multiple length scales. With the advancement of manufacturing technology, there has been increasing research on biomimetic multi-scale hierarchical materials, which are also gaining favor in the field of BTE. Therefore, there is an urgent need to review multi-scale hierarchical porous BTE scaffolds. This paper aims to review the role and fabrication methods of multi-scale porous BTE scaffolds at different length scales, the design and manufacturing of new BTE scaffolds for bone regeneration.

Rollover prevention of partially-filled tank trucks is an industry teaser, with the core challenge being real-time perception and observation of the liquid state inside the tank. In order realize re-liable observation of sloshing liquid, this article firstly proposes a sloshing modeling method based on multi-degree-of-freedom pendulum model, and derives the double mass trammel pendulum model (DMTP, 2DOF) accordingly, which accurately reflects the sloshing dynamics under more pervasive working conditions. Secondly, a free surface fluctuation sensor is designed based on magnetostriction, capable of measuring the inclination and height of the liquid level inside tanks filled with hazardous chemical. Finally, the unscented Kalman filter (UKF) is utilized to synthesize the information of the two, establishing a credible real-time observation of the sloshing liquid. Verified through vehicle-fluid coupled co-simulation, under condition of con-secutive double lane change, observation error of the proposed method is only 25.9% that of the open-loop calculation, providing a secure guarantee for the observation of the state variables of the single pendulum model (SP) used for most kinds of anti-rollover controller.

Due to a shortage of funding and other market challenges, Small and Medium-sized Enterprises (SMEs) have a tough time adopting new technologies. Numerous technological obstacles nega-tively impact the long-term commercial achievement of SMEs. The deployment of Industry 4.0 might resolve several technological challenges. A sustainable city is a difficult structure whose economical, societal, and ecological components interact and compete with one another. There is a dearth of actual methodologies for measuring interaction. The objective of Industry 4.0 is to obtain a better degree of performance effectiveness and profitability, and greater automation. Conse-quently, the purpose of the research is to determine the influence of Industry 4.0 in fostering economic efficiency in small and medium enterprises' sustainability. A Sustainable City using Multi-Criteria Decision Making (SC-MCDM) system is designed in this research to test and achieve sustainable developmental goals. This paper then gives a technique for calculating the interaction between various standards, such as static interactions and dynamical pattern resemblance, as well as the weight variables of every indication generated by the connection. Furthermore, the ap-plication of the suggested technique is proved by assessing the sustainable development goals of twelve Chinese cities within the Triple Bottom Line (TBL) paradigm. From a geographic-temporal viewpoint, spatial variations in city sustainability reveal regional inequalities in sustainability. Indicator scores suggest that the lack of research spending, falling financing in stationary assets, shortage of financial development, and inadequate shared transit are the most significant limiting factors for most communities. Furthermore, the growth of tertiary industries, the improvement of energy performance, the expansion of green areas, and the reduction of pollution emissions are the key driving forces for enhancing sustainability. Compared to other methodologies, Multi-Criteria Decision Making (MCDM) considers the interplay between conditions, which is an excellent way to assess the sustainability of a city. The experimental findings show the impact of MCDM and sustainability to achieve sustainable development goals.

Some tumors occur in anatomical regions that are hard to biopsy with a needle. Such regions include the brain, spinal cord, liver, and lungs. For the latter two, magnetic nanoparticle-loaded macrophages could be intravenously infused and driven via an MRI machine into the tumor or tumors. Once there, they can be induced to phagocytose whole tumor cells. They would keep their target in a non-digested form by inhibiting phagosome maturation - and be directed via magnetotaxis or chemotaxis to an extraction point in the body where they can be more easily collected via needle.

Recently, deep learning models have been widely applied to modulation recognition, which have become a hot topic due to their excellent end-to-end learning capabilities. However, current methods are mostly based on uni-modal inputs, which suffer from incomplete information and local optimization. To complement the advantages of different modalities, we focus on the multi-modal fusion method. Therefore, we introduce an iterative dual-scale attentional fusion (iDAF) method to integrate multimodal data. Firstly, two feature maps with different receptive field sizes are constructed using local and global embedding layers. Secondly, the feature inputs are iterated into the Iterative Dual Scale Attention Module (iDCAM), where the two branches capture the details of high-level features and the global weights of each modal channel, respectively. The iDAF not only extracts the recognition characteristics of each specific domains, but also complements the strengths of different modalities to obtain a fruitful view. Our iDAF achieves a recognition accuracy of 93.5\% at 10dB and 0.6232 at full SNR. The comparative experiments and ablation studies effectively demonstrate the effectiveness and superiority of the iDAF.

To improve the accuracy of short-term multi-energy load prediction models for integrated energy systems, the historical development law of the multi-energy loads must be considered. Moreover, understanding the complex coupling correlation of the different loads in the multi-energy systems and accounting for other load-influencing factors, such as weather, may further improve the forecasting performance of such models. In this study, a two-stage fuzzy optimization method is proposed for the feature selection and identification of the multi-energy loads. To enrich the information content of the prediction input feature, we introduced a copula correlation feature analysis in the proposed framework, which extracts the complex dynamic coupling correlation of multi-energy loads and applies Akaike information criterion (AIC) to evaluate the adaptability of the different copula models presented. Furthermore, we combined a NARX neural network with Bayesian optimization and an extreme learning machine model optimized using a genetic algorithm to effectively improve the feature fusion performances of the proposed multi-energy load prediction model. The effectiveness of the proposed short-term prediction model was confirmed by the experimental results obtained using the multi-energy load time-series data of an actual integrated energy system.

In order to perform multi-degree-of-freedom motion measurements of marine machinery such as ship-borne mechanical platform in an absolute environment without a reference, absolute measurement methods using acceleration sensors and tilt gyroscopes are typically employed. However, due to the influence of wave forces on ship-borne mechanical platform, the coupling between different degrees of freedom can cause mutual interference, resulting in significant sensor measurement disturbances that make efficient computation and real-time analysis challenging. Specifically, when ship-borne mechanical platform swings, the proof mass of the acceleration sensor produces an undesirable signal output in the vertical direction, which leads to imprecise acceleration integration, thereby affecting accurate motion collection and posture estimation. To address these challenges, by analyzing the influence of the inclination angle of the ship-borne mechanical platform on the sensor measurement, and using the working principle of the acceleration sensor and angle sensor, a correction method for the motion measurement of the ship-borne mechanical platform based on multi-sensor fusion is proposed. In this article, we first analyze the influence of inclination angle on the integral effect in the heave direction. Then the configuration using four groups of acceleration sensors to correct the integral effect is proposed. Finally, the optimal inclination angle is determined through Kalman filtering based on the measured value of angle sensors and estimated values from the acceleration sensor sets. Experiments have proved that the average error of the corrected heave displacement signal is 25.34 mm, which is better than the integral displacement signal of a single acceleration sensor. At the same time, the acceleration sensor is used to calculate the roll angle and pitch angle of the ship-borne mechanical platform, and combined with the angle sensor signal to perform Kalman filtering, which filters out the errors caused by the shaking and instability of the mechanical platform, and can more accurately estimate the true inclination of the platform. Therefore, this method can enhance the precision and accuracy of the ship-borne mechanical platform motion signal acquisition, providing more valuable experimental data for research in marine engineering and related fields.

A single paragraph of about 200 words maximum. For research articles, abstracts should give a pertinent overview of the work. We strongly encourage authors to use the following style of structured abstracts, but without headings: (1) Background: Place the question addressed in a broad context and highlight the purpose of the study; (2) Methods: briefly describe the main methods or treatments applied; (3) Results: summarize the article’s main findings; (4) Conclusions: indicate the main conclusions or interpretations. The abstract should be an objective representation of the article and it must not contain results that are not presented and substantiated in the main text and should not exaggerate the main conclusions. This study presents a comprehensive literature review on the convergence of affective computing, interactive installation art, multi-dimensional sensory stimulation, and artificial intelligence (AI) in measuring emotional responses. It addresses the problem of understanding emotional response and measurement in the context of interactive installation art under artificial intelligence (AI). The study aims to fill the existing research gaps by examining three key aspects: sensory stimulation, multi-dimensional interactions, and engagement, which have been identified as significant contributors to profound emotional responses in interactive installation art. The study proposed approach involves conducting a process analysis of emotional responses to interactive installation art, aiming to develop a conceptual framework that explores the variables influencing emotional responses. The study will formulate hypotheses that make specific predictions about the relationships between sensory stimulation, multi-dimensional interactions, engagement, and emotional responses. By employing the ASSURE model combined with experimental design, the research methodology ensures a systematic and comprehensive study implementation. The implications of this project lie in advancing the understanding of emotional experiences in interactive installation art under AI, providing insights into the underlying mechanisms that drive these experiences. The contributions of this research include bridging the identified research gaps, refining theoretical frameworks, and guiding the design of more impactful and emotionally resonant interactive artworks. Ultimately, this research aims to contribute to the broader field of human-computer interaction and enhance the development of immersive and emotionally engaging interactive installations.

In recent years, how to combine intelligent prospecting algorithms such as random forest with a large number of geological and mineral data for quantitative prediction of exploration geochemistry has become an important topic of concern to quantitatively improve the accuracy of target delineation. The ore-forming geological conditions in the central Kunlun area of Xinjiang are great and have good prospecting prospects. However, due to the exhaustion of shallow deposits and the lag of geological prospecting work in the past ten years, there has been no expected breakthrough in the search for large and super-large metal deposits for many years. There has been a serious shortage of reserve resources. The use of new theories, new methods and new technologies for mineral resources investigation and evaluation has become an urgent need in the current prospecting work. In view of this, based on the existing spatial database of geological and mineral resources in the central Kunlun of Xinjiang, combined with the geological characteristics, genesis and metallogenic regularity of the area, this paper carried out a series of studies on gold polymetallic minerals with the help of geographic information system and data science programming software platform. The researchers integrated geological and regional geochemical data, and constructed a random forest metallogenic discriminant model based on two different sampling methods (integrated random undersampling and selection of training samples) to predict the mineralization of gold polymetallic minerals in the central Kunlun area of Xinjiang and delineate the metallogenic target area. The quantitative prediction of gold polymetallic mineral resources in the central Kunlun area of Xinjiang by two random forest models is compared and discussed: the known ore spots, fault structures and geochemical information are extracted, and the known gold polymetallic ore spots and geochemical data are used to form a training set and a prediction set to construct a machine learning random forest model. The results of prediction evaluation and metallogenic prospect division show that for different sampling methods, the performance evaluation parameters of the training process show that the prediction accuracy of the selected training samples is higher, and the selected training samples are more reliable because they can fully learn the complex information of the original data. In the metallogenic prospect prediction and metallogenic potential division, the random forest model of selecting training samples has more reference value and further exploration research significance in the production problem considering the actual exploration cost because of its small area of high potential prediction area and high proportion of ore bearing per unit area. At the same time, this study innovatively improves the prediction accuracy, reduces the exploration risk, and expands the prospecting idea of machine learning algorithm in mathematical geology in the central Kunlun area of Xinjiang. The delineated metallogenic potential area has positive guiding significance for the actual gold polymetallic prospecting work in this area.

Missing observation is a common problem in scientific and industrial experiments, particularly in a small-scale experiment. They often present significant challenges when experiment repetition is infeasible. In this research, we propose a multi-objective genetic algorithm as a practical alternative for generating optimal mixture designs that remain robust in the face of missing observation. Our algorithm prioritizes designs that exhibit superior D-efficiency while maintaining a high minimum D-efficiency due to missing observation. The focus on D-efficiency stems from its ability to minimize the impact of missing observations on parameter estimates, ensure reliability across the experimental space, and maximize the utility of available data. We study problems with three mixture components where the experimental region is an irregularly shaped polyhedral within the simplex. Our designs have proven to be D-optimal designs, demonstrating exceptional performance in terms of D-efficiency and robustness against missing observations. We provide a well-distributed set of optimal designs derived from the Pareto front, enabling experimenters to select the most suitable design based on their priorities using the desirability function.

Unmanned construction machinery vehicles mostly carry work in bridges, tunnels, and outdoor open spaces. Obtaining accurate pose estimation of the entire vehicle and establishing a map of the surrounding environment is of great significance for path planning and control in the later stage. Traditional simultaneous localization and mapping (SLAM) schemes, which mostly use a single sensor, but there are problems with localization drift and mapping failure in scenarios where there are few geometric features and the environment is prone to degradation. Currently, the multi-sensor fusion strategy has been proven to be an effective solution and widely used in the field of unmanned vehicle localization and mapping. This paper proposes a SLAM framework that tightly couples a LiDAR, IMU and camera to achieve accurate and reliable pose estimation. The framework is based on LiDAR-inertial system(LIS) and factor graph optimization theory. Texture information provided by vision is integrated into the LiDAR-inertial odometry to generate a new visual-inertial subsystem(VIS).The two subsystems, VIS and LIS, can assist each other and work jointly. Through real vehicle tests, the system can perform incremental, real-time state estimation, reconstruct dense 3D point cloud maps,and effectively solve the problems of localization drift and mapping failure in the lack of geometric features or challenging construction environments. Meanwhile, the system has a safety redundancy mechanism. When any subsystem fails, the system can also operate normally, to ensure the reliability and robustness of vehicle positioning.

The need for cohesive detection and defence methods against cyberattacks is significant now more than ever before to enforce security and privacy of user data and information. The inevitable increase in demand for home and flexible working from employees quite recently has meant there is a lack of awareness and training for cyberattacks. Hence, they have become prominent as attackers are aware of this and are benefitting from individuals’ lack of knowledge in how to better protect themselves and their confidential information. Employees are becoming more susceptible to such attacks and falling victim to these, resulting in economic losses for companies, data losses and decreased faith.

Multi-chiplet technique is expected to be a promising solution to achieve high-density system integration with low power consumption and high usage ratio. This technique can be integrated with glass interposer to accomplish a competitive low fabrication cost compared with the silicon-based interposer architecture. In this study, process-oriented stress simulation is performed by the element activation and de activation technique in finite element analysis architecture. Submodeling technique is also utilized to mainly conquer the scale mismatch and difficulty in mesh gridding design. It is used as well to analyze the thermomechanical responses of glass interposer with chiplet arrangement and capped epoxy molding compound (EMC) during curing. A three-factor, three-level full factorial design is applied using the analysis of variance method to explore the significance of various structural design parameters on stress generation. Analytic results reveal that the maximum first principal stresses of 130.75 and 17.18 MPa are introduced on the sidewall of Cu-filled via and the bottom of glass interposer, respectively. Moreover, the EMC thickness and through glass via pitch are the dominant factors in the adopted vehicle. They significantly influence the stress magnitude during heating and cooling.

Target detection and segmentation in synthetic aperture radar (SAR) images are vital steps for many remote sensing applications. In the era of data-driven deep learning, this task is extremely challenging due to the limited labeled data. Few-shot Learning has the ability to learn quickly from few samples with supervised information. Inspired by this, a few-shot learning framework named MSG-FN is proposed to solve the segmentation of ship targets in heterologous SAR images with few annotated samples. The proposed MSG-FN adopts a dual-branch network consisting of a support branch and a query branch. The support branch is used to extract features with an encoder, and the query branch uses a U-shaped encoder-decoder structure to segment the target in the query image. The encoder of each branch is composed of well-designed residual blocks combined with filter response normalization to capture robust and domain-independent features. A multi-scale similarity guidance module is proposed to improve the scale adaptability of detection by applying hand-on-hand guidance of support features to query features of various scales. In addition, a SAR dataset named SARShip-4i is built to evaluate the proposed MSG-FN and the experimental results show that the proposed method achieves superior segmentation results compared with the state-of-the-arts.

Water pollution is the main cause of global ecological degradation and seriously affects people's water supply. In order to respond to the water environmental protection policy and provide management departments with a basis for refining water quality, this paper used the environmental Gini coefficient (EGC) method based on four indicators such as water environmental capacity, population, land area, and gross domestic production (GDP) to represent social factors, economic factors, and environmental factors, respectively. After the optimization, for COD, the EGC based on the land area was 0.30, EGC based on population was 0.21, EGC based on environment capacity was 0.02, and the EGC based on GDP was 0.45, and the sum of EGC was 0.962. From this result, we observed that the change in the Gini coefficient of each indicator was not very big. Hence, the most significant change in the Gini coefficient was that of GDP, with a higher rate than other criteria. Then, the COD, AND, and TP discharge allocation model was constructed to obtain the total allocated discharge permit in Lushui Basin. The results found that the total discharge permit allocation of COD, AN, and TP to the Lushui basin were 51483.304 tons/year, 843.119 tons/year, and 340.926 tons/year, respectively. Based on the GIS spatial analysis technology, the distribution of unfair factors that cause pollution inequity was investigated. Finally, the reduction measures were proposed to implement environmental supervision and strengthen water environment management strictly.

As a new distributed machine learning (ML) approach, federated learning (FL) shows the great potential to preserve data privacy by enabling distributed data owners to collaboratively build a global model without sharing their raw data. However, the heterogeneity in terms of data distribution and hardware configurations make it hard to select participants from the thousands of nodes. In this paper, we propose a multi-objective node selection approach to improve time-to-accuracy performance while resisting malicious nodes. We firstly design a deep reinforcement learning assisted FL framework. Then the problem of multi-objective node selection under this framework is formulated as a Markov decision process (MDP), which aims to reduce the training time and improve model accuracy simultaneously. Finally, a deep Q-netwok (DQN) based algorithm is proposed to efficiently solve the optimal set of participants for each iteration. Simulation results show that the proposed method not only significantly improves the accuracy and training speed of FL, but has stronger robustness to resist malicious nodes.

Fast convergence routing is an important issue for LEO constellation network, due to its dynamical topology changing and time varying transmission requests. Most of existing research focus on the OSPF routing algorithm, which cannot handle the frequently links state changing of network. In this paper, we propose a Fast-Convergence Reinforcement Learning Satellite Routing Algorithm (FRL-SR) for LEO satellite networks, in which the satellite gets the network links status fast and adjusts its routing strategy. In FRL-SR, each satellite node is regarded as an agent. The agent selects the port for packet forwarding according to its own routing policy. When the satellite network state changes, agent would send ’hello’ packets to the neighbor node to update the neighbor node’s routing policy. Compared with traditional reinforcement learning, FRL-SR can perceive network information faster, and then converge faster. Also, FRL-SR can mask the dynamics of satellite network topology and adaptively adjust the forwarding strategy according to the link state. Various simulation is constructed, the results show that the proposed FRL-SR algorithm out performance the Dijkstra algorithm in performance of average delay, packet arriving ratio, network load balance.

The study sought to investigate the effect of Multi-choice Goal programming in project Portfolio Analysis, using Lagos State Project Portfolio from between 2017-2021 as a study case. Specifically, the objectives examined the effectiveness of multi-choice goal programming in analyzing the project Portfolio of Lagos State Government and investigated the possible lapses in the use of Multi-choice Goal programming in analyzing the project Portfolio of Lagos State Government. Data were gathered from the State financial Statements and analyzed using Lingo-17 Software. Based on the analysis, the study discovered that the goals formulated can be optimally and minimally attained as the positive deviational and negative deviational variables depict zero. This indicates that the cost incurred on the project portfolio was absolutely minimized during the period and at the same time; Lagos State Government derived the most preferred benefits from it. The study therefore concluded that the State minimized the project costs and at the same time maximized benefits while meeting its overall objectives.

In current study we have obtained Co2FeSi-glass coated microwires with different geometrical aspect ratio, ρ = d/Dtot (diameter of metallic nucleus, d and total diameter, Dtot). The structure and magnetic properties are investigated at a wide range of temperature. XRD analysis illustrates a notable changing in the microstructure by increasing the aspect ratio of Co2FeSi glass coated microwires. Amorphous structure is detected for the sample with the lowest aspect ratio (ρ = 0.23), whereas a growth of crystalline structure is observed in the other samples (aspect ratio ρ = 0.30 and 0.43). This change at the microstructure properties correlates with dramatic changing in magnetic properties. For the sample with the lowest ρ -ratio, non-perfect square loops are obtained with low normalized remanent magnetization. A notable enhancement in the squareness and coercivity are obtained by increasing ρ -ratio. Changing the internal stresses strongly affects the microstructure, resulting in a complex magnetic reversal process. The thermomagnetic curves show large irreversibility for the Co2FeSi with low ρ -ratio. Meanwhile, if we increase the ρ -ratio, the sample shows perfect ferromagnetic behavior without irreversibility. The current result illustrates the ability to control the microstructure and magnetic properties of Co2FeSi-glass-coated microwires by changing only their geometric properties without performing any addition heat treatment. The modification of geometric parameters of Co2FeSi glass-coated microwires allows to obtain microwires which exhibit an unusual magnetization behavior that offers opportunities to understand the phenomena of various types of magnetic domain structures, which is essentially helpful for designing sensing devices based on thermal magnetization switching.

This lack of information is due to the primary role of HSTs in fungal pathogenesis, which often masks the functions of NSTs and CWDEs. So, the toxic effects of A. alternata metabolites due to NSTs and CWDEs have received minor attention than those reported for HSTs mycotoxins [11]. A wider study of the activity of isolated fungal metabolites can allow the identification of compounds directly related to the pathogenic activity of the fungus, making it possible to create chemo libraries that facilitate the linking of the structure of the compounds with the species that produce it and its effect on host and non-host crops, as well as with biosynthetic features [12]. In this context, our work reports a study focused on NSTs and CWDEs used by an A. alternata strain isolated from infected pears in Italy. To this aim, the characterization of hydrolytic enzyme activities of A. alternata and the identification of the metabolites produced in vitro were performed. Furthermore, the phytotoxic activity of the isolated compounds was evaluated on pear (host and non-host varieties) and lemon fruits [13]. Finally, the competition of A. alternata with other pathogens was evaluated to investigate the role of NSTs on co-infections.

In order to improve the operation performance of the multi-stage double-suction centrifugal pump and reduce the internal energy loss of the pump, this paper proposes a single-objective optimization design method based on non-hierarchical response surface model (RSM) and the multi-island genetic algorithm (MIGA). Nine parameters, such as the blade outlet width and blade wrap angle, were used as design variables, and the optimization objective was the efficiency under design conditions. In total, 149 sets of valid data were obtained under the latin hypercube sampling method (LHS), the corresponding thresholds were set for efficiency and head, and 99 sets of valid data were obtained. A cross-validation analysis of the sieved data was carried out based on non-hierarchical RSM, global optimization of the efficiency was carried out using MIGA, and numerical verification was carried out via CFD. The research results show that compared with hierarchical RSM, non-hierarchical RSM can approximate the nonlinear relationship between the objective function and the design variables with higher accuracy, and the model fitting R2 value was 0.919. The efficiency was improved by 3.717% after optimization. The overall prewhirl of the impeller inlet after optimization decreased, the internal speed of the volute significantly improved, the large-area vortex at the volute and the outlet pipe was eliminated, the impact loss at the volute separating tongue disappeared, and the overall hydraulic performance of the pump was improved. The total entropy output value of the optimized pump was reduced by 4.79 (W/K), mainly concentrated in the reduction in the entropy output value of the double volute, and the overall energy dissipation of the pump was reduced.

Background: While mankind is still dealing with the COVID-19 pandemic, on May 7, 2022, a case of monkeypox virus (MPXV) has been reported to the WHO. Monkeypox is a viral zoonotic disease with characteristics comparable to those seen in smallpox cases in the past. It has been a public health threat, particularly in Africa, but recently have been circulating the world, consequently, may become a global public health threat in a very short period. Thus, the current work was planned and then constructed a multi-epitope vaccine that can evoke an immunological response against MPXV utilizing cell surface-binding protein as a target in order to develop a novel vaccine that is both safe and almost free of side effects. Results: The proposed vaccine composed of 304 amino acids and was shown to be antigenic in Vaxijen server (0. 5311) and nonallergenic in AllerTop server. The 3D structure of the designed vaccine is predicted, refined and validated by various in silico tools to assess the stability of the vaccine. Moreover, solubility of the vaccine construct was found greater than the average solubility provided by protein-Sol server indicating the solubility of the vaccine construct. Moreover, the most promising epitopes bound to MHC I and MHC II alleles were found having good binding affinities with low energies ranging between ₋7.0 - ₋8.1kcal/mol. Conclusion: We conclude from our research that the cell surface-binding protein is one of the primary proteins involved in MPXV pathogenesis. The most promising epitopes were selected using a rigorous procedure and used for vaccine design. As a result, our study will aid in the development of appropriate therapeutics and prompt the development of future vaccines against MPXV, which could serve as an important milestone in the production of an antiviral vaccine against MPXV.

Additive manufacturing has already been established as a highly versatile manufacturing technique with demonstrated potential to completely transform conventional manufacturing in the future. The objective of this paper is to review the latest progress and challenges associated with the fabrication of multi-material parts using additive manufacturing technologies. Various manufacturing processes and materials used to produce functional components were investigated and summarized. The latest applications of multi-material additive manufacturing (MMAM) in automotive, aerospace, biomedical and dentistry field were demonstrated. Investigation on the current challenges were also carried out to predict the future direction of MMAM processes. It is concluded that the further research and development needed in the design of multi-material interfaces, manufacturing processes and material compatibility of MMAM parts are necessary.

This research aimed to establish the relationship between carbon-nitrogen nutritional factors and copper sulfate on laccase activity (LA) by Pleurotus ostreatus. Culture media composition was tested to choose the nitrogen source. Yeast extract (YE) was selected as a better nitrogen source than ammonium sulfate. Then, the effect of glucose and YE concentrations on biomass production and LA as response variables was evaluated using central composite experimental designs with and without copper. The results showed that the best culture medium composition was glucose 45 gL-1 and YE 15 gL-1, simultaneously optimizing these two response variables. The fungal transcriptome was obtained in this medium with or without copper, and the differentially expressed genes were found. Main up-regulated transcripts included three laccase genes (lacc2, lacc6, and lacc10) regulated by copper, whereas the principal down-regulated transcripts included a copper transporter (ctr1) and a regulator of nitrogen metabolism (nmr1). These results suggest that Ctr1, which facilitates the entry of copper in the cell, is regulated by nutrient-sufficiency conditions. Once inside, copper induces transcription of laccase genes. This finding could explain why a 10 to 20-fold increase in LA occurs with copper compared to cultures without copper when using the optimal concentration of YE as nitrogen sources.

Under the goal of carbon peak and carbon neutrality, the carbon emission reduction of the automobile industry has attracted more and more attention in recent years. Electric vehicle has the dual attributes of power load and energy storage unit. With the increase of the number of electric vehicles, reducing carbon emissions through the collaborative interaction between electric vehicle and power network will become an important way to control carbon emissions in the automotive field. In this study, an optimization model of emission reduction benefits based on integrated development of electric vehicle and power grid is proposed, which explores the best technical way of synergy between power grid and electric vehicle, achieves the best carbon reduction effect and provides a model basis for large-scale demonstration application. Numerical simulations based on the real case in Beijing are conducted to validate the effectiveness of the proposed method.

Existing Reynolds Averaged Navier-Stokes based transition models do not accurately predict separation induced transition for low pressure turbines. Therefore, in this study, a novel framework based on computational fluids dynamics driven machine learning coupled with multi-expression and multi-objective optimization is explored to develop models which can improve the transition prediction for the T106A low pressure turbine at an isentropic exit Reynolds number of Re2is=100,000. Model formulations are proposed for the transfer and laminar eddy viscosity terms of the laminar kinetic energy transition model using seven non-dimensional pi groups. The multi-objective optimization approach makes use of cost functions based on the suction-side wall-shear stress and the pressure coefficient. A family of solutions is thus developed, whose performance is assessed using Pareto analysis and in terms of physical characteristics of separated-flow transition. Two models are found which bring the wall-shear stress profile in the separated region at least two times closer to the reference high-fidelity data than the baseline transition model. As these models are able to accurately predict the flow coming off the blade trailing edge, they are also able to significantly enhance the wake-mixing prediction over the baseline model.

A multi-methodic analysis was performed on 5 samples of fly ashes coming from different biomasses. The aim of the study was to evaluate their possible re-use and their dangerousness for men and environment. Optical granulometric analyses indicate that the average diameter of the studied fly ashes is around 20 µm, whereas only ~1 vol% has diameter lower that 2.5 µm. The chemical composition, investigated with electron probe microanalysis, indicates that all the samples have a prevalent Ca composition, followed by Si and Al. A large content in K and P was observed in some samples, whereas the content in potentially toxic elements is always below the Italian law thresholds. Polycyclic aromatic hydrocarbons are completely absent in all the samples coming from combustion plants, whereas they are present in the fly ashes from the gasification center. Quantitative mineralogical content, determined by Rietveld analysis of X-ray powder diffraction data, indicates that all the samples have a large amorphous content, likely enriched in Ca, and several K and P minerals, such as sylvite and apatite. The results obtained from the performed chemo-mineralogical study allowed to point out that the biomass fly ashes could be interesting materials (1) as amending in clayey soils, in substitution to lime, to stimulating pozzolanic reaction and improve their geotechnical properties, on the one hand, avoiding to mine raw materials and, on the other hand, re-cycling wastes; (2) as agricultural fertilizes made by a new and ecological source of K and P.

Timely diagnosis of Alzheimer's diseases(AD) is crucial to obtain more practical treatments. In this paper, a novel approach Based on Multi-Level Fuzzy Neural Networks (MLFNN) for early detection of AD is proposed. The focus of study was on the problem of diagnosing AD and MCI patients from healthy people using MLFNN and selecting the best feature(s) and most compatible classification algorithm. In this way, we achieve an excellent performance using only a single feature i.e. MMSE score, by fitting the optimum algorithm to the best area using optimum possible feature(s) namely one feature for a real life problem. It can be said, the proposed method is a discovery that help patients and healthy people get rid of painful and time consuming experiments. Experiments shows the effectiveness of proposed method in current research for diagnosis of AD with one of the highest performance (accuracy rates of 96.6%), ever reported in the literature.

A heterogeneous disease like cancer is activated through multiple pathways and different perturbations. Depending upon the activated pathway(s), patients’ survival vary significantly and show different efficacy to various drugs. Therefore, cancer subtype detection using genomics level data is a significant research problem. Subtype detection is often a complex problem, and in most cases, needs multi-omics data fusion to achieve accurate subtyping. Different data fusion and subtyping approaches have been proposed, such as kernel-based fusion, matrix factorization, and deep learning autoencoders. In this paper, we compared the performance of different deep learning autoencoders for cancer subtype detection. We performed cancer subtype detection on four different cancer types from The Cancer Genome Atlas (TCGA) datasets using four autoencoder implementations. We also predicted the optimal number of subtypes in a cancer type using the silhouette score. We observed that the detected subtypes exhibit significant differences in survival profiles. Furthermore, we also compared the effect of feature selection and similarity measures for subtype detection. To evaluate the results obtained, we selected the Glioblastoma multiforme (GBM) dataset and identified the differentially expressed genes in each of the subtypes identified by the autoencoders; the obtained results coincide well with other genomic studies and can be corroborated with the involved pathways and biological functions. Thus, it shows that the results from the autoencoders, obtained through the interaction of different datatypes of cancer, can be used for the prediction and characterization of patient subgroups and survival profiles.

Due to the tremendous progress in the automotive industry, the growth of the urban population, the number of vehicles is increasing and this creates parking challenges. Intelligent parking management systems offer an optimal solution for finding empty parking space so that drivers can quickly find their car parking space. To solve these problems, it is necessary to design an intelligent parking system, in addition to providing comfort to drivers, which is also economically viable. This paper proposes an intelligent multi-storey car parking system with the help of RFID technology and examining user preferences that can effectively solve car parking problems. The proposed method is a multi-objective decision-making method to reduce the problem of car parking, which is called MODM-RPCP. Therefore, the proposed MODM-RPCP method can allocate the best space for their stopping place by using the decision-making system and based on the priorities considered by the users. The simulation results show that the MODM-RPCP reduces the average booking time more than 19.2% and 27.1%, and decreases the response time of central parking management server more than 20.1% and 29.78% compared to MOGWOLA and ODPP approaches.

The world faces two seemingly unrelated challenges—a shortfall in the STEM workforce and increasing antibiotic resistance among bacterial pathogens. We address these two challenges with Tiny Earth, an undergraduate research course that excites students about science and creates a pipeline for antibiotic discovery.

Stability considerations play a central role in structural dynamics to determine states that are robust against perturbations during the operation. Linear stability concepts, such as the complex eigenvalue analysis, constitute the core of analysis approaches in engineering reality. However, most stability concepts are limited to local perturbations, i.e. they can only measure a state’s stability against small perturbations. Recently, the concept of basin stability has been proposed as a global stability concept for multi-stable systems. As multi-stability is a well-known property of a range of nonlinear dynamical systems, this work studies the basin stability of bi-stable mechanical oscillators that are affected and self-excited by dry friction. The results indicate how the basin stability complements the classical binary stability concepts for quantifying how stable a state is given a set of permissible perturbations.

This review provides a snapshot of chronic bacterial infections through the lens of Burkholderia pseudomallei; detailing its ability to establish multi-nucleated giant cells (MNGC) within the host, leading to the formation of pyogranulomatous lesions. We explore the role of MNGC in melioidosis disease progression and pathology by comparing the similarities and differences of melioidosis to tuberculosis, outlining the concerted events in pathogenesis that lead to MNGC formation, discussing the factors that influence MNGC formation and how they fit into clinical findings reported in chronic cases. Finally, we speculate about future models and techniques that can be used to delineate the mechanisms of MNGC formation and function.

As the aileron mass parameter and its position on the velocity and frequency of the flutter is an important problem in design of the aircraft wings, the optimization of the composite wing with an aileron is represented in this paper. Mass properties and its distribution have a great influence on the multi-disciplinary optimization procedure based on speed and frequency of flutter. At first, flutter speed was obtained with and without aileron, then aileron was mass-equilibrated and other studies were performed using the proposed method. It is deduced that changing the position and mass properties of the aileron the speed and frequency of the flutter changed. The position of the aileron was determined for better wing performance in flutter instability and minimizing the composite stress. In the present study, it has been attempted to model the aerodynamics of the problem under ultrasound with the panel method, and the structure has been modeled using finite element method and coupled with the aerodynamics. Using the p-k method, the equations are solved and the results are extracted.

With the every passing day, the demand for data traffic is increasing and this demand forces the research community not only to look for alternating spectrum for communication but also urges the radio frequency planners to use the existing spectrum smartly. Cell size is shrinking with the every upcoming communication generation which makes the base station placement planning complex and cumbersome. In order to make the next-generation cost-effective, it is important to design the network in such a way which utilizes minimum number of base stations while ensure coverage and quality of service. This paper aims at develop a new approach using hybrid metaheuristic and metamodel applied in multi-transmitter placement planning (MTPP) problem. We apply radial basis function (RBF) metamodel to assist particle swarm optimizer (PSO) in a constrained simulation-optimization (SO) of MTPP to mitigate the associated computational burden of optimization procedure. We evaluate the effectiveness and applicability of proposed algorithm in a case study by simulating MTPP model with two, three, four and five transmitters.

Green Infrastructures (GI) are considered key to reconcile ecological and social benefits by providing multiple functions. The concept is increasingly promoted and guidelines for its implementation have been developed in many countries and regions of the Western Hemisphere. However, for other parts of the world, especially for countries with less developed infrastructures, promotion, guidance for decision-making and manuals for GI are often lacking. But the state of infrastructure development and often unplanned character of settlements in the Global South differ and result in specific constraints as well as demands to GI that need to be addressed explicitly. This study presents a methodological approach to explicitly address the specific conditions and physical limitations to GI development in urban areas of the Global South. A four step methodology was developed to assess the implementation potential for retrofitted and multifunctional urban green infrastructure in public areas. An initial site analysis (1) and the definition of design criteria as well as general strategies (2) to achieve the different dimensions of multi-functionality are the basis to derive spatial typologies (3) for GI elements and finally the spatial suitability assessment for potential placements (4). An application of the methodology to a study area in the metropolitan region of San José, Costa Rica, shows exemplarily that the potential to improve the hydrological conditions (up to 34% of surface runoff reduction), ecological conditions (increase of green space by 2,2 %, creation of 1500 m length of roadside greenery and two new habitat types), and social conditions (2.200 m of road type upgrading) of multi-functionality of the site through Green Infrastructures. These assessment results of different multi-functionality dimension can serve as a guidance for GI promotion and implementation in urban areas of the Global South.

Many clustering approaches succeed in pattern segmentation in many applications. This unsupervised segmentation should be effective to reduce an expert labelling time: i.e, they must be able to detect the number of patterns and identify them in a sequence or map with the right cuts. Several direct and hierarchical clustering approaches are compared for this task. A divisive spectral clustering architecture with a no-cut criteria is also proposed. This new algorithm achieves promise segmentation of spatial UCI databases and marine time series compared to other approaches.

Big Data in medicine includes possibly fast processing of large data sets, both current and historical in purpose supporting the diagnosis and therapy of patients' diseases. Support systems for these activities may include pre-programmed rules based on data obtained from the interview medical and automatic analysis of test results diagnostic results will lead to classification of observations to a specific disease entity. The current revolution using Big Data significantly expands the role of computer science in achieving these goals, which is why we propose a Big Data computer data processing system using artificial intelligence to analyze and process medical images.

The commonly used words ‘transformation’ and ‘transition’ tend to lose their edge when used for any significant change process as is rather often the case. Partners and wider stakeholders in initiatives related to ‘sustainability transitions’ therefore often entertain different perspectives on what the strategic orientation of an initiative is or is meant to be. Common planning and design processes such as situation analysis and theories of change, however, often do not sufficiently cater to this dynamic. As a result, different actors may be pulling the initiative in different directions, undermining the overall partnership efforts. In this short contribution a strategic scoping canvas and an associated facilitation process are presented as a way of addressing such situations. Illustrations are provided of initial application in three cases related to food system transitions in Peru, Ethiopia, and Bangladesh, exploring the connectivity with approaches commonly used in the context of system transformations, including the Multi-Level Perspective on sustainability transitions, the Leverage Points approach, Capability Approach, and the theory of Large System Change. We conclude that the canvas and associated facilitation approach has proved useful in different contexts, offering opportunities for complementing existing methodologies, and potentially enhancing their efficacy in facilitated multi-stakeholder processes.

Prediction of the likely evolution in the traffic scenes is a challenging task because of high uncertainty of sensing technology and dynamic environment. It leads to failure of planning for intelligent agents like autonomous vehicles. In this paper, we propose a fluid-based physical model to present the influence of surrounding object's motion on driving safety. In our pipeline, the input sensor could be LiDAR, camera, or multi-modal data. We use a Kalman filter to estimate the state space of each detected object, and adopt the properties of stable fluid to build a riskmap based on the density field. The noisy state space are then modeled as the boundary conditions in the simulation of advection and diffusion process. We test our approach on the public KITTI dataset and find this model could handle the short-term prediction in case of misdetection and tracking failure caused by object occlusion, which shows promising in collision risk assessment on road scenes.

Marine mortar was the goal material and its multi-scale physical-chemical-mechanical characteristics were the principal interest in this study. The on-line multi-scale damage detection experiments art was designed to quantify the characteristics mathematically and graphically. The normal cylinder specimen with 70-day age was produced and investigated by dynamically global MSHCT scan and local detection of EDS, SEM and XRD. The experiments results indicated that the marine mortar offered the appreciable strength at the early age at least, although some saline minerals were generated during the preparation. The micro-interfacial behavior and the parental foci controlled the damage development of the marine mortar the performance of which was still the adjustable one by the composition optimization.

The aim of this article is to extend the local as well as the semi-local convergence analysis of multi-point iterative methods using center Lipschitz conditions in combination with our idea, of the restricted convergence region. It turns out that this way a finer convergence analysis for these methods is obtained than in earlier works and without additional hypotheses. Numerical examples favoring our technique over earlier ones completes this article.

Tree condition, pruning and orchard management practices within intensive horticultural tree crop systems can be determined via measurements of tree structure. Multi-spectral imagery acquired from an unmanned aerial system (UAS) has been demonstrated as an accurate and efficient platform for measuring various tree structural attributes, but research in complex horticultural environments has been limited. This research established a methodology for accurately estimating tree crown height, extent, plant projective cover (PPC) and condition of avocado tree crops, from a UAS platform. Individual tree crowns were delineated using object-based image analysis. In comparison to field measured canopy heights, an image-derived canopy height model provided a coefficient of determination (R2) of 0.65 and relative root mean squared error of 6%. Tree crown length perpendicular to the hedgerow was accurately mapped. PPC was measured using spectral and textural image information and produced an R2 value of 0.62 against field data. A random forest classifier was applied to assign tree condition into four categories in accordance with industry standards, producing out-of-bag accuracies >96%. Our results demonstrate the potential of UAS-based mapping for the provision of information to support the horticulture industry and facilitate orchard-based assessment and management.

The application of multiple criteria decision-making (MCDM) techniques in real-life problems has increased in recent years. The need to build advanced decision models with higher capabilities that can support decision making in a broad spectrum of applications, promotes the integration of MCDM techniques with applicable systems, including artificial intelligence, and Geographic Information Systems (GIS). The Analytic Hierarchy Process (AHP) and Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) are amongst the most widely adopted MCDM techniques capable of resolving water resources challenges. A critical problem associated with water resource management is dam site selection. This paper presents a comparative analysis of TOPSIS and AHP in the context of decision making using GIS for dam site selection. The comparison was made based on geographic and water quality criteria. A ratio estimation procedure was used to determine the weights of these criteria. Both methods were applied for selection of optimal sites for dams in the Sistan and Baluchestan province, Iran. The results show that the TOPSIS method is better suited to the problem of dam site selection for this case study. Actual locations of dams constructed in the area were used to verify the results of both methods.

The optimization of the production process of metal mines has been traditionally driven only by economic benefits while ignoring resource efficiency. However, it has become increasingly aware of the importance of resource efficiency since mineral resource reserves continue to decrease while the demand continues to grow. To better utilize the mineral resources for sustainable development, this paper proposes a multi-objective optimization model of the production process of metal mines considering both economic benefits and resource efficiency. Specifically, the goals of the proposed model are to maximize the profit and resource utilization rate. Then, the fast and elitist Non-Dominated Sorting Genetic Algorithm (NSGA-II) is used to optimize the multi-objective optimization model. The proposed model has been applied to the optimization of the production process of a stage in the Huogeqi Copper Mine. The optimization results provide a set of Pareto-optimal solutions that can meet varying needs of decision makers. Moreover, compared with those of the current production indicators, the profit and resource utilization rate of some points in the optimization results can increase respectively by 2.99% and 2.64%. Additionally, the effects of the decision variables (geological cut-off grade, minimum industrial grade and loss ratio) on objective functions (profit and resource utilization rate) were discussed using variance analysis. The sensitivities of the Pareto-optimal solutions to the unit copper concentrate price were studied. The results show that the Pareto-optimal solutions at higher profits (with lower resource utilization rates) are more sensitive to the unit copper concentrate prices than those obtained in regions with lower profits.

One control challenge in prosthetic legs is seamless transition from one gait mode to another. User intent recognition (UIR) is a high-level controller that tells a low-level controller to switch to the identified activity mode, depending on the user’s intent and environment. We propose a new framework to design an optimal UIR system with simultaneous maximum performance and parsimony for gait mode recognition. We use multi-objective optimization (MOO) to find an optimal feature subset that creates a trade-off between these two conflicting objectives. The main contribution of this paper is two-fold: (1) a new gradient-based multi-objective feature selection (GMOFS) method for optimal UIR design; and (2) the application of advanced evolutionary MOO methods for UIR. GMOFS is an embedded method that simultaneously performs feature selection and classification by incorporating an elastic net in multilayer perceptron neural network training. Experimental data are collected from six subjects, including three able-bodied subjects and three transfemoral amputees. We implement GMOFS and four variants of multi-objective biogeography-based optimization (MOBBO) for optimal feature subset selection, and we compare their performances using normalized hypervolume and relative coverage. GMOFS demonstrates competitive performance compared to the four MOBBO methods. We achieve a mean classification accuracy of 97.14% ± 1.51% and 98.45% ± 1.22% with the optimal selected subset for able-bodied and amputee subjects, respectively, while using only 23% of the available features. Results thus indicate the potential of advanced optimization methods to simultaneously achieve accurate, reliable, and compact UIR for locomotion mode detection of lower-limb amputees with prostheses.

Many research work has demonstrated that taken the Combined Cooling Heating and Power system (CCHP) as the core equipment, the integrated energy system (IES) can bring obvious benefit to energy efficiency, CO2 emission reduction and operation economy in urban areas. Compared with isolated IES, integrated energy micro-grid (IEMG) which is formed by connecting multiple regions IES together, through distribution and thermal network, can further improve the reliability, flexibility, cleanliness and economy of regional energy supply. Based on the existing IES model, this paper describes the basic structure of IEMG and built a IEMG planning model. The planning based on the mixed integer linear programming, and economically construction planning scheme are calculated by using known electricity, heating and cooling loads information and the given multiple equipment selection schemes. At last, the model is validated by a case study. The results show that the application of IEMG can effectively improve the economy of regional energy supply.

This is the second of a two-paper series describing a multi-scale modeling approach developed to simulate crack sensing in polymer fibrous composites by exploiting interruption of electrically conductive carbon nanotube (CNT) networks. The approach is based on the finite element (FE) method. FE models at three different scales, namely the micro-scale, the meso-scale and the macro-scale, have been developed using the ANSYS PDL environment. In the present paper, the meso- and macro-scale analyses are described. In the meso-scale, a two-dimensional model of the CNT/polymer matrix reinforced by carbon fibers is used to develop a crack sensing methodology from a parametric study which relates the crack position and length with the reduction of current flow. In the meso-model, the effective electrical conductivity of the CNT/polymer computed from the micro-scale is used as input. In the macro-scale, the final implementation of the crack sensing methodology is performed on a CNT/polymer/carbon fiber composite volume using as input the electrical response of the cracked CNT/polymer derived at the micro-scale and the crack sensing methodology. Analyses have been performed for cracks of two different lengths. In both cases, the numerical model predicts with good accuracy both the length and position of the crack. These results highlight the prospect of conductive CNT networks to be used as a localized structural health monitoring technique.

Accurate assessment of the breast cancer deterioration degree plays a crucial role in making medical plan, and the important basis for degree assessment is the number of mitoses in a given area of the pathological image. We utilized deep multi-scale fused fully convolutional neural network (MFF-CNN) combing with conditional random felid (CRF) to detect mitoses in hematoxylin and eosin stained histology image. Analyze the characteristics of mitotic detection ----scale invariance and sparsity, as well as the difficulties ---- small amount of data , inconsistent image staining and sample class unbalanced. Based on this, mitotic detection model is designed. In this paper, a tissue-based staining equalization method is used, and to establish an effective training sample set, we select training samples by using CNN. A mitotic detection model fusing multi-level and multi-scale features and context information was designed, and the corresponding training strategy was made to reduce over-fitting. As preliminarily validated on the public 2014 ICPR MITOSIS data, our method achieves a better performance in term of detection accuracy than ever recorded for this dataset.

Multi-cameras system is widely applied in 3D computer vision especially when multiple cameras are distributed on both sides of the measured object. The calibration methods of multi-cameras system are critical to the accuracy of vision measurement and the key is to find an appropriate calibration target. In this paper, a high-precision camera calibration method for multi-cameras system based on transparent glass checkerboard and ray tracing is described, which is used to calibrate multiple cameras distributed on both sides of the glass checkerboard. Firstly, the intrinsic parameters of each camera is obtained by Zhang’s calibration method. Then, multiple cameras capture several images from the front and back of the glass checkerboard with different orientations, and all images contain distinct grid corners. As the cameras on one side are not affected by the refraction of glass checkerboard, extrinsic parameters can be directly calculated. However, the cameras on another side are influenced by the refraction of glass checkerboard, and the direct use of projection model will produce calibration error. A multi-cameras calibration method using refractive projection model and ray tracing is developed to eliminate this error. Furthermore, both synthetic and real data are employed to validate the proposed approach. The experimental results of refractive calibration show that the error of the 3D reconstruction is smaller than 0.2 mm, the relative errors of both rotation and translation are less than 0.014%, and the mean and standard deviation of reprojection error of 4-cameras system are 0.00007 and 0.4543 pixel. The proposed method is flexible, high accurate, and simple to carry out.

This article addresses reinsurance decision making process, which involves the insurance company and the reinsurance company, and is negotiated through reinsurance intermediaries. The article proposes a decision flow to model the reinsurance design and selection process. In contrast to existing literature on pure proportional reinsurance or stop-loss reinsurance, this article focuses on the combination into Proportional-Stop-loss reinsurance design which better addresses interest of both parties. In terms of methodology, the significant contribution of the study is to incorporate Multiple Attribute Decision Making (MADM) into modelling the reinsurance selection. The Multi-Objective Decision Making (MODM) model is applied in designing reinsurance alternatives. Then MADM is applied to aid insurance companies in choosing the most appropriate reinsurance contract. To illustrate the feasibility of incorporating intelligent decision supporting system in reinsurance market, the study includes a numerical case study using simulation software @Risk in modeling insurance claims, and programming in MATLAB to realize MADM. Managerial implications could be drawn from the case study results. More specifically, when choosing the most appropriate reinsurance, insurance companies should base their decision on multiple measurements instead of single-criteria decision making models for their decisions to be more robust.

This paper presents a system for identification of wind features, such as gusts and wind shear. These are of particular interest in the context of energy-efficient navigation of Small Unmanned Aerial Systems (UAS). The proposed system generates real-time wind vector estimates and a novel algorithm to generate wind field predictions. Estimations are based on the integration of an off-the-shelf navigation system and airspeed readings in a so-called direct approach. Wind predictions use atmospheric models to characterize the wind field with different statistical analyses. During the prediction stage, the system is able to incorporate, in a big-data approach, wind measurements from previous flights in order to enhance the approximations. Wind estimates are classified and fitted into a Weibull probability density function. A Genetic Algorithm (GA) is utilized to determine the shaping and scale parameters of the distribution, which are employed to determine the most probable wind speed at a certain position. The system uses this information to characterize a wind shear or a discrete gust and also utilizes a Gaussian Process regression to characterize continuous gusts. The knowledge of the wind features is crucial for computing energy-efficient trajectories with low cost and payload. Therefore, the system provides a solution that does not require any additional sensors. The system architecture presents a modular decentralized approach, in which the main parts of the system are separated in modules and the exchange of information is managed by a communication handler to enhance upgradeability and maintainability. Validation is done providing preliminary results of both simulations and Software-In-The-Loop testing. Telemetry data collected from real flights, performed in the Seville Metropolitan Area in Andalusia (Spain), was used for testing. Results show that wind estimation and predictions can be calculated at 1 Hz and a wind map can be updated at 0.4 Hz. Predictions show a convergence time with a 95% confidence interval of approximately 30 s.

An active power dispatch method for a microgrid (MG) with multi-type loads, renewable energy sources (RESs) and distributed energy storage devices (DESDs) is the focus of this paper. The MG operates in a grid-connected model, and distributed power sources contribute to the service for load demands. The outputs of multiple DESDs are controlled to optimize the active power dispatch. Our goal with optimization is to reduce the economic cost under time-of-use (TOU) price, and to adjust the excessively high or low load rate of distributed transformers (DTs) caused by the peak-valley demand and load uncertainties. To simulate a practical environment, the stochastic characteristics of multi-type loads are formulated. The transition matrix of system state is provided. Then, a finite-horizon Markov decision process (FHMDP) model is established to describe the dispatch optimization problem. A learning-based technique is adopted to search the optimal joint control policy of multiple DESDs. Finally, simulation experiments are performed to validate the effectiveness of the proposed method, and the fuzzification analysis of the method is presented.

Quorum Sensing (QS) and Machine Learning (ML) hybrid systems represent a groundbreaking innovation in synthetic biology, offering unprecedented control and adaptability in microbial gene regulation and metabolic processes. QS, a microbial communication mechanism, is crucial for coordinating gene expression in response to population density, impacting behaviors such as biofilm formation, virulence, and resource optimization. However, traditional QS systems are constrained by their reliance on static, pre-programmed feedback loops, limiting their flexibility in dynamic, complex environments. This review highlights how integrating advanced ML algorithms—such as reinforcement learning and deep learning—into QS systems can overcome these limitations by enabling real-time data processing, predictive modeling, and dynamic feedback control. Through these innovations, QS-ML systems can autonomously adjust gene expression and metabolic outputs, making them more efficient and scalable in applications ranging from pathogen control to precision medicine and industrial biomanufacturing. Key case studies illustrate the successful deployment of QS-ML systems to combat antimicrobial resistance, optimize bio-production, and enhance therapeutic precision in cancer and immune modulation. Despite the clear advantages, challenges remain in data integration, system robustness, and regulatory oversight. Addressing these hurdles through interdisciplinary collaboration and developing scalable, multi-omics data platforms will be critical for advancing QS-ML systems from experimental settings to real-world applications. This review underscores the transformative potential of QS-ML systems in revolutionizing synthetic biology, with profound implications for personalized medicine, sustainable biomanufacturing, and environmental health.Quorum Sensing (QS) and Machine Learning (ML) hybrid systems represent a groundbreaking innovation in synthetic biology, offering unprecedented control and adaptability in microbial gene regulation and metabolic processes. QS, a microbial communication mechanism, is crucial for coordinating gene expression in response to population density, impacting behaviors such as biofilm formation, virulence, and resource optimization. However, traditional QS systems are constrained by their reliance on static, pre-programmed feedback loops, limiting their flexibility in dynamic, complex environments. This review highlights how integrating advanced ML algorithms—such as reinforcement learning and deep learning—into QS systems can overcome these limitations by enabling real-time data processing, predictive modeling, and dynamic feedback control. Through these innovations, QS-ML systems can autonomously adjust gene expression and metabolic outputs, making them more efficient and scalable in applications ranging from pathogen control to precision medicine and industrial biomanufacturing. Key case studies illustrate the successful deployment of QS-ML systems to combat antimicrobial resistance, optimize bio-production, and enhance therapeutic precision in cancer and immune modulation. Despite the clear advantages, challenges remain in data integration, system robustness, and regulatory oversight. Addressing these hurdles through interdisciplinary collaboration and developing scalable, multi-omics data platforms will be critical for advancing QS-ML systems from experimental settings to real-world applications. This review underscores the transformative potential of QS-ML systems in revolutionizing synthetic biology, with profound implications for personalized medicine, sustainable biomanufacturing, and environmental health.

The hospital indoor environment plays a significant role in shaping the microbial exposures that humans encounter. Resistance to antibiotics is one of the mechanisms employed by bacteria to develop resilience against stress in indoor environments. The extensive usage of antibiotics has been a key factor in driving changes in the ecological function of antibiotic resistance genes (ARGs) and their acquisition by pathogenic bacteria. By integrating the 16S rRNA Illumina sequencing and high throughput-qPCR approaches with water and air dust samples across seven departments at Peking University Shenzhen Hospital, China, this study yielded intriguing findings regarding the department-specific variation, transmission, and correlation of bacteria, ARGs and MGEs within the hospital indoor environment. One notable observation was that the seasonal variation played a vital role in shaping the bacterial composition in the overall hospital indoor environment across seven studied departments. Nevertheless, a similar significant seasonal impact was only observed in the blood test room and emergency departments, rather than in the other five departments. Another intriguing finding was the correlation between ARGs and MGEs abundance. This correlation was evident in the overall hospital indoor environment, which was conversely not found in the emergency, pneumology and gynecology departments. Additionally, while there was no significant relationship that occurred between bacterial communities and ARGs/MGEs within the hospital, the gynecology department demonstrated a close link between bacterial communities and the presence of ARGs/MGEs. Notably, the gynecology department also stood out as an important source of bacteria and ARGs/MGEs for other departments. This study underscores the need for careful surveillance and monitoring of antibiotic resistance, particularly in Legionella spp. in man-made water systems. The findings also show the importance of monitoring and understanding the genetic elements such as Tp614 involved in gene transfer and recombination, as well as their impact on antimicrobial treatment efficacy.

Despite extensive use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics for over a decade, neovascular age-related macular degeneration (nAMD) or choroidal neovascularization (CNV) continues to be a major cause of irreversible vision loss in developed countries. Many nAMD patients demonstrate persistent disease activity or experience declined responses over time despite anti-VEGF treatment. The underlying mechanisms of anti-VEGF resistance are poorly understood, and no effective treatment strategies are available to date. Here we review evidence from animal models and clinical studies that supports the roles of neovascular remodeling and arteriolar CNV formation in anti-VEGF resistance. Cholesterol dysregulation, inflammation, and ensuing macrophage activation are critically involved in arteriolar CNV formation and anti-VEGF resistance. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV.

Steel damper columns (SDCs) are energy-dissipating members that are suitable for reinforced concrete (RC) moment-resisting frames (MRFs) and those often used for multistory housing. In a previous study, an energy-based prediction procedure for the peak and cumulative response of an RC frame building with SDCs was proposed. In this procedure, the accuracy of the equivalent velocity of the maximum momentary input energy (V_ΔE1^*)–peak equivalent displacement (D₁^*_max) relationship is essential for improved prediction. In this article, the seismic capacity curve (V_ΔE1^*–D₁^*_max relationship) of RC MRFs with and without SDCs is evaluated using incremental critical pseudo-multi impulse analysis (ICPMIA). In the ICPMIA, which is based on a study by Takewaki and coauthors, the structure is subjected to various intensities of critical pseudo-multi impulsive lateral force. An ICPMIA of four 8- and 16-story RC MRFs with and without SDCs is performed to obtain their structural behaviors under various intensities of pulsive input. Then, the seismic capacity curve obtained from the ICMPIA results are compared with the predicted results based on the simplified equations. The main findings of this article are as follows. (i) The seismic capacity curve of RC MRFs without SDCs strongly depends on the number of impulsive lateral forces (N_p). As N_p increases, the seismic capacity decreases. The predicted seismic capacity curve severely underestimates that obtained from the ICMPIA in the case of large N_p. This trend is notable when the level of pinching behavior in the RC members is severe. (ii) In the case of an RC MRF with SDCs, however, the influence of N_p on its seismic capacity curve is small. The predicted seismic capacity curve agrees very well with that obtained from the ICMPIA. The influence of the level of pinching behavior in RC members on the seismic capacity curve is small.

Background/Objectives: Camptothecin (CPT) is a well-known chemical compound recognized for its significant anticancer properties. However, its clinical application remains limited due to challenges related to CPT’s high hydrophobicity and the instability of its active form. To address these difficulties, our research focused on the development of four novel nanoparticulate systems intended for either oral or intravenous administration; Methods: These nanosystems were based on a poly(amidoamine) (PAMAM) dendrimer/CPT complex, which had been coated with biodegradable homo- and copolymers, designed with appropriate physicochemical properties and chain microstructures; Results: The resulting nanomaterials, with diameters ranging from 110 to 406 nm and dispersity values between 0.10 and 0.67, exhibited a positive surface charge and were synthesized using biodegradable poly(L-lactide) (PLLA), poly(L-lactide-co-ε-caprolactone) (PLACL), and poly(glycolide-co-ε-caprolactone) (PGACL). Biological assessments, including cell viability and hemolysis tests, indicated that all polymers demonstrated less than 5% hemolysis, confirming their hemocompatibility for potential intravenous use. Furthermore, fibroblasts exposed to these matrices showed concentration-dependent viability. The entrapment efficiency (EE) of CPT reached up to 27%, with drug loading (DL) values as high as 17%. The in vitro drug release studies lasted over 400 h with the use of phosphate buffer solutions at two different pH levels, demonstrating that time-dependent processes allowed for a gradual and controlled release of CPT from the developed nanosystems. The release kinetics of the active compound at pH 7.4 ± 0.05 and 6.5 ± 0.05 followed near-first-order or first-order models, with diffusion and Fickian/non-Fickian transport mechanisms. Importantly, the nanoparticulate systems enabled the stabilization of the pharmacologically active form of CPT, while providing protection against hydrolysis, even in physiological environments; Conclusions: In our opinion, these results underscore the promising future of biodegradable nanosystems as effective drug delivery systems (DDSs) for targeted cancer treatment, offering stability and efficacy over short, medium, and long-term applications.

Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic nucleic acid-like molecules provide unique advantages over traditional pharmacological treatments, including the ability to target previously "undruggable" genes. Despite this promise, several biological barriers severely limit their clinical efficacy Upon administration, ASOs primarily enter cells through endocytosis, becoming trapped inside membrane-bound vesicles known as endosomes. Studies estimate that only 1-2% of ASOs successfully escape endosomal compartments to reach the cytosol, and ultimately the nucleus, where they bind target mRNA and exert their therapeutic effect. Endosomal entrapment and inefficient nuclear localization are therefore critical bottlenecks in the therapeutic application of ASOs. This review explores the current understanding of endosomal escape, and nuclear transport of ASOs. Furthermore, we examine strategies aimed at overcoming these challenges, including the use of endosomal escape agents, peptide-ASO conjugates, non-viral delivery vehicles, and nuclear localization signals. By improving both endosomal escape and nuclear localization, significant advances in ASO-based therapeutics can be realized, ultimately enhancing their potency and expanding their clinical utility

Objective:This study aims to evaluate the impact of drug-eluting bead transarterial chemoembolization (DEB-TACE) compared to conventional transarterial chemoembolization (cTACE) in patients with hepatocellular carcinoma (HCC), with a specific focus on liver fibrosis progression. By utilizing propensity score matching (PSM), the study seeks to examine the effects of both treatments on liver fibrosis and survival rates, providing evidence to inform clinical decision-making. Methods:This retrospective analysis included HCC patients who underwent DEB-TACE or cTACE at Xuzhou Cancer Hospital between October 2020 and September 2023. Propensity score matching (PSM) was employed to ensure comparability between the two groups based on baseline characteristics, with a 1:1 matching ratio. The primary endpoints included liver fibrosis markers (such as hyaluronic acid, type III procollagen, type IV collagen, and laminin), liver function trends (ALT, AST, TBIL, ALB), and adverse events. Kaplan-Meier methods were used to evaluate progression-free survival (PFS) and overall survival (OS). Results:After PSM, 92 patients were included (46 in the DEB-TACE group and 46 in the cTACE group). Results demonstrated that the DEB-TACE group showed superior outcomes in reducing liver fibrosis markers (e.g., PC-III, IV-C, and LN) compared to the cTACE group. Additionally, the incidence of nausea, vomiting, and postoperative pain was significantly lower in the DEB-TACE group (p < 0.001). Kaplan-Meier analysis revealed that PFS and OS were significantly longer in the DEB-TACE group compared to the cTACE group (p < 0.05). Multivariate logistic regression analysis further confirmed the independent protective effect of DEB-TACE in reducing liver fibrosis progression (OR = 2.39, p = 0.044). Conclusion:This study confirms the advantages of DEB-TACE in treating patients with intermediate to advanced HCC, particularly in slowing liver fibrosis progression and improving survival outcomes. The use of propensity score matching enhances the reliability of these findings. Future studies should continue to explore the potential of DEB-TACE in broader patient populations to optimize treatment strategies for HCC.

The rapid advancement of 3D printing technology has revolutionized the fabrication of microneedle arrays (MNAs), which hold great promise in biomedical applications such as drug delivery, diagnostics, and therapeutic interventions. This review provides an exploration of the diverse materials used in the production of 3D-printed MNAs, including photopolymer resins, biocompatible materials, composite resins, and cutting-edge materials designed to improve mechanical properties, biocompatibility, and functional performance. By analyzing recent research and technological innovations, this paper presents an assessment of material characteristics, fabrication techniques, and their alignment with application-specific requirements. Additionally, it discusses future directions and addresses potential challenges in advancing the field of 3D-printed MNAs.

Animal venoms are complex mixtures of bioactive peptides and enzymes that have garnered significant interest for their therapeutic potential, particularly in drug delivery systems. Among these peptides, cell-penetrating peptides (CPPs) have emerged as promising candidates due to their ability to traverse cellular membranes and deliver a variety of molecular cargos, including drugs, imaging agents, and nanoparticles. Recent advancements in omics technologies have enhanced our understanding of the structural and functional properties of CPPs, leading to their classification based on conformation, origin, and physicochemical characteristics. This review discusses the diverse types of CPPs, including three-finger toxins, disintegrins, and bradykinin-potentiating peptides, highlighting their roles in targeted drug delivery and therapeutic applications. The potential of venom-derived peptides in developing novel strategies for drug delivery and disease treatment is explored, emphasizing their impact on biotechnological and biomedical research.

Drug–targeted integrated nanofiber development is a current research trend. Potential materials for the development of such systems include Poly (vinyl alcohol) (PVA) and chitosan (CS) nanofibers, which are traditionally fabricated by electrospinning aqueous solutions of these polymers with acetic acid. To improve drug integration, the binary-solvent system was converted into a multi–solvent system by the adding of ethanol. This caused noticeable shifts in the solvent system's solubility parameter, the interaction of the various component forces, and optical and rheological properties of PVA-CS solution. The results show that solution containing 4% PVA, 3% CS, 15% ethanol and 45% acetic acid is optimal for the increasing of manufacturing productivity, improving the morphology and diameter of PVA–CS nanofibers, without changing in chemical bonding composition. The XRD spectrum revealed that the alterations in the crystal lattice and diameter of the PVA–CS nanofibers leaded to the variation in their thermal and tensile properties.

Amidst the ongoing global challenge of the SARS-CoV-2 pandemic, the quest for effective antiviral medications remains paramount. This comprehensive review delves into the dynamic landscape of FDA-approved medications repurposed for COVID-19, categorized as antiviral and non-antiviral agents. Our focus extends beyond conventional narratives, encompassing vaccination targets, repurposing efficacy, clinical studies, innovative treatment modalities, and future outlooks. Unveiling the genomic intricacies of SARS-CoV-2 variants, including the WHO-designated Omicron variant, we explore diverse antiviral categories such as Fusion inhibitors, Protease inhibitors, Transcription inhibitors, Neuraminidase inhibitors, Nucleoside reverse transcriptase, and non-antiviral interventions like Importin α/β1-mediated nuclear import inhibitors, Neutralizing antibodies and convalescent plasma. Notably, Molnupiravir emerges as a pivotal player, now licensed in the UK. This review offers a fresh perspective on the historical evolution of COVID-19 therapeutics, from repurposing endeavors to the latest developments in oral anti-SARS-CoV-2 treatments, ushering in a new era of hope in the battle against the pandemic.

The use of natural health products (NHP) is constantly increasing worldwide. Among the most NHP consumed are the resins of Commiphora myrrha (C. myrrha) tree. Consumption of C. myrrha may result in herb-drug interactions that can lead to serious health consequences. This study aims to determine the herb-drug interactions based on the induction of drug-metabolizing enzyme cytochrome P-450 (CYP) 2C9 by a non-toxic boiled aqueous extract of C. myrrha and to unveil the potential involvement of xenobiotic-sensing nuclear receptors such as Pregnane X Receptor (PXR), a well-known CYP 2C9 transcription factor. Tested at low concentrations (0.01-10 g/mL) devoid of anti-proliferative effects, boiled C. myrrha resin aqueous extract upregulated CYP 2C9 gene and protein expressions in a dose-dependent manner, reaching a mean expression level exceeding 3.0-fold change in Hep G2 cells, compared with the basal level expressed in untreated cells. Furthermore, chemical analysis using mass spectrometry and computational molecular docking using in silico studies revealed that few C. myrrha resin-derived metabolites are strongly bound to PXR. In particular, the identified metabolite named diayangambin exhibited a predicted molecular docking score close to that of a native PXR ligand. The use of the nuclear receptor binding assays confirmed the binding between C. myrrha metabolite(s) and PXR, while no binding to the other xenobiotic-sensing nuclear receptor, the constitutive androstane receptor (CAR), was observed, suggesting that C. myrrha metabolite(s) are potential PXR agonists. In conclusion, although in vivo studies are needed, this study cautions patients, healthcare providers, and governmental regulators against the consumption of C. myrrha and diayangambin-rich preparations with a high potential for herb-drug interactions through drug-metabolizing CYP 2C9 enzyme induction, which could affect drug efficacy.

Drug development is a lengthy process with a high failure rate. Increasingly, machine learning is utilized to facilitate the drug development processes. These models aim to enhance our understanding of drug characteristics, including their activity in biological contexts. However, a major challenge in drug response (DR) prediction is model interpretability as it aids in the validation of findings. This is important in biomedicine, where models need to be understandable in comparison with established knowledge of drug interactions with proteins. drGAT, a graph deep learning model, leverages a heterogeneous graph composed of relationships between proteins, cell lines, and drugs. drGAT is designed with two objectives: DR prediction as a binary sensitivity prediction and elucidation of drug mechanism from attention coefficients. drGAT has demonstrated superior performance over existing models, achieving 78\% accuracy (and precision), and 76\% F1 score for 269 DNA-damaging compounds of the NCI60 drug response dataset. To assess the model's interpretability, we conducted a review of drug-gene co-occurrences in Pubmed abstracts in comparison to the top 5 genes with the highest attention coefficients for each drug. We also examined whether known relationships were retained in the model by inspecting the neighborhoods of topoisomerase-related drugs. For example, our model retained TOP1 as a highly weighted predictive feature for irinotecan and topotecan, in addition to other genes that could potentially be regulators of the drugs. Our method can be used to accurately predict sensitivity to drugs and may be useful in the identification of biomarkers relating to the treatment of cancer patients.

Cell membrane-derived liposomes, termed Memposomes, serve as promising carriers for drug delivery due to their ability to closely mimic cells and efficiently target specific cells. Liposomes derived from cancer cell membranes, in particular, exhibit homologous targeting capabilities, making them potential candidates for cancer-specific drug delivery. However, the underlying mechanisms and specific proteins responsible for this homologous targeting phenomenon remain debated. This study focuses on the role of E-cadherin, a cell adhesion molecule implicated in homophilic adhesion, in influencing the homologous targeting ability of Memposomes derived from cancer cell membranes. E-cadherin expression patterns were assessed in various cell lines, categorizing them into E-cadherin-positive and -negative groups. Memposomes were produced for each group, and their targeting tendencies were evaluated. The study confirmed that E-cadherin expression significantly influenced the homologous targeting ability of Memposomes. Cell lines with higher E-cadherin expression levels exhibited a more pronounced homologous targeting effect. This research demonstrates that cell adhesion molecules, particularly E-cadherin involved in homophilic adhesion, play a pivotal role in influencing the cell targeting ability of Memposomes. The study further validates the stability, safety, and purity of Memposomes, emphasizing their potential as effective drug delivery vehicles for the development of cell-specific therapies.

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacody-namics and pharmacokinetics of many medicaments used in clinical care. The ability of medica-tions to cross the blood-brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various central nervous system (CNS) medications at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with various CNS medications. These transporters appear to have a role in BBB pharmacogenetics. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature.

New strategies for enhancing drug delivery to the blood–brain barrier (BBB) represents a major challenge in treating cerebral diseases. Nano-emulsion based nanocarriers represent an ideal candidate to improve drug delivery thanks to their versatility in functionalization and cargo protection. In this work, a paclitaxel loaded nano-emulsion has been firstly functionalized and stabilized with two layers constituted of chitosan and hyaluronic acid, and, secondly, the latter has been conjugated to the CRT peptide. CRT is a bioactive peptide that selectively recognizes bEnd.3 cells, model of the BBB, thanks to its interactions with transferrin (Tf) and its receptor (TfR). Cytotoxic results showed a higher uptake of CRT functionalized nano-emulsion 41.5 % more than the negative control, demonstrating the ability of this novel tool to be accumulated on the brain endothelium tissue. Thanks to these results, our approach can be fully generalizable to the design of multifunctional nanocarriers for delivery of therapeutic agents to the central nervous systems.

Drug-target binding is a crucial parameter in drug discovery and design, ensuring drug efficacy and specificity. Semaglutide, a potent GLP-1 receptor agonist, is widely used to treat type 2 diabetes mellitus by regulating blood glucose levels and promoting weight loss. This study introduces a novel approach utilizing the concept of a general intermolecular binding affinity calculator (GIBAC) for designing semaglutide analogues with enhanced binding affinity to GLP-1R. For the first time, a Val27-Arg28 exchange was manually introduced to strengthen the semaglutide-GLP-1R binding affinity. A comprehensive structural and biophysical analysis was conducted to explore the semaglutide-GLP-1R sequence space, leading to the identification of promising analogues. Among these, one semaglutide analogue demonstrated a binding affinity to GLP-1R that is more than two orders of magnitude (113.3 times) higher than native semaglutide, achieving a Kd of 3.0 x 10^-8 M compared to the Kd of 3.4 x 10^-6 M for native semaglutide. This article proposes a promising structural biophysical approach for developing GLP-1 receptor agonists with improved efficacy. The prototype GIBAC, termed semaGIBAC, represents a paradigm shift in precise drug discovery and design, advocating for the construction of a full-scale GIBAC to be prioritized within the drug discovery and design community.

Antibiotic beads were used to treat surgical infections. In this study, polylactide–polyglycolide (PLGA) was mixed with vancomycin, osteogenic enhancer lithium chloride (LiCl), and hot com-pressing to form PLGA-vancomycin-LiCl delivery beads to treat bone infection. An elution method was employed to characterize the in vitro release characteristics of the vancomycin and the Li over a 42-day period. The released profiles lasted for more than 42 days for vancomycin and 28 days for Li. The concentration of vancomycin in each sample was well above the breakpoint sensitivity. Lithium co-treatment enhanced the bactericidal effect of vancomycin. Released Li and vancomycin increased mRNA or protein expressions of osteogenic markers of mesenchymal stem cells (MSCs). In vivo, the PLGA delivery systems were implanted into the rabbit distal femoral cavities and the cavity fluid content was aspirated and analyzed at each time point. The released Li and vancomycin lasted more than 6 weeks, and vancomycin concentrations were much above the breakpoint sensitivity. Four rabbits in each group were killed at 8 weeks for histologic observation. More mature bone tissue was shown in the Li treatment group. This study provides a PLGA drug delivery system to meet the requirements of patients with bone infections.

In the domain of drug discovery and design, the acquisition of precise structural and intermolecular Kd data for biological molecules is paramount. However, conventional methods for obtaining such data are often beset by challenges including high costs, time intensiveness, and inherent limitations in scalability and diversity. This article puts forward a high-throughput approach for in silico generation of structural and intermolecular binding affinity (Kd) data, which keeps exploring the uncharted territories of drug discovery & design by harnessing computational methodologies to synthetically generate diverse datasets. Through a meticulously designed workflow encompassing molecular structural modeling, structural biophysics-based calculations of intermolecular binding affinity (Kd), this innovative methodology transcends the constraints of traditional experimentation, offering a cost-effective, scalable, and efficient alternative. By simulating molecular interactions and binding interfaces and predicting binding affinities with reasonable accuracy, this approach not only expedites the drug development process but also enables the exploration of vast molecular space, thereby facilitating the discovery of novel therapeutics beyond conventional drug modality as a form factor. Moreover, the versatility of synthetic data extends beyond virtual screening and lead optimization, encompassing applications such as dataset augmentation, model validation, and benchmarking against experimental data. This article elucidates the conceptual underpinnings, methodological intricacies, validation strategies, and potential ramifications of in silico generated data, heralding a paradigm shift in drug discovery paradigms. By fostering synergy between computational and experimental research domains, this innovative approach promises to accelerate the pace of drug discovery, enhance the robustness of predictive models, and pave the way for transformative advancements in the entire pharmaceutical industry.

The delivery of therapeutical molecules through the skin, particularly to its deeper layers is impaired due to the stratum corneum layer, which acts as barrier to foreign substances. Thus, for the past years, scientists have focused on the development of more efficient methods to deliver molecules to skin distinct layers. Microneedles, as a new class of biomedical devices, consists on an array of microscale needles. This particular biomedical device had been drawing attention due to their ability to breach the stratum corneum, forming micro-conduits to facilitate the passage of therapeutical molecules. The microneedle device has several advantages over conventional methods, such as better medication adherence, easiness and painless self-administration. Moreover, it is possible to deliver the molecules swiftly or over time. Microneedles can vary in shape, size and composition. The design process of a microneedle device must take in account several factors, like the location delivery, the material and manufacturing process. Microneedles have been used in a large number of fields from drug and vaccine application, cosmetics, therapy, diagnosis, tissue engineering, sample extraction, cancer research, wound healing, among others.

Background: Targeting Hepatitis B virus (HBV) infection in human is crucial due to its adverse. Herbal medicine has long been significant in this regard, with flavonoids demonstrating promising results. Hence, establishing a way of identifying flavonoids with anti-HBV activities is the aim of the present study. Methods: Flavonoid structures with anti-HBV activities were retrieved. A flavonol-based pharmacophore model was established using LigandScout v4.4. Screening was performed using the PharmIt server. A QSAR equation was developed and validated with independent sets of compounds. Applicability domain (AD) was defined using Euclidean distance calculations for model validation. Results: The best model, consisting of 57 features was generated. HTS using the flavonol-based model resulted in 509 unique hits. The model's sensitivity and specificity were 71% and 100%, respectively. The QSAR model with two predictors, x4a and qed, exhibited strong predictive performance with an adjusted-R² value of 0.85 and 0.90 of Q2. Conclusion: The QSAR model has been validated with two separate chemical sets, guaranteeing the model's reproducibility and usefulness for other flavonols by utilizing the predictive characteristics of X4A and qed. These results provide new possibilities for discovering future anti-HBV drugs by integrating modeling and experimental research.

Background: Cell proliferation and the cell cycle are fundamental to tumor development, with mitosis playing a crucial role in cell division. Understanding the complexities of the cell cycle and mitosis is critical for cancer research, especially in the context of developing therapeutic strategies. Objective: This review highlights mitotic poisons as potential anti-cancer pharmacotherapeutics, particularly their structural and functional group diversity presenting opportunity for semi-synthesis of new derivatives with multi-target mechanisms relevant for cancer pharmacotherapeutics. Also, the review explores naturally occurring mitotic poisons and inhibitors of microtubule-dependent molecular motors as promising cancer pharmacotherapeutics. Methods: A comprehensive review of literature from 2004 to 2023 was conducted, covering studies on cell proliferation, mechanism of cell cycle regulation, mitosis, cytokinesis, and anti-cancer drug development. The published literature was collected primarily from PubMed, Scopus, Medline, Web of Science Core Collections, Google Scholar and other relevant scientific databases using keywords including but not limited to mitotic poisons and cancer, sources of mitotic poisons, mechanism of mitotic poisons, targets of mitotic poisons and structural diversity of mitotic poisons. The efficacy and limitations of various mitotic poisons and their impact on different cancer types were examined. Recent advancements in targeted therapeutic interventions for various cancers were also explored. Results: The effectiveness and limitations of mitotic poisons, including Taxanes, Epothilones, Colchicine, Vinca alkaloids, Berberine, Laulimalide, and Pseudolaric acid B, were highlighted. Drugs targeting mitotic kinases such as CDKs, Aurora kinases, PLK1, and WEE1 inhibitors were reported. Inhibiting kinesin motor proteins such as Eg5 and KIF15 to interfere with spindle formation and cell division were discussed, along with specific genomic alterations in KIF genes and the discovery of KIFC1 as potential for future research and drug development. Conclusion: Targeting microtubules and mitotic kinases, along with inhibiting kinesin motor proteins, show promise for cancer pharmacotherapeutics. The combination of targeted therapies, patient stratification based on biomarkers (such as low alpha-1 acid glycoprotein and high p63 expression), and exploration of alternative natural sources of mitotic poisons and analogues can significantly advance cancer pharmacotherapy to improve patient outcomes.

This narrative review provides a thorough examination of medication-related osteonecrosis of the jaw (MRONJ), encompassing its etiology, the role of drug holidays, and contemporary treatment approaches. By systematically analyzing literature from 2022 to 2023, this paper synthesizes the latest findings and trends in MRONJ research. The study emphasizes the importance of a holistic understanding of MRONJ, beginning with its etiological factors, assessing the therapeutic implications of drug holidays, and evaluating the efficacy of current treatment modalities. This review aims to offer clinicians and researchers a consolidated resource, highlighting the intricacies of MRONJ management and proposing directions for future research. Through this comprehensive approach, the paper seeks to advance the understanding and treatment of MRONJ, ensuring an evidence-based, patient-centric approach in clinical practice.

Ganoderma lucidum, commonly known as the "Lingzhi" or "Reishi" mushroom, has long been recognized for its potential health benefits, and medicinal properties in traditional Chinese medicine. In recent years, the emerging field of nanotechnology has opened up new possibilities in order to use the remarkable properties of G. Lucidum at the nanoscale. The unique combination of bioactive compounds present in G. Lucidum, such as triterpenoids, polysaccharides, and peptides, has inspired interest in leveraging their therapeutic potential through nanotechnological approaches. Various nanomaterials, including nanoparticles, nanofibers, and nanocomposites, have been employed to encapsulate and deliver these bioactive components to target cells or tissues, enhancing stability, controlled release, and consequently their bioavailability. Nanotechnology-based strategies have been investigated for the efficient extraction and purification of bioactive compounds from G. Lucidum. The use of nanoscale materials has facilitated the extraction process, enhancing the yield and purity of the active components. Additionally, nanocarriers and nanoformulations have been developed to protect these sensitive bioactive compounds from degradation, ensuring their stability during storage and transportation. The use of G. Lucidum-based nanomaterials has shown promising results in several biomedical applications. Nanoparticles loaded with bioactive compounds derived from G. Lucidum have exhibited potent anticancer activity by targeting cancer cells, inducing apoptosis, and inhibiting tumor growth. Additionally, nanotechnology-based formulations have demonstrated immunomodulatory effects, promoting the activation of immune cells and enhancing the body's defense mechanisms. GL, combined with the potential of nanotechnology, presents an exciting frontier in the development of novel therapeutic and biomedical applications. The utilization of nanomaterials for extraction, delivery, and integration of bioactive compounds from G. Lucidum has shown immense potential for improving drug delivery, tissue engineering, and disease treatment. Further research and development in this interdisciplinary field are warranted to fully exploit the synergistic benefits offered by G. Lucidum, and nanotechnology, ultimately leading to innovative solutions for human health and well-being.

(1) Background: There is a need to assess the availability of essential antimicrobials as the availability of an antimicrobial is a critical element of its rational use. We aimed to assess the availability of antimicrobials listed in National List of Essential Medicines 2015, India (primary list) and a selected (secondary) list comprising of agents indicated for commonly encountered infectious illnesses in various healthcare settings and to identify the reasons for their non-availability. (2) Methods: A cross-sectional survey of 25 public, private, and other sector pharmacies was carried out in Rohtak, a district of North Indian state of Haryana, from April to June 2022. (3) Results: Most of the antimicrobials surveyed were optimally available in various sector pharmacies with the exception of benzathine benzyl penicillin, benzyl penicillin, cloxacillin, cefazolin, cefuroxime, cefadroxil, amphotericin B and antimalarials. Most frequent reasons for limited availability were low demand, no prescriptions and non-listing of drugs in state essential medicine list. (4) Conclusions: Enough evidence needs to be generated with respect to status of availability of essential antimicrobials from different regions of India as well as other lower-middle income countries to devise measures for ascertaining better availability of these agents especially antibiotics at regional, national and global scales.

Background: Poisoning is a growing public problem that has shown increased prevalence in many countries worldwide, contributing to increased costs and mortalities. A lack of or insufficient information regarding the circumstances, chemicals, drugs and people at risk due to imperfect reporting system is regarded as a barrier to successful poisoning prevention and intervention efforts. In Saudi Arabia, poisoning cases are monitored at the central level in the Ministry of Health, with meticulous follow-up of cases across country areas through public health departments. The current study's objective was to describe the poisoning notification and reporting system in Makkah.Subjects and methods: All reports of chemical and drug overdose poisoning delivered to the environmental health and occupational safety department in Makkah Almukarramah over two years (2018-2019) were reviewed, together with verification of all systems, rules and guidelines organizing the performance of the department.Results: The total number of cases reported in 2018 was 209 cases, while it reached 42 cases in 2019. The overwhelming majority of the cases were Saudi (91.6%), with a slight predominance of males (57.4%) over females (42.6%). Generally, almost two-thirds of the cases occurred in children below 13 years (61.4%), most of the poisoning cases resulted from drug overdose (63.3%), while 34.7% were chemical poisoning. The most common drug poisoning was attributed to analgesics followed by antiepileptics, antihypertensive drugs, antipsychotics and antimicrobials, while cleaning and detergent agents were the most commonly poisoned chemicals. The majority of these agents were taken by the oral route. Children's chemical poisoning was significantly higher than that in older age groups (p<0.05). All intentional poisoning occurred in adults; the great majority of them (88.9%) used drug overdosing rather than chemical substances.Conclusion and recommendations: The current study results are consistent with most of the previous studies carried out in different regions in Saudi Arabia. Reviewing the performance and adherence of the “Environmental Health and Occupational Safety Department” to the guidelines and instruction regulating monitoring, notification and reporting of poison cases are satisfactory and the poisoning surveillance system is effective. Further in-depth studies are needed to elaborate other socioeconomic and demographic factors associated with chemical and drug overdose poisoning. Public health plans, policies and legislations should be implemented to reduce these factors, including prohibition over-the-counter pharmaceutical sales, selling the possibly harmful substances in kid-proof bottles and additional stringent rules governing chemical sale and storage. Intensive supervision of children is needed. Suicidal poisoning patients should seek psychiatric help to limit the possibility of attempting suicide again in the future. Furthermore, efforts are needed to plan and implement health education programs and campaigns about the factors proven in the current study to be significantly related to chemical and drug overdose poisoning to raise public knowledge about exposure to chemicals and its consequences. Popular communication media, commercial malls, road ads, learning institutions and workplaces can be used to deliver health education campaigns and programs. Advice on how to store chemicals safely and how to keep kids safe should be focused on during such programs.

Cytochrome P450 oxidoreductase (POR) is an essential redox partner for steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR lead to metabolic disorders, including congenital adrenal hyperplasia, and affect the metabolism of steroids, drugs, and xenobiotics. In this study, we examined approximately 450 missense variants of the POR gene listed in the Genome Aggregation Database (gnomAD) using eleven different in silico prediction tools. We found that 64 novel variants were consistently predicted to be disease-causing by most tools. To validate our findings, we conducted population analysis and selected two variations in POR for further investigation. The human POR wild type, along with the R268W and L577P variants, were expressed in bacteria and subjected to enzyme kinetic assays using model substrate. We also examined the activities of several cytochrome P450 proteins in the presence of POR (WT or variants) by combining P450 and reductase proteins in liposomes. We observed a decrease in enzymatic activities (ranging from 35% to 85%) of key drug metabolizing enzymes, supported by POR variants R288W and L577P compared to WT-POR. These results validate our approach of curating a vast amount of data from genome projects and provide an updated and reliable reference for diagnosing POR deficiency.

(1) Background: Type-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medication to cure T2DM, the review of the literature found that various Pyrimidine derivative act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic beta-cells and its mechanism of action with fewer adverse effects.; (2) Methods: In the present research work, in-silico investigations were carried out to investigate the potential of Pyrimidine analogue as an agonists to the protein target GPR119 receptor. We performed exhaustive molecular modelling and protein modelling methodologies such as homology mod-elling, molecular docking along with various drug designing tools such as 3D-QSAR and pharmacophore mapping to ascertain the design of better GPR119 agonists.; (3) Results: On the basis of in-depth computa-tional studies, we designed new pyrimidine moiety and analyzed them for GPR-119 receptor agonist and fur-ther explored the ADME properties. Designed compounds found to exhibit better predicted activities as com-pared to reference compound; (4) Conclusions: The current research on pyrimidine derivatives, using molec-ular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of −11.696, -9.314 and -8.721 respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidate for the treatment of diabetes acting via GPR119 agonist mechanism.

Culinary herbs and spices are widely used in daily diets. Pakistan flora is enriched with phytochemicals due to a diverse range of land. Phytochemicals, including volatile and non-volatile compounds, have captured much interest due to their numerous health advantages and significance in daily diet. The present study aimed to conduct in-depth metabolomic profiling of Pakistani-grown fenugreek leaves (Trigonella foenum-graecum), fennel seeds (Foeniculum vulgare), mint leaves (Mentha royleana), coriander seeds (Coriandrum sativum) and basil leaves (Ocimum basilicum) by using liquid chromatography–mass spectrometry (LC-MS/MS) and gas chromatography–mass spectrometry (GC-MS). The first study was conducted to optimize extraction using different solvents (methanol, ethanol, chloroform, acetone, and water). Total phenolic content (TPC), total flavonoid content (TFC), and total condensed tannins (TCT) were quantified along with the antioxidant and anti-diabetic activities. The highest TPC (125.42 ± 10.89 mg GAE/g) and the highest antioxidant and anti-diabetic potential were quantified in mint. Seventy-one phytochemical metabolites were identified using LC-MS/MS, while forty-nine volatile constituents were identified using the GC-MS. A positive correlation was identified between phenolic contents and their biological activities. Furthermore, molecular docking helped to find drug molecules with more excellent anti-diabetic activity based on their binding affinities. This study suggests that selected medicinal herbs from Pakistan have significant nutraceutical and phytopharmaceutical potential. This study could further help in drug discovery.

Background: This study assessed the nephrotoxicity of oral BRAF inhibitors (BRAFi), regorafenib (REG) and encorafenib (ENC), in metastatic colorectal cancer (mCRC), through an analysis of re-ports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) da-tabase. Methods: A descriptive and disproportional analyses were performed for all reports with ENC and REG as the primary suspect. Results: A total of 379 reports had at least one renal ADR, mainly related to REG (93.1%). Potential safety signals for REG particularly included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92-16.16; IC = 2.36, IC025-IC075 = 2.06-2.66), hydronephrosis (10; 8.70, 4.67-16.19; 1.85, 1.23-2.47), nephrotic syn-drome (7; 5.73, 2.73-12.03; 1.47, 0.73-2.21), renal impairment (53; 4.16, 3.17-5.45; 1.39, 1.12-1.66), dys-uria (19; 3.06, 1.95-4.81; 1.06, 0.61-1.52), renal failure (38; 1.66, 1.20-2.28; 0.49, 0.17-0.81), and acute kidney injury (AKI) (43; 1.46, 1.08-1.97; 0.37, 0.07-0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09-6.90; IC = 1.32, IC025-IC075 = 0.72-1.91) and dysuria (4; 6.50, 2.43-17.39; 1.86, 0.88-2.85). Conclusions: These findings highlighted some not extensively reported renal ADRs that required further investigations to better characterize the safety profile of BRAFi in patients with mCRC.

Social media platforms are increasingly enabling the propagation of content from groups related to drug use, thus posing risks for the wider population and, in particular, individuals who are amenable to drug use and drug addiction. The detection of drug use content on social media platforms is a priority for governments, technology companies, and drug law enforcement organizations. To counter this issue, various techniques have been developed to identify and promptly remove drug use content, while also blocking its creators from network access. In this paper, we introduce a manually annotated Twitter dataset, comprising 156,521 tweets published between 2008 and 2022, specifically compiled for the purpose of drug use detection. The dataset underwent annotation by several group of expert annotators who classified the tweets as either drug use or non-drug use. Exploratory data analysis was conducted to comprehend the dataset's characteristics. Various classification algorithms, including SVM, XGBoost, RF, NB, LSTM, and BERT were employed using the dataset. Among the traditional machine learning models, SVM utilizing term frequency-inverse document frequency features achieved the highest F1-Score (0.9017). However, BERT with textual features concatenated with numerical and categorical features in ensemble method surpassed the performance of traditional models, attaining F1-Score of 0.9112. To facilitate future research and enhance English online drug use classification accuracy, the dataset will be made publicly available.

Transdermal drug delivery (TDD) is one of the key approaches for treating diseases, avoiding first-pass effects, reducing systemic adverse drug reactions and improving patient compliance. Microneedling, iontophoresis, electroporation, laser ablation and ultrasound facilitation are often used to improve the efficiency of TDD. Among them, microneedling is a relatively simple and efficient means of drug delivery. Microneedles usually consist of micron-sized needles (50-900 μm in length) in arrays that can successfully penetrate the stratum corneum and deliver drugs in a minimally invasive manner below the stratum corneum without touching the blood vessels and nerves in the dermis, improving patient compliance. Hydrogel-forming microneedles (HFMNs) are safe, non-toxic, no residual matrix material, high drug loading capacity, controlled drug release and are suitable for long-term, multiple drug delivery. This work reviewed the characteristics of skin structure and transdermal drug delivery; introduced TDD strategies based on hydrogel microneedles; summarised the characteristics of HFMNs TDD systems and the evaluation methods of HFMNs; and the application of HFMNs drug delivery systems in disease treatment. The HFMNs drug delivery system has a wide scope for development, but the translation to clinical application still has more challenges.

Background: Currently, limited number of therapeutic options are available to treat Diabetes mellitus, and to find a potential candidate, laboratory work takes time and also needs animal studies. So, the aim of this study was to determine the efficacy of some natural phytocompounds with the aid of molecular docking, bioinformatics and in silico drug design approaches. Method: Two proteins (Human CYP3A4 linked to metformin and Human dipeptidyl peptidase-IV) were selected and molecular docking studies were conducted using Pymol, AutoDock Vina, PyRx, and Discovery Studio. Different important pharmacokinetic parameters like ADME and toxicity data were obtained from online databases SwissADME and pkCSM program. Results: It was found that human dipeptidyl peptidase-IV (PDB ID: 4A5S) has exhibited a maximal affinity of -9.7 Kcal/mol for bryonolic acid and hesperidin, but only -6.7 kcal/mol for metformin hydrochloride. Similarly, the highest affinity of hesperidin for human CYP3A4 bound to metformin (PDB ID: 5G5J) is -10.7 Kcal/mol compared to metformin hydrochlor (-6.3 Kcal/mol). Besides, all the compounds have been documented outstanding ADMET profile, and accepted by drug-likeness or Lipinski rule. Conclusions: The present study suggested that these compounds can be further investigated in vitro and in vivo to establish them as lead compounds against Diabetes mellitus..

Antibody-Drug Conjugates (ADCs) are a powerful therapeutic modality for cancer treatment. ADCs are multi-functional biologics in which a disease-targeting antibody is conjugated to an effector payload molecule through a linker. The success of currently used ADCs has been largely attributed to the development of linker systems which allow targeted release of cytocidal payload drugs inside cancer cells. Many lysosomal proteases are over-expressed in human cancers. They can effectively cleave a variety of peptide sequences, which can be exploited in the design of ADC linker systems. As a well-established linker, valine-citrulline-p-aminobenzyl carbamate (ValCitPABC) is used in many ADCs that are already approved or under preclinical and clinical development. Although ValCitPABC and related linkers are readily cleaved by cathepsins in the lysosome while remaining reasonably stable in human plasma, many studies have shown that they are susceptible to carboxylesterase 1C (Ces1C) in mouse and rat plasma, which hinders preclinical evaluation of the ADCs. Furthermore, neutropenia and thrombocytopenia, two of the most commonly observed dose-limiting adverse effects of ADCs, are believed to result from the premature hydrolysis of ValCitPABC by human neutrophil elastase. In addition to cathepsin-cleavable linkers, there is also growing interest in legumain-sensitive linkers for ADC development. Increasing plasma stability while maintaining lysosomal cleavability of ADC linkers is an objective of intensive current research. This review reports recent advances in the design and structure-activity relationship studies of various peptide/peptidomimetic linkers in this field.

Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to considerable infiltrative ability of glial cells. The efficacy of current multimodal therapeutic strategies is, furthermore, limited by the lack of specific therapies against malignant cells, and, therefore, the prognosis these in patients is still very unfavorable. The limitation of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors are major reasons for this unsolved clinical problem. The major problem in brain drug delivery is the presence of the blood brain barrier which limits the delivery of many chemotherapeutic agents. Nanoparticles, thanks to their chemical configuration, are able to go through the blood-brain barrier carrying drugs or genes targeted against gliomas. Carbon nanomaterials show distinct properties including electronic properties, penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, large surface area and easy modification with molecules, which render them as a suitable candidate to deliver drugs. In this review we will focus on the potential effectiveness of the use of carbon nanomaterials in the treatment of malignant gliomas discussing the current progress of in vitro and in vivo researches of carbon nanomaterials-based drug delivery to brain.

Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood-brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A Blood-brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10µl/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly open the BBB. BBB opening was confirmed visually and microscopically using Evans’s blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of the overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It has been early on recognized that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical composition has recently been used as a means to enhance their targeting or absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.

(1)Aims of the study: calculating the underreporting ratio for two different medications, a fixed combination of 0.5% timolol + 0.2% brimonidine + 2.0% dorzolamide (antiglaucoma) and a fixed combination of sodium hyaluronate 0.1% + chondroitin sulfate 0.18% (artificial tear) and characterizing the features influencing the reporting of adverse drug reactions (ADRs) in spontaneous reporting; (2) Methods: the underreporting ratio was calculated by comparing the adverse drug reactions reported in the spontaneous reporting database for every 10,000 defined daily doses marketed and the adverse drug reactions from an active surveillance study for every 10,000 defined daily doses used for different drugs (antiglaucoma and artificial tear). The factors related to the report in spontaneous reporting through statistical tests were also determined; (3) Results: The underreporting ratio of spontaneous reporting was 0.006029% for antiglaucoma and 0.003552% for artificial tear; additionally, statistically significant differences were found for severity, unexpected adverse drug reactions, and incidence of adverse drug reactions in females; (4) Conclusions: The underreporting ratio of ADRs related to ophthalmic medications indicates worry since the cornerstone of pharmacovigilance focuses on spontaneous reporting. Besides, since underreporting seems to be selective, the role of certain aspects like gender, seriousness, severity, and unexpected ADRs, must be considered in future research.

Natural products (NPs) are a rich source of structurally novel molecules, and the chemical space they encompass is far from being fully explored. Over history, NPs have represented a significant source of bioactive molecules and have served as a source of inspiration for developing many drugs on the market. On the other hand, computer-aided drug design (CADD) has contributed to drug discovery research, mitigating costs and time. In this sense, compound databases represent a fundamental element for the CADD. This work reviews the progress toward developing compound databases of natural origin, particularly databases developed in Latin America, and their practical applications in the drug discovery area. We also survey the computational methods, emphasizing chemoinformatic approaches to profile natural product databases.

Background: Oral cancer (OC) is serious health concerning issue that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. Methods: Publicly available repository the Gene Expression Omnibus (GEO) was responsible to collect OC-related datasets. GSE74530, GSE23558, and GSE3524 microarray datasets were collected to apply analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to figure out the up-regulated and down-regulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and Pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein-protein interaction (PPI) networks were built to identify the most performed genes, clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study deeply about OC-associated DEGs. Finally, top gene performers from PPI networks were used to apply drug signature analysis. Results: After applying filtration and cut-off criteria 2508, 3377, and 670 DEGs were found for GSE74530, GSE23558, and GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the Cell cycle and Influenza A. The PPI network holds 88 nodes and 492 edges and CDC6 had the highest number of connections. 4 clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of the pathophysiology and the development of new therapies for OC.

Ocular drug delivery is one of the most challenging administration routes due to the very low drug bioavailability. In this work, we produce and characterize mucoadhesive mixed polymeric micelles (PMs) made of chitosan and poly(vinyl alcohol) backbones graft-hydrophobized with short poly(methyl methacrylate) blocks and use them to encapsulate cannabidiol (CBD), an anti-inflammatory cannabinoid. CBD-loaded mixed PMs are physically stabilized by ionotropic crosslinking of the CS domains with sodium tripolyphoshate and spray-drying. These mixed PMs display CBD loading capacity of 20% w/w and sizes of 100-200 nm, and spherical morphology (cryogenic-transmission electron microscopy). The good compatibility of the unloaded and CBD-loaded PMs is assessed in a human corneal epithelial cell line. Then, we confirm the permeability of CBD-free PMs and nanoencapsulated CBD in cornea cell monolayers under liquid-liquid and air-liquid conditions. Overall, our results highlight the potential of these polymeric nanocarriers for ocular drug delivery.

Blood-brain-barrier is a major obstacle in treating brain-related disorders as it does not allow to deliver drugs in the brain. In order to facilitate delivery of drugs in brain, we developed a method for predicting blood-brain-barrier penetrating peptides. These blood-brain barriers penetrating peptides (B3PPs) can act as therapeutic as well as drug delivery agents. We trained, tested, and evaluated our models on blood-brain-barrier peptides obtained from the B3Pdb database. First, we compute a wide range of peptide features then we select relevant peptide features. Finally, we developed numerous machine learning-based models for predicting blood-brain-barrier peptides using selected features. Our model based on random forest performed best on the top 80 selected features and achieved a maximum 85.08% accuracy with 0.93 AUROC. We also developed a web server, B3pred that implements our best models. It has three major modules that allow users to; i) predict B3PPs, ii) scanning B3PPs in a protein sequence, and iii) designing B3PPs using analogs. Our web server and standalone software is freely available at https://webs.iiitd.edu.in/raghava/b3pred/.

Self-assembled structures mostly arises through enzyme-regulated phenomena in nature under persistent conditions. Enzymatic reactions are one of main biological processes in fabrication and construction of supramolecular hydrogel networks required for biomedical applications. The enzymatic processes provide a unique opportunity to integrate hydrogel formation. In most of cases, structure and substrates of hydrogels are adjusted by enzyme catalysis due to the chemo-, regio- and stereo-selectivity of enzymes. Hydrogels processed by using various enzyme schemes showed remarkable characteristics as dynamic frames for cells, bioactive molecules and drugs in biomedical applications. A novel class of enzyme-mediated crosslinking hydrogels mimics the extracellular matrices by displaying unique physicochemical properties and functionalities like water-retention capacity, drug loading ability, biodegradability, biocompatibility, biostability, bioactivity, optoelectronic properties, self-healing ability, shape memory ability. In recent years, many enzymatic systems investigated hydrogel cross-linking. Results of biocompatible hydrogel products show that these mechanisms of crosslinking can fulfill requirements for variety of biomedical applications including tissue engineering, wound healing and drug delivery.

Due to their short range (2–500 nm), Auger electrons (Auger e-) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Au-ger e-, it remains challenging to maximize the interaction between Auger e- and DNA. To assess the DNA-damaging effect of Auger e- released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [189, 191Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by im-munofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incuba-tion), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by release of Auger e- very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger e-.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare and potentially life-threatening systemic drug reaction with skin involvement. We present the unusual case of DRESS in a 16-year-old male that was treated with TMP-SMX for acne and was initially misdiagnosed with Steven Johnson Syndrome. Our case serves as an example to healthcare providers treating adverse drug reactions to having a high clinical suspicion for DRESS as delay in diagnosis and treatment can result in disseminated disease and higher patient mortality risk.

Hydrogels are used for various biomedical applications due to their biocompatibility, capacity to mimic the extracellular matrix, and ability to encapsulate and deliver cells and therapeutics. However, traditional hydrogels have a few shortcomings, especially regarding their physical properties, thereby limiting their broad applicability. Recently, researchers have investigated the incorporation of nanoparticles (NPs) into hydrogels to improve and add to the physical and biochemical properties of hydrogels. This brief review focuses on papers that describe the use of nanoparticles to improve more than one property of hydrogels. Such multifunctional hydrogel nanocomposites have enhanced potential for various applications, including tissue engineering, drug delivery, wound healing, bioprinting and biowearable devices.

The interactions of chemotherapeutic drugs with nanocage protein apoferritin (APO) are the key features in the effective encapsulation and release of highly toxic drugs in APO-based controlled drug delivery systems. The encapsulation enables mitigating the drugs side effects, collateral damage to healthy cells, and adverse immune reactions. Herein, the interactions of anthracycline drugs with APO were studied to assess the effect of drug lipophilicity on their encapsulation excess n and in vitro activity. Anthracycline drugs, including doxorubicin (DOX), epirubicin (EPI), daunorubicin (DAU), and idarubicin (IDA), with lipophilicity P from 0.8 to 15, were investigated. We have found that in addition to hydrogen-bonded supramolecular ensemble formation with n = 24, there are two other competing contributions that enable increasing n under strong polar interactions (APO(DOX)) or under strong hydrophobic interactions (APO(IDA) of the highest efficacy). The encapsulation/release processes were investigated using UV-Vis, fluorescence, circular dichroism, and FTIR spectroscopies. In vitro cytotoxicity/growth inhibition tests and flow cytometry corroborate high apoptotic activity of APO(drugs) against targeted MDA-MB-231 adenocarcinoma and HeLa cancer cells, and low activity against non-tumorigenic MCF10A cells, demonstrating targeting ability of nanodrugs. A model for molecular interactions between anthracyclines and APO nanocarriers was developed, and the relationships derived compared with experimental results.