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Excess nitrogen and phosphorus inputs are the main causes of aquatic environmental deterioration. Accurately quantifying and dynamically assessing the regional nitrogen and phosphorus pollution emission (NPPE) loads and influencing factors is crucial for local authorities to implement and formulate refined pollution reduction management strategies. In this study, we constructed a methodological framework for evaluating the spatio-temporal evolution mechanism and dynamic simulation of NPPE. We investigated the spatio-temporal evolution mechanism and influencing factors of NPPE in the Yangtze River Economic Belt (YREB) of China through the pollution load accounting model, spatial correlation analysis model, geographical detector model, back propagation neural network model, and trend analysis model. The results show that the NPPE inputs in the YREB exhibit a general trend of first rising and then falling, with uneven development among various cities in each province. Nonpoint sources are the largest source of land-based NPPE. Overall, positive spatial clustering of NPPE is observed in the cities of the YREB, and there is a certain enhancement in clustering. The GDP of the primary industry and cultivated area are important human activity factors affecting the spatial distribution of NPPE, with economic factors exerting the greatest influence on the NPPE. In the future, the change in NPPE in the YREB at the provincial level is slight, while the nitrogen pollution emissions at the municipal level will develop towards a polarization trend. Most cities in the middle and lower reaches of the YREB in 2035 will exhibit medium to high emissions. This study provides a scientific basis for the control of regional NPPE, and it is necessary to strengthen cooperation and coordination among cities in the future, jointly improve the nitrogen and phosphorus pollution tracing and control management system, and achieve regional sustainable development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Due to their proteinaceous structure, monoclonal antibodies (mAbs) are susceptible to irreversible aggregation, with harmful consequences on drug efficacy and patient safety. To mitigate this risk in modern biopharmaceutical processes, it is critical to comply with current good manufacturing practices (cGMP) and pursue operating strategies minimizing irreversible aggregation whilst also maximizing mAb throughput. These conflicting objectives are targeted in this study by formulating and analyzing an integrated dynamic model accounting for both cultivation and aggregation of mAbs from a Chinese Hamster Ovary (CHO) cell line. Two manipulated dynamic variables are considered here in simulation studies: firstly temperature manipulation within a batch reactor, and secondly feed flow manipulation within a series of isothermal fed-batch reactors. Following this, dynamic optimization investigations have been conducted, firstly with the single objective of maximizing mAb throughput and secondly with multiple (two) objectives of maximizing mAb throughput while also minimizing irreversible aggregate content, simultaneously. The study provides key insight into tradeoffs of how simultaneous temperature and feed flowrate manipulation affects mAb throughput and aggregation inside bioreactors., (© 2024 The Author(s). Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Microbes have been extensively utilized for their sustainable and scalable properties in synthesizing desired bio-products. However, insufficient knowledge about intracellular metabolism has impeded further microbial applications. The genome-scale metabolic models (GEMs) play a pivotal role in facilitating a global understanding of cellular metabolic mechanisms. These models enable rational modification by exploring metabolic pathways and predicting potential targets in microorganisms, enabling precise cell regulation without experimental costs. Nonetheless, simplified GEM only considers genome information and network stoichiometry while neglecting other important bio-information, such as enzyme functions, thermodynamic properties, and kinetic parameters. Consequently, uncertainties persist particularly when predicting microbial behaviors in complex and fluctuant systems. The advent of the omics era with its massive quantification of genes, proteins, and metabolites under various conditions has led to the flourishing of multi-constrained models and updated algorithms with improved predicting power and broadened dimension. Meanwhile, machine learning (ML) has demonstrated exceptional analytical and predictive capacities when applied to training sets of biological big data. Incorporating the discriminant strength of ML with GEM facilitates mechanistic modeling efficiency and improves predictive accuracy. This paper provides an overview of research innovations in the GEM, including multi-constrained modeling, analytical approaches, and the latest applications of ML, which may contribute comprehensive knowledge toward genetic refinement, strain development, and yield enhancement for a broad range of biomolecules.

Reducing methane (CH 4 ) emissions is increasingly recognized as an urgent greenhouse gas mitigation priority for avoiding ecosystem 'tipping points' that will accelerate global warming. Agricultural systems, namely ruminant livestock and rice cultivation are dominant sources of CH 4 emissions. Efforts to reduce methane from rice typically focus on water management strategies that implicitly assume that irrigated rice systems are consistently flooded and that farmers exert a high level of control over the field water balance. In India most rice is cultivated during the monsoon season and hydrologic variability is common, particularly in the Eastern Gangetic Plains (EGP) where high but variable rainfall, shallow groundwater, and subtle differences in topography interact to create complex mosaics of field water conditions. Here, we characterize the hydrologic variability of monsoon season rice fields ( n = 207) in the Indian EGP ('Eastern India') across two contrasting climate years (2021, 2022) and use the D e n itrification D e c omposition (DNDC) model to estimate GHG emissions for the observed hydrologic conditions. Five distinct clusters of field hydrology patterns were evident in each year, but cluster characteristics were not stable across years. In 2021, average GHG emissions (8.14 mt CO 2 -eq ha -1 ) were twice as high as in 2022 (3.81 mt CO 2 -eq ha -1 ). Importantly, intra-annual variability between fields was also high, underlining the need to characterize representative emission distributions across the landscape and across seasons to appropriately target GHG mitigation strategies and generate accurate baseline values. Simulation results were also analyzed to identify main drivers of emissions, with readily identified factors such as flooding period and hydrologic interactions with crop residues and nitrogen management practices emerging as important. These insights provide a foundation for understanding landscape variability in GHG emissions from rice in Eastern India and suggest priorities for mitigation that honor the hydrologic complexity of the region., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors.)

Transient receptor potential vanilloid 1 protein (TRPV1) is expressed widely in skin and sensory neurons that contribute to pain/heat sensation in the human system. TRPV1 gene polymorphisms are susceptible to multiple diseases and it is considered a therapeutic target for various inflammatory conditions. Among the TRPV1 variants, rs8065080 (1911 A > G) plays a vital role in painful osteoarthritis and migraine. The presence of rs8065080 polymorphism may render drug efficacy. This study aimed to identify better antagonists against wild-type and variant TRPV1 that may help in the relief of pain/inflammation. We constructed suitable TRPV1 protein structures for wild-type and rs8065080 variant through a homology modelling approach. A total of 3363 anti-inflammatory compounds with high chemical diversity and good drug-like properties were collected and screened against the generated structures. Molecular docking showed that nobilamide B had the highest binding affinity (-5.83 kcal/mol) towards the wild-type. Whereas, isoquinoline analogue displayed highest binding potency with the variant TRPV1 (-11.65 kcal/mol). Besides those, C18H15F3N4O showed affinity towards both wild-type (-5.53 kcal/mol) and variant TRPV1 (-9.75 kcal/mol). Then, molecular dynamic simulation revealed stable conformation in wild-type and variant TRPV1 upon binding of nobilmaide B, isoquinoline analogue and C18H15F3N4O. Additionally, density functional theory (DFT) using B3LYP hybrid function showed high chemical reactiveness of nobilamie B, isoquinoline analogue and C18H15F3N4O. Overall, our systematic investigations provide, C18H15F3N4O could be a potential analgesic inhibiting both wild-type and variant TRPV1 against inflammatory conditions.

Delta-opioid receptor protein (OPRD1) is one of the potential targets for treating pain. The presently available opioid agonists are known to cause unnecessary side effects. To discover a novel opioid agonist, our research group has synthesized a chimeric peptide MCRT and proved its potential activity through in vivo analysis. Non-synonymous SNPs (nsSNPs) missense mutations affect the functionality and stability of proteins leading to diseases. The current research was focused on understanding the role of MCRT in restoring the binding tendency of OPRD1 nsSNPs missense mutations on dynamic nature in comparison with Deltorphin-II and morphiceptin. The deleterious effects of nsSNPs were analyzed using various bioinformatics tools for predicting structural, functional, and oncogenic influence. The shortlisted nine nsSNPs were predicted for allergic reactions, domain changes, post-translation modification, multiple sequence alignment, secondary structure, molecular dynamic simulation (MDS), and peptide docking influence. Further, the docked complex of three shortlisted deleterious nsSNPs was analyzed using an MDS study, and the highly deleterious shortlisted nsSNP A149T was further analyzed for higher trajectory analysis. MCRT restored the binding tendency influence caused by nsSNPs on the dynamics of stability, functionality, binding affinity, secondary structure, residues connection, motion, and folding of OPRD1 protein., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

One of the most challenging issues scientists face is finding a suitable non-invasive treatment for cancer, as it is widespread around the world. The efficacy of phytochemicals that target oncogenic pathways appears to be quite promising and has gained attention over the past few years. We investigated the effect of docking phytochemicals isolated from the rhizomes of the Cimicifuga foetida plant on different domains of the IκB kinase alpha (IKK1/alpha) protein. The Cimicifugoside H-2 phytochemical registered a high docking score on the activation loop of IKK1/alpha amongst the other phytochemicals compared to the positive control. The interaction of the protein with Cimicifugoside H-2 was mostly stabilized by hydrogen bonds and hydrophobic interactions. A dynamic simulation was then performed with the Cimicifugoside H-2 phytochemical on the activation loop of IKK1/alpha, revealing that Cimicifugoside H-2 is a possible inhibitor of this protein. The pharmacokinetic properties of the drug were also examined to assess the safety of administering the drug. Therefore, in this in silico study, we discovered that the Cimicifugoside H-2 phytochemical inhibits the actively mutated conformation of IKK1/alpha, potentially suppressing the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway.

The emission of nitrous oxide （N 2 O） during wastewater treatment cannot be ignored. The analysis of statistical data from literature based on 126 empirical studies revealed that the geographical factors of wastewater treatment plants （WWTPs） had a significant impact on N 2 O emission factors. However, the N 2 O emission factors of WWTPs in all regions of the world were generally lower than the Intergovernmental Panel on Climate Change （IPCC） recommended values. In China, the N 2 O emission factors （in N 2 O-N/N influent ） of WWTPs were approximately 0.000 35-0.065 20 kg·kg -1 . Meanwhile, the N 2 O emission factors of different wastewater treatment processes were also significantly different, especially since the sequencing batch reactor （SBR） process had higher emissions. The use of uniform default emission factors for accounting was prone to overestimate N 2 O emissions, and it is recommended that countries conduct actual monitoring or modeling studies to develop categorical emission factors suitable for local conditions. In addition, the N 2 O emission factor based on total nitrogen （TN） removal was weakly negatively correlated with TN removal in 126 empirical data, which was more in line with bioprocessing stoichiometry and could provide an accurate accounting method for N 2 O. To this end, a digital twin model was developed to dynamically simulate a case anaerobic-anoxic-aerobic （AAO） WWTP to comprehensively quantify the dynamic emission behavior of N 2 O, which demonstrated that N 2 O emissions had significant seasonal and daily variability and were only equivalent to 11% of the calculated value of the emission factor based on the IPCC recommendation. Comparing the scatter linear fitting and categorical mean exponential fitting methods, it was found that the latter could more accurately reflect the negative correlation between the N 2 O emission factors and the TN removal rate, and an exponential regression equation between the average N 2 O emission factor based on the amount of TN removed and the TN removal rate was further developed to predict the N 2 O emission. The dynamic simulation and categorical index fitting methods provided in this study are important references for the accurate accounting of N 2 O emissions in similar WWTPs and provide help for understanding and responding to the N 2 O emission problems.

Purpose: To assess prevalence and incidence of severe visual impairment (VI) and blindness due to uveitis in Northrhine, Germany., Methods:  A random sample of 5088 out of 20 390 cases of the blindness registry in Northrhine was evaluated. The number of cases of severe VI and blindness were projected up to the year 2030., Results: The prevalence of registered severe VI and blindness due to uveitis was 1123.9 (95% CI: 1059.5 to 1191.2) per 100 000 in our study cohort and 550.31 (95% CI: 365.98-794.38) per 100 000 in Northrhine, respectively. The incidence of registered severe VI and blindness due to uveitis was 311.8 per 100 000 PYs (95% CI: 149.6-572.7) in our study cohort and 11.1 per 100 000 (95% CI: 5.6-19.8) in Northrhine, respectively., Conclusions: We report prevalence and incidence of severe VI and blindness due to uveitis in a large German cohort.

Motivation: This study aims to investigate non-covalent and non-peptide inhibitors of M pro , a crucial protein target, by employing a comprehensive approach that integrates molecular docking, molecular dynamics simulations, and top-hits activity predictions. The focus is on elucidating the non-covalent and non-peptide binding modes of potential inhibitors with M pro ., Methods: We employed a semi-flexible molecular docking methodology, binding score and ADME screening, which are based on structure, to screen compounds from CMNPD and HERB in silico. These methodologies allowed us to find potential candidates depending on their binding values and interactions with the binding site of main protease. To further evaluate the stability of these interactions, we conducted molecular dynamics simulations and calculated binding energies. Ultimately, a top-hits activity prediction method was employed to prioritize compounds based on their predicted inhibitory potential., Results: Through a combination of binding energy calculations and activity predictions, we identified six potential inhibitor molecules exhibiting promising activity against M pro . These compounds demonstrated favorable binding interactions and stability profiles, making them attractive candidates for further experimental validation and drug development efforts targeting M pro ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Targeted herbicide application refers to precise application of herbicides in weed-infested areas according to the location and density of farmland weeds. At present, targeted herbicide application in wheat fields generally faces problems including the low herbicide adhesion rate, leading to omission and excessive loss of herbicides., Methods: To solve these problems, changes in the impact force of herbicide and the weed leaves in the operation process of a spraying system were studied from the interaction between weeds and herbicides applied. A dynamic model of weed leaves was established. On this basis, the research indicated that the herbicide adhesion rate is highest under spraying pressure of 0.4 MPa and flow rate of 0.011 kg/s when the spray height is 300 mm. To study the dynamic deformation of weed leaves and the distribution of liquid herbicides in the external flow field under weed-herbicide interaction, a dynamic simulation model of herbicide application was built using the finite element method., Results and Discussion: The results show that when the spray height is 300 mm, the maximum weed leaf deformation index (LDI) is 0.43 and the velocity in the external flow field is 0 m/s under spraying pressure of 0.4 MPa and flow rate of 0.011 kg/s. This finding indicates that the herbicide is not splashed elsewhere and the turbulence intensity in the weed area is 2%, implying steady flow of the herbicide, most of which can be retained on weed leaves. Field test results of application quality of the herbicide show that the maximum LDI is 0.41 and the coverage of the herbicide in the sheltered area below the leaves is 19.02% when the spraying pressure is 0.4 MPa, flow rate is 0.011 kg/s, and spray height is 300 mm. This solves the problem of a low rate of utilization of herbicides because the herbicide passes through weed plants, and achieves the precision herbicide application in wheat fields., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xie, Song, Wen, Cao, Zhu and Ni.)

Multiple drug-resistant fungal species are associated with the development of diseases. Thus, more efficient drugs for the treatment of these aetiological agents are needed. Rondonin is a peptide isolated from the haemolymph of the spider Acanthoscurria rondoniae . Previous studies have shown that this peptide has antifungal activity against Candida sp. and Trichosporon sp. strains, acting on their genetic material. However, the molecular targets involved in its biological activity have not yet been described. Bioinformatics tools were used to determine the possible targets involved in the biological activity of Rondonin. The PharmMapper server was used to search for microorganismal targets of Rondonin. The PatchDock server was used to perform the molecular docking. UCSF Chimera software was used to evaluate these intermolecular interactions. In addition, the I-TASSER server was used to predict the target ligand sites. Then, these predictions were contrasted with the sites previously described in the literature. Molecular dynamics simulations were conducted for two promising complexes identified from the docking analysis. Rondonin demonstrated consistency with the ligand sites of the following targets: outer membrane proteins F (id: 1MPF) and A (id: 1QJP), which are responsible for facilitating the passage of small molecules through the plasma membrane; the subunit of the flavoprotein fumarate reductase (id: 1D4E), which is involved in the metabolism of nitrogenous bases; and the ATP-dependent Holliday DNA helicase junction (id: 1IN4), which is associated with histone proteins that package genetic material. Additionally, the molecular dynamics results indicated the stability of the interaction of Rondonin with 1MPF and 1IN4 during a 10 ns simulation. These interactions corroborate with previous in vitro studies on Rondonin, which acts on fungal genetic material without causing plasma membrane rupture. Therefore, the bioprospecting methods used in this research were considered satisfactory since they were consistent with previous results obtained via in vitro experimentation., Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00224-1., Competing Interests: Conflict of interestThe authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

This works proposes a dynamic thermoeconomic analysis of a liquefied biomethane production plant to meet the fuel demand of a fleet of heavy duty trucks in the south of Italy. The biomethane is obtained from the upgrading of the biogas produced by means of anaerobic digestion through a plug flow reactor fed by organic fraction of municipal solid waste. The upgrading of the biogas is realized using a three-stage membrane compression process, producing a 96 % pure biomethane. The biomethane liquefaction is realized using a single-mixed refrigerant process and compared to a Linde cycle process. The whole system is assisted by solar energy to reduce the fossil energy consumption of the process and feed-in tariffs are considered as funding policy. The models for the anaerobic digestion, the biogas upgrading, and the biomethane liquefaction are in detail developed in MatLab. The anaerobic digestion model is based on the ADM1 biological model, integrated with a suitable heat transfer model. The biogas upgrading model is based on a simplified Fick model. The liquefaction model is based on an equivalent two heat-exchangers model, taking into account the transient heat transfer. All the components are then integrated in TRNSYS to perform the dynamic simulation for one operating year of the whole system. Results from the thermoeconomic analysis are outstanding in terms of profitability, showing a payback period of less than 2 years and a Net Present Value of the system of 402 M€. The great environmental impact is also confirmed by a Primary Energy Saving of 91 % and a dramatic reduction of 86 % of the CO 2 equivalent emissions., Competing Interests: Declaration of competing interest The corresponding author confirms that all the other authors have read and approved the manuscript and no ethical issues and conflict of interest are involved. In particular the authors confirm that have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Phytophthora infestans (Mont.) de Bary, the oomycotic pathogen responsible for potato late blight, is the most devastating disease of potato production. The primary pesticides used to control oomycosis are phenyl amide fungicides, which cause environmental pollution and toxic residues harmful to both human and animal health. To address this, an antimicrobial peptide, NoPv1, has been screened to target Plasmopara viticola cellulose synthase 2 (PvCesA2) to inhibit the growth of Phytophthora infestans ( P. infestans ). In this study, we employed AlphaFold2 to predict the three-dimensional structure of PvCesA2 along with NoPv peptides. Subsequently, utilizing computational methods, we dissected the interaction mechanism between PvCesA2 and these peptides. Based on this analysis, we performed a saturation mutation of NoPv1 and successfully obtained the double mutants DP1 and DP2 with a higher affinity for PvCesA2. Meanwhile, dynamics simulations revealed that both DP1 and DP2 utilize a mechanism akin to the barrel-stave model for penetrating the cell membrane. Furthermore, the predicted results showed that the antimicrobial activity of DP1 was superior to that of NoPv1 without being toxic to human cells. These findings may offer insights for advancing the development of eco-friendly pesticides targeting various oomycete diseases, including late blight.

Context: A computational representation was used to model the doping and nanomodification of ZnO nanoparticles incorporated in Au/Fe nanocomposite. Au/Fe nanostructure was geometrically and discussed to investigate its electronic properties such electronic band structure and PDOS spectra. Moreover, the ZnO interacted with Au/Fe system was illustrated concerning the modified properties present on the surface of the nanocomposite as it may behave different attribution of band gap evaluated after ZnO modification included. Molecular dynamic simulation of the whole nano system was studied to predict the system stability concerning temperature and energy parameters during 100 ps simulation time. The most effective models under investigation were evaluated using adsorption annealing computations associated with the adsorption energy surface. A highly stable energetic adsorption system was anticipated by the periodic adsorption-annealing calculation., Methods: Au and Fe pure metals nanostructures were studied as a separate molecule with (0 0 1) plane surface for optimum energy minimization. Dmol 3 module in/materials studio software was utilized for this protocol. The designed Au/Fe layers for nanostructure building material was computationally optimized, where DFT level was considered involving generalized gradient approximation (GGA) with Perdew-Burke-Ernzerh (PBE) exchange functional. In the computations of the structure matrix simulation, the global orbital cutoff was selected. To address the weak quantification of the standard DFT functionals, Tkatchenko-Schefer (TS) (DFT + D) was utilized to precisely correct the pairwise dispersion of the functionals. The electrical parameters were interpreted using the reciprocal space of the ultrasoft pseudopotential representation. To overcome the issues of self-electron interaction, the nonlocal hybrid functional with PBE0 method was utilized to calculate the electronic properties of the studied systems. The computations generated are predicated on a particular trajectory of the gamma k-point band energy interpolations proposed in this examination. An investigation into the position of adsorption came after geometric optimization. Adsorbed on an optimized Au/Fe surface, ZnO nanostructure was computationally explored using the Dmol 3 simulation software., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Context: Electronic durable behavior on the material surface was accompanied by a class of antipsychotic drugs (APD) to describe the surface modification in the designed adsorption model. Hierarchically Zn-MOF system was utilized for estimating its capacity for drug molecule removal. Geometrically optimized strategy on the studied systems was performed using DFT/GGA/PBE. FMOs analysis was depicted based on the same level of calculations, and molecular electrostatic potential surface (MEP) was generated for unadsorbed and adsorbed systems to illustrate the variation in the surface-active sites. By interpreting the electronic density of states (DOS), the atomic orbital can be identified as a major or minor electronic distribution by PDOS graph. Adsorption locating behavior was considered to detect the significant surface interaction mode between APD and Zn-MOF surface based on lower adsorption energy. The stability of the adsorbed model was best described through dynamic simulation analysis with time through elevated temperatures. The non-covalent interactions were described using RDG/NCI analysis to show the major favorable surface interaction predicting the highly stable adsorption system., Methods: The most accurate geometrical computations were performed using the materials studio software followed by surface cleavage and vacuum slab generation. The first principle of DFT was used to apply CASTEP module with GGA/PBE method for band structure and DOS calculations. Three systems of antipsychotic drugs were computationally studied using CASTEP simulation package and adsorbed on an optimized Zn-MOF surface. Adsorption locator module predicted the preferred adsorption mechanistic models, in which the first model was arranged to be more stable, to confirm the occurrence of some interactions in the adsorption mechanism., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

During robot-assisted reduction of pelvic fracture, blood vessels are susceptible to tensile and shear forces, making them prone to injury. Considering the impact of pelvic reduction on the risk of arterial injury, the biomechanical characteristics of arteries during the pelvic fracture reduction process are studied, and a refined coupled composite model of the damaged pelvic structure is established. Dynamic simulations of pelvic fracture reduction are conducted based on the planned reduction path. The simulation results show that during the reduction process, when the affected side is rotated, the stress and strain of the artery are maximum, particularly at the locations of the iliac common artery, internal iliac artery, and the superior gluteal artery arch endure significant stress and strain. After reduction, the maximum stress is observed in the right superior gluteal artery, and the maximum strain occurs at the intersection of the right iliac common artery. The stretch ratio of both the left and right iliac common arteries is considerable. Therefore, it can be concluded that the superior gluteal artery and the internal iliac artery are prone to injury, particularly the segment from the origin of the superior gluteal artery to its passage around the greater sciatic notch. After reduction, substantial traction on the iliac common artery, which makes it more susceptible to deformation, carries a risk of arterial rupture and aneurysm formation. This study provides a reference for planning the safe reduction path of pelvic fracture surgery and improving safety.

Bacteria need to adjust their metabolism and protein synthesis simultaneously to adapt to changing nutrient conditions. It's still a grand challenge to predict how cells coordinate such adaptation due to the cross-regulation between the metabolic fluxes and the protein synthesis. Here we developed a dynamic Constrained Allocation Flux Balance Analysis method (dCAFBA), which integrates flux-controlled proteome allocation and protein limited flux balance analysis. This framework can predict the redistribution dynamics of metabolic fluxes without requiring detailed enzyme parameters. We reveal that during nutrient up-shifts, the calculated metabolic fluxes change in agreement with experimental measurements of enzyme protein dynamics. During nutrient down-shifts, we uncover a switch of metabolic bottleneck from carbon uptake proteins to metabolic enzymes, which disrupts the coordination between metabolic flux and their enzyme abundance. Our method provides a quantitative framework to investigate cellular metabolism under varying environments and reveals insights into bacterial adaptation strategies., (Copyright © 2024 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

A musculoskeletal (MSK) model is a valuable tool for assessing complex biomechanical problems, estimating joint torques during motion, optimizing motion in sports, and designing exoskeletons and prostheses. This study proposes an open-source upper body MSK model that supports biomechanical analysis of human motion. The MSK model of the upper body consists of 8 body segments (torso, head, left/right upper arm, left/right forearm, and left/right hand). The model has 20 degrees of freedom (DoFs) and 40 muscle torque generators (MTGs), which are constructed using experimental data. The model is adjustable for different anthropometric measurements and subject body characteristics: sex, age, body mass, height, dominant side, and physical activity. Joint limits are modeled using experimental dynamometer data within the proposed multi-DoF MTG model. The model equations are verified by simulating the joint range of motion (ROM) and torque; all simulation results have a good agreement with previously published research.

A musculoskeletal (MSK) model is an important tool for analysing human motions, calculating joint torques during movement, enhancing sports activity, and developing exoskeletons and prostheses. To enable biomechanical investigation of human motion, this work presents an open-source lower body MSK model. The MSK model of the lower body consists of 7 body segments (pelvis, left/right thigh, left/right leg, and left/right foot). The model has 20 degrees of freedom (DoFs) and 28 muscle torque generators (MTGs), which are developed from experimental data. The model can be modified for different anthropometric measurements and subject body characteristics, including sex, age, body mass, height, physical activity, and skin temperature. The model is validated by simulating the torque within the range of motion (ROM) of isolated movements; all simulation findings exhibit a good level of agreement with the literature.

In part due to the resilience of cellular feedback pathways that develop therapeutic resistance to targeting the EGFR alone, using EGFR inhibitors alone was demonstrated to be unsuccessful in clinical trials. The over-activation of the signal transducer/activator of transcription 3 (STAT3) during the administration of an EGFR inhibitor is expected to play a substantial part in the failure and resistance of EGFR inhibitor treatment. Therein, we proposed a hypothesis that induced STAT3-mediated resistance to EGFR inhibition therapy could be addressed by a dual inhibition of EGFR and STAT3 method. To this end, we tried to discover new thieno[2,3-d]pyrimidine derivatives "5a-o". Results from the screening on A549 and MCF7 cancer cell lines revealed that compounds 5j and 5k showed two-digit nanomolar with appropriate safety towards the WI-38 cell line. The best molecules, 5j and 5k, were subjected to γ-radiation, and their cytotoxic efficacy didn't change after irradiation, demonstrating that not having to use it avoided its side effects. Compounds 5j and 5k demonstrated the highest inhibition when their potency was tested as dual inhibitors on EGFR 67 and 41 nM, respectively, and STAT3 5.52 and 3.34 nM, respectively, proved with in silico molecular docking and dynamic simulation. In light of the results presented above, the capacity of both powerful compounds to alter the cell cycle and initiate the apoptotic process in breast cancer MCF7 cells was investigated. Caspase-8, Bcl-2, Bax and Caspase-9 apoptotic indicators were studied., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diabetes is a prevalent metabolic disorder associated with various complications. Inhibition of α-glucosidase and α-amylase enzymes is an effective strategy for managing non-insulin-dependent diabetes mellitus. This study aimed to investigate the antioxidant and antidiabetic potential of Ormocarpum cochinchinense leaf through in vitro and in silico approaches. The methanol extract exhibited the highest phenolic and flavonoid content over solvent extracts aqueous, acetone, hexane, and chloroform, the same has been correlating with strong antioxidant activity. Furthermore, the methanol extract demonstrated significant inhibitory effects on α-amylase and α-glucosidase enzymes, indicating its potential as an antidiabetic agent. Molecular docking analysis identified compounds, including myo-inositol, with favorable binding energies comparable to the standard drug metformin. The selected compounds displayed strong binding affinity towards α-amylase and α-glucosidase enzymes. Structural dynamics analysis revealed that myo-inositol formed a more stable complex with the enzymes. These findings suggest that O. cochinchinense leaf possesses antioxidant and antidiabetic properties, making it a potential source for developing therapeutic agents., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

A profound green transformation of China's heavy industrial aggregation regions is required to conquer severe air pollution, and fulfill carbon peak pledge. Here, to clarify the coordinated mechanism and an optimal roadmap for the reduction of CO 2 and gaseous pollutants, we integrated input-output modelling, system dynamics, and multi-objective programming to construct a CO 2 and gaseous pollutants synergistic reduction model initially; investigated incentive approaches from 2020 to 2035; Hebei, with the largest steel production in China, was adopted as a demonstrative region. Results revealed that intensive dual control of efficiency and structure in energy and industry can accelerate achieving carbon peak in 2029. In optimal case, CO 2 emission intensity can reach a 75.2% reduction compared to 2020, and gaseous pollutants continue decline simultaneously (SO 2 and NOx can drop by 63% and 48%); and the synergistic reduction level is expected to improve. Thus, vigorously develop decoupling between economy-air pollution-carbon reduction in Hebei. As opposed to efficiency improvement, structural adjustments were demonstrated to be more effective than short-term efficiency improvements. In addition, the estimated development potential of traditional heavy industries such as steel and petrochemicals is limited, whereas the equipment manufacturing industry, closely linked to traditional industries, is expected to continue its development. Furthermore, although in the electrification process, coal consumption is still needed because of its indispensable role in the production process of heavy industries. The results can facilitate policy-making for heavy industrial aggregation areas' green transformation in shaping policies and actions with clear objectives, effective measures, and sound coordination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Isoxazolidine derivatives were designed, synthesized, and characterized using different spectroscopic techniques and elemental analysis and then evaluated for their ability to inhibit both α-amylase and α-glucosidase enzymes to treat diabetes. All synthesized derivatives demonstrated a varying range of activity, with IC 50 values ranging from 53.03 ± 0.106 to 232.8 ± 0.517 μM (α-amylase) and from 94.33 ± 0.282 to 258.7 ± 0.521 μM (α-glucosidase), revealing their high potency compared to the reference drug, acarbose (IC 50 = 296.6 ± 0.825 µM and 780.4 ± 0.346 µM), respectively. Specifically, in vitro results revealed that compound 5d achieved the most inhibitory activity with IC 50 values of 5.59-fold and 8.27-fold, respectively, toward both enzymes, followed by 5b . Kinetic studies revealed that compound 5d inhibits both enzymes in a competitive mode. Based on the structure-activity relationship (SAR) study, it was concluded that various substitution patterns of the substituent(s) influenced the inhibitory activities of both enzymes. The server pkCSM was used to predict the pharmacokinetics and drug-likeness properties for 5d , which afforded good oral bioavailability. Additionally, compound 5d was subjected to molecular docking to gain insights into its binding mode interactions with the target enzymes. Moreover, via molecular dynamics (MD) simulation analysis, it maintained stability throughout 100 ns. This suggests that 5d possesses the potential to simultaneously target both enzymes effectively, making it advantageous for the development of antidiabetic medications.

This study aimed to assess the dynamic simulation models provided by Aspen adsorption (ASPAD) and artificial neural network (ANN) in understanding the adsorption behavior of atenolol (ATN) on gasified Glyricidia sepium woodchips activated carbon (GGSWAC) within fixed bed columns for wastewater treatment. The findings demonstrated that increasing the bed height from 1 to 3 cm extended breakthrough and exhaustion times while enhancing adsorption capacity. Conversely, higher initial ATN concentrations resulted in shorter breakthrough and exhaustion times but increased adsorption capacity. Elevated influent flow rates reduced breakthrough and exhaustion times while maintaining constant adsorption capacity. The ASPAD software demonstrated competence in accurately modeling the crucial exhaustion points. However, there is room for enhancement in forecasting breakthrough times, as it exhibited deviations ranging from 6.52 to 239.53% when compared to the actual experimental data. ANN models in both MATLAB and Python demonstrated precise predictive abilities, with the Python model (R 2 = 0.985) outperforming the MATLAB model (R 2 = 0.9691). The Python ANN also exhibited superior fitting performance with lower MSE and MAE. The most influential factor was the initial ATN concentration (28.96%), followed by bed height (26.39%), influent flow rate (22.43%), and total effluent time (22.22%). The findings of this study offer an extensive comprehension of breakthrough patterns and enable accurate forecasts of column performance., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

New 5-cyano-6-oxo-pyridine-based sulfonamides (6a-m and 8a-d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5-cyanopyridine derivatives 6e and 6l on cell-cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

During the stance phase of a normal gait, the triceps surae muscle controls the advancement of the tibia, which contributes to knee extension. Plantar flexor weakness results in excessive dorsiflexion, and consequently, the knee loses this contribution. However, increasing knee flexion is also seen in patients with cerebral palsy who do not have plantar flexor weakness. We aimed to understand this mechanism through the use of a musculoskeletal dynamic model. The model consists of solid segments connected with rotatory joints and springs to represent individual muscles. It was positioned at different degrees of ankle plantarflexion, knee flexion, and hip flexion. The soleus muscle was activated concentrically to produce plantarflexion and push the foot against the ground. The resulting knee extension was analyzed. The principal determinant of knee flexion or extension associated with ankle plantarflexion was the position of the knee joint center. When this was anterior to the line of action of the ground reaction force (GRF), the soleus contraction resulted in increased knee flexion. The knee extension was obtained when the knee was flexed less than approximately 25°. The relation between joint angles, anthropometric parameters, and the position of the GRF was expressed in a mathematical formulation. The clinical relevance of this model is that it explains the failure of plantar flexor control on knee extension in patients with cerebral palsy, when increased knee flexion can occur even if there is a normal or plantarflexed foot position.

Context: Electronic sustainable behavior on the material surface and in situ metal configuration were accompted with some metal atoms like Li, Na, and K elements. Metal-doped ZrO 2 crystal exported modified characteristics related to electronic conduction and exhibited some dynamic modification around the surface of the metal oxide. Computational perturbations were considered to discuss the modification behavior in addition to the studied Li, Na, and K metals. Optimization of the three doping systems was achieved followed by generating DOS and electronic band structure maps. A dynamic simulation was performed with temperature over 2000 k: the presence of the metal on the surface and prediction of its ZrO 2 inclusion leading to access adsorption behavior, besides generating predictive designed models described the adsorption affinity on the solid-state surface. It cannot be neglected the importance of various metals as a main role in chemotherapy. Molecular docking investigation was considered to predict the binding behavior of the studied metal ZrO 2 carrier system as an anticancer agent. Also, docking affinity was helpful in comparing the active sites binding for the studied metals, resulting in a notable binding affinity for both Li- and Na-zirconia incorporation., Methods: The program PWSCF, which is a component of the quantum ESPRESSO suite for quantum simulation of materials, was used to construct geometric systems. The generalized gradient approximation in the Perdew-Burke-Ernzerhof (GGA/PBE) function with D3 correction (Becke-Jonson damping) was applied to the exchange-correlation energy. As the last step in the DFT postulation and design, adsorption locator annealing was carried out on the convergent models using the Materials Studio simulation package. The main roles played by metal atoms are in protein binding and the suppression of bio-active regions. For the docking process, the protein was produced using AutoDock 4.2 and Discovery Studio software in accordance with the usual methodology. Chimera and Discovery Studio were used to examine the docking data that was processed after generating specific grid box dimensions for 7BTN., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The spread of multidrug resistant bacteria has fueled the development of new antibiotics to combat bacterial infections. Disrupting the quorum sensing (QS) mechanism with biomolecules is a promising approach against bacterial infections. Plants used in Traditional Chinese Medicine (TCM) represent a valuable resource for the identification of QS inhibitors. In this study, the in vitro anti-QS activity of 50 TCM-derived phytochemicals against the biosensor Chromobacterium violaceum CV026 was tested. Among the 50 phytochemicals, 7-methoxycoumarin, flavone, batatasin III, resveratrol, psoralen, isopsoralen, and rhein inhibited violacein production and showed good QS inhibitory effects. Batatasin III was selected as the best QS inhibitor based on drug-likeness, physicochemical properties, toxicity, and bioactivity score prediction analyses using SwissADME, PreADMET, ProtoxII, and Molinspiration. At 30 μg/ mL, Batatasin III inhibited violacein production and biofilm formation in C. violaceum CV026 by more than 69% and 54% respectively without affecting bacterial growth. The in vitro cytotoxicity evaluation by MTT assay demonstrated that batatasin III reduced the viability of 3T3 mouse fibroblast cells to 60% at 100 μg/mL. Furthermore, molecular docking studies showed that batatasin III has strong binding interactions with the QS-associated proteins CViR, LasR, RhlR, PqsE, and PqsR. Molecular dynamic simulation studies showed that batatasin III has strong binding interactions with 3QP1, a structural variant of CViR protein. The binding free energy value of batatasin III-3QP1 complex was -146.295 ± 10.800 KJ/mol. Overall results suggested that batatasin III could serve as a lead molecule that could be developed into a potent QS inhibitor.Communicated by Ramaswamy H. Sarma.

Acidic partial nitritation (PN) is a promising technology to achieve low-cost and energy-efficient shortcut nitrogen removal from wastewater. However, a comprehensive understanding of the acidic PN under dynamic changes of pH in a sequencing batch reactor (SBR) is still lacking. In this study, we successfully established acidic PN (NO 2 - accumulation ratio >80%) under dynamic pH variation from 7.0 to 4.5 in a lab-scale SBR. By accumulating in situ free nitrous acid (FNA) generation based on the dynamic pH change, acidic PN maintained stability even at a low NH 4 + concentration of 100 mg N L -1 . The microbial community analysis revealed that two ammonium-oxidizing bacteria (AOB) genera, Nitrosospira and Nitrosomonas , successfully coexisted and cooperated during acidic PN. None of the species of nitrite-oxidizing bacteria (NOB) showed adaptation to intermittent inhibition of in situ FNA even under high DO conditions (>4.0 mg O 2 L -1 ). Furthermore, we innovatively incorporated the classic nitrification model with the growth and decay of different nitrifying bacterial species and their inhibition by pH, FNA, and free ammonia (FA) to predict the nitrifying microbial communities shifting for establishing acidic PN. The extended model was calibrated by using short-term batch experiments and was validated by using long-term dynamic data of the nitrifying microbial community during SBR operation. The validated model was further used to identify feasible influent conditions for the SBR PN process, including influent HCO 3 - concentration, NH 4 + concentration and molar ratio (HCO 3 /NH 4 + ). Outcomes from this study support the optimal design of acidic PN-based short-cut nitrogen removal processes for future application.

Exoskeletons can protect users' lumbar spine and reduce the risk of low back injury during manual lifting tasks. Although many exoskeletons have been developed, their adoptability is limited by their task- and movement-specific effects on reducing burden. Many studies have evaluated the safety and effectiveness of an exoskeleton using the peak/mean values of biomechanical variables, whereas the performance of the exoskeleton at other time points of the movement has not been investigated in detail. A functional analysis, which presents discrete time-series data as continuous functions, makes it possible to highlight the features of the movement waveform and determine the difference in each variable at each time point. This study investigated an assessment method for exoskeletons based on functional ANOVA, which made it possible to quantify the differences in the biomechanical variables throughout the movement when using an exoskeleton. Additionally, we developed a method based on the interpolation technique to estimate the assistive torque of an exoskeleton. Ten men lifted a 10-kg box under symmetric and asymmetric conditions five times each. Lumbar load was significantly reduced during all phases (flexion, lifting, and laying) under both conditions. Additionally, reductions in kinematic variables were observed, indicating the exoskeleton's impact on motion restrictions. Moreover, the overlap F-ratio curves of the lumbar load and kinematic variables imply that exoskeletons reduce the lumbar load by restricting the kinematic variables. The results suggested that at smaller trunk angles (<25°), an exoskeleton neither significantly reduces the lumbar load nor restricts trunk movement. Our findings will help increasing exoskeleton safety and designing effective products for reducing lumbar injury risks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xiang, Tanaka, Umeno, Kikuchi and Kobayashi.)

A crown ether-loaded hybrid adsorbent suitable for the separation and enrichment of strontium from high-level liquid waste was synthesized. 4',4'(5″)-di(tert-butylcyclohexano)-18-crown-6 (DtBuCH18C6) and its modifiers dodecyl benzenesulfonic acid (DBS) and 1-dodecanol were impregnated into silica-based polymer support. The hybrid adsorbent exhibited excellent Sr(II) selectivity ability, and effective chromatographic separation and recovery of Sr(II) from simulated high-level liquid waste could be achieved with a (DtBuCH18C6 + DBS + dodec)/SiO 2 -P packed column. The recovery rate of Sr(II) calculated based on the mass balance was approximately 99% and over 80% for the other coexisting metal ions. An appropriate increase in the concentration of Na-DTPA eluent was favorable to improve the efficiency of the elution process because of the increased complexation capacity of [DTPA] 5- to Sr(II). The developed theoretical model can simulate the dynamic breakthrough curves of the material on the basis of short column data, thereby predicting the scale-up column of the practical operation. Density functional theory calculation was used to explore the action mechanism of DBS modifiers on the Sr(II) complexation process of crown ether groups. Two Sr(II) complexation isomeric models of DtBuCH18C6 were established, and the calculation results revealed a similar complexation ability. DtBuCH18C6 could form a stable Sr(II) complexation structure with DBS coordination, which further indicated that DBS could be a ligand to promote the Sr(II) adsorption ability of crown ether materials.

Wildland fire extent varies seasonally and interannually in response to climatic and landscape-level drivers, yet predicting wildfires remains a challenge. Existing linear models that characterize climate and wildland fire relationships fail to account for non-stationary and non-linear associations, thus limiting prediction accuracy. To account for non-stationary and non-linear effects, we use time-series climate and wildfire extent data from across China with unit root methods, thus providing an approach for improved wildfire prediction. Results from this approach suggest that wildland area burned is sensitive to vapor pressure deficit (VPD) and maximum temperature changes over short and long-term scenarios. Moreover, repeated fires constrain system variability resulting in non-stationarity responses. We conclude that an autoregressive distributed lag (ARDL) approach to dynamic simulation models better elucidates interactions between climate and wildfire compared to more commonly used linear models. We suggest that this approach will provide insights into a better understanding of complex ecological relationships and represents a significant step toward the development of guidance for regional planners hoping to address climate-driven increases in wildfire incidence and impacts., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this study, the effect of anaerobic hydrolysis rate on biogas production was investigated with mesophilic digesters in seven large-scale wastewater treatment plants. A linear correlation was determined between the percentage of primary sludge mass in the total sludge fed to the digester and the overall anaerobic hydrolysis rate. The anaerobic hydrolysis rate of primary sludge was determined to be three times higher than that of biological sludge. The reduction factors for anaerobic hydrolysis (η HYD,ana ) were identified in the range of 0.11-0.30 which is lower compared to the recommended range (0.30-0.50) given in the literature. This study proposes a new model approach where anaerobic degradation kinetics of influent originated (X B ) and decay originated (X B,E ) particulate biodegradable organics are separated. Current plant-wide models with a single kinetic expression required recalibration of the model for calculating biogas flowrate for each treatment facility with different primary and secondary sludge ratios fed to the digesters. The new model structure is able to predict biogas production of all wastewater treatment plants without any recalibration effort by segregating degradation kinetics of two particulate biodegradable organic fractions (X B , X B , E )., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Constructed wetland (CW) is an important method of ecological water treatment, and CW has obvious advantage in treating low-pollution water. In order to improve the treatment efficiency of CW, the first-order and second-order kinetics simulations of pollutant removal in CW were carried out to optimize operating conditions. The experimental study of city tail water treatment under unmodified biochar (different additions) or different modified biochar conditions showed that the first-order kinetic equation relatively accurately reflect the removal of pollutants by substrate. The relatively optimal range of biochar addition (2.21-3.79%) in the first-order kinetic analysis covered the relatively optimal mass ratio (2.95%). The first-order kinetic equation fitting showed that the half-life of ammonia nitrogen removal by NaOH (0.1 mol·L -1 )-modified biochar was reduced by about 10% without plant. The half-life of total phosphorus removal by KMnO 4 (0.1 mol·L -1 ) modified biochar was reduced by about 50%. The half-life of chemical oxygen demand removal by H 2 SO 4 (0.75 mol·L -1 ) + 8 freeze-thaw cycles modified biochar was reduced by about 9.0%. When the half-life was small, the pollutant removal rate was high. The results of this study further confirmed the effectiveness of the simulation results of pollutant removal in CW with biochar by the first-order kinetic equation. This study further optimized the CW operating conditions and improved the treatment efficiency of nitrogen and phosphorus in the CW., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Cancer is one of the leading causes of death worldwide. Recently, it was shown that many natural extracts have positive effects against cancer, compared with chemotherapy or recent hormonal treatments. A. annua is an annual medicinal herb used in the traditional Chinese medicine. It has also been shown to inhibit the proliferation of various cancer cell lines., Methods: Multi-level modes of action of A. annua constituents in cancer therapy were investigated using an integrated approach of network pharmacology, molecular docking, dynamic simulations and in-vitro cytotoxicity testing on both healthy and cancer cells., Results: Network pharmacology-based analysis showed that the hit Artemisia annua constituents related to cancer targets were 3-(2-methylpropanoyl)-4-cadinene-3,11-diol, artemisinin G, O-(2-propenal) coniferaldehyde, (2-glyceryl)-O-coniferaldehyde and arteamisinin III, whereas the main cancer allied targets were NFKB1, MAP2K1 and AR. Sixty-eight significant signaling KEGG pathways with p < 0.01 were recognized, the most enriched of which were prostate cancer, breast cancer, melanoma and pancreatic cancer. Thirty-five biological processes were mainly regulated by cancer, involving cellular response to mechanical stimulus, positive regulation of gene expression and transcription. Molecular docking analysis of the top hit compounds against the most enriched target proteins showed that 3-(2-methylpropanoyl)-4-cadinene-3,11-diol and O-(2-propenal) coniferaldehyde exhibited the most stabilized interactions. Molecular dynamics simulations were performed to explain the stability of these two compounds in their protein-ligand complexes. Finally, confirmation of the potential anticancer activity was attained by in-vitro cytotoxicity testing of the extract on human prostate (PC-3), breast (MDA-MB-231), pancreatic (PANC-1) and melanoma (A375) cancerous cell lines., Conclusion: This study presents deeper insights into A. annua molecular mechanisms of action in cancer for the first time using an integrated approaches verifying the herb's value., (© 2023. BioMed Central Ltd., part of Springer Nature.)

FLT3 is considered a potential target of acute myeloid leukemia therapy. In this study, we applied a computer-aided methodology unifying molecular docking and pharmacophore screening to identify potent inhibitors against FLT3. To investigate the pharmacophore area and binding mechanism of FLT3, the reported co-crystallized Gilteritinib ligand was docked into the active site using Glide XP. Based on the docking results, we identified structure-based pharmacophore characteristics resistant to potent FLT3 inhibitors. The best hypothesis was corroborated using test and decoy sets, and the verified hypo was utilized to screen the chemical database. The hits from the pharmacophore-based screening were then screened again using a structure-based method that included molecular docking at various precisions; the selected molecules were further examined and refined using drug-like filters and ADMET analysis. Finally, two hits were picked out for molecular dynamic simulation. The results showed two hits were expected to have potent inhibitory activity and excellent ADMET characteristics, and they might be used as new leads in the development of FLT3 inhibitors.Communicated by Ramaswamy H. Sarma.

The interaction of an antiviral drug Molnupiravir ( MOL ) with calf thymus DNA (CT-DNA) was investigated using a series of biophysical techniques. A significant hyperchromism with a blue shift  nm in the UV-Vis spectra indicated a high binding affinity of MOL for CT-DNA with binding constants in the order of 10 5 M -1 . Competitive fluorescent dye displacement assays with ethidium bromide (EB) and Hoechst 33258 suggested an intercalative mode of binding of MOL with CT-DNA. Thermodynamic profiles determined using fluorescence titration and isothermal titration calorimetric (ITC) analysis matched well with each other. The negative free energy change revealed that the MOL /CT-DNA complexation is a spontaneous process. The negative values of enthalpy and entropy changes indicated that H-bonding and van der Walls interactions play dominant roles in stabilizing the complex. A decrease in viscosity of CT-DNA solution upon adding MOL indicated a partial intercalation mode of binding which was well supported by circular dichroism (CD) spectral and effect of KI and denaturation studies. Molecular docking and metadynamics simulation studies clearly showed the partial intercalation of the pyrimidine ring of MOL into the base pairs of DNA. Free energy surface (FES) contour indicated that the drug/DNA complex is stabilized by H-bonding and pi-pi/pi-cation interactions.Communicated by Ramaswamy H. Sarma.

Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from -5.5 kcal/mol to -6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from -7.5 kcal/mol to -9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = -9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity.

Background: Endophytic Aspergillus species produce countless valuable bioactive secondary metabolites. In the current study, Aspergillus flavus an endophyte from the soft coral Sarcophyton ehrenbergi was chemically explored and the extracted phytoconstituents were subsequently evaluated for antimicrobial activity. This is accomplished by employing nuclear magnetic resonance (NMR) spectroscopy and computational techniques. Additionally, An in vitro anticancer analysis of A. flavus total extract against breast cancer cells (MCF-7) was investigated., Result: Six compounds were separated from the crude alcohol extract of the endophytic Aspergillus flavus out of which anhydro-mevalonolactone was reported for the first time. The anti-fungal and anti-Helicobacter pylori properties of two distinct compounds (Scopularides A and B) were assessed. Additionally, computational research was done to identify the binding mechanisms for all compounds. Both the compounds were found to be active against H. pylori with minimum inhibitory concentration (MIC) values ranging from 7.81 to 15.63 µg/ mL as compared with clarithromycin 1.95 µg/ mL. Scopularides A was potent against both Candida albicans and Aspergillus niger with MIC values ranging from 3.9 to 31.25 µg/ mL, while scopularides B only inhibits Candida albicans with MIC value of 15.63 µg/ mL and weak inhibitory activity against A. niger (MIC = 125 µg/ mL). Furthermore, cytotoxic activity showed a significant effect (IC 50 : 30.46 mg/mL) against MCF-7 cells., Conclusion: Our findings report that cytotoxic activity and molecular docking support the antimicrobial activity of Aspergillus flavus, which could be a promising alternative source as a potential antimicrobial agent., (© 2023. The Author(s).)

The Covid-19 outbreak raised great attention to the importance of indoor air quality in buildings. Even if the Covid-19 epidemic is nearing an end, all stakeholders agree that increasing outside air flow rates is beneficial for decreasing the likelihood of contagion, lowering the risk of future pandemics, and enhancing the general safety of the interior environment. Indeed, diverse concerns raised about whether the ventilation standards in place are still adequate. In this context, this research intends to assess the suitability of current ventilation standards in addressing the current pandemic scenario and to offer novel criteria and guidelines for the design and operation of HVAC systems, as well as useful guidance for the creation of future ventilation standards in a post-Covid-19 scenario. To that end, a comprehensive analysis of the ANSI/ASHRAE 62.1 is carried out, with an emphasis on its effectiveness in reducing the risk of infection. Furthermore, the efficacy of various ventilation strategies in reducing the likelihood of contagion has been investigated. Finally, because building ventilation is inextricably linked to energy consumption, the energy and economic implications of the proposed enhancements have been assessed. To carry out the described analysis, a novel method was developed that combines Building Energy Modelling (BEM) and virus contagion risk assessment. The analyses conducted produced interesting insights and criteria for ventilation system design and operation, as well as recommendations for the development of future standards., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Elsevier Ltd. All rights reserved.)

Thoracoabdominal asynchrony (TAA), the asynchronous volume changes between the rib cage and abdomen during breathing, is associated with respiratory distress, progressive lung volume loss, and chronic lung disease in the newborn infant. Preterm infants are prone to TAA risk factors such as weak intercostal muscles, surfactant deficiency, and a flaccid chest wall. The causes of TAA in this fragile population are not fully understood and, to date, the assessment of TAA has not included a mechanistic modeling framework to explore the role these risk factors play in breathing dynamics and how TAA can be resolved. We present a dynamic compartmental model of pulmonary mechanics that simulates TAA in the preterm infant under various adverse clinical conditions, including high chest wall compliance, applied inspiratory resistive loads, bronchopulmonary dysplasia, anesthesia-induced intercostal muscle deactivation, weakened costal diaphragm, impaired lung compliance, and upper airway obstruction. Sensitivity analyses performed to screen and rank model parameter influence on model TAA and respiratory volume outputs show that risk factors are additive so that maximal TAA occurs in a virtual preterm infant with multiple adverse conditions, and addressing risk factors individually causes incremental changes in TAA. An abruptly obstructed upper airway caused immediate nearly paradoxical breathing and tidal volume reduction despite greater effort. In most simulations, increased TAA occurred together with decreased tidal volume. Simulated indices of TAA are consistent with published experimental studies and clinically observed pathophysiology, motivating further investigation into the use of computational modeling for assessing and managing TAA. NEW & NOTEWORTHY A novel model of thoracoabdominal asynchrony incorporates literature-derived mechanics and simulates the impact of risk factors on a virtual preterm infant. Sensitivity analyses were performed to determine the influence of model parameters on TAA and respiratory volume. Predicted phase angles are consistent with prior experimental and clinical results, and influential parameters are associated with clinical scenarios that significantly alter phase angle, motivating further investigation into the use of computational modeling for assessing and managing thoracoabdominal asynchrony.

Drug repurposing opens new avenues in cancer therapy. Drug repurposing, or finding new uses for existing drugs, can substantially reduce drug discovery time and costs. Cheminformatics, genetics, and systems biology advances enable repositioning drugs. Clinical usage of PD-1/PD-L1 blocking has been approved because of its efficacy in improving prognosis in select groups. The PD-1/PD-L1 axis was considered to represent a mechanism for tumour evasion of host tumour antigen-specific T-cell immunity in early preclinical research. The expression of PD-L1 in cancer cells causes T lymphocytes to become exhausted by transmitting a co-inhibitory signal. A better understanding of how PD-L1 is regulated in cancer cells could lead to new therapeutic options. In this view, the study was aimed to repurpose the existing FDA-approved drugs as a potential PD-L1 inhibitor through e-Pharmacophore modelling, molecular docking and dynamic simulation. e-Pharmacophore screening retrieved 324 FDA-approved medications with the fitness score ≥ 1. The top 10-docked FDA candidates were compared with IN-35 (Clinical trial candidate) for its interaction pattern with critical amino acid residues. Mirabegron and Indacaterol exhibited a greater affinity for PD-L1 with docking scores of - 9.213 kcal mol -1 and - 8.023 kcal mol -1 , respectively. Mirabegron retain interactions at all three major hotspots in the PD-L1 dimer interface similar to IN-35. MM-GBSA analyses indicated that Mirabegron uses less energy to create a more stable complex and retains all of the inhibitor's positive interactions found in clinical trial ligand IN-35. Molecular dynamics simulation analysis of the Mirabegron complex showed a similar pattern of deviation in correlation with IN-35, and it retains the interaction with the active key amino acids throughout the simulation time. Our present study has shown Mirabegron as a powerful inhibitor of PD-L1 expression in cancer cells using a drug-repurposing screen., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This research investigated the antihypertensive effects of tamarind products and compared their potentials based on an animal model's data verified by molecular docking, multitarget interactions, and dynamic simulation assays. GC-MS-characterized tamarind products were administered to cholesterol-induced hypertensive albino rat models. The two-week-intervened animals were dissected to collect their serum and organs and respectively subjected to analyses of their hypertension-linked markers and tissue architectures. The lead biometabolites of tamarinds interacted with eight target receptors in the molecular docking and dynamic simulation studies and with multitarget in the network pharmacological analyses. The results show that the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), C-reactive protein (CRP), troponin I, and lipid profiles were maximally reinstated by the phenolic-enriched ripened sour tamarind extract compared to the sweet one, but the seed extracts had a smaller influence. Among the tamarind's biometabolites, ϒ-sitosterol was found to be the best ligand to interact with the guanylate cyclase receptor, displaying the best drug-likeliness with the highest binding energy, -9.3 Kcal. A multitargeted interaction-based degree algorithm and a phylogenetic tree of pathways showed that the NR3C1 , REN , PPARG , and CYP11B1 hub genes were consistently modulated by ϒ-sitosterol to reduce hypertension and related risk factors. The dynamic simulation study showed that the P-RMSD values of ϒ-sitosterol-guanylate cyclase were stable between 75.00 and 100.00 ns at the binding pocket. The findings demonstrate that ripened sour tamarind extract may be a prospective antihypertensive nutraceutical or supplement target affirmed through advanced preclinical and clinical studies.

By linking the cation and anion motifs of ionic liquids (ILs), zwitterionic liquids (ZILs) exhibit at least 146-2740 and 112-1550 folds less cytotoxicity in human gastric and colon cells than those of the structurally related ILs. Computer simulation shows that ZIL molecules hardly penetrate the cell membranes in contrast to ILs. These findings reveal a novel mechanism for ZILs to evade cytotoxicity, establishing a structure-based design principle for the next generation of sustainable ZILs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The effects of mango active volatile components (VOCs) on protein function were investigated from the perspective of nutrient transport. The active volatile components of five varieties of mango were analyzed by headspace solid phase microextraction gas chromatography-mass spectrometry (HS-SPME/GC-MS). The interaction mechanism between active volatile components and three carrier proteins was discussed by fluorescence spectroscopy, molecular docking and dynamic simulation. The results showed that there were 7 active components in the five mango varieties. The aroma components represented by 1-caryophyllene and β-pinene were selected for further study. The interaction between VOCs small molecules and proteins is a static binding process, and its main force is hydrophobic interaction. The results of molecular simulation and spectral experiments showed that the binding ability of 1-caryophyllene and β-pinene to β-Lg was strong, so mango VOCs could possess a certain nutritional value in dairy products, expanding its application in dairy products in the food industry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Infectious Spleen and Kidney Necrosis Virus (ISKNV) is linked to severe infections that cause significant financial losses in global aquaculture. ISKNV enters the host cell through its major capsid protein (MCP), and the resulting infection can lead to mass mortality of fish. Even though several drugs and vaccines are at various stages of clinical testing, none are currently available. Thus, we sought to assess the potential of seaweed compounds to block viral entrance by inhibiting the MCP. The Seaweed Metabolite Database (1110 compounds) was assessed for potential antiviral activity against ISKNV using high throughput virtual screening. Forty compounds with docking scores of ≥8.0 kcal/mol were screened further. The inhibitory molecules BC012, BC014, BS032, and RC009 were predicted by the docking and MD techniques to bind the MCP protein significantly with binding affinities of -9.2, -9.2, -9.9, and -9.4 kcal/mol, respectively. Also, ADMET characteristics of the compounds indicated drug-likeness. According to this study, marine seaweed compounds may operate as viral entrance inhibitors. For their efficacy to be established, in-vitro and in-vivo testing is required., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Sk Injamamul Islam reports statistical analysis was provided by 10.13039/501100016172Jashore University of Science and Technology. Sk Injamamul Islam reports a relationship with 10.13039/501100016172Jashore University Of Science and Technology that includes: non-financial support. Sk Injamamul Islam has patent pending to Assignee. Not applicable., (© 2023 Published by Elsevier Ltd.)

Recently, the dual-fluorescent phenomena of excited state intramolecular thiol proton transfer (ESIPT) for 3-thiolflavone derivative (3NTF) were reported by Chou and coworkers for the first time [J. Am. Chem. Soc. 143 (2021) 12715-12724], which opened a new chapter in the field of ESIPT. Based on density functional theory (DFT) and time-dependent density functional theory (TDDFT), the proton transfer processes of 3NTF in toluene, dichloromethane and acetonitrile were studied. By optimizing the structure of the ground (S0) state and first excited (S1) state of 3NTF in different solvents, the hydrogen-bond parameters and proton-transfer potential energy curves were calculated. It was shown that although photo-excitation enhanced the intramolecular hydrogen bonding strength and thus promoted the occurrence of ESIPT, the solvent polarities inhibited the enhancement of the hydrogen bond of S1 state, which was not conducive to ESIPT. The electron spectra analyses were consistent with experimental data, which confirmed the rationality of molecular configurations. The time-evolved excited state dynamics simulation was performed based on the optimized structure of 3NTF, indicating that the ESIPT was an ultrafast photochemical reaction less than 180 fs. Moreover, we compared the potential energy surfaces of ESIPT, electronic structures based on natural transition orbitals (NTOs) method and electron-hole isosurfaces for the 3NTF and the traditional flavone molecule (3NHF), concluded that the unusually large Stokes shift fluorescence of 3NTF was mainly caused by the coupling of ESIPT and twisting intramolecular charge transfer (TICT), and the 3NTF isomer had the more nπ* character in the electron transition process. The nπ* ICT significantly increased with the decrease of solvent polarities, affecting the molecular photophysical properties, this made it more widely used in biomedical, photochemical, materials science and other fields., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cyclospora cayetanensis infections, also known as cyclosporiasis, persist to be the prevalent emerging protozoan parasite and an opportunist that causes digestive illness in immunocompromised individuals. In contrast, this causal agent can affect people of all ages, with children and foreigners being the most susceptible populations. For most immunocompetent patients, the disease is self-limiting; in extreme circumstances, this illness can manifest as severe or persistent diarrhea as well as colonize on secondary digestive organs leading to death. According to recent reports, worldwide 3.55% of people are infected by this pathogen, with Asia and Africa being more prevalent. For the treatment, trimethoprim-sulfamethoxazole is the only licensed drug and does not appear to work as well in some patient populations. Therefore, the much more effective strategy to avoid this illness is immunization through the vaccine. This present study uses immunoinformatics for identifying a computational multi-epitope-based peptide vaccine candidate for Cyclospora cayetanensis. Following the review of the literature, a highly efficient, secure, and vaccine complex based on multi-epitopes was designed by utilizing the identified proteins. These selected proteins were then used to predict non-toxic and antigenic HTL-epitopes, B-cell-epitopes, and CTL-epitopes. Ultimately, both a few linkers and an adjuvant were combined to create a vaccine candidate with superior immunological epitopes. Then, to establish the vaccine-TLR complex binding constancy, the TLR receptor and vaccine candidates were placed into the FireDock, PatchDock, and ClusPro servers for molecular docking and iMODS server for molecular-dynamic simulation. Finally, this selected vaccine construct was cloned into Escherichia coli strain-K12; thus, the constructed vaccines against Cyclospora cayetanensiscould improve the host immune response and can be produced experimentally., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In the current energy and environmental framework, the environmental impact of the road transport sector and the urban waste management and disposal are extremely important for highly crowded cities. This work assesses the energy, economic and environmental performance of an innovative paradigm for the full decarbonisation of the road transport sector. This problem is integrated with the management of the organic fraction of municipal solid waste. In particular, the proposed technology is based on an anaerobic digestion plant coupled with a biogas upgrading unit, for the production of biomethane. In addition, photovoltaic panels and solar thermal collectors are also considered for matching electrical and thermal demands, in order to achieve a fully-renewable system. To this scope, the system also includes suitable thermal and electric storages. The economic analysis also considers specific public funding policies, currently available for this technology. This system aims to be a novel paradigm in the energy scenario of waste disposal and road transport sector refurbishment. TRNSYS software was adopted to perform an accurate dynamic simulation for a one-year operation of the system. The anaerobic digestion model is developed by the authors in MatLab and integrated in TRNSYS, for dynamic simulation purpose. Results show that the plant is almost self-sufficient due to the integration of storage systems for both the thermal and electric energy. The photovoltaic system is able to reduce by 45% the energy dependence from the grid. Energy and environmental analyses show a Primary Energy Saving of 126% and a reduction of CO 2 equivalent emissions by 112%. The economic feasibility analysis shows a promising Simple Payback period of 6 years., Competing Interests: The authors declare no conflict of interest., (©2023TheAuthors.PublishedbyElsevierLtd.)