There are various biomaterials in nature, but none fulfills all the requirements. Cellulose, eco-friendly material-based biopolymers, have been advanced biomedicine to satisfy most market demand and circumvent many ecological concerns. This review aims to present an overview of the state of the art in cellulose's knowledge and technical biomedical applications. It included an extensive bibliography of recent research findings for fundamental and applied investigations. The chemical structure of cellulose allows modifications and simple conjugation with several materials, including nanoparticles, without tedious efforts. Cellulose-based materials were used for biomedicine applications such as antibacterial agents, antifouling, wound healing, drug delivery, tissue engineering, and bone regeneration. They advanced the applications to be cheap, biocompatible, biodegradable, easy for shaping and processing into different forms, with suitable chemical, mechanical and physical properties.

Molecularly imprinted polymers (MIPs) have been widely used in nanomedicine during the last few years. However, their potential is limited by their intrinsic properties resulting, for instance, in lack of control in drug release processes or complex detection for in vivo imaging. Recent attempts in creating hybrid nanomaterials combining MIPs with inorganic nanomaterials succeeded in providing a wide range of new interesting properties suitable for nanomedicine. Through this review, we aim to illustrate how hybrids molecularly imprinted polymers may improve patient care with enhanced imaging, treatments and combination of both.

Candida glabrata is a yeast of increasing medical relevance, particularly in critically ill patients. It is the second most isolated Candida species associated with invasive candidiasis (IC) behind C. albicans. The attributed higher incidence is primarily due to an increase in the acquired immunodeficiency syndrome (AIDS) population, cancer, and diabetes patients. The elderly population and the frequent use of indwelling medical devices are also predisposing factors. The work aimed to review various virulence factors that facilitate the survival of pathogenic C. glabrata in IC. The available published research articles related to the pathogenicity of C. glabrata were retrieved and reviewed from four credible databases, mainly Google Scholar, ScienceDirect, PubMed, and Scopus. The articles highlighted many virulence factors associated with pathogenicity in C. glabrata, including adherence to a susceptible host surface, evading host defences, and producing hydrolytic enzymes (e.g., phospholipases, proteases, and haemolysins). The factors facilitate infection initiation. Other virulent factors include iron regulation and genetic mutations. Accordingly, biofilm production, tolerance to high-stress environments, and development of resistance to the antifungal drug, notably to fluconazole and other azole derivatives, were reported. The review provided evident pathogenic mechanisms and antifungal resistance associated with C. glabrata in ensuring its sustenance and survival.

Galangin(Gal) is a natural active flavonoid compound separated from the roots and rhizomes of Alpinia ofcinarum Hance. Modern pharmacological studies have shown that Gal has a variety of biological activities such as anti-tumor, anti-fungal, anti-bacterial, anti-inflammatory, anti-ischemic stroke, suppressing vitiligo and Alzheimer’s disease, etc. The purpose of this research was to prepare a galangin self-microemulsion drug delivery system (Gal-SMEDDS) and compare its anti-oxidant activity and pharmacokinetics with free Gal.The average particle size of the prepared Gal-SMEDDS was approximately 21.33 nm, the polydispersity index was 0.096, the zeta potential was -4.09 mV, and the entrapment efficiency was 96.74%. Compared with free Gal, the release of Gal-SMEDDS was improved in vitro release experiment. Cell experiments showed that Gal had obvious anti-oxidation effect, and the effect of Gal-SMEDDS was better than that of free Gal. In vivo pharmacokinetic experiments showed that the pharmacokinetic parameters of Gal-SMEDDS were better than that of free Gal, which indicated that the self-microemulsion drug delivery system(SMEDDS) effectively increases the oral bioavailability of Gal and alters its pharmacokinetic parameters, such that it may be effective in the treatment of anti-oxidant.

Artificial learning and machine learning is playing a pivotal role is the society especially in the field of medicinal chemistry and drug discovery. Particularly its algorithms, neural networks or other recurrent networks drive this area. In this review, we have taken into account the diverse use of AI in a number of pharmaceutical industries including discovery of drugs, repurposing, development of pharmaceutical drug and its clinical trials. In addition, the efficiency of these artificial or machine learning programs in achieving the target drugs in short time period, along with accurate dosage and cost effectively of the drug has also been discussed. Numerous applications of AI in property prediction such as ADMET have been used for prediction of strength of this technology in QSAR. In case of de-novo synthesis, it results in generation of novel drug molecules with unique design proving this a promising field fir drug design. Moreover, its involvement in synthetic planning, ease of synthesis and much more contribute to automated drug discovery in near future.

This review revisits clinical use of antibiotics for most common acute oro-dental conditions; we aim to provide evidence governing antibiotics use when access to oral healthcare is not available, as during the ongoing outbreak of the severe acute respiratory syndrome coronavirus 2. In this rapid review, articles were retrieved after conducting a search on PubMed and Google Scholar. Relevant publications were selected and analyzed. Most recent systematic reviews with/without meta-analyses and societal guidelines were selected. Data were extracted, grouped, and synthesized according to the respective subtopic analysis. There were evidence supporting the use of antibiotics in common oro-dental conditions as temporary measure when immediate care is not accessible, such as in case of localized oral swellings as well as to prevent post-extraction complications. No sufficient evidence could be found in support of antibiotic use for pain resulting from pulpal origin. Consequently, antibiotic use may be justified to defer treatment temporarily or reduce risk of complications in case of localized infection and tooth extraction, when no access to immediate dental care is possible.

Abstract: Targeted ubiquitination and proteasomal degradation regulates various cellular pathways, and the discovery that CPT induced rapid proteasomal degradation of topoI is the primary mechanism of CPT resistance was novel and compelling. CPTs are used extensively to treat various solid tumors like colorectal, gastric, pancreatic, ovarian and small cell lung cancer. The response rate is low and the classical mechanisms of drug resistance are yet to be validated. Remarkably, CPT resistant cells degrade topoI rapidly by UPP and recently we’ve published the molecular determinants of this pathway. To further understand the UPP mediated CPT resistance mechanism we used targeted proteasome prohibition by ixazomib (MLN9708) to stabilize topoI and determine its impact on CPT resistance. CPT resistant and sensitive cancer lines were both treated with ixazomib in combination with CPT. The CPT induced rate of topoI degradation, and its stabilization by ixazomib, was visualized and estimated by immunohistochemistry, immunofluorescence and immunoblotting assays, MTT and subG1 assays provided the drug sensitivity. Our results demonstrate that cells that degrade topoI rapidly are very resistant to CPT, and ixazomib significantly inhibits CPT induced topoI degradation. Notably, inhibition of proteasomal degradation by ixazomib overcomes the drug resistance and sensitizes the cells for CPTs.

Hydrogels obtained from the combination of different polymers are an interesting strategy for the development of controlled release system platforms and tissue engineering scaffolds. In this study, the applicability of sodium alginate-g-(QCL-co-HEMA) hydrogels for these biomedical applications was evaluated. Hydrogels were synthesized by free-radical polymerization using different concentration of the components. The hydrogels were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and swelling degree; betamethasone release as well as the in vitro cytocompatibility with chondrocytes and fibroblast cells were also evaluated. Scanning electron microscopy confirmed the porous surface morphology of the hydrogels in all cases. The swelling percent was determined at different pH and was observed to be pH-sensitive. The controlled release behavior of betamethasone from the matrices was investigated in PBS media (pH = 7.4) and the drug was released in a controlled manner up to 8 h. Human chondrocytes and fibroblasts were cultured on the hydrogels. The MTS assay shown that almost all hydrogels are cytocompatibles and an increase the proliferation in both cell types after one week of incubation was observed by Live/Dead® assay. These results demonstrate that these hydrogels are attractive materials for pharmaceutical and biomedical applications due to their characteristics, their release kinetics and biocompatibility.

Among various metal-based nanoparticles, silver nanoparticles (AgNPs) manifest superior inhibitory effect against several microorganisms. In fact, the AgNPs based therapy has been reported to inhibit both sensitive as well resistant isolates of bacteria and other disease causing microbes with equal propensity. Keeping this fact into consideration, we executed bio-mediated synthesis of AgNPs employing Hibiscus rosa sinensis flower extract. The as-synthesized AgNPs were evaluated for their potential to inhibit Streptococcus mutans (S. mutans), one of the main causative bacteria for dental caries. Beside several other reasons, orthodontic appliances have also been reported to facilitate infliction of oral cavity with a range of microbes including S. mutans. To determine the growth inhibitory and anti-adherence activity of AgNPs on orthodontic appliance, we performed microbiological assays employing AgNPs adsorbed on to the orthodontic wires. Topographic analysis of orthodontic wires was executed by scanning electron microscopy. In addition to antimicrobial and antibiofilm activity against oral S. mutans, the as-fabricated AgNPs demonstrated significant inhibitory and anti-biofilm properties against other biofilm forming bacteria such as Escherichia coli and Listeria monocytogenes as well.

Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 65 million cases and one point five million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We created a novel computational pipeline aimed to speed up the process of repurposable candidate drug identification. Compared with current drug repurposing methodologies, our strategy is centered on filtering the best candidate among all selected targets focused on the introduction of a mathematical formalism motivated by recent advances in the fields of algebraic topology and topological data analysis (TDA). This formalism allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 endoribonuclease, and NSP12 RNA-dependent RNA polymerase), which included rutin, dexamethasone, and vemurafenib among others. To our knowledge, it is the first time that a TDA based strategy has been used to compare a massive amount of protein structures with the final objective of performing drug repurposing

Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most of normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.

In the present study the synthesis of gold nanoparticles (AuNPs) loaded with methotrexate (MTX) has been carried out in order to obtain controlled size and monodispersed nanocarriers, around 20nm. Characterization study shows metallic AuNPs with MTX polydispersed on the surface. MTX is linked by a replacement of citrate by the MTX carboxyl group. The drug release profiles showed faster MTX release when it is conjugated, which leads to the best control of plasma concentration. Also, the enhanced release observed at pH 5 could take advantage of the pH gradients that exist in tumor microenvironments to achieve high local drug concentrations. AuNPs-MTX conjugates were tested by flow cytometry against lung (A-549) and colon (HTC-116) cancer cell lines. Results for A-549 showed a lighter dose-response effect than for colon cancer ones. This could be related to the presence of folate receptors in line HTC-116 on the contrary than line A-549, supporting the specific uptake of folate-conjugated AuNPs-MTX by folate receptor positive tumor cells. Conjugates exhibited considerably higher cytotoxic effects compared with the effects of equal doses of free MTX. Anexin V-PI test sustain as cell death mechanism apoptosis, which is normally disabled in cancer cells.

Drug abuse is a major issue worldwide. Methylphenidate (MPH) and alprazolam (ALZ) are commonly prescribed drugs for the treatment of ADHD and anxiety disorders, respectively. The limited studies suggest that abusers primarily use benzodiazepines to counteract adverse effects associated with methylphenidate usage. The main aim of this study was to investigate the interaction of drugs with DNA using spectroscopic methods. Female Wistar rats were administered with MPH (10, 20, 40 mg/kg) and ALZ (5, 10, 20 mg/kg) alone and in combination for a period of 28 days. The FT-IR and UV results reveal some spectral changes in a dose-dependent manner, which indicates interactions of drugs with DNA. Thus, the changes in spectral peaks provide some insight into the mechanism of the interaction of drugs with DNA.

Background: Most modern studies about human marijuana use have been made under a set of arbitrary cultural standards and policies not related to drug harm potential, loosely called Prohibition. Here we asked if potential health hazards generated by Prohibition are addressed in research design and analysis. Methods: For this, we have searched PubMed database (from inception to December 2017) for citations of prevalent contaminants of illegal street cannabis: fungi and pesticides. In addition, we performed full text evaluation of 23 studies selected from, and including, 2 meta-analysis reviews investigating potential health hazards from cannabis use. Results: Different combinations of the keywords cannabis, prohibition, pesticides, fungi, contaminants, cancer, schizophrenia, psychosis, show that these words coincide in less than 1% of the cannabis human studies within the database. In the scope of 141 abstracts in which the terms, cannabis and pesticides coincide, none is directed to distinguish cannabis and pesticide adverse effects on CNS. A similar picture emerges when fungi is the paired word. Full text evaluation shows that all but one of the studies analyzed, completely neglect or comment on the nature of cannabis source, legal status, or contamination as a confounding factor. Discussion: Our results show a potential bias on scientific investigation that may affect data reliability in informing about the health hazards of cannabis use. This finding suggests that other aspects of the Prohibition environment may also go unacknowledged. Conclusion: Prohibition related health risks usually go unacknowledged and unaccounted for in biomedical research on Cannabis.

Novel SARS-CoV-2, a bat based virus originated in Wuhan, China that caused a global pandemic in December, 2019 belongs to the Betacorona virus family and contains single stranded genome of ~29Kbp. The host cell invasion of SARS-CoV-2 is facilitated by interaction of C-Terminal Domain (CTD) of Spike (S) protein of virus and host ACE2 receptor in the presence of TMPRSS seine protease secreted by the host cell. In this study the mutation hotspots of S-protein will be identified and the impact of such mutation in the binding affinity will be studied. Additionally, the lead molecule which can bind to the mutated protein also will be identified. Multiple sequence alignment of the spike protein sequence of SARS-CoV-2 shows the number of single amino acid mutation hotspots such as L5F, R214L, R408I, G476S, V483A, H519Q, A520S, T572I, D614G and H655Y. Among these mutations D614G has 57.5% occurrence and G476S, V483A has 7.5% occurrence. The mutated proteins were modelled based on wild type homolog and docked to ACE2 receptor. When the mutated S protein is docked, the ∆G (binding free energy) value is very minimal in mutated protein showed the stability of variants. By the drug repurposing method, 1000 FDA approved drugs were virtually screened for its binding to RBD of S1 domain. Among these drugs Digitoxin, Gliquidone and Zorubicin Hcl binds to spike proteins with higher docking score (lesser than -8.5 Kcal/mol) to both wild type and mutants.

The delivery of Cytochrome c (Cyt c) to the cytosol stimulates apoptosis in cells were its release from mitochondria and apoptosis induction is inhibited. We developed a drug delivery system consisting of Cyt c nanoparticles decorated with folate-poly(ethylene glycol)-poly(lactic-co-glycolic acid)-thiol (FA-PEG-PLGA-SH) to deliver Cyt c into cancer cells and test their targeting in the Lewis Lung Carcinoma (LLC) mouse model. Cyt c-PLGA-PEG-FA nanoparticles (NPs) of 253 ± 55 and 354 ± 11 nm were obtained by Cyt c nanoprecipitation, followed by surface decoration with the co-polymer SH-PLGA-PEG-FA, and compared to a nanoparticle-free formulation. Overexpression of FA in LLC cells and internalization of Cyt c-PLGA-PEG-FA nanoparticles (NPs) was confirmed by confocal microscopy. Caspase activation assays show NPs retain 88-96% Cyt c activity. The NP formulations were more efficient in decreasing LLC cell viability than the NP-free formulation, with IC50: 49.2 to 70.1 μg/ml versus 129.5 μg/ml, respectively. Our NP system is thrice as selective towards cancerous than normal cells. In-vivo studies using tagged nanoparticles show accumulation in mouse LLC tumor 5 min post-injection. In conclusion, our NP delivery system for Cyt c shows superiority over the NP-free formulation and reaches a folic acid-overexpressing tumor in an immune-competent animal model.

Nanodiamonds of detonation origin are promising delivery agents of anti-cancer therapeutic compounds in a whole organism like mouse, owing to their versatile surface chemistry and ultra-small 5 nm average primary size compatible with natural elimination routes. However, to date, little is known about tissue distribution, elimination pathways and efficacy of nanodiamonds-based therapy in mice. In this report, we studied the capacity of cationic hydrogenated detonation nanodiamonds to carry active small interfering RNA (siRNA) in a mice model of Ewing sarcoma, a bone cancer of young adult due in the vast majority to the EWS-Fli1 junction oncogene. Replacing hydrogen gas by its radioactive analog tritium gas led to the formation of labeled nanodiamonds and allowed us to investigate their distribution throughout mouse organs and their excretion in urine and feces. We also demonstrated that siRNA directed against EWS-Fli1 inhibited this oncogene expression in tumor xenografted on mice. This work is a significant step to establish cationic hydrogenated detonation nanodiamond as an effective agent for in vivo delivery of active siRNA.

A novel coronavirus called 2019-nCoV was recently found in Wuhan, Hubei Province of China, and now is spreading across China and other parts of the world. 2019-nCoV spreads more rapidly than SARS-CoV. Unfortunately, there is no drug to combat the virus. It is of high significance to develop a drug that can combat the virus effectively before the situation gets worse. It usually takes a much longer time to develop a drug using traditional methods. For 2019-nCoV, it is now better to rely on some alternative methods to develop drugs that can combat such a disease effectively since 2019-nCoV is highly homologous to SARS-CoV. In this paper, we first collected virus RNA sequences from the GISAID database, translated the RNA sequences into protein sequences, and built a protein 3D model using homology modeling. Coronavirus main protease is considered to be a major therapeutic target, thus this paper focused on drug screening based on the modeled 2019-nCov_main_protease structure. The deep learning based method DFCNN, developed by our group, can identify/rank the protein-ligand interactions with relatively high accuracy. DFCNN is capable of performing virtual screening quickly since no docking or molecular dynamic simulation is needed. DFCNN identifies potential drugs for 2019-nCoV protease by performing drug screening against 4 chemical compound databases. Also, we performed drug screening for all tripeptides against the binding site of 2019-nCov_main_protease since peptides often show better stability, more bio-availability and negligible immune responses. In the end, we provided the list of possible chemical ligands and peptide drugs for experimental validation.

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as Sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of Sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW < 300) compounds. One of the first challenges in implementing a FBDD approach is the design of a fragment library, and more specifically, the choice of its size and individual members. A diverse set of fragments is required to maximise the chances of discovering novel hit compounds. However, the exact diversity of a certain collection of fragments remains underdefined, which hinders direct comparisons among different selections of fragments. Based on structural fingerprints, we herein introduced quantitative metrics for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database, from which libraries with sizes ranging from 100 to 100,000 compounds were selected. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results demonstrated that while library size does matter for its diversity, there exists an optimal size for structural diversity. It is also suggested that such quantitative measures can guide the design of diverse fragment libraries under different circumstances.

Japanese encephalitis is a zoonotic disease caused by Japanese encephalitis virus (JEV). It is mainly epidemic in Asia with an estimated 69,000 cases occurring per year. However, no approved agents are available for the treatment of JEV infection, and existing vaccines cannot resist various types of JEV strains. Drug repurposing is a new concept for finding new indication of existing drugs, and recently, it has been used to discover new antiviral agents. Identifying host proteins involved in the progress of JEV infection and using these proteins as targets are the center of drug repurposing for JEV infection. In this study, based on the gene expression data of JEV infection and the phenome-wide association study (PheWAS) data, we identified 286 genes participating in the progress of JEV infection using the systems biology methods. The enrichment analysis of these genes suggested that the genes identified by our methods were predominantly related to viral infection pathways and immune response-related pathways. We found that bortezomib which can target these genes may have potential effect on the treatment of JEV infection. Subsequently, we evaluated the antiviral activity of bortezomib using the JEV-infected mice model. The results showed that bortezomib can lower JEV-induced lethality in mice, alleviate suffering in JEV-infected mice and reduce the damage in brains caused by JEV infection. This work provides a new method for the development of antiviral agents.

Introduction Pharmacovigilance may detect safety issues after marketing of medications, and this can result in regulatory action such as direct healthcare professional communications (DHPC). DHPC can be effective in changing prescribing behaviour, however the extent to which prescribers vary in their response to DHPC is unknown. This study aims to explore changes in prescribing and prescribing variation among GP practices following a DHPC on the safety of mirabegron, a medication to treat overactive bladder (OAB). Methods This is an interrupted time series study of English GP practices from 2014-2017. NHS Digital provided monthly statistics on aggregate practice-level prescribing and practice characteristics (practice staff and registered patient profiles, Quality & Outcomes Framework indicators, and deprivation of the practice area). The primary outcome was monthly mirabegron items as a percentage of all OAB drug items. The exposure was a DHPC issued by the European Medicines Agency in September 2015. Variation between practices in mirabegron prescribing before and after the DHPC was assessed using the systematic component of variation (SCV). Multilevel segmented regression with random effects quantified the change in level and trend of prescribing after the DHPC. Practice characteristics were assessed for their association with a reduction in prescribing following the DHPC. Results This study included 7,408 practices. During September 2015, 88.9% of practices prescribed mirabegron and mirabegron composed a mean of 8.2% (SD 6.8) of OAB items. Variation between practices was classified as very high and the median SCV did not change significantly (p=0.11) in the 6 months after the September 2015 DHPC (12.4) compared to before (11.6). Before the DHPC, there was a monthly trend of 0.294 (95%CI, 0.287, 0.301) percentage points increase in mirabegron percentage. There was no significant change in the month immediately after the DHPC (-0.023, 95% CI -0.105 to 0.058) however there was a significant reduction in trend (-0.036, 95% CI -0.049 to -0.023). Higher numbers of registered patients and patients aged ≥65 years, and practice area deprivation were associated with having a significant decrease in level and slope of mirabegron prescribing post-DHPC. Conclusion Variation in mirabegron prescribing was high over the study period and did not change substantively following the DHPC. There was no immediate prescribing change post-DHPC, although the monthly growth did slow. Knowledge of the degree of variation in and determinants of response to safety communications may allow those that do not change prescribing to be provided with additional supports.

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable ‘genetic escape’. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata will be highlighted.

Owing to their unique physicochemical properties, nanoparticles are used in a variety of ways in the field of cancer treatment, including imaging, drug delivery, and photothermal and photodynamic therapies. The fascinating properties of nanoparticles are determined by their size, morphology, and constituent elements, and various synthetic methods and post-synthetic techniques have been applied to control these factors. Herein, we present examples of shape and composition control through galvanic replacement, a technique that exploits redox potential differences between elements to induce spontaneous ion-exchange and highlight its specific contributions to cancer treatment applications. The present article identifies the recent advances in nanoparticle formation techniques and discusses the future outlook of the field.

African trypanosomes are an early branch in eukaryotic evolution and developed a unique endomembrane system as an adaptation to their parasitic life style. The key virulence mechanism of many pathogens is successful immune evasion to enable survival within the host, which is a feature requiring both genetic events and membrane transport in African trypanosomes. Intracellular trafficking not only plays a role in immune evasion, but also in homeostasis of intracellular and extracellular compartments and interactions with the environment. Significantly, historical and recent work has unravelled some of the connections between these processes and highlighted how immune evasion mechanisms associated with adaptations in membrane trafficking may have, paradoxically, provided specific sensitivity to drugs. Here we explore these advances in understanding the membrane composition of the trypanosome plasma membrane and organelles and provide a perspective for how transport could be exploited for therapeutic purpose.

2017 was an excellent year in terms of new drugs (chemical entities and biologics) approved by the FDA, with a total of forty-six. In turn, one of the highlights was the number of peptides (six) included in this list. Here, the six peptides are analysed in terms of chemical structure, synthetic strategy used for their production, source, biological target, and mode of action.

The interpretation of the local microenvironment of extracellular matrix for malignant tumor cells is in intimate relation with metastatic spread of cancer cells involving the associated issues of cellular proliferation and drug responsiveness. This study was aimed to assess the combination of both surface topographies (fiber alignments) and different stiffness of the polymeric substrates (PLLA and PCL) and collagen substrates (coat and gel) to elucidate the effect of the cellular morphology on cellular proliferation and drug sensitivities of two different types of breast cancer cells (MDA-MB-231 and MCF-7). The morphological spreading parameter of (Nuclear/Cytoplasm) induced by the anthropogenic substrates has correlated intimately with the cellular proliferation and the drug sensitivity (IC₅₀) of cancer cells. This study demonstrated the promising results of the parameter for the evaluation of cancer cell malignancy.

This article focuses on the leader-following consensus of fuzzy fractional order singular perturbation multi-agent systems (FOSPMASs) with order in 0,2. By employing the T-S fuzzy modeling approach, a fuzzy FOSPMAS is constructed. Subsequently, a fuzzy observer-based controller is designed and the error system corresponding to each agent is derived. Through a series of equivalent transformations, the error system is decomposed into fuzzy singular fractional order systems (SFOSs). According to the admissibility of SFOSs, the consensus conditions of the fuzzy FOSPMAS are obtained based on linear matrix inequalities (LMIs) without equality constraint. Finally, the effectiveness of the criteria is verified through an RLC circuit model.

This study explores the efficacy of using EEG-based parameters to diagnose bipolar disorder. A synthetic dataset was generated, including both correctly diagnosed and misdiagnosed cases, simulating realistic clinical conditions. EEG features such as theta-alpha mean, beta band mean, and coherence measures were used to train a multi-layer perceptron (MLP) model. The model achieved a validation accuracy of 92%, demonstrating strong potential for EEG-based diagnostics. However, challenges such as standardization of electrode configurations and addressing equipment differences are crucial for broader applicability and validity of the findings in diverse clinical settings.

With LiDAR (Light Detection and Ranging) time series being used for various applications, optimal realisation of a common geodetic datum over many epochs is a highly important prerequisite with direct impact on accuracy and reliability of derived measures. In our work, we develop and define several approaches to the adjustment of multi-temporal LiDAR data in a given software framework. These approaches ranging from pragmatic to more rigorous solutions are applied to an 8 year time series with 21 individual epochs. The analysis of the respective results suggests that a sequence of bi-temporal adjustments brings the best results while being more flexible and computationally viable than the most extensive approach of using all epochs in one single multi-temporal adjustment. With a combination of sparse control patches measured in the field and one selected reference block, we obtain relative datum discrepancies in the range of 1-2 cm for the complete time series. Based on our findings, we formulate design criteria for setting up and adjusting future time series with the proposed method.

Proton Exchange Membrane Fuel Cell (PEMFC) is a fast-developing battery technology, and the key to its reliability and lifespan improvement lies in the accurate assessment of durability. However, the degradation mechanism of PEMFC is hard to determine and its internal parameters are highly coupled. Thus, the development of the more accurate life prediction model that meets the actual scenarios is urgent to investigate. To solve this problem, a multi-feature fusion life prediction method based on Temporal Convolutional Network-Gated Recurrent Unit (TCN-GRU) is proposed. A TCN algorithm is used as the prediction base model, and two GRU modules are included to the model to strengthen the model expression ability and improve its predictive accuracy. Two widely recognized datasets and two operating conditions are utilized for model training and prediction, respectively. Comparisons are made with single-feature parameter models in terms of Root Mean Square Error (RMSE) and Determination Coefficient (R2). The results show that the prediction accuracy of the TCN-GRU multi-feature fusion model is higher than that of the single-feature models in terms of stability and anti-interference under both operating conditions. Furthermore, with the increase of input feature parameters, the TCN-GRU model is closer to the real value, which proves once again that the proposed model can meet the accuracy requirements of the life prediction of PEMFC.

This comprehensive article explores Massive MIMO (M-MIMO) design and its associated concepts, focusing on the seamless integration requirements for Beyond 5G (B5G) and 6G networks. Addressing critical aspects such as RF chain reduction, pilot contamination, Cell-Free MIMO, and security considerations, the article delves into the intricacies of M-MIMO in the evolving landscape of B5G. Moreover, the emerging MIMO concepts in this article include AI-enabled M-MIMO three-dimensional beamforming, reconfigurable intelligent surfaces, visible light communication, and THz spectrum utilization. This review highlights challenges and open research issues, including Narrow Aperture Antenna Nodes, Plasmonic Antenna Arrays, Integrated Sensing with M-MIMO, and the application of Federated Learning in M-MIMO systems. By examining these cutting-edge developments, the article aims to contribute to advancing knowledge in the field and inspire future research directions in the exciting realm of B5G and 6G networks.

Sharing confidential information is a critical concern in today’s world. Secret sharing schemes facilitate the sharing of secrets in a way that ensures only authorized participants (shareholders) can access the secret using their allocated shares. Hierarchical secret sharing schemes (HSSSs) build upon Shamir’s scheme by organizing participants into different levels based on priority. Within HSSS, participants at each level can reconstruct the secret if a specified number, denoted as the threshold value (t), or more of them are present. Each level has a predetermined threshold value. If the number of participants falls below the threshold at any level, higher-level participants must be involved in reconstructing the secret at lower levels. Our paper proposes schemes that implement hierarchical access structures and enable the sharing of multiple secrets. Additionally, our proposed scheme includes share verification. We have analyzed potential attacks and demonstrated the scheme’s resistance against them. Through security analysis and comparison with existing schemes, we highlight the novelty and superiority of our proposed approach, contributing to advancements in secure information sharing practices.

With the development of deep learning, several Graph Neural Networks (GNN)-based approaches have been utilized for text classification. However, GNNs encounter challenges in capturing contextual text information within a document sequence. To address this, a novel text classification model RB-GAT is proposed by combining RoBERTa-BiGRU embedding and a multi-head Graph ATtention Network (GAT). First, the pre-trained RoBERTa model is exploited to learn word and text embeddings in different contexts. Second, the Bidirectional Gated Recurrent Unit (BiGRU) is employed to capture long-term dependencies and bidirectional sentence information from the text context. Next, the multi-head graph attention network is applied to analyze this information, which serves as a node feature for the document. Finally, the classification results are generated through a Softmax layer. Experimental results on three benchmark datasets demonstrate that our method can achieve an accuracy of 71.48%, 98.45%, and 80.32% on Ohsumed, R8, and MR, which is superior to the existing nine text classification approaches.

ABSTRACT Lubricants play a crucial role in reducing friction and wear between surfaces in relative motion. Engine oil, as a lubricant, is specifically designed to minimize friction and wear between the moving parts of different equipment and machinery. Engine oil blending serves the purpose of adjusting the variety of lubricants available to meet specific performance requirements. Through blending, it is possible to tailor the characteristics of the lubricating oil, such as viscosity, stability, and additive content, to optimize its effectiveness in reducing friction, protecting engine components, and enhancing overall equipment performance. By customizing lubricant formulations through blending, manufacturers can address the diverse lubrication needs of modern engines and machinery, ensuring smooth operation, longevity, and efficiency.To enhance the quality of the lubricant and achieve the desired high-performance multi-grade engine oil, a systematic approach was followed. The process began with testing the specific gravity of the oil using a hydrometer and thermometer to ensure accurate measurements. Subsequently, 5 liters of base oil were carefully measured and poured into a stainless steel reactor pot to serve as the blending vessel. Following this, 1 liter of paraffin oil (100N) was added to the base oil to introduce specific properties to the blend. To further optimize the formulation, 0.42 kg (7% of the total blend) of additives, including a selection of specific performance-enhancing compounds, was incorporated. These additives, such as Aspen, Tackifier, and other essential components like anti-wear, corrosion inhibitors, detergents, dispersants, and antioxidants, were meticulously measured and added to the mix. Through this precise blending process, the goal was to craft a high-quality multi-grade engine oil that meets the stringent performance requirements for various operating conditions and equipment types. After the melted Aspen and dissolved tackifier were added to the mixture, thorough stirring was carried out to ensure uniform distribution until a homogeneous blend was achieved. The mixture was then exposed to heat to facilitate the reaction between the base oil and additives, reaching a temperature of 70°C for optimal blending. Subsequently, 0.5 kg of viscosity index improver was introduced into the mixture and stirred continuously for a period of 5 minutes to ensure proper integration. Following this step, 5 grams of dye were carefully added to the mixture, and stirring was continued to evenly disperse the coloring agent throughout the blend. This meticulous process aimed to ensure that all components were effectively incorporated, facilitating the production of a high-quality, customized multi-grade engine oil with enhanced performance characteristics and optimal lubricating properties. After subjecting the mixture to a temperature of 70°C, the heat source was removed, allowing the product to gradually cool down to room temperature, which was estimated to be around 30°C. Following this cooling process, the product underwent a filtration step to remove any residual impurities present in the mixture. A sample of the purified product was then extracted for further analysis. Quality control tests were meticulously carried out on the sample to ensure that the product met the rigorous standards set by the Standard Organization of Nigeria (SON). The results obtained from the quality control tests were highly promising, indicating that the product indeed complied with the stringent specifications outlined by the regulatory body. This adherence to quality standards is essential in ensuring the product's reliability and performance in various applications. The successful outcome of the quality control test underscores the meticulous attention to detail and commitment to excellence in the production process. The rigorous quality control procedures implemented in the analysis of the product highlight the commitment to upholding high standards of quality and safety in the manufacturing process. By consistently meeting and exceeding industry regulations and standards, the product not only demonstrates its reliability but also reflects a dedication to customer satisfaction and product excellence. The adherence to the SON standards showcases a commitment to producing top-quality products that meet the needs and expectations of consumers and industry stakeholders alike.

The multi-objective optimization design of hydraulic climbing mechanism (the core mechanism of gantry crane) was realized by using the method of combining central composite design (CCD), Kriging and multi-objective genetic algorithm (MOGA). Firstly, the hydraulic climbing mechanism model was established and the appropriate design variables were selected. The mass, maximum deformation and maximum equivalent stress of the hydraulic climbing mechanism was taken as the optimization objectives. Through the comparative analysis of the parameters of wedge block, anchor block, anchor plate、baffle, the parameters that have the greatest impact on the optimization objectives are selected as geometric constraints. Then, according to the results of experimental design, Kriging model was used to establish the response surface optimization model of objective function. Finally, the optimal results were obtained by using MOGA method. The experimental results show that the optimization strategy is reliable, and the mass of the optimized model is reduced by 10.28%. While meeting the actual production requirements, the lightweight design of the hydraulic climbing mechanism is realized, which saves the design cost and improves the material utilization rate.

The satellite Earth observation (EO) sector is burgeoning with hundreds of commercial satellites being launched each year, delivering a rich source of data that could be exploited for societal benefit. Data streams from the growing constellation of commercial satellites are of variable quality, limiting the potential for their combined use in science applications that need long time-series data from multiple sources. The quality of calibration performed on optical sensors onboard many satellite systems is highly variable due to calibration methods, sensor design, mission objective, budget, or other operational constraints. A small number of currently operating well-characterised satellite systems with onboard calibration, such as Landsat-8/9, Sentinel-2, and planned future missions like the NASA Climate Absolute Radiance and Refractivity Observatory (CLARREO) Pathfinder, the European Space Agency (ESA) Traceable Radiometry Underpinning Terrestrial and Helio Studies (TRUTHS), and LIBRA from China, are considered benchmarks for optical data quality due to their traceability to international measurement standards. This paper describes the concept of a space-based transfer calibration radiometer called the Satellite Cross-Calibration Radiometer (SCR) that would enable the calibration parameters from satellites such as Landsat-8/9, Sentinel-2, or other benchmark systems to be transferred to a range of commercial optical EO satellite systems while in orbit. A description of the key characteristics of the SCR to successfully operate in orbit and transfer calibration from Reference systems to Client systems is presented. A system like the SCR in orbit could complement SI-Traceable satellites (SITSats) to improve data quality and consistency and facilitate the interoperable use of data from multiple optical sensor systems for delivering higher returns on the global investment in EO.

This paper focuses on improving the tracking accuracy for servo systems and increasing the contouring performance of precision machining. The dynamic friction during precision machining is analyzed using the LuGre model. The dynamic and static parameters in the friction model are efficiently and accurately identified using the improved Drosophila Swarm Algorithm based on cross-mutation. The friction tracking error can be deduced by the friction state space and an expression is derived. To compensate for the tracking error caused by friction, a feedforward compensation control is designed to avoid signal lag in traditional friction controllers. Furthermore, the factors of multi-axis parameter mismatching that impact the machining profile accuracy are analyzed for multi-axis control. An adaptive cross-coupled control-based pre-compensation strategy of contour error is designed to reduce both the tracking error and the contour error. The effectiveness of the proposed method is validated through several experiments, which demonstrate a remarkable improvement in tracking performance and contour accuracy.

The sustainable development and operation of mining enterprises as major sources of economic growth in many countries is determined by both a balance of economic, environmental, and social objectives and the resources required to achieve these objectives. Transportation is one of the main resources at open pits. It accounts for up to 70% of open pit operating expenses. Various parameters of transportation means should be coordinated both with the parameters of the open pit and meet the conditions of its operation. The problem of selecting a dump truck model in the paper is solved using a universal system of selection criteria developed using an original methodology. The two-level system of criteria includes all currently known selection criteria. The peculiarity of the methodology is the use of the multi-criteria FUCOM method for ranking the criteria. In addition, it is proposed to differentiate the criteria evaluations according to the experts' competence levels. Sets of criteria for evaluation by experts of different levels are proposed. The obtained criterion ranks are recommended to be used by managers of mining enterprises to choose a dump truck model. The presented methodology is suitable for the development of new systems of criteria, considering significant changes in operating conditions or the emergence of factors not considered in this study. Evaluation of all models of dump trucks on the market using the developed system of criteria is envisaged by the authors in a future study.

The dynamic factors in the environment violate the static environment assumption of the SLAM algorithm, leading to a decrease in the accuracy of camera positioning. In recent years, many studies have attempted to address dynamic objects by combining semantic constraints and geometric constraints, but issues such as poor real-time performance, the potential for mistakenly treating humans as rigid objects, and subpar performance in high-dynamic scenes still persist. This paper proposes a dynamic scene visual SLAM algorithm called Dynamic SLAM based on target tracking and multi-view geometry (TKG-SLAM), based on object detection, Kalman filters, and multi-view geometry. This algorithm takes into consideration both real-time performance and algorithm accuracy. It combines semantic constraints and multi-view geometry constraints, selectively running the algorithm in different scenarios, filtering and preserving static points for camera pose estimation. Experimental results demonstrate that, compared to current state-of-the-art dynamic SLAM methods, our approach achieves optimal performance in some scenarios and exhibits stronger real-time capabilities.

This article deals with the queueing-inventory system, composed of c junior servers, a senior server, two finite waiting halls, and an infinite orbit. On occasion, junior servers encounter challenges during customer service. In these instances, they approach the senior server for guidance in resolving the issue. Suppose the senior server is engaged with another junior server. The approaching junior servers await their turn in a finite waiting area with a capacity of c for consultation. Concerning this, we study the performance of junior servers approaching the senior server in the retrial queueing-inventory model with the two finite waiting halls dedicated to the primary customers and the junior servers for consultation. We formulate a level-dependent QBD process and solve its steady-state probability vector using Neuts and Rao’s truncation method. The stability condition of the system is derived, and the R matrix is computed. Optimum total cost has been obtained, and sensitivity analyses, which include expected total cost, waiting time of customers in waiting hall and orbit, number of busy servers, and fraction of successful retrial rate of the model, are done numerically.

Remote distributed generation control and demand response is nowadays a basic need, especially for the Distributed Network Operators (DNOs). The integration of Renewable Energy Sources (RES) with stochastic production characteristics into the grid in conjunction with the newly appeared stochastic demand consumers (i.e., electric vehicles) hardens the ef-forts of the DNOs to keep the grid’s operation within safe limits and prevent cascading black-outs while staying in compliance with the SAIDI and SAIFI indices during maintenance and re-pair operations. Taking also under consideration the aging of the existing grid infrastructure, making it year by year more prone to failure, it is yet of great significance for the DNOs to have access to real-time feedback from grid’s infrastructure, fast, with low-cost upgrade interventions, easily deployed on the field and with fast response potential, in order to be able to perform real-time grid management (RTGM). In this article, we describe the architecture, development and deployment of a hybrid real-time control system of distributed generation (DG) units, which has the potential to be applied easily to DNO’s substations, RES plants and consumers (i.e. electric vehicles’ charging stations), that combines a low-cost minimum intervention into the electricity grid and its components and eliminates all communication interoperability problems between the different vendors’ installed electrical equipment.

Multi-cancer early detection (MCED) tests are being developed, but little is known about patient receptivity to their use for cancer screening. The current study assessed patient interest in such testing. Our team conducted a prospective, observational study among primary care patients in a large, urban health system. They were asked to complete a telephone survey that briefly described a new blood test in development to identify multiple types of cancer, but was not currently recommended or covered by insurance. The survey included items to assess respondent background characteristics, perceptions about MCED testing, and interest in having such an MCED test. We also used multivariable analyses to identify factors associated with patient interest in test use. In 2023, we surveyed 159 (32%) of 500 identified patients. Among respondents, 125 (79%) reported a high level of interest in having an MCED test. Interest was not associated with personal background characteristics, but was positively associated with the following expectations: testing would be recommended for cancer screening, be convenient, and be effective in finding early-stage disease (OR=11.70, 95% CI: 4.02, 34.04, p < 0.001). Research is needed to assess patient interest and actual uptake when detailed information on testing is presented in routine care.

The benefits of multi-robot systems are substantial, bringing gains in efficiency, quality, and cost, and are useful in a wide range of environments from warehouse automation, to agriculture, and even extend in part to entertainment. In multi-robot system research, the main focus is on ensuring efficient coordination in the operation of the robots, both in task allocation and navigation. However, much of this research seldom strays from theoretical bounds; there are many reasons for this, with the most prominent and impactful being resource limitations. This is especially true for research in areas such as multi-robot path planning (MRPP) and navigation coordination. This is a large issue in practice as many approaches are not designed with meaningful real-world implications in mind and are not scalable to large multi-robot systems. This survey aims to look into the coordination and path-planning issues and challenges faced when working with multi-robot systems, especially those using a prioritised planning approach and identify key areas which are not well-explored and the scope of applying existing MRPP approaches to real-world settings.

Building facade design plays an essential role in enhancing energy efficiency and reducing environmental impact in high-performance building design. Balancing the conflicts among various building facade design parameters to satisfy different optimization objectives constitutes a highly complex optimization problem. The rapidly increasing number of studies demonstrates a significant interest in implementing multi-objective optimization methods to tackle building facade optimization problems. This study conducts a systematic review of optimization methods for building facade optimization (BFO). The optimization objectives and design variables are categorized based on their characteristics. The efficiency and effectiveness of optimization algorithms in addressing BFO problems are compared. Building optimization techniques and tools are showcased, along with their functions and limitations. Key findings highlight the robust feasibility and effectiveness of optimization algorithms, methods, and techniques in resolving a diverse range of BFO challenges. The limitations, challenges, and future potential of these methods are summarized and proposed.

Autophagy is an evolutionarily conserved mechanism for degrading and recycling different cellular components in both normal development and stress conditions. Our recent research demonstrated that autophagy-mediated compartmental cytoplasmic deletion is essential for pollen germination. However, how autophagy regulates pollen germination to ensure its fertility remains largely unknown. Here, we applied multi-omic analyses to investigate the downstream pathways of autophagy in the process of pollen germination. Although ATG2 and ATG5 play similar roles in regulating pollen germination, high-throughput transcriptomic analysis reveals that silencing ATG5 has greater impact on the transcriptome than silencing ATG2. Cross-comparisons of transcriptome and proteome analysis reveal that gene expression at mRNA level and protein level are differentially affected by autophagy. Furthermore, high-throughput metabolomics analysis demonstrates that pathways related amino acid metabolism and aminoacyl-tRNA biosynthesis can be affected by both ATG2 and ATG5 silencing. Collectively, our multi-omic analyses reveal a central role of autophagy in cellular metabolism, which is critical for the initiation of pollen germination and the guarantee of pollen fertility.

The protein extract of Ulva australis hydrolyzed with alcalase and flavourzyme investigated multi-functional properties, including total antioxidant capacity (TAC), collagenase inhibitory and antibacterial activities. The #5 fraction (SP5) and #7 fraction (SP7) of U. australis hydrolysate from cation-exchange chromatography showed significantly high TAC, collagenase inhibitory and antibacterial effects against Propionibacterium acnes, and only Q3 fraction from anion-exchange chromatography showed high multi-functional activities. The eight peptides among 42 peptides identified by MALDI-TOF/MS and Q-TOF/MS/MS were selected from the results to screen molecular docking on target proteins, and were synthesized. Thr-Gly-Thr-Trp (TGTW) showed ABTS [2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)] radical scavenging activity. Effect TAC as Trolox equivalence was dependent on the concentration of TGTW. The Asn-Arg-Asp-Tyr (NRDY) and Arg-Asp-Arg-Phe (RDRF) possessing collagenase inhibitory activity increased according to the increase of concentration and the IC50 values of them were 0.95 mM and 0.84 mM, respectively. Peptides, RDRF and His-Ala-Val-Tyr (HAVY) showed anti-P. acnes effects with IC50 values of 8.57 mM and 13.23 mM, respectively. These results suggest that the U. australis hydrolysate could be a resource for the application of effective nutraceuticals and cosmetics.

As an important means of controlling the spread of cities, large-scale urban green belts have been widely used in the planning and construction of green space systems in various mega-size cities around the world. In previous studies, there has been more research on the overall isolation effect of green belts, while there has been less research on changes in their internal structure. There have been more perspectives on the land-use change (LUC) caused by urban expansion, and less systematic research on the dual driving factors of LUC. In this paper, we constructed a multi-dimensional index system to measure the "contraction-expansion" mechanism of land use in the overlapping vegetation areas of large green belts under the dual influence of urban expansion and urban greening, from the perspectives of quantity, space, and connectivity during different construction periods. Taking the boundary of two green belts in Beijing as an example, we hope to provide scientific support for the construction and ecological protection of Beijing's green belts.

With the proliferation and development of social media platforms, social media data has become an important source for acquiring spatio-temporal information on various urban events. Providing accurate spatio-temporal information for events contributes to enhancing the capabilities of urban management and emergency response. However, existing research on mining spatio-temporal information of events often focuses solely on textual content, neglecting data from other modalities such as images and videos. Therefore, this study proposes an innovative spatio-temporal information extraction method for multi-modal social media data (MIST-SMMD), which extracts the spatio-temporal information of events from multi-modal data on Weibo at coarse and fine-grained hierarchical levels, serving as a beneficial supplement to existing urban event monitoring methods. This paper takes the "July 20th Zhengzhou Heavy Rainfall" incident as an example, to evaluate and analyze the effectiveness of the proposed method. The results indicate that in the coarse-grained spatial information extraction using only textual data, our method achieves a Spatial Precision of 87.54% within a 60m range, and reaches 100% Spatial Precision for ranges beyond 200m. For fine-grained spatial information extraction, the introduction of other modal data such as images and videos results in a significant improvement in Spatial Error. These results demonstrate the ability of the MIST-SMMD method to extract spatio-temporal information from urban events at both coarse and fine levels, and confirms the significant advantages of multi-modal data in enhancing the precision of spatial information extraction.

Nowadays, cyber-physical systems (CPSs) are composed of more and more agents and the demand for designers to develop ever larger multi-agent systems is a fact. When the number of agents increases, several challenges related to control or communication problems arise due to the lack of scalability of existing solutions. It is important to develop tools that allow control strategies evaluation of large-scale systems. In this paper, it is considered that a CPS is a heterogeneous robot multi-agent system that cooperatively performs a formation task through a wireless network. The goal of this research is to evaluate the system's performance when the number of agents increases. To this end, two different mixed reality frameworks developed with the open-source tools Gazebo and Webots are used. These frameworks enable combining both real and virtual agents in a realistic scenario allowing scalability experiences. They also reduce the costs required when a significant number of robots operate in a real environment, as experiences can be conducted with a few real robots and a higher number of virtual robots by mimicking the real ones. Currently, the frameworks include several types of robots being the aerial robot Crazyflie 2.1 and differential mobile robots Khepera IV those used in this work. To illustrate the usage and performance of the frameworks, an event-based control strategy for rigid formations varying the number of agents is analyzed. The agents should achieve a formation defined by a set of desired Euclidean distances to their neighbors. To compare the scalability of the system in the two different tools, the following metrics have been used: formation error, CPU usage percentage, and the ratio between the real-time and the simulation time. The results show the feasibility of using Robot Operating System (ROS) 2 in distributed architectures for multi-agent systems in mixed reality experiences regardless of the number of agents and their nature. However, the two tools under study present different behaviors when the number of virtual agents grows in some of the parameters, and such discrepancies are analyzed.

Memristor has attracted a lot of interest due to its high processing speed, low power consumption and high integration ability, which is critical for electronic systems and memory-centric computing. However, the memristor programming circuit and strategy are still inflexible and complex, since the signal generator/collector and stimulate pulse must be carefully matched and designed based on memristor intrinsic characteristics without reconfigurable. Here, a simple and effective circuit only consists a parallel reference-resistor-and-NMOS is designed to program memristor with a more than 99% memristance precision. And the amplitude and width of stimulate pulse are fixed to ±4V and 5ms, respectively. In order to cope with the device variation, such as ±10% tolerance of transition voltage, an optimized programming strategy was proposed and demonstrated great robustness. Additionally, a set of reference resistors and NMOSs have been added to facilitate multi-level memristance operation without requiring any changes to the circuit structure. This program circuit was also employed to program memristor crossbar remains 99% precision. In the end, a memristor-based convolutional neural network which controlled by our optimized programming circuit was used for image recognition, and 89.36% accuracy can be achieved even under 15.8% memristance tolerance. This novel circuit demonstrates a simple and flexible strategy in memristor programming, providing a new way to control memristor crossbar for practical application.

In this work, an novel flow-electric field coupling configuration for enhanced Zn-Cd cementation was designed and utilized. A series of tests were conducted to explore the optimization of Zn-Cd cementation process and its mechanism.Firstly, the various characterisations of the cadmium sponge at different locations in the device were compared and it was concluded that the purity of the cadmium sponge was optimal from the anode surface. The generation and stripping of cadmium sponge was revealed for the first time by cross-sectional electron microscopy. The four stages of the apparent reaction in the system were analysed in relation to the pH, cadmium concentration and cadmium sponge flaking at each flow rate. It was proved that the separation of cadmium sponge mainly occurred in the third phase. Secondly, by comparing the morphology and specific surface area of cadmium sheep at different flow rates, the optimum flow field velocity was identified as 30 ml/s. Six flow field configurations were compared and preferred. The results demonstrate that the LCAH modulation results in a more sparse structure of the cadmium sponge, which is more easily exfoliated from the zinc anode surface by fluid impact. This was considered to be the most beneficial flow field configuration for improving the cadmium cementation rate and reducing the cost of the reaction. Further, the reaction steps of the system were analysed. The diffusion process under different flow field configurations was confirmed by calculations to follow first order kinetics. The diffusion coefficient of LACH proved to be the highest in the comparative tests and this result was also supported by the apparent experimental results.

This article presents a wide-band antenna designed for the Cube Satellite (CubeSat). Based on a quadrifilar structure, the antenna provides circular polarization radiation, which is suitable for satellite communication. Moreover, the antenna is designed and fabricated using two 1.6 mm thickness FR4-Epoxy boards that connect together by the metal pins. In order to improve the robustness, a ceramic spacer is placed in the centerboard, and four screws at the corners are added to fix the antenna with the CubeSat structure. These additional parts reduce antenna damage caused by vibrations in the launch vehicle lift-off stage. The proposal has a dimension of 77mm x 77mm x 10mm and covers the LoRa frequency bands of 868 MHz, 915 MHz, and 923 MHz. According to the measurements in an anechoic chamber, antenna gains are obtained with the values of 2.3 dBiC and 1.1 dBiC for the 870 MHz and 920 MHz, respectively. Finally, the antenna is integrated into a 3U CubeSat that was launched by a Soyuz launch vehicle. The terrestrial-to-space communication link was measured, and the antenna performance was confirmed in the real-life scenario.

The link of fracture analysis of large ships is an essential part of the structural safety of ships. However, the finite element analysis of large structure according to the traditional method not only has high requirements on the computer, but also the influence of the mesh encryption at special locations makes further requirements on the accuracy of the ship. In this paper, based on the extended finite element method (XFEM) and the multi-point constraint method (MPC), the dynamic crack expansion process of the rectangular plate containing cracks under the multi-scale model is comparatively studied by using ABAQUS simulation software Finally, the applicability of the method is verified by applying the multi-scale model of ship nodes. The results show that the computational effort of the multi-scale model is significantly reduced with the same accuracy and allowable error, which proves the accuracy and efficiency of the method.

According to the Global Report on Internal Displacement (GRID, 2022), the number of displaced people worldwide at the end of 2021 was 59.1 million, with 53.2 million of them being the result of conflicts and violence, and 5.9 million caused by climate-related disasters. Furthermore, the In-ternational Organization for Migration (IOM) predicts that the climate crisis will be solely re-sponsible for one billion migrants by 2050. In this context, the research examines the issue of coastal multi-risk arising from a combination of heavy rainfall, river's overflow, and sea-level rise phenomena, analysing it through the disciplinary perspective of urban planning. Specifically, the study focuses on the need to upgrade the Local Urban Plan from a climate-proof perspective by defining a method aimed at updating the territory's cognitive framework through the preparation of a multi-risk map (which considers different time horizons), as well as the prescriptive apparatus of the Plan through the definition of a toolkit of site-specific design actions oriented towards urban adaptation. The proposed methodology is verified on the case study of Isola Sacra, Fiumicino (Italy), and it is intended to be applicable to other territorial contexts. The research aims to outline guidelines for updating urban planning tools from a climate-proof perspective to promote long-term resilient urban development in risk-prone areas.

Purpose: Emotional voice conveys important social cues that demand listeners’ attention and timely processing. This event-related potential study investigated the feasibility of a multi-feature oddball paradigm to examine adult listeners’ neural responses to detecting emotional prosody changes in non-repeating naturally spoken words. Method: Thirty-three adult listeners completed the experiment by passively listening to the words in neutral and three alternating emotions while watching a silent movie. Previous research documented pre-attentive change-detection electrophysiological responses (e.g., MMN, P3a) to emotions carried by fixed syllables or words. Given that the MMN and P3a have also been shown to reflect extraction of abstract regularities over repetitive acoustic patterns, the current study employed a multi-feature oddball paradigm to compare listeners’ MMN and P3a to emotional prosody change from neutral to angry, happy, and sad emotions delivered with hundreds of non-repeating words in a single recording session. Results: Both MMN and P3a were successfully elicited by the emotional prosodic change over the varying linguistic context. Angry prosody elicited the strongest MMN compared to happy and sad prosodies. Happy prosody elicited the strongest P3a in the centro-frontal electrodes, and angry prosody elicited the smallest P3a. Conclusions: The results demonstrated that listeners were able to extract the acoustic patterns for each emotional prosody category over constantly changing spoken words. The findings confirm the feasibility of the multi-feature oddball paradigm in investigating emotional speech processing beyond simple acoustic change detection, which may potentially be applied to pediatric and clinical populations.

Background: The first few minutes after birth are the most dangerous for the survival of an infant. Babies in neonatal intensive care units are either under heated or overheated, and hypothermic infants remain hypothermic or develop a fever. As a result, special attention must be paid to monitoring and maintaining the time of recovery from hypothermia states. Despite numerous studies, only a few have examined the transition from neonatal hypothermia and associated risk factors in depth. Method: A retrospective observational study was conducted to track axillary temperatures taken at the time of neonatal intensive care unit admission, which were then tracked every 30 minutes until the newborn's temperature stabilized. All hypothermic neonates admitted to the neonatal intensive care unit between January 2018 and December 2020 was included in the study. Temperature data were available at birth and within the first three hours of admission for 391 eligible hypothermic neonates. The effect of factors on the transition rate in different states of hypothermia was estimated using a multi-state Markov model. Result: The likelihood of progressing from mild to severe hypothermia was 5%, while the likelihood of progressing to normal was 34%. The average time spent in a severe hypothermia state was 48, 35, and 24 minutes for three different levels of birth weight, and 53, 41, and 31 minutes for low, moderate, and normal Apgar scores, respectively. Furthermore, the mean sojourn time in a severe hypothermia state was 48, 39, and 31 minutes for three different levels of high, normal, and low pulse rate, respectively. Conclusion: For hypothermic survivors within the first three hours of life, very low birth weight, low Apgar, and high pulse rate had the strongest association with hypothermia and took the longest time to improve/recover. As a result, there is an urgent need to train all levels of staff dealing with maintaining the time of recovery from neonatal hypothermia.

In this note we describe a new approach to the option pricing problem by introducing the notion of the safe (and acceptable) for the writer price of an option, in contrast to the fair price used in the Black-Scholes model. Our starting point is that the option pricing problem is closely related with the hedging problem by practical techniques. Recalling that the Black - Scholes model does not give us the price of the option but the initial value of a replicating portfolio we observe easily that has a serious disadvantage because assumes the building of this replicating portfolio continuously in time and this is a disadvantage of any model that assumes such a construction. Here we study the problem from the practical point of view concerning mainly the over the counter market. This approach is not affected by the number of the underlying assets and is particularly useful for incomplete markets. In the usual Black-Scholes or binomial or some other approaches one assumes that one can invest or borrow at the same risk free rate $r>0$ which is not true in general. Even if this is the case one can immediately observes that this risk free rate is not a universal constant but is different among different people or institutions. So, the fair price of an option is not so much fair! Moreover, the two sides are not, in general, equivalent against the risk therefore the notion of a fair price has no meaning at all. We also define a variant of the usual binomial model, by estimating safe upward and downward rates $u,d$, trying to give a cheaper safe or acceptable price for the option.

Short-term changes in shallow bathymetry affect the coastal zone and therefore their monitoring is an essential task in coastal planning projects. This study provides a novel approach for monitoring shallow bathymetry change based on drone multispectral imagery. Particularly we apply a shallow water inversion algorithm on two composite multispectral datasets being acquired five months apart in a small Mediterranean sandy embayment (Chania, Greece). Initially, we perform radiometric corrections using proprietary software and following we combine the bands from standard and multispectral cameras resulting in a six-band composite image suitable for applying the shallow water inversion algorithm. Bathymetry inversion results showed good correlation and low errors (< 0.3m) with sonar measurements collected with an uncrewed surface vehicle (USV). Bathymetry maps and true-color orthomosaics assist in identifying morphobathymetric features representing crescentic bars with rip channel systems. The temporal bathymetry and true-color data reveal important erosional and depositional patterns, which were developed under the impact of winter storms. Furthermore, bathymetric profiles show that the crescentic bar appears to migrate across and along-shore over the 5-months period. Drone-based multispectral imagery proves to be an important and cost-effective tool for shallow seafloor mapping and monitoring when it is combined with shallow water analytical models.

Marketing is the manner of how to make our sales the best in the market, our prices the most accessible, our clients satisfactory, and thus our brand is the largest distributed. This needs sophisticated and advanced understanding of the total network related. Indeed, marketing data may be seen in different forms such as qualitative and quantitative. However, in the literature, it is easily noticed that large bibliography may be collected about qualitative studies, against few studies on the quantitative point of view. This is a major drawback that makes the marketing science still focusing on the design, although the market is strongly depending on quantities such as money and time. Indeed, marketing data may be a time series such as brand sales per specified periods, brand related-prices over specified periods, market shares, ..., etc. The purpose of the present work is to investigate some marketing models based on time series due to brands. We will precisely study the effect of the time scale on the persistence of brands sales in the market and on the forecasting of such a persistence according to the characteristics of the brand and the related market competition or competitors. Our study is acted on a sample of Saudi brands during the period November 22, 2017 to December 30, 2021.

The incidence and prevalence of food allergy (FA) are increasing. While several studies have established the safety and efficacy of early introduction of single allergens in infants for the prevention of FA, the exact dose, frequency, and number of allergens that can be safely introduced to infants particularly in those at high or low risk of atopy are still unclear. This 1-year study evaluated the safety of early introduction of single foods (milk, egg, or peanut), vs. two foods (milk/egg, egg/peanut, milk/peanut), vs. multiple foods (milk/egg/peanut/cashew/almond/shrimp/walnut/wheat/fish/soy at low, medium, or high doses) vs no early introduction in infants between 4-6 months of age. At the end of the study, they were evaluated for plasma biomarkers associated with food reactivity with standardized blood tests. Two to four years after the start of the study, participants were evaluated by standardized food challenges. The serving sizes for the single, double, and low dose mixtures were 300 mg total protein per day. The serving sizes for the medium and high dose mixture was 900 mg and 3000 mg total protein, respectively. Equal parts of each protein were used for double or mixture foods. All infants were breastfed until at least 6 months of age. Results demonstrate that infants at either high or low risk for atopy were able to tolerate early introduction of multiple allergenic foods with no increases in any safety issues, including eczema, FA, or food protein induced enterocolitis. The mixtures of foods at either low, medium, or high doses demonstrated trends for improvement in food challenge reactivity and plasma biomarkers compared to single and double food introductions. The results of this study suggest that early introduction of foods, particularly simultaneous mixtures of many allergenic foods is efficacious for preventing FA and can occur safely.

Often, engineers with machining experience often judge machining state and tool life according to chips’ features. Engineers' experience is digitized in this study. During the cutting process, the cutting tool coming in contact with the workpiece produces a shear zone, which causes plastic deformation and shear slip. The chips closest to the shear zone can directly show the state of the tool and workpiece when the material is SKD61. This study used chip color, vibration, and current signal integration for prediction of machining state and cutting tool life. When the cutting tool wears increased, the chip surface color changed in the following way: purpleè purple blueè blue ècyan, or even green and yellow. When the cutting tool was in the accelerating wear phase, the color change was particularly obvious. The Back-Propagation Levenberg–Marquardt (BP-LM) predictive methodology was used to compare the predictive ability of voltage, vibration signal, and chip color. The Mean Absolute Percentage Error (MAPE) for the voltage signal was 12.28%, for the vibration signal it was 11.38%, and for the chip color combined with multi-sensor characteristics it was 7.85%. The MAPE of the chip color was the smallest. Using the General Regression Neural Network (GRNN) methodology, the MAPE for the voltage signal was 10.74%, for the vibration signal 7.96%, and for the chip color combined with multi-sensor characteristics was 6.59%. The MAPE of the chip color was the smallest. Obviously, the chip color combined with multi-sensor signals provided better predictive results than the vibration signal or voltage signal alone. There is currently no research on the usefulness of monitoring chip color for tool life prediction.

In the mold machining process, the cutting tool is worn with machining time, thereby affecting the surface accuracy, leading to poor workpiece dimensions, even fracture. At present, many studies have used multiple sensors to detect the machining conditions of cutting tool and workpiece, including indirect measurement method and direct measurement method. The indirect measurement method, which has been studied widely, mainly uses sensors to capture signals for subsequent data analysis; the direct measurement method mainly analyzes the state of cutting shear zone. Due to the cut-in of cutting tool in the machining process, the workpiece is dislocated rapidly, generating considerable amount of heat, which is transferred to the chips, inducing color change on the surface of chips. Many engineers with machining experience often judge the machining state and tool life according to the chips. The engineers' experience is digitized in this study, and indirect measuring sensors are used to predict the tool life, so as to attain the objective for smart manufacturing, the average percentage error of MAPE using single vibration and voltage eigenvalues as input features is 10%, the voltage signal characteristic values and vibration signal characteristic values are combined. Finally, the chip surface chromaticity eigenvalue is combined with signal characteristic value. The average prediction error of BP-LM method is 7.85%, the average prediction error of GRNN method is 6.59%. Therefore, when the eigenvalue of chip surface chromaticity is added to the prediction result, it can enhance the accuracy of cutting tool wear value prediction more effectively than single sensor signal characteristic value.

Autofocus is an essential part of the SAR imaging process. Multi-subaperture autofocus algorithm is a commonly used autofocus algorithm for processing SAR stripmap mode data. The multi-subaperture autofocus algorithm has two main steps, the first is to estimate the phase error gradient within the subaperture, the second is to splice the phase error gradient, that is, to remove the shift amount between the estimated adjacent subapertures’ error gradients. Previous gradient-splicing algorithms assume that the estimation of subaperture error is accurate, but when the estimation of subaperture phase error gradients is not accurate enough, these algorithm performance will be degraded. A new phase error gradient splicing algorithm is proposed in this paper. It roughly estimates the shift amount first, and then finely estimates the shift amount based on the minimum-entropy criterion, which can improve the robustness of splicing especially when the estimation of the phase error gradients of the subaperture is not accurate enough. To speed up the algorithm, a variable-step-size search method is used. Simulation and experimental results show that the algorithm has enough accuracy and still has good performance when other splicing algorithms doesn’t perform well.

Evolutionary convergence provides natural opportunities to investigate how, when, and why novel traits evolve. Many convergent traits are complex, highlighting the importance of explicitly considering convergence at different levels of biological organization, or ‘multi‐level convergent evolution’. To investigate multi‐level convergent evolution, we propose a holistic and hierarchical framework that emphasizes breaking down traits into several functional modules. We begin by identifying long‐standing questions on the origins of complexity and the diverse evolutionary processes underlying phenotypic convergence to discuss how they can be addressed by examining convergent systems. We argue that bioluminescence, a complex trait that evolved dozens of times through either novel mechanisms or conserved toolkits, is particularly well suited for these studies. We present an updated estimate of at least 94 independent origins of bioluminescence across the tree of life, which we calculated by reviewing and summarizing all estimates of independent origins. Then, we use our framework to review the biology, chemistry, and evolution of bioluminescence, and for each biological level identify questions that arise from our systematic review. We focus on luminous organisms that use the shared luciferin substrates coelenterazine or vargulin to produce light because these organisms convergently evolved bioluminescent proteins that use the same luciferins to produce bioluminescence. Evolutionary convergence does not necessarily extend across biological levels, as exemplified by cases of conservation and disparity in biological functions, organs, cells, and molecules associated with bioluminescence systems. Investigating differences across bioluminescent organisms will address fundamental questions on predictability and contingency in convergent evolution. Lastly, we highlight unexplored areas of bioluminescence research and advances in sequencing and chemical techniques useful for developing bioluminescence as a model system for studying multi‐level convergent evolution.

This investigation explores a novel path-planning and optimization strategy for multiple cooperative robotic agents, applied in a fully observable and dynamically changing obstacle field. Current dynamic path planning strategies employ static algorithms operating over incremental time-steps. We propose a cooperative multi-agent (CMA) based algorithm, based on natural flocking of animals, using vector operations. It is preferred over more common graph search algorithms like A* as it can be easily applied for dynamic environments. CMA algorithm executes obstacle avoidance using static potential fields around obstacles, that scale based on relative motion. Optimization strategies including interpolation and Bezier curves are applied to the algorithm. To validate effectiveness, CMA algorithm is compared with A* using static obstacles due to lack of equivalent algorithms for dynamic environments. CMA performed comparably to A* with difference ranging from -0.2% to 1.3%. CMA algorithm is applied experimentally to achieve comparable performance, with an error range of -0.5% to 5.2%. These errors are attributed to the limitations of the Kinect V1 sensor used for obstacle detection. The algorithm was finally implemented in a 3D simulated space, indicating that it is possible to apply with drones. This algorithm shows promise for application in warehouse and inventory automation, especially when the workspace is observable.

Understanding the detailed timing of crop phenology and their variability enhances grain yield and quality by providing precise scheduling of irrigation, fertilization, and crop protection mechanisms. Advances in information and communication technology (ICT) provide a unique opportunity to develop agriculture-related tools that enhance wall-to-wall upscaling of data outputs from point-location data to wide-area spatial scales. Because of the heterogeneity of the worldwide agro-ecological zones where crops are cultivated, it is unproductive to perform plant phenology research without providing means to upscale results to landscape-level while safeguarding field-scale relevance. This paper presents an advanced, reproducible, and open-source software for plant phenology prediction and mapping (PPMaP) that inputs data obtained from multi-location field experiments to derive models for any crop variety. This information can then be applied consecutively at a localized grid within a spatial framework to produce plant phenology predictions at the landscape level. This software supports the development of process-oriented and temperature-driven plant phenology models by intuitively and interactively leading the user through a step-by-step progression to the production of spatial maps for any region of interest. Maize (Zea mays L.) was used to demonstrate the robustness, versatility, and high computing efficiency of the resulting modeling outputs of the PPMaP. The framework is implemented in R, providing a flexible and easy‐to‐use GUI interface. Since this allows appropriate scaling to the larger spatial domain, the software can effectively be used to determine the spatially explicit length of growing period (LGP) of any variety.

Recent research has enabled the integration of traditional Volt-VAr Control (VVC) resources, such as capacitors banks and transformer tap changers, with Distributed Energy Resources (DERs), such as photo-voltaic sources and energy storage, in order to achieve various Volt-VAr Optimization (VVO) targets, such as Conservation Voltage Reduction (CVR), minimizing VAr flow at the transformer, minimizing grid losses, minimizing asset operations and more. When more than one target function can be optimized, the question of multi-objective optimization is raised. In this work, we propose a general formulation of the multi-objective Volt-VAr optimization problem. We consider the applicability of various multi-optimization techniques and discuss the operational interpretation of these solutions. We demonstrate the methods using simulation on a test feeder.

Biological gels (bio-gels) are hydrated polymer networks that serve diverse biological functions, which often lead to intentional or unintentional exposure to particulate matter. In this work, we derive a microscopically motivated framework that enables the investigation of penetration mechanisms into bio-gels. We distinguish between two types of mechanisms: spontaneous (unforced) penetration and forced penetration. Using experimental data available in literature, we exploit the proposed model to characterize and compare between the micro-structures of respiratory, intestinal, and cervicovaginal mucus and two types of biofilms. Next, we investigate the forced penetration process of spherical and ellipsoidal particles into a locally quadrilateral network. The proposed framework can be used to improve and complement the analysis of experimental findings in vitro, ex vivo, and in vivo. Additionally, the insights from this work pave the way towards enhanced designs of nano-medicines and allow to assess risk factors related to the nano-pollutants exposure.

A method for classification is introduced in this article, and it is tested on ADNI database to diagnose alzheimer’s disease (AD). It is obvious that tunning the performance of a classification to get better results is a complicated problem, and when we want model’s accuracy or other peformance measurments higher than 90%, the problem will be more complicated. In this study, we tried and succeeded to discover a method to solve this problem. The final feature set can be used clustering too, because outgrowth feature set of the proposed method is invigorated. In the recent years, a lot of activities is done to develop computer aided systems (CAD) for alzheimer’s disease diagnosis. Most of these recently developed systems concenterated on extracting and combining features from MRI, PET, CSF, and …; in this article, we made attempt to do so and utilized one more technique to increase classification performance. Finding and producing the best features to solve three binary classification problems of AD vs. Normal Control (NC), Mild Cognitive Impairment (MCI) vs. NC, and MCI vs. AD are the purposes of this article. Experiments indicate performance and effectiveness rates of the proposed method, which are accuracies of 98.81%, 81.61%, and 81.40% for AD vs. NC, MCI vs. NC, and AD vs. MCI classification problems, respectively. As can be seen, using this method increased the performance of the three binary problems incredibly.

The thermal lubrication of an entangled polymeric liquid in wall-driven shear flows between parallel plates is investigated by using a multiscale hybrid method coupling molecular dynamics and the hydrodynamics (i.e., the synchronized molecular dynamics method). The temperature of the polymeric liquid rapidly increases due to viscous heating once the drive force exceeds a certain threshold value. The rheological properties of the polymeric liquid drastically change at around the critical drive force. In the weak viscous-heating regime, the conformation of polymer chains is dominated by the local shear flow so that the anisotropy of the bond orientation tensor grows as the drive force increases. However, in the large viscous-heating regime, the conformation dynamics is dominated by the thermal agitation of polymer chains so that the bond orientation tensor recovers more uniform and random structures as the drive force increases, even though the local shear flows are further enhanced. Remarkably, these counter-intuitive transitional behaviors give an interesting re-entrant transition in the stress--optical relation, where a linear formalism in the stress--optical relation approximately holds even though each of the macroscopic quantities behaves nonlinearly. The robustness of the linear stress--optical relation is also confirmed in the spatiotemporal evolution at the hydrodynamic level.

Digital Elevation Models (DEMs) are widely used in geographic and environmental studies. In the current work, the fusion of multi-source DEMs is investigated to improve the overall accuracy of public domain DEMs. Multi-scale decomposition is an important analytical method in data fusion. Three multi-scale decomposition methods – the wavelet transform (WT), bidimensional empirical mode decomposition (BEMD) and nonlinear adaptive multi-scale decomposition (N-AMD) - are applied to the 1-arc-second Shuttle Radar Topography Mission Global digital elevation model (SRTM-1 DEM) and the Advanced Land Observing Satellite World 3D – 30 m digital surface model (AW3D30 DSM) in China. Of these, the WT and BEMD are popular image fusion methods. A new approach for DEM fusion is developed using N-AMD (which is originally invented to remove the cycle from sunspots). Subsequently, a window-based rule is proposed for the fusion of corresponding frequency components obtained by these methods. Quantitative results show that N-AMD is more suitable for multi-scale fusion of multi-source DEMs, taking the ice cloud and land elevation satellite (ICESat) global land surface altimetry data as a reference. The vertical accuracy of the fused DEM shows significant improvements of 29.6% and 19.3% in a mountainous region and 27.4% and 15.5% in a low-relief region, compared to the SRTM-1 and AW3D30 respectively. Furthermore, a slope position-based linear regression method is developed to calibrate the fused DEM for different slope position classes, by investigating the distribution of the fused DEM error with topography. The results indicate that the accuracy of the DEM calibrated by this method is improved by 16% and 13.6%, compared to the fused DEM in the mountainous region and low-relief region respectively, proving that it is a practical and simple means of further increasing the accuracy of the fused DEM.

Multi-task Gaussian processes (MTGPs) are a powerful approach for modeling structured dependencies among multiple tasks. Researchers on MTGPs have contributed to enhance this approach in various ways. Current MTGP methods, however, cannot model nonlinear task correlations in a general way. In this paper we address this problem. We focus on spectral mixture (SM) based kernels and propose an enhancement of this type of kernels, called multi-task generalized convolution spectral mixture (MT-GCSM) kernel. The MT-GCSM kernel can model nonlinear task correlations and mixtures dependency, including time and phase delay, not only between different tasks but also within a task at the spectral mixture level. Each task in MT-GCSM has its own generalized convolution spectral mixture kernel (GCSM) with a different number of convolution structures and all spectral mixtures from different tasks are dependent. Furthermore, the proposed kernel uses inner and outer full cross convolution between base spectral mixtures, so that the base spectral mixtures in the tasks are not necessarily aligned. Extensive experiments on synthetic and real-life datasets illustrate the difference between MT-GCSM and other kernels as well as the practical effectiveness of MT-GCSM.

An adaptive operation strategy for on-demand control of DMFC system is proposed as an alternative method to enhance the voltage stability. Based on a single-cell DMFC stack, a newly simplified semi-empirical model is developed from the uniform-designed experimental results to describe the I-V relationship. Integrated with this model, the multi-objective optimization method is utilized to develop an adaptive operation strategy. Although the voltage instability is frequently encountered in unoptimized operations, the voltage deviation is successfully decreased to a required level by adaptive operations with operational adjustments. Moreover, the adaptive operations are also found to be able to extend the range of operating current density or to decrease the voltage deviation according to ones requirements. Numerical simulations are implemented to investigate the underlying mechanisms of the proposed adaptive operation strategy, and experimental adaptive operations are also performed on another DMFC system to validate the adaptive operation strategy. Preliminary experimental study shows a rapid response of DMFC system to the operational adjustment, which further validates the effectiveness and feasibility of the adaptive operation strategy in practical applications. The proposed strategy contributes to a guideline for the better control of output voltage from operating DMFC systems.

This research proposes a framework to assist wind energy developers to select the optimum deployment site of a wind farm by considering the Round 3 zones in the UK. The framework includes optimisation techniques, decision-making methods and experts’ input in order to help stakeholders with investment decisions. Techno-economic, Life Cycle Costs (LCC) and physical aspects for each location are considered along with experts’ opinions to provide deeper insight into the decision making process. A process on the criteria selections is also presented and seven conflicting criteria are being considered in TOPSIS methods in order to suggest the optimum location that was produced by the NSGAII algorithm. Seagreen Alpha was the most probable solution, followed by Moray Firth Eastern Development Area 1, which demonstrates by example the effectiveness of the newly introduced framework that is also transferable and generic. The outcomes are expected to help stakeholders and decision makers to make more informed and cost-effective decisions under uncertainty when investing in offshore wind energy in the UK.

The development of printing technologies has enabled the realization of electric circuit fabrication on flexible substrate. However, the current technique remains restricted to single-layer patterning. In this paper, we demonstrate a fully solution-processable patterning approach for multi-layer circuits using a combined method of laser sintering and ablation. Selective laser sintering of silver (Ag) nanoparticle-based ink is applied to make conductive patterns on a heat-sensitive substrate and insulating layer. The laser beam path and irradiation fluence are controlled to create circuit patterns for flexible electronics. Microvia drilling using femtosecond laser through the polyvinylphenol-film insulating layer by laser ablation, as well as sequential coating of Ag ink and laser sintering, achieves an interlayer interconnection between multi-layer circuits. The dimension of microvia is determined by a sophisticated adjustment of laser focal position and intensity. Based on these methods, the flexible electronic circuit with chip-size-package light-emitting diodes was successfully fabricated and demonstrated with functional operations.

In this paper, we tackle air quality forecasting by using machine learning approaches to predict the hourly concentration of air pollutants (e.g., Ozone, PM_2.5 and Sulfur Dioxide). Machine learning, as one of the most popular techniques, is able to efficiently train a model on big data by using large-scale optimization algorithms. Although there exists some works applying machine learning to air quality prediction, most of the prior studies are restricted to small scale data and simply train standard regression models (linear or non-linear) to predict the hourly air pollution concentration. In this work, we propose refined models to predict the hourly air pollution concentration based on meteorological data of previous days by formulating the prediction of 24 hours as a multi-task learning problem. It enables us to select a good model with different regularization techniques. We propose a useful regularization by enforcing the prediction models of consecutive hours to be close to each other, and compare with several typical regularizations for multi-task learning including standard Frobenius norm regularization, nuclear norm regularization, ℓ_2,1 norm regularization. Our experiments show the proposed formulations and regularization achieve better performance than existing standard regression models and existing regularizations.

Multi-step ahead streamflow forecasting is of practical interest for the operation of hydropower reservoirs. We provide generalized results on the error evolution in multi-step ahead forecasting by conducting several large-scale experiments based on simulations. We also present a multiple-case study using monthly time series of streamflow. Our findings suggest that some forecasting methods are more useful than others. However, the errors computed at each time step of a forecast horizon within a specific case study strongly depend on the case examined and can be either small or large, regardless of the forecasting method used and the time step of interest.

Remote sensing has considerable potential to contribute to the identification and reconstruction of lost hydrological systems and networks. Remote sensing-based reconstructions of palaeo-river networks have commonly employed single or limited time-span imagery, which limits their capacity to identify features in complex and varied landscape contexts. This paper presents a seasonal multi-temporal approach to the detection of palaeo-rivers over large areas based on long-term vegetation dynamics and spectral decomposition techniques. The use of multi-temporal data has allowed the overcoming of seasonal cultivation patterns and long-term visibility issues related to crop selection, large-scale irrigation and land use patterns. The application of this approach on the Sutlej-Yamuna interfluve (northwest India), a core area for the Bronze Age Indus Civilisation, has enabled the reconstruction of an unsuspectedly complex palaeo-river network comprising more than 8000 kms of palaeo-channels. It has also enabled the definition of the morphology of these relict courses, which provides insights into the environmental conditions in which they operated. These new data will contribute to a better understanding of the settlement distribution and environmental settings in which this, often considered riverine, civilisation operated.

This article considers the concepts of sustainability and sustainable development in relation to disaster risk reduction and climate change adaptation. We conceptualize sustainability from a social systemic perspective, that is, from a perspective that encompasses the multiple functionalities of a social system and their interrelationships in particular environmental contexts. The systems perspective is applied in our consideration and analysis of disaster risk reduction (DRR), climate change adaptation (CCA), and sustainable development (SD). Section 1 introduces briefly sustainability and sustainable development, followed by a brief presentation of the theory of complex social systems (Section 2). The theory conceptualizes interdependent subsystems, their multiple functionalities, and the agential and systemic responses to internal and external stressors on a social system. Section 3 considers disaster risk reduction (DRR) and climate change adaptation (CCA), emerging in response to one or more systemic stressors. It illustrates these with disaster risk reduction in the cases of food and chemical security regulation in the EU. CCA is illustrated by initiatives and developments on the island of Gotland, Sweden and in the Gothenburg Metropolitan area, which go beyond a limited CCA perspective, taking into account long-term sustainability issues. Section 4 discusses the limitations of DRR and CCA, not only their technical limitations but economic, socio-cultural, and political limitations, as informed from a sustainability perspective. It is argued that DRRs are only partial subsystems and must be considered and assessed in the context of a more encompassing systemic perspective. Part of the discussion is focused on the distinction between sustainable and non-sustainable DRRs and CCAs. Section 5 presents a few concluding remarks about the importance of a systemic perspective in analyzing DRR and CCA as well as other similar subsystems in terms of sustainable development.

This paper proposes a new approach for multi-focus images fusion based on Region Mosaicing on Contrast Pyramids (REMCP). A density-based region growing method is developed to construct a focused region mask for multi-focus images. The segmented focused region mask is decomposed into a mask pyramid, which is then used for supervised region mosaicking on a contrast pyramid. In this way, the focus measurement and the continuity of focused regions are incorporated and the pixel level pyramid fusion is improved at the region level. Objective and subjective experiments show that the proposed REMCP is more robust to noise than compared algorithms and can fully preserves the focus information of the multi-focus images meanwhile reducing distortions of the fused images.

In this paper, the technical aspects of a multi-lidar instrument, the long-range WindScanner system, will be presented accompanied by an overview of the results from several field campaigns. The long-range WindScanner system consists of three spatially separated coherent Doppler scanning lidars and a remote master computer that coordinates them. The lidars were carefully engineered to perform arbitrary and time controlled scanning trajectories. Their wireless coordination via the master computer allows achieving and maintaining lidars’ synchronization within ten milliseconds. As a whole, the long-range WindScanner system can measure an entire wind field by emitting and directing three laser beams to intersect, and then by moving the beam intersection over the points of interest. The long-range WindScanner system was developed to tackle the need for high-quality observations of wind fields from scales of modern wind turbine and wind farms. It has been in operation since 2013.

Drug functionalization through formation of hydrophilic groups is the norm in phase I metabolism of drugs for modification of drug action. The reactions involved are mainly oxidative catalyzed mostly by CYP isoenzymes. The benzene ring, as phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e. the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e. the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retaining, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues have been presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design and drug development.

Candidiasis is one of the global public health problems. In fluconazole resistant Candida spp. (FRCS), mutations in ergosterol biosynthesis gene 11 (ERG 11) have been commonly found. This study aimed to determine the profile of FRCS isolates and to detect mutations in part of ERG 11 gene in fluconazole resistant Candida albicans (FRCA) isolates. Study was conducted on 150 isolates of FRCS obtained from patients admitted in a tertiary care hospital, South India from September 2019 to December 2021. Candida spp. was identified by MALDI-TOF MS and fluconazole resistance was detected by VITEK 2 system. Following which a part of the ERG 11 gene of the FRCA isolates were amplified, purified, sequenced and a phylogenetic tree was constructed. Out of the 150 FRCS, the most common FRCS was C. auris followed by C. glabrata, C. krusei, C. parapsilosis, C. albicans, C. tropicalis and C. guilliermondii. Sequencing of amplicons detected a single missense mutation and 44 silent mutations. We opined that fluconazole resistance in FRCA isolates may be due to mecha-nisms other than the studied one in our region. Phylogenetic analysis of amplified sequences of 12 FRCA isolates observed three clusters and all 12 sequences showed relatedness to Malaysian 2019 isolates.

In interepidemic periods, a sapronoses typically employs a variety of mechanisms for maintaining viability of its causative agent in terrestrial parasitic systems, associated with different adaptive strategies utilized by its populations to survive. Unlike spore-forming bacteria, causative agents of sapronoses use resistant cell forms, which is a viable but nonculturable (VBNC) state, and persistence. Implementation of these strategies is conditioned by effects of various stress factors of the habitat and is characterized by decreased metabolism, alteration of the morphology and physiology of bacterial cell, and cessation of its replication. It is important that the resistant forms of cells retain virulence and, as favorable conditions come, turn back into the active vegetative form again. The discovery of the genetic modules of bacterial toxin–antitoxin systems in recent years has made it possible to identify a number of complicated regulatory molecular mechanisms responsible for maintaining the pathogenic potential of resistant forms of causative agents of natural-focus sapronoses in interepidemic periods.

We describe a new approach for integrating multiple views of data into a common latent space using non-negative tensor factorization (NTF). This approach, which we refer to as the "Integrated Sources Model" (ISM), consists of two main steps: embedding and analysis. In the embedding step, each view is transformed into a matrix with common non-negative components. In the analysis step, the transformed views are combined into a tensor and decomposed using NTF. Noteworthy, ISM can be extended to process multi-view data sets with missing views. We illustrate the new approach using two examples: the UCI digit dataset and a public cell type gene signatures dataset, to show that multi-view clustering of digits or marker genes by their respective cell type is better achieved with ISM than with other latent space approaches. We also show how the non-negativity and sparsity of the ISM model components enable straightforward interpretations, in contrast to latent factors of mixed signs. Finally, we present potential applications to single-cell multi-omics and spatial mapping, including spatial imaging and spatial transcriptomics, and computational biology, which are currently under evaluation. ISM relies on state-of-the-art algorithms invoked via a simple workflow implemented in a Jupyter Python notebook.

In recent years, demand has been increasing for target detection and tracking from aerial imagery via drones using onboard powered sensors and devices. We propose a very effective method for this application based on a deep learning framework. A state-of-art embedded hardware system empowers small flying robots to carry out the real-time onboard computation necessary for object tracking. Two types of embedded modules were developed: one is designed using a Jetson TX or AGX Xavier, and the other is based on an Intel Neural Compute Stick. These are suitable for real-time onboard computing power on small flying drones with limited space. A comparative analysis of current state-of-art deep-learning-based multi-object detection algorithms was carried out utilizing the designated GPU-based embedded computing modules to obtain detailed metric data about frame rates as well as the computation power. We also introduce an effective target tracking approach for moving objects. The algorithm for tracking moving objects is based on the extension of simple online and real-time tracking. It was developed by integrating a deep-learning-based association metric approach (Deep SORT), which uses a hypothesis tracking methodology with Kalman filtering and a deep-learning-based association metric. In addition, a guidance system that tracks the target position using a GPU-based algorithm is introduced. Finally, we demonstrate the effectiveness of the proposed algorithms by real-time experiments with a small multi-rotor drone.

Long COVID, also referred to as post-COVID-19 condition, describes the lingering after-effects of COVID-19 infection. This complex syndrome encompasses a range of symptoms affecting physical well-being, cognitive function, and mental health. The widespread impact of long COVID extends beyond individual sufferers, placing significant strain on healthcare systems and causing far-reaching socioeconomic consequences. The scale of this multifaceted health crisis is unparalleled in recent history, affecting millions globally and challenging our understanding of post-viral conditions. This study aimed to explore the possibility of targeting G protein-coupled receptors (GPCRs) signaling pathway-related genes as therapeutics for long COVID using computational analysis. Targeting GPCRs and their signaling pathways holds significant promise for long COVID therapeutics, as these receptors are involved in crucial physiological processes including immune regulation, inflammation control, and neurotransmission. All of these are implicated in the diverse and persistent symptoms of long COVID, potentially offering a versatile approach to addressing multiple aspects of the condition simultaneously. This study identified 21 genes associated with GPCRs for further exploration as potential targets. Notably, GPCR genes such as HRAS, KRAS, GNAQ, and GNA11 were determined to be possible therapeutic targets for the pathophysiological mechanisms of long COVID. FDA-approved drugs targeting these genes were identified, including Binimetinib, Cabozantinib, Selumetinib, Panitumumab, Cetuximab, Adagrasib, Tipifarnib, and Sotorasib. Additionally, Naltrexone and Tipifarnib have emerged as potential new treatment options for long COVID. SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport, contributing to the pathophysiology of pulmonary edema in patients with COVID-19. Further research is required to translate the findings into the development of therapeutics and to investigate the relationship between viral infection and GPCR signalling.

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen-alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial cell line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases (RDDs). This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium iodate (SI)-induced retinal degeneration. The findings indicated that CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants.

Beginning in December 2019, a novel coronavirus known as SARS-CoV-2 has caused an international outbreak of respiratory illness termed COVID-19. This disease may cause mild to moderate respiratory illness. However, older individuals and those with underlying medical conditions like diabetes, cancer, and cardiovascular disease are more likely to develop serious illnesses (progressive pneumonia, multi-organ failure, and even death) (1). The main target for antiviral therapy for COVID-19 is the 3CL protease (3CLpro, Main protease, Mpro, Nsp5). The 3CL protease plays an integral role in viral replication and is often known as the “Achilles heel” of the SARS-CoV-2 virus (2). Thus, NLC Pharma utilized a unique and novel technology termed Quantum Core Technology (QCT) to design a mechanism-based potent inhibitor against the SARS-Cov-2 3CL protease. 3CL Pharma has designed an oral anti-viral for COVID-19 called Tollovir. Biochemical assays have revealed that 40uM of Tollovir in PBS can achieve 90% maximum inhibition of 3CL protease. Furthermore, the oral anti-viral has completed clinical trial phase 2b/3. Tollovir has proven to be safe and significantly decreases mortality rates of hospitalized patients with COVID-19 infection.

In this study, Cu2O nanoparticles were synthesized using the sol-gel technique and subsequently functionalized with extracts from plants of the Rauvolfioideae subfamily and citrus fruits. Com-prehensive characterization techniques, including UV-Vis spectroscopy, FT-IR, XRD, BET, SEM, and TEM, were employed to evaluate the structural and surface properties of the synthesized nanoparticles. The results demonstrated that both functionalized Cu2O nanoparticles exhibit mesoporous structures, as confirmed by nitrogen adsorption-desorption isotherms and pore size distribution analysis. The Green Extract functionalized nanoparticles displayed a more uniform pore size distribution compared to those functionalized with the Orange Extract. The study un-derscores the potential of these functionalized Cu2O nanoparticles for applications in drug de-livery, catalysis, and adsorption processes, highlighting the influence of the functionalization method on their textural properties and performance in antibacterial efficacy.

For centuries, humans have relied on natural products to prevent and treat numerous health issues. However, biologically active compounds from natural sources, such as polyphenols, face significant challenges, including low solubility, rapid metabolism, and instability, which hinder their effectiveness. Advances in science and nanotechnology have provided solutions to overcoming these problems through the use of porous silica materials. These materials possess unique properties, such as a high specific surface area, adjustable particle and pore sizes, and a surface that can be easily and selectively modified. In this review, we summarize and discuss findings on how the pore and particle size, structure, and surface modification of silica materials influence the preparation of efficient delivery systems for biologically active polyphenols from natural sources. The available data demonstrate how parameters such as adsorption capacity, release and antioxidant properties, bioavailability, solubility, stability, etc. of the studied delivery systems could be affected by the structural and chemical characteristics of the porous silica carriers.

The unique structure of G4.0 PAMAM dendrimers allows the drug to be enclosed in internal spaces or immobilized on the surface. In the conducted research, the conditions for the formation of the active G4.0 PAMAM complex with doxorubicin (DOX) were optimized. The physicochemical properties of the system were monitored using DLS, CD, and fluorescence spectroscopy. The QCM-D method was chosen to determine the preferential conditions for the complex formation. The highest binding efficiency of the drug to the cationic dendrimer was observed under basic conditions when the DOX molecule was deprotonated. The decrease in the zeta potential of the complex confirms that DOX immobilizes through electrostatic interaction with the carrier's surface amine groups. The binding constants were determined from the fluorescence quenching of the DOX molecule in the presence of G4.0 PAMAM. The two-fold way of binding doxorubicin in the structure of dendrimers was visible in the ITC isotherm. Fluorescence spectra and release curves identified reversible binding of DOX to the nanocarrier. Among the selected cancer cells, the most promising anticancer activity of G4.0-DOX was observed in A375 malignant melanoma cells. Moreover, the preferred intracellular location of the complexes concerning the free drug was found, which is important from a therapeutic point of view.

The current 2019-2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019-2021 was published by researchers in 42 countries and contributed novel mechanism of action pharmacology for 171 structurally characterized marine compounds. The peer-reviewed marine natural products pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis,and antiviral mechanism of action studies for 49 compounds, 87 compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while another group of 51 compounds demonstrated novel miscellaneous mechanisms of action, which upon further investigation, may contribute to several pharmacological classes. Thus, in 2019-2021, a very active preclinical marine natural product pharmacology pipeline provided novel mechanism of actions as well as new lead chemistry for the clinical marine pharmaceutical pipeline targeting the therapy of several disease categories.

The management of brain tumors presents numerous challenges, despite the employment of multimodal therapies including surgical intervention, radiotherapy, chemotherapy, and immunotherapy. Owing to the distinct location of brain tumors and the presence of the blood-brain barrier (BBB), these tumors exhibit considerable heterogeneity and invasiveness at a histological level. Recent advancements in hydrogel research for the local treatment of brain tumors have sought to overcome the primary challenge of delivering therapeutics past the BBB, thereby ensuring efficient accumulation within brain tumor tissues. This article elaborates on various hydrogel-based delivery vectors, examining their efficacy in the local treatment of brain tumors. Additionally, it reviews the fundamental principles involved in designing intelligent hydrogels that can circumvent the BBB and penetrate larger tumor areas, thereby facilitating precise, controlled drug release. Hydrogel-based drug delivery systems (DDSs) are posited to offer a groundbreaking approach in addressing the challenges and limitations inherent in traditional oncological therapies, which are significantly impeded by the unique structural and pathological characteristics of brain tumors.

Institutionalized older adults often face complex medication regimens, increasing their risk of adverse drug events due to polypharmacy, overprescribing, medication interactions or the use of Potentially Inappropriate Medications (PIM). However, data on medication use and associated risks in this population remain scarce. This pilot study aimed to characterize the sociodemographic, clinical and pharmacotherapeutic profiles and the use of PIM among institutionalized elders residing in Residential Structures for Elderly People (ERPI) in the Faro municipality, located in the Portuguese region of the Algarve. We conducted a cross-sectional study in a non-randomized sample of 96 participants (mean age: 86.6 ±7.86 years) where trained researchers reviewed medication profiles and identified potentially inappropriate medications using the EU(7)-PIM list. Over 90% of participants exhibited polypharmacy (≥5 medications), with an average of 9.1 ± 4.15 medications per person. About 92% had potential drug interactions, including major and moderate interactions. More than 86% used at least one potentially inappropriate medication, most commonly central nervous system drugs. This pilot study demonstrates that institutionalized older adults may be at high risk of potential medication-related problems. Implementing comprehensive medication review programs and promoting adapted prescribing practices are crucial to optimize medication use and improve the well-being of this vulnerable population.

Drugs are known to cause substantial liver injury, with hepatotoxicity ranging from asymptomatic increase of liver enzymes to hepatic failure. HIV/AIDS patients, with compromised immune systems, are especially vulnerable to opportunistic infections such as tuberculosis (TB). Patients with co-infection frequently get combined antiretroviral (ART) and antitubercular (ATD) regimens, which can cause hepatotoxicity. Hepatotoxicity has been linked to commonly administered antiretroviral drug regimens as well as first-line antitubercular agents such isoniazid, rifampin, and pyrazinamide, which are required for the treatment of both drug-sensitive and drug-resistant tuberculosis. As a result, there is an urgent need to investigate treatments based from traditional herbs known for their hepatoprotective abilities against ART and ATD-induced liver injury. Many researchers have investigated the effectiveness of medicinal plants in treating chemically caused hepatotoxicity. Medicinal plants are high in phytochemicals and secondary metabolites, both of which have a variety of medicinal benefits. Currently, there is a lack of specific therapeutic regimens to address this adverse effect, and management often relies on symptomatic treatment or therapy withdrawal. Traditional medicinal plants may have the potential to restore normal liver function, enzyme activity, and cellular structure in response to ART and ATD-induced hepatotoxicity. This review aims to examine the scientific evidence supporting the use of medicinal plants as hepatoprotective agents against liver damage induced by ART and ATDs.

Drug hypersensitivity reactions (DHR) to platinum-based compounds (PC) are on the rise, and their personalized and safe management is essential to enable first-line treatment of these cancer patients. This study aimed to evaluate the usefulness of basophil activation test by flow cytometry (BAT-FC) and the newly developed sIgE-microarray and BAT-microarray in diagnosing IgE-mediated hypersensitivity reactions to PC. 24 patients with DHR to PC (20 oxaliplatin and four carboplatin) were evaluated: 13 patients diagnosed as allergic with positive skin tests (STs) or drug provocation tests (DPTs), six patients diagnosed as non-allergic with negative STs and DPTs, and five patients classified as suspected allergic because DPTs could not be performed. In addition, four carboplatin-tolerant patients were included as controls. BAT-FC was positive in 2 of 13 allergic patients, with a sensitivity of 15.4% and specificity of 100%. However, the sIgE- and BAT-microarrays were positive in 11 of 13 DHR patients, giving a sensitivity of over 84.6% and a specificity of 90%. Except for one patient, all samples from the non-allergic and control group were negative for the sIgE- and BAT-microarrays. Our experience indicates that sIgE- and BAT-microarray could be helpful in the endophenotyping of IgE-mediated hypersensitivity reactions to PC and may provide an advance in decision-making for drug provocation testing.

Tumor immunotherapy represented by immune target blocking and chimeric antigen receptor cell therapy has developed rapidly. Among them, Natural Killer Cell (NK) is gradually becoming another preferred immunotherapy method after T cell immunotherapy because of its unique killing effect in innate immunity and adaptive immunity. Although NK cell therapy has achieved promising results in clinical trials, there are still some problems, such as low efficacy in solid tumors, insufficient penetration of NK cells and high cost of treatment. Nanomaterials are expected to be an excellent tool to improve the anti-tumor immune response of NK cells due to their advantages such as chemical specificity, biocompatibility and simple synthesis. Nanomaterials can enhance the cytotoxicity of NK cells, participate in the modification and noninvasive cell-tracking patterns of NK cells，and mediate their homing and infiltration, and thus significantly improve the efficiency of NK cell immunotherapy. In this review, we will briefly introduce the methods and mechanisms of tumor immunotherapy, emphasize the research progress of NK cell-based immunotherapy and imaging, and finally summarize the direction and research progress of nanomaterials in NK cell-based immunotherapy.