Fungi are rich sources of secondary metabolites of agrochemical, pharmaceutical and food importances, such as mycotoxins, antibiotics and antitumor agents. Secondary metabolites play vital roles in fungal pathogenesis, growth and development, oxidative status modulation, and adaptation/resistance to various environmental stresses. LaeA contains an S-adenosylmethionine binding site and displays methyltransferase activity. The members of velvet proteins include VeA, VelB, VelC, VelD and VosA, for each member with a velvet domain. LaeA and velvet proteins can form multimeric complexes such as VosA-VelB and VelB-VeA-LaeA. They belong to global regulators and are mainly impacted by light. One of their most important functions is to regulate gene expression that are responsible for secondary metabolite biosynthesis. The aim of this mini-review is to represent the newest cognition on the biosynthetic regulation of mycotoxins and other fungal secondary metabolites by LaeA and velvet proteins. In most cases, LaeA and velvet proteins positively regulated production of fungal secondary metabolites. The regulated fungal species mainly belong to the toxigenic fungi from the genera of Alternaria, Aspergillus, Botrytis, Fusarium, Magnaporthe, Monascus, and Penicillium for the production of mycotoxins. We can control secondary metabolite production to inhibit the production of harmful mycotoxins while promoting the production of useful metabolites by global regulation of LaeA and velvet proteins in fungi. Furthermore, the regulation by LaeA and velvet proteins should be a practical strategy in activating silent biosynthetic gene clusters (BGCs) in fungi to obtain previously undiscovered metabolites.

Background. Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries by the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods. Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females', receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. Uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA in spite upregulated TfR expression. Conclusions. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

In this paper, we introduce a specialized, fully automated experimental arrangement designed for assessing the effectiveness of augmented and virtual reality technologies in healthcare setting and explore its design principles focusing on depth sensor characterization. The main goal of this project is to establish a robust benchtop platform for the quantitative evaluation of extended reality technologies in a controlled environment, emphasizing the practical assessment of augmented reality head-mounted devices. We outline a design concept and considerations for an experimental configuration aimed at creating a realistic testing environment. This apparatus comprises an observation platform mounted on a three-degree-of-freedom motorized system and a test phantom stage. Focusing on real-case scenarios, we utilized a range of sensors, including readily available range-sensing cameras and commercial augmented reality headsets, such as the Intel RealSense L515 LiDAR camera, mounted on the motion control system. The setup enabled automated data collection and facilitates controlled assessments and validation of various facets of augmented reality technologies, including object, hand, and head tracking, as well as static and dynamic image registration. This paper describes the system architecture, the process of automated data collection, and presents several evaluation studies conducted with this setup, providing insights into the quality and temporal noise associated with static or moving objects or observers in augmented reality applications.

Hematological malignancies refer to a heterogeneous group of neoplastic conditions of lymphoid and hematopoietic tissues classified in leukemias, Hodgkin and non-Hodgkin lymphomas and multiple myeloma, according to their presumed cell of origin, genetic abnormalities, and clinical features. Metabolic adaptation and immune escape, which influence various cellular functions including proliferation and survival of hematological malignant tumor cells, are major aspects of these malignancies that lead to therapeutic drug resistance. Targeting specific metabolic pathways is emerging as novel therapeutic strategy in hematopoietic neoplasms, particularly in acute myeloid leukemia and multiple myeloma. In this context, CD147, also known as Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) or Basigin, is one target-candidate involved in reprogramming metabolism in different cancer cells, including hematological malignant tumor cells. CD147 overexpression significantly contributes to the metabolic transformation of these cancer cells, by mediating signaling pathway, growth, metastasis and metabolic reprogramming, through its interaction, direct or not, with various membrane proteins related to metabolic, regulation including monocarboxylated transporters, integrins, P-glycoprotein and Glucose Transporter 1. This review explores the metabolic functions of CD147 and its impact on the tumor microenvironment, influencing the progression and neoplastic transformation in leukemias, myeloma and lymphomas. Furthermore, we highlight new opportunities for the development of targeted therapies against CD147, potentially improving the treatment of hematologic malignancies.

Existing research indicates that mineralization of Carlin-type gold deposit is related to geological structures, but current studies mostly focus on the qualitative association, and lack quantitative analysis of the relationship between mineralization and structural features, which limits the potential for predictive mineral exploration. In this study, the Nibao Carlin-type gold deposit was selected as the research area to conduct three-dimensional geological modeling, spatial analysis, and three-dimensional prospectivity modeling. Spatial analysis revealed that the majority of gold ore bodies are situated near the main fault, with gold mineralization primarily occurring within a spatial range of approximately -80 meters to 20 meters from the main fault plane. This spatial distribution predominantly aligns in a SW-NE direction. Spatial characteristic extraction of fault slope indicators suggests that the slope angles are conducive to the migration and accumulation of ore-forming hydrothermal fluids, with ore body metal content rapidly increasing within an angle range of approximately 20° to 60°. The shape analysis of the mainfault indicates that the principal spaces of mineralization enrichment are within -10m to 20m of the fault plane undulations, where gold resources are concentrated in a relatively flat area. However, the degree of mineralization is more pronounced in the protruding sections than in the depressed areas. The areas with significant dip changes in faults display higher variations in orebody attitudes, with mineralization noticeably weaker in areas where the fault steepness changes markedly. Ore-bearing units exhibit significantly higher grades within the -17° to 3° interval of fault steepness transition. This interval also sees a rapid accumulation of gold resources. The Nibao gold mine's mineralization is derived from deep, ore-bearing hydrothermal fluids ascending along major fractures, precipitating, and accumulating in favorable ore-hosting spaces (faults, anticline cores) and lithological combinations (sedimentary tuffs, tuffs). Three deep potential gold targets were identified, highlighting the deep western edge of the F1 fault and the deep southeast-trending lower plate as prospective areas for future exploration. This study underscores the effectiveness of 3D prospective modeling as an indispensable tool for elucidating the spatial distribution of fault-controlled Carlin-type gold deposits and their tectonic determinants.

Precision metagenomic approaches using Oxford Nanopore Technology (ONT) sequencing has been shown to allow recovery of complete genomes of Escherichia coli O157:H7 from overnight enrichments of agricultural waters. This study tests the applicability of a similar approach for Cronobacter genome recovery from powdered infant formula (PIF) overnight enrichments, where Cronobacter typically dominates the overall microbiome (>90%). In this study, we aimed to test whether using ONT sequencing of overnight PIF enrichments could recover a completely closed Cronobacter genome for further genomic characterization. Ten PIF samples, each inoculated with different Cronobacter strains, covering Cronobacter sakazakii, C. muytjensii, C. dublinensis, C. turicensis, and C. universalis, were processed according to the Bacteriological Analytical Manual (BAM) protocol. qPCR was used for initial screening (detection and quantification) of the overnight enrichments and confirmed that the spiked PIF samples after the overnight enrichment have high levels of Cronobacter (107 to 109 CFU/mL). DNA from overnight PIF enrichments was extracted from the enrichment broth and sequenced using ONT. Results showed that ONT sequencing could accurately identify, characterize, and close the genomes of Cronobacter strains from overnight PIF enrichments in 3 days, much faster than the nearly two weeks required by the current BAM method. Complete genome recovery and species differentiation were achieved. This suggests that combining qPCR with ONT sequencing provides a rapid, cost-effective alternative for detecting and characterizing Cronobacter in PIF, enabling timely corrective actions during outbreaks.

The present grievous situation of the tuberculosis disease can be improved by efficient case management and timely follow-up evaluations. With the advent of digital technology this can be achieved by quick summarization of the patient-centric data. The aim of our study was to assess the effectiveness of the ODK Scan paper-to-digital system during testing period of three months. A sequential, explanatory mixed-method research approach was employed to elucidate technology use. Training, smartphones, application and 3G enabled SIMs were provided to the four field workers. At the beginning, baseline measures of the data management aspects were recorded and compared with endline measures to see the impact of ODK Scan. Additionally, at the end, users’ feedback was collected regarding app usability, user interface design and workflow changes. 122 patients’ records were retrieved from the server and analysed for quality. It was found that ODK Scan recognized 99.2% of multiple choice bubble responses and 79.4% of numerical digit responses correctly. However, the overall quality of the digital data was decreased in comparison to manually entered data. Using ODK Scan, a significant time reduction is observed in data aggregation and data transfer activities, however, data verification and form filling activities took more time. Interviews revealed that field workers saw value in using ODK Scan, however, they were more concerned about the time consuming aspects of the use of ODK Scan. Therefore, it is concluded that minimal disturbance in the existing workflow, continuous feedback and value additions are the important considerations for the implementing organization to ensure technology adoption and workflow improvements.

Iron (Fe) is co-factor for enzymes of the developing brain necessitating sufficient supply. We investigated the effects of administering ferric derisomaltose/Fe isomaltoside (FDI) subcutaneously to Fe deficient (ID) pregnant rats on cerebral and hepatic concentrations of essential metals and gene expression of ferroportin and hepcidin. Pregnant rats subjected to ID were injected with FDI on the day of mating (E0), 14 days into pregnancy (E14), or the day of birth (Postnatal (P0)). The efficacy was evaluated by determination of cerebral and hepatic Fe in pups on P0 and as adults on P70, and the concentration of copper (Cu) and zinc (Zn). Females fed an ID diet (5.2 mg/kg Fe) had offspring with significantly lower cerebral and hepatic Fe compared to female controls fed a standard diet (158 mg/kg Fe). Cerebral Cu increased irrespective of supplying a standard diet or administering FDI combined with the standard diet. Hepatic hepcidin was significantly lower following ID, whereas cerebral hepcidin was virtually undetectable in all experimental groups. In conclusion, administering FDI subcutaneously to ID pregnant rats on EO normalizes cerebral Fe in the fetus, but when applied at later gestational ages, additional Fe to the offspring is needed to normalize cerebral and hepatic Fe.

We evaluated the immunogenicity persistence of different immunization regimens of freeze-dried human rabies vaccine (Vero cells) in the 10–60 years age group of the Chinese population. Based on phase III clinical trials of Vero cells, participants who completed the full course of immunization were continuously enrolled in four-dose trial, five-dose, and five-dose control groups. Venous blood samples were collected 12 months after completion of the full immunization for rabies virus-neutralizing antibody (RVNA) testing, and the antibody-positive rate and geometric mean concentration (GMC) were calculated. Analysis of variance was used to compare three groups. The four-dose trial, five-dose trial, and five-dose control groups included 200, 186, and 214 participants, respectively. Twelve months after full immunization, the overall RVNA-positive rates were 97.00%, 93.55%, and 94.86% in the four-dose trial, five-dose control, and five-dose trial groups, respectively. The post-immunization RVNA GMCs values were 2.50, 2.05, and 2.04 IU/mL, respectively, with no statistically significant differences between them. Twelve months after full immunization, the overall RVNA-positive rate remained high, demonstrating satisfactory immunogenicity persistence for both immunization regimens.

Water samples for bacterial microbiome studies undergo a biomass concentration, DNA extraction and taxonomic identification steps. Through benchmarking, we studied the applicability of Skimmed milk flocculation (SMF) for bacterial enrichment, an adapted in-house DNA extraction protocol, and six 16S rRNA databases (16S-DBs). Surface water samples from two rivers were treated with SMF and Vacuum filtration (VF) and subjected to amplicon or shotgun metagenomics. A mock community standard underwent five DNA extraction protocols, taxonomical identification with six different 16S-DBs and evaluated by the Measurement Integrity Quotient (MIQ) score. In SMF samples, the skimmed milk was metabolized by members of lactic acid bacteria or genera such as Polaromonas, Macrococcus, and Agitococcus, resulting in increased relative abundance (p < 0.5) up to 5.0 log fold change compared to VF, rendering SMF inapplicable for bacterial microbiome studies. The best performing DNA extraction protocols were FastSpin Soil, the in-house method and EurX. All 16S-DBs yielded comparable MIQ scores within each DNA extraction kit, ranging from 61-66 (ZymoBIOMICs) up to 80-82 (FastSpin). DNA extraction kits exert more bias to the composition than the 16S-DBs. This benchmarking study presented valuable insights to inform future water metagenomic study designs.

The efficacy and safety of organic UV-filters could benefit from their incorporation into lipid nanoparticles because of the ability of such carriers to reflect solar radiations, thus acting synergically as physical sunscreens. In this work, bemotrizinol (BMTZ), a broad-spectrum UV-filter, was loaded into nanostructured lipid carriers (NLC) whose lipid matrix contained different oils to assess the effects of the lipid core composition on the properties of the resulting NLC. Subsequently, the effects of incorporating different concentrations of optimized BMTZ-loaded NLC on the technological properties of O/W emulsions (pH, viscosity, spreadability, occlusion factor, in vitro BMTZ release and skin permeation, in vitro sun protection factor) were assessed. Optimized BMTZ-loaded NLC showed mean size=190.6±9.8 nm, PDI=0.153±0.013, ζ-potential=-10.6±1.7 mV, loading capacity=8% w/w. The incorporation of increasing concentrations of optimized BMTZ-loaded into emulsions provided slight increase of spreadability, lower viscosity and no change of pH, occlusion factor and BMTZ release compared to the control. No BMTZ skin permeation was observed from all formulations. About 20% increase of sun protection factor values was obtained for vehicles containing BMTZ-loaded NLC. Therefore, BMTZ-loaded NLC incorporation into emulsions could be a promising strategy to develop safer and more effective sunscreen formulations.

The necessity for precise and current data concerning the dynamics of land cover change in Indonesia is crucial for efforts to reduce natural vegetation cover due to agricultural expansion. The functionality of monitoring systems that incorporate Terra-MODIS is currently compromised by the limited availability of data for the immediate future. This study seeks to assess the potential of VIIRS satellite imagery in developing an early warning system for monitoring vegetation cover change in Indonesia. The Normalized Differential Open Area Index (NDOAI) computed from the 8-day’ VIIRS data was employed to detect changes in vegetation cover based on pixel-by-pixel subtraction in the NDOAI data time series. Evaluating the pixel-level accuracy of change detection is complicated due to the fact that we evaluate a change map at a coarser resolution than the Landsat-based reference map. The results revealed that increasing the threshold percentage is associated with improved accuracy. In change detection, there is often a trade-off between accuracy and sensitivity. A threshold that is too low may result in false positives, while a threshold that is too high may lead to missed changes. This study demonstrates that when a threshold value of less than 20% is applied, Landsat can identify vegetation cover changes at an earlier stage. Conversely, when a threshold value greater than 20% is employed, VIIRS will detect the change 4.5 days earlier than Landsat. Additionally, VIIRS is capable of detecting changes 25.4 days and 54.8 days faster than Landsat, respectively, when using thresholds of 40% and 75%.

African swine fever virus (ASFV), a highly contagious pathogen characterized by a complex structure and a variety of immunosuppression proteins, causes hemorrhagic, acute, and aggressive infectious disease that severely injure the pork product and industry. However, there is no effective vaccine or treatment. The main reasons are not only the complex mechanisms that lead to immunosuppression, but also the unknown functions of various proteins. This review summarizes the interaction between ASFV and host immune system, along with the involvement of virulence related genes and proteins, as well as the corresponding molecular mechanism of immunosuppression of ASFV, encompassing pathways such as cGAS-STING, NF-κB, JAK/STAT, apoptosis, and other modulation. The aim is to summarize the dynamic process during the ASFV infection and entry into host cell, provide a rational insight into development of vaccine and a better clear knowledge of how ASFV impacts host.

Therapeutic Drug Monitoring (TDM) is potentially a useful tool that can be employed to increase the efficacy and decrease the toxicity of antifungal drugs. The aim of this narrative review is to provide an overview of the current use of TDM in clinical practice, and to present the evidence available regarding its use in proactive clinical settings for preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations in everyday practice. Articles concerning the use of TDM of triazoles in the treatment of fungal infections were retrieved through an electronic search using PubMed. In clinical practice, TDM has an increasingly important role in the management of antifungal drugs as a consequence of the improvement in the knowledge of the pharmacokinetics and pharmacodynamics of these drugs. The currently available evidence shows a direct exposure-response relationship for triazoles, though the PK/PD profile is unpredictable. Current guidelines and treatment consensus statements recommend the proactive TDM of voriconazole, posaconazole, and itraconazole to optimize dosage regimens and improve outcomes for adult and pediatric patients.

Oritavancin is a novel long-acting lipoglycopeptide with in vitro activity against methicillin-resistant (MR) Gram-positive pathogens and a good bactericidal activity even in presence of biofilm forming bacteria. It has been approved for acute bacterial skin and skin structure infections (ABSSSI), but recent reports have demonstrated possible off-label uses, as for prosthetic joint infections (PJI), which, in more than half of cases, are caused by MR Gram positive organisms. We reported a case of a man in his eighties with a late shoulder PJI caused by methicillin resistant Staphyloccus epidermidis (MRSE) with contraindications for surgical replacement and few oral therapeutic options for a long term suppressive antibiotic therapy. The prosthesis was retained, and the patient received ten outpatient sequential doses of 1200 mg of oritavancin during 28 weeks, based on therapeutic drug monitoring (TDM) as a guide for correct timing of administration of each dose. During oritavancin administration, the patient achieved clinical cure, with disappearance of the pain and regaining pre-infection joint mobility, with no side effects reported and no further surgery or hospitalization needed. The treatment is ongoing as a long-lasting suppressive antimicrobial therapy. Oritavancin could represent an excellent solution for treating PJI caused by MR organism, especially in patients who need a long-term suppressive therapy.

Glioblastoma (GBM) is the most common malignant primary brain tumor, with a median survival rate of less than two years. Currently, there is no cure for GBM, underscoring the urgent need for innovative treatment approaches. Vaccine design emerges as a crucial strategy, offering a safe and effective means for both preventive and therapeutic interventions against GBM. In this study, we targeted four GBM-associated mutated surface proteins—urokinase plasminogen activator sur-face receptor (PLAUR), integrin beta-3 (ITGB3), and the B-41 alpha chain (HLA-B) and A-24 alpha chain (HLA-A) of the HLA class I histocompatibility antigens—to design a peptide-based vaccine. The vaccine construct includes cytotoxic T lymphocyte (CTL) and T helper cell (Th cell) epitopes, and was meticulously evaluated for antigenicity, allergenicity, and toxicity. The results indicate that the vaccine is antigenic and non-allergenic, making it a promising candidate. Additionally, the physico-chemical properties of the vaccine suggest stability and suitability for further de-velopment. Immune simulation studies predict efficient immune responses upon vaccine ad-ministration. Our vaccine shows promise as a potential tool in the fight against GBM, offering new hope for patients facing this devastating disease.

Biopolymer gels have gained tremendous potential for therapeutic applications due to their biocompatibility, biodegradability, and ability to adsorb and bind biological fluids, making them attractive for drug delivery and therapy. The versatility of biopolymer gels in theranostic backgrounds, with a focus on integrating imaging features and facilitating real-time monitoring of drug delivery. Different methods of delivery are explored imaging agents into biopolymer gels, including encapsulation, surface functionalization, nanoparticle encapsulation and layer-by-layer assembly techniques. Integration of Agents and Real-Time Monitoring Drug Delivery We summarize the synthesis methods, general properties, and mechanisms of biopolymer gels functionality, demonstrating their broad applications as multimodal systems for imaging-based therapeutics. These techniques not only enable multiple imaging but also provide signal enhancement and imaging a targeted facilitates, increasing the diagnostic accuracy and therapeutic efficacy. In addition, current techniques for incorporating imaging agents into biopolymer gels are discussed, and their role in precise drug delivery and monitoring.

The knowledge in chemical composition of propolis is crucial for understanding the characteristics of products of different origin, but also for quality control and regulatory purposes. To date, offical monographs or official analyses that allow to evaluate propolis in a proper way have not yet been released. This study focuses on the characterization of twenty-seven Italian propolis and the identification of chemical markers that define its geographical provenance. Total polyphenol (TP) and total flavonoid (TF) content, alongside the quantification of pinocembrin, chrysin, galangin, and caffeic acid phenethyl ester (CAPE), were identified as as potential markers. Additionally, DPPH assays was conducted to evaluate antiradicalic activity of propolis samples. Our findings demonstrated that TP, TF and pinocembrin differed in propolis of different origin, especially in samples from the islands. However, the quantification of the sum of chrysin and galangin and CAP provided a clear distinction of the geographical origin of the propolis samples. In contrast, the DPPH assay did not prove useful for this purpose, as most results were similar and, therefore, not significant. This study lays the groundwork for future research on propolis. These findings could contribute to the development of more refined methods for distinguishing propolis origins, enhancing the understanding, valuation and quality control of this natural product in various applications.

Danyore Valley area is a new prospect of copper-gold mineralization in the Gilgit-Baltistan province, Kohistan terrane, northern Pakistan. The mineralization is Cu-Au vein-type, localized within quartz veins and controlled by a fracture system mainly trending NW and NE. The host units belong to the Ladakh-Kohistan arc terrane, which covers northern Pakistan and north-western India and mainly comprises Precambrian basement units, Paleozoic to Cenozoic magmatic rocks, and sedimentary strata. The mineralized wall rocks consist of Mesozoic gabbro and diorite, which have undergone an intensive hydrothermal alteration. The study area, Danyore Valley, has yet to be explored. The geological background and mineralization type in literature are scarce. Moreover, the tectonic setting, petrogenesis, age, and magmatic evolution of the gabbro-diorite hosting unit still need to be better understood. Furthermore, the sources of metals and mineralized fluids and the types of mineralization and alteration are also unexplored. This research's contribution presents the field investigation, microscopic observations, whole rock geochemistry (major, trace, and REE), mineral analysis (EPMA), in situ LA–ICP–MS zircon U–Pb age dating, and zircon trace elements data for Danyore Valley Cu-Au prospect of Kohistan Batholith. The current research work's objectives are to (a) constrain the emplacement ages of the Danyore Valley host rocks, (b) determine the petrogenesis and tectonic environment of the gabbro-diorite wall rocks, and (c) identify the mineralization style and alteration patterns of Cu-Au occurrences. The U-Pb isotopic data of studied zircons from Danyore Valley diorite specimens yielded concordia ages from 111.60 ± 0.90 Ma to 112.18 ± 0.74 Ma. Correspondingly, the gabbro rock sample displayed a concordia age of 110.21 ± 0.99 Ma, indicating the crystallization time of the host bodies is mainly the early cretaceous period (∼110 Ma). The findings of this study reveal that the calc-alkaline affinity and arc-like geochemical characteristics of the gabbro and diorite rocks have been characterized by a significant enrichment in large-ion lithophile elements and an apparent depletion in high-field strength elements. The parent magma probably originated from a partial melting process of mantle depletion, and geochemical traits are characteristic of magmas associated with subduction zones. The Danyore Valley area of Kohistan terrane is defined by the existence of several mineralized quartz veins, which are mainly sulfide assemblages. The sulfide ore is mainly comprised of chalcopyrite, pyrite, and bornite, with a smaller amount of covellite and sphalerite and significant traces of gold, which are distributed mainly in sulfides. Copper and gold mineralization of Danyore Valley is associated with phyllic, propylitic, and carbonatization alteration assemblages. Metal-rich quartz veins exhibit a spatial correlation with diorite and gabbro rocks. The discovery of several surface Cu-Au vein-type mineralized areas accompanying outcrops of copper supergene enrichment at the Danyore Valley prospect is significant evidence (predictor patterns) of porphyry-style deposits in the Gilgit district, Kohistan terrane, northern Pakistan. This work also advocates the importance of the Danyore Valley prospect and Kohistan Batholith region for further detailed geological studies.

Delivering nucleic acid therapeutics across cell membranes is a significant challenge. Cell-penetrating peptides (CPPs) containing arginine (R), tryptophan (W), and histidine (H) show promise for siRNA delivery. To improve siRNA delivery and silencing a model STAT3 gene, we hypothesized that oleyl acylation to CPPs, specifically (WRH)n, would enhance STAT3 silencing efficiency in breast and ovarian cancer cells. Using Fmoc/tBu solid-phase peptide chemistry, we synthesized, purified, and characterized the oleyl-conjugated (WRH)n (n = 1-4) peptides. The peptide:siRNA complexes were non-cytotoxic at N/P 40 (~20 μM) against MDA-MB-231, MCF-7, SK-OV-3, and HEK-293 cells after 72 h incubation. All peptide:siRNA complexes showed serum stability at N/P ≥40. The synthesized conjugates, with a diameter of <100 nm, formed nano complexes with siRNA and exhibited stable range of zeta potential values (13-18 mV at N/P 40). Confocal microscopy and flow cytometry analysis provided qualitative and quantitative evidence of successful cellular internalization of siRNA. Peptides oleyl-(WRH)3 and oleyl-(WRH)4 showed ~60% and ~75% cellular uptake of siRNA, respectively, in both MDA-MB-231 and SK-OV-3 cells. Western blot analysis of oleyl-(WRH)4 demonstrated effective silencing of the STAT-3 gene, with ~75% silencing in MDA-MB-231 cells and ~45% in SK-OV-3 cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and memory loss. Oxidative stress (OS) has emerged as a central element in the pathophysiology of AD, linking various pathological features including amyloid-β (Aβ) plaque formation, tau hyperphosphorylation, and synaptic dysfunction. This review comprehensively examines the role of OS in AD, focusing on the mechanisms of reactive oxygen species (ROS) production, mitochondrial dysfunction, and their impact on neuronal integrity. Additionally, the review highlights recent advances in antioxidant therapy. Elevated ROS levels in the aging brain exacerbate oxidative damage to lipids, proteins, and DNA, contributing to neuronal atrophy and synaptic loss. Mitochondrial dysfunction further amplifies OS, disrupting cellular energy metabolism and promoting neurodegeneration. Despite the strong association between OS and AD, antioxidant therapies have shown inconsistent clinical outcomes. Emerging strategies targeting offer promising avenues for therapeutic intervention. This review highlights the need for a multifaceted approach in understanding and mitigating OS-related damage in AD, aiming to pave the way for more effective treatments and improved patient outcomes.

To improve efficacy and safety of sunscreen emulsions, UV‐filter skin permeation could be kept as low as possible by reducing UV‐filter content or changing emulsion composition. In this work, different lipid phase ratio (12, 14 and 16% w/w) were assessed for their ability to affect the technological and sensory properties of O/W emulsions in which bemotrizinol (BMTZ), a broad spectrum sunscreen agent, was incorporated free or loaded into nanostructured lipid nanocarriers (NLC) to reduce its release from the vehicle and, hence, its skin permeation. The following technological properties were evaluated in vitro by suitable methodologies: spreadability, viscosity, pH, occlusion factor, BMTZ release, sun protection factor (SPF). Sensory attributes were assessed by trained panelists in three different phases: before/during pick‐up, rub‐in, after application. Raising the lipid phase ratio led to an increase of viscosity and to a corresponding drop of spreadability while the incorporation of BMTZ‐loaded NLC determined a decrease of occlusion factor and an increase of SPF. No BMTZ release was observed from all emulsions. Sensory attributes were mainly affected by lipid phase ratio. These results suggest that lipid phase ratio and BMTZ incorporation into NLC could contribute to determine technological and sensory properties of O/W emulsions.

Leukocyte migration is an essential function of innate and adaptive immune responses. Chemokines and their receptors control the migration system. The abundance of chemokines is controlled by atypical chemokine receptors (ACKRs), chemokine receptor-like molecules that do not couple to the G protein signaling pathways. Among them, ACKR4 regulates dendritic cell migration by controlling the ligands and is involved in tumor development in mouse models. Because no anti-mACKR4 mAb for flow cytometry has been reported, this study aimed to develop a novel monoclonal antibody (mAb) for mouse ACKR4 (mACKR4). Among the established anti-mACKR4 mAbs, A₄Mab-1 (rat IgG_2b, kappa), A₄Mab-2 (rat IgG_2b, kappa), and A₄Mab-3 (rat IgG_2b, kappa) recognized mACKR4-overexpressed Chinese hamster ovary-K1 (CHO/mACKR4) by flow cytometry. The dissociation constant (K_D) values of A₄Mab-1, A₄Mab-2, and A₄Mab-3 for CHO/mACKR4 were determined as 3.5 × 10⁻⁹ M, 6.0 × 10⁻⁹ M, and 1.6 × 10⁻⁹ M, respectively. Furthermore, A₄Mab-1 and A₄Mab-2 could detect mACKR4 by western blotting. These results indicated that A₄Mab-1, A₄Mab-2, and A₄Mab-3 help to detect mACKR4 by flow cytometry and western blotting and obtain the proof of concept in preclinical models.

Bladder cancer (BC) is one of the most lethal genitourinary malignancies owing to its propensity for recurrence and poor survival. The biochemical pathway, signal transducer and activator of transcription 3 (STAT3), has gained significance as a molecular pathway that promotes proliferation, invasion, and chemoresistance. In this study, we explored the targeting of STAT3 with TTI-101 and SH5-07 in bladder cancer (BCa) and elucidated the mechanisms in three-dimensional (3D) spheroid and tumoroid models. We optimized the growth of spheroids from human, rat, and mouse BCa cell lines (J82, NBT-II, and MB49, respectively), and tumoroids from BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine) induced rat bladder tumors. Cell viability was assessed using MTT and trypan blue assays. ATP production, ROS production, and calcium AM (CA)/EtBr staining were used to measure the spheroid and organoid inhibition and mitochondrial function. Western blot analysis was performed to evaluate the pharmacodynamic markers involved in cell proliferation, apoptosis, cancer stem cells (CSCs), and STAT3 signaling in BCa. We found that targeting STAT3 (using TTI-101 and SH5-07) significantly reduced the proliferation of BCa spheroids, and tumoroids, which was accompanied by decreased expression of pSTAT3, Cyclin D1, and PCNA. Our data also demonstrated that treatment with STAT3 inhibitors induced ROS production and cell death in BCa spheroids and organoids. STAT3 inhibition induced cell death was associated with the activation of caspase 3/7 and PARP cleavage. Moreover, TTI-101 and SH5-07 targets cancer stem cells by downregulating the expression of CD44 and CD133 in 3D models. This study provides the first evidence for the prevention of bladder cancer with small-molecule inhibitors TTI101 and SH5-07 via suppression of CSCs and STAT3 signaling.

Aging is the important risk factor for tumorigenesis. Metabolic reprogramming is hallmark of both aging and tumor initiation. However, how the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, termed as MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to depict age-related metabolic plasticity using pan-cancer bulk RNA-seq data. Through MMP3C analysis across 17 age-related cancer types, a high metabolic organized heterogeneity was found across those cancer types. Subsequent analysis revealed a higher degree of glycolysis and impaired oxidative phosphorylation in older patients. Similar phenomenon was also observed at the single cell resolution. Many energy generation pathways, i.e., TCA cycle, oxidative phosphorylation were weakened in activated T cells and macrophages, while it increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter the utilization of glucose, thereby influencing immune function and resulting in the remodeling of the tumor microenvironment. This study provides new insights into the associations between tumor metabolism and TME mediated by aging, linking with novel strategies for cancer therapy.

CD44 is a type I transmembrane glycoprotein, which is associated with poor prognosis in various solid tumors. Since CD44 plays critical roles in tumor development by regulating cell adhesion, survival, proliferation, and stemness, it has been considered a target for tumor therapy. Anti-CD44 monoclonal antibodies (mAbs) have been developed and applied to antibody-drug conjugates and chimeric antigen receptor-T cell therapy. We previously developed anti‐pan-CD44 mAbs, C₄₄Mab-5 and C₄₄Mab-46, which can recognize both CD44 standard (CD44s) and variant isoforms. In the present study, a defucosylated mouse IgG_2a version of the anti-pan-CD44 mAbs (5-mG_2a-f and C₄₄Mab-46-mG_2a-f) was generated to evaluate the antitumor activities against CD44-positive cells. Both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f recognized CD44s-overexpressed CHO-K1 (CHO/CD44s) cells and esophageal tumor cell line (KYSE770) in flow cytometry. Furthermore, both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could activate effector cells in the presence of CHO/CD44s cells and exhibited the complement‐dependent cytotoxicity against both CHO/CD44s and KYSE770 cells. Furthermore, the administration of 5-mG_2a-f and C₄₄Mab-46-mG_2a-f significantly suppressed CHO/CD44s and KYSE770 xenograft tumor development compared with the control defucosylated mouse IgG_2a. These results indicate that 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could exert antitumor activities against CD44-positive cancers and could be a promising therapeutic regimen for tumors.

One of the G protein-coupled receptors, C-C chemokine receptor 5 (CCR5), is an important regulator for the activation of T and B lymphocytes, dendritic cells, natural killer cells, and macrophages. Upon binding to the ligands, CCR5 activates downstream signaling, which plays critical roles in the innate and adaptive immune response through the promotion of lymphocyte migration and the secretion of pro-inflammatory cytokines. Anti-CCR5 monoclonal antibodies (mAbs) have been developed and evaluated in clinical trials for tumors and inflammatory diseases. In this study, we developed novel mAbs for mouse CCR5 (mCCR5) using the N-terminal peptide immunization. Among the established anti-mCCR5 mAbs, C₅Mab-4 (rat IgG_2a, kappa) and C₅Mab-8 (rat IgG₁, kappa), recognized mCCR5-overexpressed Chinese hamster ovary-K1 (CHO/mCCR5) and an endogenously mCCR5-expressing cell line (L1210) by flow cytometry. The dissociation constant (K_D) values of C₅Mab-4 and C₅Mab-8 for CHO/mCCR5 were determined as 3.5 × 10⁻⁸ M and 7.3 × 10⁻⁹ M, respectively. Furthermore, both C₅Mab-4 and C₅Mab-8 could detect mCCR5 by western blotting. These results indicated that C₅Mab-4 and C₅Mab-8 are useful for detecting mCCR5 by flow cytometry and western blotting and provide a possibility to obtain the proof of concept in preclinical studies.

The Tisza River is the longest tributary of the Danube, draining the eastern part of the Carpathian Basin (Central Europe). Five countries share its catchment with different waste production and management practices. Large amounts of waste, including macroplastics (MaPs), are washed into the river. Some of the litter is trapped by the riparian vegetation forming litter accumulations. The study aimed to map the amount of litter by a citizen science program and remote sensing data and to compare the MaP data to the amount of microplastic fragments in sediments. Volunteers reported 3216 riverine litter accumulations from five countries along the entire length of the Tisza (2016–2022). The results suggest that low flow conditions (e.g., impoundment by dams) support litter and MaP trapping. The volume of large accumulations registered by the citizens showed a good correlation with the area of drifting litter revealed on Sentinel-2 images (2015–2021) using machine learning algorithms. Though the MaPs probably fragmentate during their fluvial transport, no clear connection was found between the volume of litter accumulations and the mean microplastic fragment content of sediments (2019–2022). The “Clean Tisza Map“ reveals the high degree of stranded pollutants along rivers and supports public cleanup activities.

C-C motif chemokine receptor-8 (CCR8) belongs to class A of G protein-coupled receptors (GPCRs). CCR8 interacts with the specific chemokine ligand CCL1/I-309 in humans, which is produced by various cells, including tumor-associated macrophages and regulatory T cells (Treg). CCR8 is highly expressed on Treg and T-helper 2 (T_H2) cells recruited to the inflammation site and is implicated in allergy, asthma, and cancer progression. The CCR8⁺Treg has been suggested to be an important regulator in the immunosuppressive tumor microenvironment (TME); therefore, it has been desired to develop sensitive monoclonal antibodies (mAbs) for CCR8. This study developed a specific mAb for human CCR8 (hCCR8), which is useful for flow cytometry by employing the Cell-Based Immunization and Screening (CBIS) method. The established anti-hCCR8 mAb, C₈Mab-21, (mouse IgM, kappa) reacted with hCCR8-overexpressed Chinese hamster ovary-K1 (CHO/hCCR8) cells, TALL-1 (acute T lymphoblastic leukemia), CCRF-HSB2 (human T-lymphoblastic leukemia), and natural killer cells, which express endogenous hCCR8 by flow cytometry. Furthermore, C₈Mab-21 demonstrated a moderate binding affinity for CHO/hCCR8 and TALL-1 with a dissociation constant of 6.5×10^-8 M and 2.0×10^-8 M, respectively. C₈Mab-21, which was established by the CBIS method, could be a useful tool for analyzing the hCCR8-related biological response using flow cytometry.

This manuscript explores significant advancements and emerging challenges in CAR T cell therapies, focusing on the production methodologies and regulatory complexities. The discussion highlights ongoing challenges like the lack of in vivo persistence, lengthy production times, and elevated costs associated with current CAR T cell therapies. It analyzes innovative solutions such as genetic engineering techniques aimed at enhancing cellular efficacy and endurance, alongside cutting-edge manufacturing processes, including closed systems and development of allogeneic products. These advancements hold promise for reducing costs and improving production efficiency, potentially increasing patient access to these transformative therapies globally. Furthermore, the manuscript underscores the necessity for expanding ongoing research and enhancing regulatory frameworks to fully realize and implement these innovations in CAR T cell manufacturing and bring these innovations to fruition.

Malaria parasites increase their host erythrocyte’s permeability to obtain essential nutrients from plasma and facilitate intracellular growth. In the human P. falciparum pathogen, this increase is mediated by the plasmodial surface anion channel (PSAC) and has been linked to CLAG3, as encoded by one member of the conserved clag multigene family. Whether paralogs encoded by other clag genes also contribute to PSAC formation or serve unrelated roles remains unknown. Here, we generated transfectant lines carrying epitope-tagged versions of each CLAG. Each paralog colocalized with CLAG3, with concordant trafficking via merozoite rhoptries to the host erythrocyte membrane of newly-invaded erythrocytes. Each also exists within infected cells in at least two forms: an alkaline-extractable soluble form and a form integral to the host membrane. Like CLAG3, CLAG2 has a variant region cleaved by extracellular protease but CLAG8 and CLAG9 are protease-resistant. Paralog knockout lines, generated through CRISPR/Cas9 transfection, exhibited uncompromised growth in PGIM, a modified medium with more physiological nutrient levels; this finding is in marked contrast to a recently reported CLAG3 knockout parasite. CLAG2 and CLAG8 knockout lines exhibited compensatory increases in transcription of remaining clags and associated rhoph genes, yielding increased PSAC-mediated uptake to specific solutes. We also report distinct transport properties of these knockout lines, suggesting partially overlapping roles of CLAG paralogs in PSAC activity. We propose that the nutrient channel pore is formed by a higher order assembly of CLAG proteins at the host membrane.

Public perception contrasts scientific findings on the depression-related effects of cannabis. However, earlier studies were performed when cannabis was predominantly illegal, its production was mostly uncontrolled, and the idea of medical cannabis was incipient only. We hypothesized that recent changes in attitudes and legislations may have favorably affected research. In addition, publication bias against cannabis may have also decreased. To investigate this hypothesis, we conducted a systematic review of research studies published over the last three years. We found 156 relevant studies. In most cross-sectional studies, depression was higher in those who consumed cannabis than in those who did not. An increase in cannabis consumption was typically followed by an increase in depression, whereas withdrawal from cannabis ameliorated depression in most cases. Albeit medical cannabis reduced depression in most studies, none of these were placebo controlled. In clinical studies published in the same period, placebo also ameliorated depression and in addition, the average effect size of placebo was larger than the average effect size of medical cannabis. We also investigated the plausibility of the antidepressant effects of cannabis by reviewing molecular and pharmacological studies. Taken together, the reviewed findings do not support the antidepressant effects of herbal cannabis.

Crop production in Afghanistan suffers from limited phosphorus (P) availability, which severely hinders national agriculture sustainability. This present study hypothesized that deep fertilizer placement could significantly enhance uptake of immobile P and thus tissue P accumulation and crop yield. A two-year pot experiment growing two maize (Zea mays) hybrid cultivars (Xida-789 and Xida-211) was therefore conducted to test these hypotheses under three contrasting fertilizer placement methods (broadcast, side band, and deep band). In doing so, P concentrations in both maize tissues and soils were compared at 45, 60, and 115 days after sowing (DAS) under nine combinations of nitrogen (N) and P fertilizer rates (kg ha-1: N112P45, N112P60, N112P75, N150P45, N150P60, N150P75, N187P45, N187P60, N187P75). Results have shown that deep band placement significantly increased P uptake efficiency, leading to greater P concentration and accumulation in maize tissues compared to other two fertilization methods. This improved P uptake was attributed to several factors associated with deep placement, including reduced P fixation, enhanced root access to P, and moisture availability for P uptake. Additionally, deep band placement combined with higher N application rates (N187 and N150) further enhanced plant P uptake by promoting P availability and utilization mechanisms. Deep band placement also resulted in significantly higher total soil P, Olsen-P, and P use efficiency than broadcast and side band methods, indicating a more efficient P fertilization strategy for maize that can improve growth and yield. This present study also found positive correlations between P concentration in plant organs and soil Olsen-P, highlighting the importance of adequate soil P levels for optimal plant growth. Overall, our results have showed that deep band fertilizer placement emerged as a superior strategy for enhancing P uptake efficiency, utilization, and maize productivity compared to broadcast and side band placement. This approach can potentially optimize P fertilizer utilization, improve maize growth and yield, while minimizing environmental P losses associated with broadcast applications.

As the world population grows, fulfilling the need for biomaterials in the healthcare system becomes increasingly important. Biomaterials, which include metals, polymers, ceramics, and composites, play an important role in the creation of medical devices that improve people's lives. The European Society for Biomaterials described biomaterials as non-biological materials used in medical devices to interact with biological systems. This definition has developed to encompass materials that treat, assess, or replace tissues or bodily functions. Biocompatibility, as defined by the FDA, is a key feature of biomaterials, as is the requirement to fulfil design requirements such as mechanical performance, geometry, and electrical control. Over the last decade, advances in regenerative medicine and tissue engineering have boosted biomaterials' usage in medical applications dramatically. Despite its promise, scientists, engineers, and physicians continue to face significant challenges due to the complexity of biomaterials. Biomaterials have various benefits, including biodegradability, non-toxicity, and biocompatibility, making them extremely useful for replacing, sustaining, or improving biological activities in damaged tissues. They are used in a wide range of applications, including tissue engineering implants, human tissue healing and regeneration, medication delivery systems, and biosensors. This study gives insights into the fundamental characteristics, case studies, and ethical issues associated with the usage and use of biomaterials, further examining their potential and significance in healthcare and medicine.

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy of AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with the potential for the treatment of AD. Previously, we demonstrated that TBN markedly improved cognitive functions and reduced Aβ, APP, BACE 1 and hyperphosphorylated tau levels in 3 × Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition still unclear. In this study, we employed the APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN on the Aβ reduction. Our results indicated that TBN significantly alleviated cognitive impairment and reduced Aβ depositions in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway and inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, as well as decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely via reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a specific subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1's mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was safe and well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is safe and well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

Carbon nanodots (CNDs) have garnered significant attention as viable drug delivery vehicles in recent years, especially in the field of phytomedicine. Although there is much promise for therapeutic applications with phytomedicine, its effectiveness is frequently restricted by its low solubility, stability, and bioavailability. This paper offers a thorough synopsis of the developing field of phytomedicine drug delivery based on CND. It explores CND synthesis processes, surface functionalization strategies, and structural and optical characteristics. Additionally, the advantages and difficulties of phytomedicine are examined, with a focus on the contribution of drug delivery methods to the increased effectiveness of phytomedicine. The applications of CNDs in drug delivery are also included in the review, along with the mechanisms that underlie their improved drug delivery capabilities. Additionally, it looks at controlled release methods, stability augmentation, and phytomedicine loading tactics onto CNDs. The potential of polymeric carbon nanodots in drug delivery is also covered, along with difficulties and prospective directions going forward, such as resolving toxicity and biocompatibility issues. In summary, the present review highlights the encouraging contribution of CNDs to the field of drug delivery, specifically in enhancing the potential of phytomedicine for therapeutic purposes.

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing the adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2)monoclonal antibody (mAb), H₂Mab-250/H₂CasMab-2. In flow cytometry and immunohistochemistry, H₂Mab-250 reacted with HER2-positive breast cancer cells but did not show the reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG₁ version of H₂Mab-250 (H₂Mab-250-hG₁) possesses compatible in vivo antitumor effects against breast cancer xenografts with trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H₂Mab-250-hG₁ and trastuzumab. Both H₂Mab-250-hG₁ and trastuzumab showed ADCC activity against CHO/HER2 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed that trastuzumab showed a more significant ADCC effect compared to H₂Mab-250-hG₁. Importantly, H₂Mab-250-hG₁ exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in mouse IgG_2a types of both H₂Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H₂Mab-250-hG₁ and trastuzumab and indicate the future direction for the clinical development of H₂Mab-250-hG₁ against HER2-positive tumors.

Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles derivatives as potent FGFR inhibitors. Compound 10a was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that compound 13a is the most potent FGFR1 inhibitor in this series with the enzyme inhibitory activity about 30.2 nM of IC50 value.

Ammonium sulfate has been utilized in agriculture; however, there is a dearth of research on its application in maize cultivation subsequent to the implementation of nitrification inhibitors or coating. This study aims to analyze the impacts of various combinations of ammonium sulfate fertilizers on soil nutrients, plant nutrient uptake, yield, and fertilizer utilization efficiency in maize cultivation to ascertain the optimal and stabilized disposal method for ammonium sulfate. A completely randomized design was employed with five treatments (AU, the control using urea; AS, treatment using ammonium sulfate; ASN, treatment using ammonium sulfate with a nitrification inhibitor; ASG, treatment using oil-coated ammonium sulfate; ASD, treatment using oil-humic acid-coated ammonium sulfate). Results showed that: (1) Compared with AU and AS, ASN, ASG and ASD decreased the leaching rates of TN, NH4+-N and NO3-N to the 10-20 cm soil layer, and more residual N was obtained in 0-10 cm soil layer. The first-order kinetic equation Nt=N0(1-e-kt) can better fit the process of nitrogen accumulation and release, and the N release rate constant is AU>CK>AS>ASH>ASN>ASD; (2) Compared with AU and AS treatments, the plant dry weight, grain dry weight, spike width, spike length, and yields of maize increased by 8.85-11.08%, 12.98-14.15%, 2.95-3.52%, 5.50-5.65%, and 43.21-51.10% under ASG treatment respectively. The impact of effective spike number on maize yield was found to be significant, as demonstrated by the path analysis conducted in this study. Furthermore, the accumulation levels of nitrogen, phosphorus, and potassium within above-ground plants significantly increased under the ASG treatment compared to the AU and AS treatments. The partial productivity of nitrogen, phosphorus, and potassium increased by 1.43-1.51-fold under ASG treatment, while grain nitrogen balance, grain phosphorus balance, and grain potassium balance increased by 1.41-1.58-fold, 1.51-1.95-fold, and 1.15-l.96-fold respectively. The oil-coated ammonium sulfate, therefore, exhibited the optimal slow-release effect of nutrients, thereby achieving superior performance in enhancing maize production and efficiency.

The clinical practice implies a research translation that helps the use of scientific data and thera-peutic evidence for patient benefits. This review critically summarizes the potential impact of cannabinoids in concomitance with other drugs in the following chronic diseases as Epilepsy, Au-tism Spectrum Disorders (ASD), Oncology, Multiple Sclerosis, and Chronic Pain. The potential in-teractions can change the predicted clinical outcomes of therapeutic protocols and need to be evaluated. Some of the effects would be additive, synergistic or antagonistic, but can also enroll changes in absorption, distribution, metabolism, particularly via cytochrome P450 (CYP) isoen-zymes (e.g CYP2C9 and CYP3A4) and excretion. For instance, the combination of canna-bis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, increases plasma concentration of Δ-9-tetrahydrocannabinol (THC) and CBD (CBD). Opposable, rifampic-in, a CYP3A4 inducer, stands out for the approximately 20-40% reduction in plasma THC levels and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Indeed, pharmacokinetic interactions have been also reported with antiseizure drugs. Moreover, pharmacodynamic interactions between cannabinoids and drugs with sympathomimetic effects (eg tachycardia, hypertension), central nervous system depressants (eg drowsiness, ataxia), and anticholinergics (eg tachycardia and drowsiness) are also expected. Even though pending further studies, there is currently clinical evidence supporting drug interaction with cannabinoids, demanding doctors evaluate the risk of drug combinations with cannabinoids. The tables herein provided were designed to facilitate the identification of bi-orelevant interactions that may compromise therapeutic efficacy and toxicity.

This paper is aimed at studying the temporal evolution of the surface displacements occurred over the past few years in the ocean-reclaimed platforms of the Shanghai megacity (China), which are mainly ascribable to consolidation processes of large dredger fills and alluvial deposits. With respect to previous analyses carried out over the same area, this work provides a joint multi-platform differential interferometry synthetic aperture radar (DInSAR) analysis, based on the application of the advanced Small BAseline Subset (SBAS) algorithm. This led us to retrieve long-term deformation time-series that are helpful for a better understanding of the on-going deformation phenomena. To this aim, we have exploited two sequences of SAR data collected by the ASAR/ENVISAT and by the COSMO-SkyMed (CSK) sensors, respectively, spanning the whole time period from 2007 to 2016. Unfortunately, the large time gap (of about three years) existing between the available ASAR/ENVISAT and CSK datasets gave rise to additional difficulties for their combination. Nevertheless, this problem has been faced by benefiting from the knowledge of a time-dependent model describing the temporal evolution of the expected deformations affecting the Shanghai ocean-reclaimed platforms.

Objectives: The aim of this study was to assess the knowledge, attitude and practice of healthcare professionals regarding adverse drug reaction [ADR] monitoring and pharmacovigilance [PV] in India. Materials and Methods: It was a questionnaire based cross sectional observational study. Data was collected with the help of data collection Google form that included the demographics and twenty two survey based questions. Data were analysed by using Microsoft Excel sheet, further analysed for results, including frequency, percentage, mean and standard deviation. Result: The questionnaire was filled by two hundred ten healthcare professionals in which 52.9 % were male and 47.10% of female. Most of the respondents were pharm d students (50.47%). Out of the total 91.4% responded to the definition of pharmacovigilance correctly. 87.6% participants said all ADR should be reported. 86.20% participants think Pharmacovigilance should be taught in detail to healthcare professionals. Most of the respondents (43.8%) always informed the patients about ADR while prescribing the medicines. Conclusion: Study revealed most of the participants have good knowledge about ADR and pharmacovigilance. Difficult to decide whether ADR occur or not and extra work load being major factors responsible for under reporting.

The main proteinase (Mpro), or 3CLpro, is a critical enzyme in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lifecycle and is responsible for breaking down and releasing vital functional viral proteins crucial for virus development and transmission. As a catalytically active dimer, its dimerization interface has become an attractive target for antiviral drug development. Recent research has extensively investigated the enzymatic activity of Mpro, focusing on its role in regulating the coronavirus replication complex and its significance in virus maturation and infectivity. Computational investigations have identified four druggable pockets, suggesting potential allosteric sites beyond the substrate-binding region. Empirical validation through site-directed alanine mutagenesis targeted residues in both the active and allosteric regions corroborated these predictions. Structural studies of drug target proteins can inform therapeutic approaches, with metadynamics simulations shedding light on the role of H163 in regulating Mpro function and providing insights into its dynamic equilibrium to the wild-type enzyme. Despite the efficacy of vaccines and drugs in mitigating SARS-CoV-2 spread, ongoing viral evolution, selective pressures, and continued transmission pose challenges, potentially leading to resistance mutations. Phylogenetic analyses indicated the existence of several resistance variations predating drug introduction to the human population, emphasizing the likelihood of drug spread. Hydrogen/deuterium-exchange mass spectrometry reveals the structural influence of the mutation, while clinical trials on 3CLPro inhibitors underscore the clinical significance of reduced enzymatic activity and offer avenues for future therapeutic exploration. Understanding the implications of 3CLPro mutations holds promise for shaping forthcoming therapeutic strategies against COVID-19. This review delves into factors influencing mutation rates and identifies areas warranting further investigation, providing a comprehensive overview of Mpro mutations, their categorization, and terminology. Moreover, we examined their associations with clinical outcomes, illness severity, unresolved issues, and future research prospects, including their impact on vaccine efficacy and potential therapeutic targeting.

With increasing numbers of older adults worldwide, multimorbidity and polypharmacy are on the rise, highlighting the risks of harmful drug-drug interactions (DDIs) to patients. As cardiovascular agents are among the most prescribed medications, we performed an observational cross-sectional study to determine the prevalence of DDIs in a cardiology department of a secondary hospital. Patient data was obtained from medical records and screened for DDIs using the Micromedex drug interaction software. Descriptive statistics, Chi-square (χ2) test, Student's t test and Pearson's correlation test were used to analyse the results. Out of 50 participants, 45 (90%) had at least one DDI. A total of 266 DDIs were identified, with more than half classified as major. At least one major DDI was found in 78% of patients. 42% of patients were at an increased risk of bleeding due to DDIs. A statistically significant relationship was found between the detection of DDIs and both patient age (p = 0.005) and the number of drugs used (p < 0.001). Our findings pose questions about the wider prevalence and risks of drug-drug interactions among patients with cardiovascular disease.

Search for the new non-invasive methods of investigating the functioning of human internal organs is an urgent task. One of these methods for assessing the functioning of the human res-piratory system is electromagnetic sensing, based on a significant difference in the dielectric permittivity of muscle tissue and air. During breathing, when the lungs are filled with air, the dielectric permittivity of the lungs decreases, which leads to a change in the level of the elec-tromagnetic signal passing through the body. Results of experiments on recording changes in the level of electromagnetic radiation passing through the human body, performed on an experimental device consisting of eight transmitting and receiving antennas located on opposite sides of the chest have been presented in the article. The possibility of visualizing the measured “pulmonograms” in the form of dynamic two-dimensional images showing the process of filling various parts of the lungs with air has been demonstrated.

Plants significantly shape root-associated microbiota, making rhizosphere microbes useful environmental indicator organisms for safety assessment. Here, we report the pyrosequencing of the bacterial 16S ribosomal RNA in rhizosphere soil samples collected from transgenic cry1Ab/cry1Ac Bt rice Huahui No. 1 (GM crop) and its parental counterpart, Minghui63. We identified a total of 2,579 quantifiable bacterial operational taxonomic units (OTUs). Many treatment-enriched microbial OTUs were identified, including 14 NonGM-enriched OTUs and 10 GM-enriched OTUs. The rhizosphere microbiota communities were influenced more strongly by growth in the field than by rice varieties. Furthermore, Huahui No. 1 transgenic Bt rice had a greater impact on the rhizosphere bacterial communities than Minghui63. Early developmental stages of the transgenic Bt rice had a significant impact on many Bacillaceae communities. While soil chemical properties were not significantly altered by the presence of transgenic Bt rice, we found peak expression level of Bt proteins during the seedling stage, which may be an intriguing factor for bacterial diversity variations. Based on these findings, we conclude that transgenic Bt rice has a significant impact on root-associated bacteria. This information may be leveraged in future environmental safety assessments of transgenic Bt rice varieties.

We have designed cell penetrating peptides that target the leucine zipper transcription factors ATF5, CE-BPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. While such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell-context-dependent manner (in about 2/3 of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell-context-dependent manner that in turn sup-presses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.

Leakage is important in groundwater cycle research and water resource management, the key is to construct the spatial distribution of aquitard. Influenced by natural and anthropogenic factors, the density of boreholes restricts the accuracy of aquitard structure. This paper explores the K-Nearest Neighbor (KNN) method to construct multi-layer aquitard structure in the hinterland of Songnen Plain, Northeast China, with limited boreholes, and compare it with Inverse Distance Weight (IDW) and Ordinary Kriging (OK) methods to evaluate the leakage. The KNN needs to first identify the eigenvalue-k of each layer, which is used to enhance the trainset to obtain the testset with a larger amount of sample data enhanced, and to make a prediction to obtain the 3-dimensional structure of aquitard. KNN is more accurate than the IDW and OK. The aquitrad structure obtained by the KNN is different from the IDW and OK, the thickness difference is 3.53%-54.00%, the area difference is 2.28%-23.91%, and the difference in leakage can be up to 24.51%. KNN also has a high degree of identification of aquitard edges, which can help the prevention of groundwater pollution. The results provide guidance for water balance analysis, borehole engineering design, water resources management and exploitation.

EphB2 is a member of the Eph family tyrosine kinase receptors. EphB2 binds to ephrin-B1, ephrin-B2, and ephrin-B3, which are critical regulators of vascular and nervous development through controlling cell migration and axon guidance. EphB2 is overexpressed in tumors, including glioma, breast cancer, hepatocellular carcinoma, and malignant mesothelioma, and it functions as a tumor promoter. Therefore, the development of monoclonal antibodies (mAbs) against EphB2 is essential for tumor diagnosis and therapy for EphB2-positive tumors. In this study, we developed novel mAbs for human EphB2 using the Cell-Based Immunization and Screening (CBIS) method. One of the established anti-EphB2 mAbs, Eb2Mab-3 (mouse IgG1, kappa), reacted with EphB2-overexpressed Chinese hamster ovary-K1 (CHO/EphB2) and an endogenously EphB2-expressing cancer cell line (LS174T) by flow cytometry. Using flow cytometry, the dissociation constant (KD) values of Eb2Mab-3 for CHO/EphB2 and LS174T were determined as 1.1 × 10−9 M and 3.6 × 10−10 M, respectively. These results indicated that Eb2Mab-3 possesses a high affinity for detecting EphB2 and could apply to tumor therapy.

Background: In treatment-refractory cancers, tumor tissues damaged by therapy initiate the repair response; therefore, tumor tissues must be exposed to an additional burden before successful repair. We hypothesized that an agent recognizing a molecule that responds to anticancer treatment–induced tissue injury could deliver an additional antitumor agent including a radionuclide to damaged cancer tissues during repair. We selected the extracellular matrix glycoprotein tenascin-C (TNC) as such a molecule, and three antibodies recognizing human and murine TNC were employed to evaluate X-irradiation–induced changes in TNC uptake by subcutaneous tumors. Methods: TNC expression was assessed by immunohistochemical staining of BxPC-3 tumors treated with or without X-irradiation (30 Gy) for 7 days. Antibodies against TNC (3-6, 12-2-7, TDEAR) and a control antibody were radiolabeled with 111In and injected into nude mice having BxPC-3 tumors 7 days after X-irradiation, and temporal uptake was monitored for an additional 4 days by biodistribution and single-photon emission computed tomography with computed tomography (SPECT/CT) studies. Intratumoral distribution was analyzed by autoradiography. Results: The immunohistochemical signal for TNC expression was faint in nontreated tumors but increased and expanded with time until day 7 after X-irradiation. Biodistribution studies revealed increased tumor uptake of all three 111In-labeled antibodies and the control antibody. However, a statistically significant increase in uptake was evident only for 111In-labeled 3-6 (35%ID/g for 30 Gy vs. 15%ID/g for 0 Gy at day 1, P < 0.01; ID, injected dose), whereas limited changes in 111In-labeled TDEAR2, 12-2-27, and control antibody were observed (several %ID/g for 0 and 30 Gy). Serial SPECT/CT imaging with 111In-labeled 3-6 or control antibody provided consistent results. Autoradiography revealed noticeably stronger signals in irradiated tumors injected with 111In-labeled 3-6 compared with each of nonirradiated tumors and the control antibody. The signals were observed in TNC-expressing stroma. Conclusion: Markedly increased uptake of 111In-labeled 3-6 in irradiated tumors supports our concept that an agent, such as an antibody, that recognizes a molecule, such as TNC, involved in tissue-injury repair could enhance drug delivery to therapy-experienced tumor tissues. The combination of antibody 3-6 coupled to a tumoricidal drug and conventional therapy has the potential to achieve better outcomes for patients with refractory cancer.

Pomegranate extract has potential benefits for women's reproductive health, including fertility enhancement, menstrual cycle regulation, pregnancy support, and polycystic ovary syndrome (PCOS) treatment. It possesses antioxidant properties, reducing oxidative stress and improving fertility. Phytoestrogens in pomegranate extract may help regulate hormonal imbalances and promote regular menstrual cycles. The extract's rich nutrient profile supports placental development and fetal growth and may reduce the risk of preterm birth. Additionally, pomegranate extract shows promise in improving insulin sensitivity and reducing inflammation and oxidative damage in PCOS. Some studies suggest its potential anticancer properties, particularly against breast cancer. However, further research, including human clinical trials, is necessary to establish its effectiveness and safety. The current evidence is limited and primarily based on in vitro studies, animal studies, and clinical trials. This review provides a comprehensive summary of the benefits of pomegranate extract for women's reproductive health and breast cancer, serving as a reference for future research.

Berberine (BER) is a natural alkaloid found in various Berberis species, used traditionally in herbal medicine and dietary supplements. BER exhibited various biological activities, including anti-inflammatory, antioxidant, antidiabetic, and anti-tumour properties by modulating cellular pathways and influencing gene expression. While BER shows promise in various health applications, its possible toxicity raises concerns. In 2023, EFSA issued a call for data on BER- and protoberberine (PROTBER)-containing products, to comprehensively assess its safety and potential health claims. With these premises, new data was collected by assessing: i) the phytochemical profile of BER- and PROTBER-containing preparations by newly developed HPLC-DAD method; ii) in silico and in vitro investigation of pharmacokinetics properties of BER; iii) in vitro cytotoxicity in different human cell lines and, iv) biological and molecular activities of extracts containing BER and PROTBER in in vitro human non-cancer cells. By testing 16 commercial Berberis extracts, the evidence collected showed a good qualitative reliability in terms of phytochemical profile and limited relapses on cytotoxicity even at 200 µg/ml after a 24h of exposure, while evidencing a good cellular bioavailability and cell migration inhibition. The potential for plant-drug interactions affecting CYP450 proved to be minimal. Overall, our work provides a useful overview to better elucidate potential concerns on botanicals containing BER and minor PROTBER commonly used in food supplement.

Diabetes is a major health concern that the next-generation of on-demand insulin releasing implants may overcome for personalized therapy. Therein, 3D-printed phenylboronic acid-containing subcutaneous implants with on-demand glucose-triggered drug release abilities are produced using high resolution stereolithography technology. To that end, the methacrylation of phenylboronic acid is targeted following a two-step reaction. The resulting photocurable phenylboronic acid derivative is accordingly incorporated within bioinert polyhydroxyethyl methacrylate-based hydrogels at varying loadings. The end result are sub-centimeter scaled 3D-printed bionert implants that can be remotely activated with 1,2-diols and 1,3-diols such as glucose for on-demand drug administration such as insulin. As a proof of concept, varying glucose concentration from hypoglycemia to hyperglycemia levels readily allow the release of pinacol, i.e. a model molecule with similar release properties than insulin, at respectively low and high rates. In addition, the results demonstrated that adjusting the geometry and size of the 3D-printed part is a simple and suitable method for tailoring the release behavior and dosage.

Microalgae are photosynthetic microorganism able to receive light from sunlight and external light sources for their growth. Despite the simplicity of cultivation and their widespread presence, the growth of microalgae is affected by several factors, light intensity being a crucial one as it is linked to external environmental conditions. On the other hand, microalgae cultivation in wastewater with high nitrogen content has become a promising alternative as a low cost nutrients substrate method. However, effluents may contain many compounds, making therefore difficult the assessment of light intensity on cells growth profile and especially on nutrients assimilation rate. The aim of this study was the examination of the effect of intensity of light source on the growth and nutrient uptake rates by a freshwater microalgae, Chlorella sorokiniana in the effluent from an anaerobic digestion plant, with nitrogen content reaching up to 5 g/L. Microalgae were cultivated using three light intensities (1,500, 5,000 and 12,000 lx) in 10% digestate mixtures in water. Samples were collected and analyzed for the presence of microalgae cells, while aqueous phase samples were subjected to the analysis of nitrogen and phosphorous content. Biomass productivity followed the light intensity pattern: the highest the light the highest the cells growth. A similar pattern was observed in the reduction rate of nitrogen and phosphorous concentrations; however, nutrients reduction rate per gram of microalgae were mainly associated to biomass growth rate, indicating that the effect of light intensity was significant for biomass growth, without however changing the main nutrients assimilation pathway. In addition, results indicated that under high light intensity, microalgae might change their metabolism towards formation of lipids against nitrogenous compounds.

Polyelectrolyte-drug complexes are interesting alternatives to improve unfavourable drugs properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use as inhalable formulations. Particulate-solid HA-VAN25 complex by spray drying from an aqueous dispersion was obtained. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern by X-ray was observed. The powder density, geometric size and morphology showed a suitable aerosolization and aerodynamic performance of the powder, indicating the capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 hours. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus, showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

Accurately predicting drug-drug interactions (DDIs) is crucial for preventing adverse drug events in clinical settings. However, existing methodologies often rely on complex models built from diverse data sources, posing challenges in computational drug discovery. To address the need for precise computational methods in predicting unknown DDIs, this study introduces a novel Deep Neural Network (DNN)-based approach. By leveraging a wide range of drug-related information, including substructure, targets, side effects, pathways, and indications, our method calculates multiple drug similarities. These similarities are then synthesized using a nonlinear fusion method to extract high-level features. Subsequently, a tailored neural network is deployed for interaction prediction. Comparative evaluation against three prominent machine learning classifiers—Extreme Gradient Boosting (XGBoost), Adaptive Gradient Boosting (AdaBoost), and Light Gradient-Boosting Machine (LGBM)—using three benchmark datasets demonstrates the superior performance of DNN. It achieves outstanding accuracy, precision, recall, and F1-score metrics, all reaching 94.6% in cross-validation. Additionally, case studies involving numerous drug pairs confirm the reliability of DNN in accurately predicting unknown DDIs. These findings underscore DNN as a potent and reliable method for DDI prediction, with promising implications for drug discovery and healthcare applications.

:Peat substrate is made from peat from drained peatlands, which is a limited resource. A realistic estimate is that 50% of the world’s wetlands have been lost. Peat is used in horticulture, especially for the cultivation of vegetables in greenhouses. The consequences of peatland exploitation are an in-crease in the greenhouse effect and a decrease in carbon stocks. Wood fiber can be used as an al-ternative to peat. The chemical properties of the growing media interact and change continuously due to the small volume of the growing media, which is limited by the growing container. This study aims to gain new knowledge on the impact of nutrient changes in the microbial degradation of carbon compounds in wood fiber and mixtures with peat substrate on the content and uptake of nutrients required by plants. Cucumbers (Cucumis sativus L.) variety “Dirigent H” developed in the Netherlands, were cultivated in growing media of peat substrate and wood fiber: (1) peat substrate (PS); (2) wood fiber (WF); (3) wood fiber and peat substrate 50/50 v/v (WF/PS 50/50); (4) wood fiber and peat substrate 25/75 v/v (WF/PS 25/75). The rates of fertilization were the following: (1) con-ventional fertilization (CF); (2) N13; (3) N23; (4) N30. The experiment was carried out in three repli-cations. As the amount of wood fiber increased, the humidity and pH of the growing medium in-creased. Fertilization of cucumbers with different rates of nitrogen influenced the nutrient uptake. Plants grown in 50/50 and 25/75 growing media had the best Cu uptake when fertilized with N23. When the plants grown in the wood fiber media and the 50/50 media were fertilized with N13, N23, and N30, the Mn content in the growing media at the end of the growing season was significantly lower than the Mn content in the media with conventional fertilization. Thus, nitrogen improved the uptake of Mn by plants grown not only in the wood fiber but also in combinations with peat sub-strate. Growing plants in wood fiber and fertilizing them with N13 can result in optimum uptake of micronutrients. The number and mass of cucumber fruits per plant were influenced by the amount of wood fiber in the growing media and the application of nitrogen fertilizer. The highest number of fruits and mass of fruits per plant was obtained significantly higher when cucumbers were grown on WF/PS 50/50 growing media with additional N13 fertilization.

One of the tools for optimal crop production is regular monitoring and assessment of crops. During the growing season of fruit trees, the bloom period has increased photosynthetic rates that correlate with the fruiting process. This paper presents the development of an image processing algorithm to detect peach blossoms on trees. Images of an experimental peach orchard were acquired from the Parma Research and Extension Center of the University of Idaho using an off-the-shelf unmanned aerial system (UAS), equipped with a multispectral camera (Near-infrared, Green, Blue). The orchard has different stone fruit varieties and different plant training system. Individual tree images (high-resolution) and arrays of trees images (low-resolution) were acquired to evaluate the detection capability. The image processing algorithm was based on different vegetation indices. Initial results showed that the image processing algorithm could detect peach blossoms and demonstrate good potential as a monitoring tool for orchard management.

The focus of this work lies in the construction of monitoring system designed in the form of a patch using a long-lasting potentiometric electrolyte concentration sensor from metal electrodes, in a galvanic cell configuration Mg(s)|NaCl(aq)|Cu(s). Initially, a mathematical analysis was conducted on the expected sensor output through the Nernst equation. The experimental phase involved conducting controlled tests in the laboratory using various molar concentrations of sodium chloride (NaCl) in aqueous solution. Results showed that the electrolyte sensor allows for monitoring electrolyte levels in NaCl in the range of 0.02 to 1 M/L, with electrode lifespan exceeding 10 days. On the other hand, when patch is using human sweat during controlled exercise routines, it showed the sensor's capability for monitoring changes in the subjects' hydration levels in real time. The sensor output potential is greater than 1.7 volts when the sensor electrodes are in contact with human sweat, which is equivalent to measuring molar concentrations at normal hydration and moderately high hydration levels. Sensor results indicate that the system can function in a self-powered manner without external batteries. Additionally, the extended lifespan of its electrodes allows for continuous monitoring of imbalances in the human body, showcasing the system capability for long-term health assessment.

To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, that selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure-activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif. Molecular dynamics simulations have determined that the solution conformation of MABA peptide 4 is more compact, underwent larger conformational changes until convergence, and spent most of the time in a single cluster. The peptides’ binding affinity has been characterized by enzyme linked immunosorbent assay in which the most potent peptide 4 inhibited with IC50 of 324±8 µM and 550±45 µM the binding of GST-α1-A domain to collagen IV fragment CB3, and the cell adhesion to collagen IV using α1-overexpressor cells, respectively. Docking studies and MM-GBSA calculations confirmed that peptide 4 binds a smaller region of the integrin near the collagen- binding site and penetrated deeper into the binding site near Trp1. Peptide 4, inhibited tube formation by endothelial cell migration in the Matrigel angiogenesis in vitro assay. Peptide 4 was acutely tolerated by mice, showed stability in human serum, decreased tumor volume and angiogenesis, and significantly increased the survival of mice injected with B16 melanoma cells. These findings propose that MABA-peptide 4 can further serve as an α1β1-integrin antagonist lead compound for further drug-optimization in angiogenesis and cancer therapy.

The opioid crisis in the United States has had devastating effects on communities across the country, leading many states to pass legislation that limits the prescription of opioid medications in an effort to reduce the number of overdose deaths. This study evaluates the impact of two categories of PDMP and Pill Mill regulations on the supply of opioid prescriptions at the level of dispensers and distributors (excluding manufacturers) using ARCOS data. The study uses a difference-in-difference method with a two-way fixed design to analyze the data. The study finds that both of the regulations are associated with reductions in the volume of opioid distribution. However, the study reveals that these regulations may have unintended consequences, such as shifting the distribution of controlled substances to neighboring states. For example, in Tennessee, the implementation of Operational PDMP regulations reduces in-state distribution of opioid drugs by 3.36% (95% CI, 2.37 to 4.3), while the out-of-state distribution to Georgia, which did not have effective PDMP regulations in place, increases by 16.93% (95% CI, 16.42 to 17.44). Our studies emphasize that policymakers should consider the potential for unintended distribution shifts of opioid drugs to neighboring states with laxer regulations as well as varying impacts on different dispenser types.

Dolichandrone spathacea is a rare and endangered semi-mangrove plant species with an extremely small population, naturally distributed only in Zhanjiang City and the east coast of Hainan Island, China. Regrettably, the present situation of the D. spathacea population in China has not yet been carefully investigated. In this study, we aim to evaluate the current resource status and population dynamic characteristics of D. spathacea on Hainan Island, China, in order to propose sustainable conservation and management strategies for future ecological restoration of its natural population. Our results show that D. spathacea on Hainan Island can be divided into four populations. All the D. spathacea populations present a state of overall dispersion, local concentration, and occasionally sporadic existence, and they exist in geographical isolation. The young, middle, and old D. spathacea plants account for 20.42%, 66.20%, and 13.38%, respectively, indicating that the overall age class of the D. spathacea population on Hainan Island belongs to a declining type. Furthermore, instead of temporal structure, we chose diameter at breast height (DBH) to establish a static life table, draw a population survival curve, and quantify the future development trend through population dynamic analysis and time-series prediction. These results directly point out that the D. spathacea population on Hainan Island is sensitive to external disturbances and possesses two main increases in mortality rate—namely, in its juvenile and mature stages—due to weak vitality, competition, and anthropogenic interferences, which are the most important reasons for its endangered status. Depending on the current conditions of the D. spathacea population, we should conserve and expand mature trees in situ, preserve their germplasm resources, rehabilitate their habitats to promote provenance restoration, and conduct artificial cultivation and spreading planting in order to realize the sustainable conservation and management of D. spathacea.

Smart agriculture is a new way of farming that uses advanced technology. It makes a significant contribution to improving the efficiency and productivity of farming practices. Systems that use drones to monitor pests and spray pesticides greatly reduce the burden on farmers. In addition, remote sensing technology facilitates the monitoring of crop growth conditions and the early detection of diseases and pests. However, the high cost of equipment to communicate sensor data is preventing farmers from adopting sensing systems. As a result, many studies have been conducted to make the sensing system available at a low cost. Nevertheless, many farmers have not yet adopted them. Therefore, this paper proposes an agricultural sensor network system using drones and optical camera communication (OCC). The proposed system aims to achieve high-density farm sensing at low cost. The proposed system uses OCC as the communication method for sensor data. Low cost light sources such as LED panels can be used as transmitters. In addition, existing agricultural drones equipped with cameras can be used as receivers. We also propose a trajectory control algorithm for the receiving drone to efficiently collect the sensor data. The proposed system is suitable for deploying sensor networks in areas with underdeveloped infrastructure and radio silence. In this paper, we conducted a preliminary experiment at a leaf mustard farm in Kamitonda-cho, Wakayama to demonstrate the effectiveness of the proposed system using a Mavic 2 Pro drone, launched by DJI Co., Ltd.

The main purpose of this study was to create a prototype of an unmanned aerial system equipped with intelligent hardware and software technologies necessary for monitoring the health and growth of crops in orchards. Another important objective was to use low-cost sensors that accurately measure ultraviolet solar radiation. The device, which needs to be attached to the commercial DJI Mini 4 Pro drone, should be small in size, portable, and have very low energy consumption. For this purpose, the widely used Vishay VEML6075 digital optical sensor was selected and implemented in a prototype, alongside a Raspberry Pi Zero 2W minicomputer. To collect data from these sensors, a program written in Python was used, containing specific blocks for data acquisition from each sensor, to facilitate the monitoring of ultraviolet (UV) radiation, or battery current. By analyzing the data obtained from the sensors, several important conclusions are drawn that may provide valuable pathways for the further development of mobile or modular equipment. Furthermore, the results of the plant condition analysis with proposed models in the Geographic Information System (GIS) environment were also presented. The visualization of maps indicating variations in vegetation condition led to the identification of problem areas like hydric stress.

In the contemporary world of science, continuous observation of specific fixed regions is required, awaiting the emergence of targets or phenomena within those areas to locate and identify them. Astronomy requires continuous monitoring of stars, swiftly pinpointing occurrences, such as flares, and acquiring their spectral data to aid identification. In military contexts, continuous observation of specific areas is essential for promptly locating enemy movements and obtaining target spectral data for deciphering enemy disguises. Additionally, continuous observation of experimental samples in biochemistry is mandatory to pinpoint localized changes and acquire spectral data from those areas. Hence, this paper develops a novel imaging spectrometer solution to monitor localized regions continuously. Specifically, this paper first elaborates on the developed instrument’s characteristics and optical structure, followed by optical design software simulations. The instrument has an F-number of 5, a focal length of 100mm, and a field of view covering the wavelength range from 400nm to 600nm. The optical path diagram indicates that the system’s dispersion and imaging images can be separated, meeting the system’s requirements. Besides, the Modulation Transfer Function (MTF) graph confirms that the image quality meets the requirements. Furthermore, a region-monitoring type imaging spectrometer was constructed to assess the instrument’s capability for spectral observation of fixed regions. The instrument can detect a fixed area, with the target placed within the detection area. Spectral data were successfully obtained by conducting image processing on the acquired images. The correlation coefficient between this data and reference data was as high as 0.9226, indicating the instrument’s successful measurement of the target’s spectrum. Thus, the developed instrument demonstrated that it can image the observed areas and acquire spectral data from targets within those regions.

Phytochemicals have a long and successful history in drug discovery. With recent advancements in analytical techniques and methodologies, discovering bioactive leads from natural compounds has become easier. Computational techniques like molecular docking, QSAR modelling and machine learning, and network pharmacology are among the most promising new tools that allow researchers to make predictions concerning natural products' potential targets, thereby guiding experimental validation efforts. Additionally, approaches like LC-MS or LC-NMR speed up compound identification by streamlining analytical processes. Integrating structural and computational biology aids in lead identification, thus providing invaluable information to understand how phytochemicals interact with potential targets in the body. Emerging computational approach is machine learning involving QSAR modelling and deep neural networks that interrelate phytochemical properties with diverse physiological activities such as antimicrobial or anticancer effects.

Background/Objectives: This review examines the evolution of lyotropic liquid crystals (LLCs) in ocular drug delivery, focusing on their ability to address the challenges associated with traditional ophthalmic formulations. The study aims to underscore the enhanced bioavailability, prolonged retention, and controlled release properties of LLCs that significantly improve therapeutic outcomes; Methods: The review synthesizes data from various studies on both bulk-forming LLCs and liquid crystal nanoparticles (LCNPs). It also considers advanced analytical techniques, including the use of machine learning and AI-driven predictive modeling, to forecast the phase behavior and molecular structuring of LLC systems. Emerging technologies in biosensing and real-time diagnostics are discussed to illustrate the broader applicability of LLCs in ocular health; Results: LLCs are identified as pivotal in promoting targeted drug delivery across different regions of the eye, with specific emphasis on the tailored optimization of LCNPs. The review highlights principal categories of LLCs used in ocular applications, each facilitating unique interactions with physiological systems to enhance drug efficacy and safety. Additionally, novel applications in biosensing demonstrate LLCs' capacity to improve diagnostic processes; Conclusions: Lyotropic liquid crystals offer transformative potential in ocular drug delivery by overcoming significant limitations of conventional delivery methods. The integration of predictive technologies and biosensing applications further enriches the utility of LLCs, indicating a promising future for their use in clinical settings. This review points to continued advancements and encourages further research in LLC technology to maximize its therapeutic benefits.

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost)-incorporated nanoparticles and imatinib, a PDGF-receptor tyrosine kinase inhibitor, -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of PAH and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for treatment of PAH.

Heparins, Unfractionated or Low Molecular Weight, are permanently at the spotlight of both clinical indications and laboratory monitoring. An accurate drug dosage is necessary for an effi-cient and safe therapy. The one-stage anti-FXa kinetics’ assays are the most widely and universally used with full automation for large series, without needing exogenous Antithrombin. WHO in-ternational standards are available for UFH and LMWH, but external quality assessment surveys still report a high inter-assay variability. This heterogeneity results from: assay formulation, designed without or with dextran sulfate to measure all heparin in blood circulation; calibrators for testing UFH or LMWH with the same curve; and automation parameters. The various factors which impact heparin measurements are reviewed, and we share our experience to optimize assays for completely testing plasma heparin. Evidence is provided on the usefulness of low molecular weight dextran sulfate to mobilize all drug present in blood circulation. Other key factors concern adjustment of assay conditions to obtain fully superimposable calibration curves for UFH and LMWH, and automation parameters. The study is illustrated by the performances of the various anti-FXa assays used for testing heparin on UFH or LMWH treated patients’ plasmas and obtained using citrate or CTAD anticoagulants. Comparable results are obtained only when CTAD anti-coagulant is used. Using citrate UFH is underestimated in the absence of dextran sulfate. Heparin calibrators, adjustment of automation parameters and data treatment contribute to other smaller differences.

Epilepsy is one of the most prevalent and serious brain disorders, affecting 70 million people worldwide. Antiseizure medications (ASMs) though relieve symptoms and prevent the occurrence of future seizures in epileptic patients have limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms for development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made and challenges facing in the development of NLRP3 inhibitors for the treatment of epilepsy.

Knowing professionals’ attitudes is the basis for the development of skills for dealing with drug dependence. These attitudes may affect patients’ clinical safety and the cost-benefit ratio of the interventions. The goal of this study was to assess emergency and mental health nurses’ attitudes and perceptions towards alcoholics. A multicenter prospective descriptive study was conducted in six hospitals with 167 emergency and mental health nurses. Nurses classified alcoholics as sick individuals, although there was a tendency to feel comfortable working with them. Results indicated that these professionals had a rejecting attitude towards moderate alcohol consumption. We found a significant association between the attitude of the nurse and gender, with the degree of rejection towards the alcoholic being higher in men than in women and with less punitive attitudes in professionals from 0 to 11 years of professional experience.

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases’ progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop of new, disease-modifying drugs to treat AD and PD, thereby decreasing the social and economic burdens linked to these NDs.

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and pre-scribed off-label for several neurological conditions like neuropathic pain, migraine and anxiety. Amitriptyline potentiates the monoaminergic transmission by blocking the reuptake of norepi-nephrine and serotonin. However, antidepressants also act on additional targets that contribute to either therapeutic or adverse effects and may suggest new indications for their repurposing. Furthermore, since depression is often a co-morbidity in patients with chronic conditions (i.e. cancer, neurodegenerative diseases) the use of antidepressants interfering with pathways in-volved in cell homeostasis may affect the progression and outcome of these pathologies. Here we investigate the effects of amitriptyline on proliferation and autophagy in human SH-SY5Y neuroblastoma cells. Dose and time-dependent upregulation of the autophagy markers LC3II and autophagy receptor p62, with accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to amitriptyline. Alteration of autophagy was accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5 -/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine suggesting that the amitriptyline’s effects on cell proliferation were not caused by the modulation of autophagy. Our findings demonstrate that amitriptyline acts on pathways that are crucial for cell and tissue homeostasis and pose the basis for further studies on the potential application of these effects and the consequences during long-term antidepressant treatment.

The real long-term influences of in utero drug exposure in pregnant women on childhood development have yet to be fully determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining therapeutic drug levels in maternal blood. Most antibody therapies used in patients with Inflammatory Bowel Disease (IBD) are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here we propose an up to date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the blood cord, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the second and third trimesters, leading to increasing maternal IFX concentrations. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance regarding the safety profile of anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable but very low and therefore it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. It is currently not recommended in patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact for making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the blood cord, the infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data currently available.

Phage therapy, the use of bacteriophages (phages) to treat bacterial infections, is regaining momentum as a promising weapon against the rising threat of multidrug-resistant (MDR) bacteria. This comprehensive review explores the historical context, the modern resurgence of phage therapy, and phage-facilitated advancements in medical and technological fields. It details the mechanisms of action and applications of phages in treating MDR bacterial infections, particularly those associated with biofilms and intracellular pathogens. The review further highlights innovative uses of phages in vaccine development, cancer therapy, and as gene delivery vectors. Despite its targeted and efficient approach, phage therapy faces challenges related to phage stability, immune response, and regulatory approval. By examining these areas in detail, this review underscores the immense potential and remaining hurdles in integrating phage-based therapies into modern medical practices.

CD44 regulates cell adhesion, proliferation, survival, and stemness and has been considered a tumor therapy target. CD44 possesses the shortest CD44 standard (CD44s) and a variety of CD44 variant (CD44v) isoforms. Since the expression of CD44v is restricted in epithelial cells and carcinomas compared to CD44s, CD44v has been considered a promising target for monoclonal antibody (mAb) therapy. We previously developed an anti‐CD44v10 mAb, C44Mab-18 (IgM, kappa) to recognize the variant exon 10-encoded region. In the present study, a mouse IgG2a version of C44Mab-18 (C44Mab-18-mG2a) was generated to evaluate the antitumor activities against CD44-positive cells compared with previously established anti-pan CD44 mAb, C44Mab-46-mG2a. C44Mab-18-mG2a exhibited higher reactivity compared with C44Mab-46-mG2a to CD44v3–10-overexpressed CHO-K1 (CHO/CD44v3–10) and oral squamous cell carcinoma cell lines (HSC-2 and SAS) in flow cytometry. C44Mab-18-mG2a exerted a superior antibody‐dependent cellular cytotoxicity (ADCC) against CD44v3–10. In contrast, C44Mab-46-mG2a showed a superior complement‐dependent cytotoxicity (CDC) against CD44v3–10. A similar tendency was observed in ADCC and CDC against HSC-2 and SAS. Furthermore, administering C44Mab-18-mG2a or C44Mab-46-mG2a significantly suppressed CD44v3–10, HSC-2, and SAS xenograft tumor growth compared with the control mouse IgG2a. These results indicate that C44Mab-18-mG2a could be a promising therapeutic regimen for CD44v10-positive tumors.

The leather industry is one of the most polluting industries in the world due to the large amounts of waste following the raw hides processing, but also due to the high content of chemicals present in their composition. The main problem of chromium-tanned leather solid waste is related to their storage, because of the ability of chromium to leach in soil or water, and also owing to the high ability of trivalent chromium to oxidize to its toxic form, hexavalent chromium. The purpose of this study is to present the latest methods for extracting trivalent chromium from the composition of solid leather wastes. The extraction methods identified in the present study are based on acid/basic/enzymatic hydrolysis and substitution with the help of organic chelators (organic acids and organic acid salts). In addition, the study includes a comparative analysis between the advantages and disadvantages of each identified extraction method. At the same time, the study also presentes alternative chromium extraction methods based on the combination of conventional extraction methods and ultrasound-assisted extraction.

The term Air Quality (AQ) pertains to the standard of air, which has a direct impact on the health and well-being of individuals. It is crucial to maintain high Air Quality (AQ), for better health and productivity. Though most of people spend more time indoors nowadays, it is not to be overlooked that the pollutant concentration in indoor air is directly linked to the outdoor air quality. Due to the changes in occupancy patterns, outdated maintenance of ventilation systems, and structural flaws in buildings, the indoor air is significantly polluted; pollutants emitted outdoors enter indoor air through open windows, ventilation systems and infiltration. In this paper, we have proposed a new technique, DTMCPM (discrete-time Markov chain (DTMC) model for the analysis and forecasting of AQ, using the power method). Specialized sensors and equipment to measure different pollutants, such as particulate matter, ozone, nitrogen dioxide, sulfur dioxide, benzene and toluene, are used to collect data by the Institute of Pakistan Air Quality Monitor in various cities; the data is converted to US EPA standard for all pollutant species. This data is used to calculate the transition matrix, steady-state values and mean return rate for the analysis of IAQ. The calculated and actual return rates have been compared and the proposed model is found to have a low average prediction error of 2.356%.

The global COVID-19 pandemic has affected all spheres of human life, resulting in millions of deaths and overwhelming medical facilities. Moreover, the world has witnessed great financial hardship because of job losses resulting in economic havoc. Many sections of society have contributed in different ways to slow the spread of the virus and protect public health. For example, medical scientists are praised for their efforts to develop COVID-19 vaccines. Clinical trials have shown that the COVID-19 vaccines are highly effective in preventing symptomatic COVID-19 infections. However, many people around the world have been hesitant to get vaccinated. Vaccine misconceptions have emerged and increased due to a combination of factors, including the availability of information on the Internet and the influence of celebrities and opinion leaders. In this context, we have analyzed ChatGPT responses to relevant queries on vaccine misconceptions. The positive responses and supportive opinions provided by the AI chatbot could be instrumental in shaping people’s perceptions of vaccines and in encouraging users to get vaccinated and reduce misconceptions.

Drug-induced liver injury (DILI) stands as a significant cause of drug attrition. To mitigate clinical DILI risks, assessing drugs using human liver models is crucial since animal studies may fall short due to species-specific liver pathway variations. Cell-based preclinical hepatotoxicity testing is often pertinent. In the present study, cells from a human liver cancer line (HepG2, HepaRG) were cultured in both formats of 2D and 3D spheroids to explore their responses to drugs. Liver-specific marker expressions across cell lines and culture formats were also examined to assess disparities in drug-induced liver injury marker expressions. In cytotoxicity assays, HepG2 cells exhibited heightened sensitivity to amiodarone HCl, while HepaRG cells showed greater sensitivity to acetaminophen. Generally, 2D cultures were more responsive to drugs than 3D cultures. Consistency was observed between cytotoxicity assays and liver injury markers AST and ALT. Variations were also noted in liver cell marker secretion, with albumin and urea concentrations declining post-drug treatment, particularly with higher baseline expression in HepaRG cells and 3D cultures. Additionally, mRNA expression levels of CYP enzymes involved in hepatocellular drug metabolism were compared following treatment with enzyme inducers. CYP1A2 and CYP2C9 were not expressed in HepG2 cells. On the other hand, CYP3A4 was expressed higher in 3D culture than in 2D culture. HepaRG cells exhibited significantly increased expression of all three enzymes post-treatment. Notably, enzyme expression was notably higher in 3D cultures than in 2D cultures. Collectively, these findings suggest that HepaRG cells and 3D cultures hold promise for evaluating DILI during early-stage drug development.

We assessed the impact of social determinants of health (SDOH) and psychosocial factors on screening behavior in a nationally representative sample of women in the US. A retrospective population-level cross-sectional sample was extracted from the 2022 Health Information National Trends Survey. Descriptive statistics were conducted for demographic characteristics and covariates. Population-based estimates with 95% confidence intervals (95% CI) were produced for Pap testing behaviors across study years. We used logistic regression models to assess Pap testing differences based on SDOH and psychosocial factors, adjusting for covariates, with a significance level of 0.05 for hypothesis testing. Women (n=2,224) with a mean age of 46.96 participated in the study. Our study found that 90% of women were interested in cervical cancer screening, with an 80% actual screening rate. Screening rates differed by age group and rurality. SDOH and psychosocial factors were associated with participants’ interest in screening and in actual screening behavior. The impacts of SDOH and psychosocial factors on screening behavior were 3% and 1%, respectively. The SDOH and psychosocial factors are associated with the uptake of cervical cancer screening among women in the United States. Policies must be directed at bridging the gap created by these SDOHs.

Cancer, characterized by abnormal cell proliferation driven by genetic mutations, remains a significant health challenge. Tailoring effective therapies depends on factors like tumor location, grade, and stage, alongside patient condition. Leveraging Nano-carrier encapsulated drugs offers a promising avenue, as they accumulate preferentially at tumor sites, enhancing therapeutic efficacy while mitigating side effects. Polymeric Nano-carriers, with their customizable properties, further optimize drug delivery efficiency and specificity. Incorporating active targeting ligands such as antibodies, carbohydrates, peptides, folates, and aptamers-onto polymeric nanoparticle surfaces through techniques like functionalization, adsorption, and conjugation plays a pivotal role in directing therapeutic agents to tumor cells. Consequently, polymeric nanoparticles emerge as the carrier of choice for delivering drugs to various tumor types, including breast, colon, lung, prostate, liver, and spleen tumors.

Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to efficiently suppress tumorigenesis. Biochemically, Pdcd4 binds with translation initiation factor 4A and represses protein translation. Beyond its role in tumor suppression, increasing evidence indicates that Pdcd4 enhances the chemosensitivity of several chemotherapeutic drugs. To date, several translational targets of Pdcd4 have been identified. These targets govern important signal transduction pathways, and their attenuation may enhance chemosensitivity or overcome drug resistance. This review will discuss the signal transduction pathways regulated by Pdcd4 and the potential mechanisms through which Pdcd4 enhances chemosensitivity or counteracts drug resistance.

The state of the grinding wheel in the grinding process directly affects the surface quality of the workpiece. The monitoring of the wear state of the grinding wheel can effectively identify the wear information of the grinding wheel and timely and effectively repair the grinding wheel. In this paper, a multi-sensor fusion precision grinding wheel wear intelligent monitoring system is established for typical difficult-to-machine aerospace material titanium alloy, and a multi-eigenvalue fusion algorithm based on improved support vector machine (SVM) is proposed. The extracted sound emission signal wavelet packet decomposition coefficient mean square value, force signal grinding force ratio, and vibration signal effective value are used as the input of the improved support vector machine, and the identification strategy is adjusted by the entropy weight evaluation method. The results show that the monitoring system established in this paper can effectively identify the wear state of the grinding wheel, and the monitoring accuracy can reach more than 92%.

Functional genomics, a multidisciplinary subject, investigates the functions of genes and their products in biological systems to better understand diseases and find new drugs. Drug repurposing is an economically efficient approach that entails discovering novel therapeutic applications for already-available medications. Genomics enables the identification of illness and therapeutic molecular characteristics and interactions, which in turn facilitates the process of drug repurposing. Techniques like gene expression profiling and Mendelian randomization are helpful in identifying possible medication candidates. Progress in computer science allows for the investigation and modelling of gene expression networks that involve large amounts of data. The integration of data from DNA, RNA, and protein activities has resemblance to pharmacogenomics, which is of utmost importance in the development of cancer drugs. Functional genomics in drug discovery, particularly for cancer, is still not thoroughly investigated, despite the existence of a significant amount of literature on the subject. Next-generation sequencing and proteomics present highly intriguing opportunities. Publicly available databases and mining techniques facilitate the development of cancer treatments based on functional genomics. Expanding the study and application of functional genomics has great promise to advance the process of discovering and repurposing drugs, especially in the field of oncology.

Seroprevalence of anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies in the postvaccination period in Kenya remains to be elucidated. This study aimed to determine the seroprevalence of anti-SARS-CoV-2 IgM and IgG and evaluate vaccination uptake in Nairobi, Kenya. This was a cross-sectional study conducted in a university setting. Serum anti-SARS-CoV-2 IgM and IgG levels were assayed using enzyme-linked immunosorbent assays. Mann–Whitney U test was used for binary comparisons and Kruskal–Wallis Test for multigroup comparisons. Statistical significance was set at p < 0.05. A total of 189 participants were enrolled (median age, 21 years; female, 50.8%). The seroprevalence of anti-SARS-CoV-2 was 12.7% for IgM and 87.8% for IgG. Anti-SARS-CoV-2 IgG titers were higher among the vaccinated vs. non-vaccinated individuals (p < 0.001, U = 2817.5), females vs. males (p = 0.024, U = 3616), and those vaccinated < 6 months before the study vs. those vaccinated >1 year earlier (p = 0.002, H = 12.359). The vaccination hesitancy rate was 43.4% and the underlying reasons included mistrust (22.4%), health concerns (19.7%), and lack of information (18.4%). Despite the high seroprevalence of anti-SARS-CoV-2 IgG, the high vaccine hesitancy rate necessitates community engagement and education prior to vaccines roll out.

There are considerable benefits in applying Artificial Intelligence to automation in modern industries including Oil and Gas Industries. Oil and Gas Industries have many complex systems in their production and flow line. The failure of gas equipment will have serious consequences including financial and environmental issues. Condition monitoring of oil and gas equipment provides the condition of components, machines, systems, equipment, data hardware, and even software. The predictive maintenance and industry 4.0 applications have more advantages in petrochemical industries to make a safer economic environment and this paper addresses the Artificial Intelligence (AI) application of condition monitoring for Oil and Gas Industries. To understand the effectiveness of AI in condition monitoring for oil and gas industries, a case study related to the condition monitoring of drilling machine is conducted and applied Artificial Neural Network (ANN) algorithm to analyze and predict the potential failures. The novelty of this work is the proposal of an approach for tool wear monitoring in drilling using acoustic emission sensors for feature extraction and considering wavelet packet decomposition for further analysis. The extracted features from WPD are given as input for ANN to identify the healthiness of the drill bit and machine. This work aims to find the effectiveness of AI-based condition monitoring in enhancing effectiveness of monitoring and the safety of equipment in Oil and Gas Industries.

It is meaningful to monitor and identify the concrete cracks as they will seriously reduce the fatigue life of pavement. In this paper a new method based on distributed long-gauge optic fiber sensing is proposed to implement the crack identification. Firstly, the damage indicator, namely strain curve envelope area ratio (SCEAR), is proposed and calculated with the measured strain in time series when the plane goes across the pavement where the sensors are installed. Then the indicators with different sensors are normalization by the value of the indicator from one referenced sensor where damage normally will not happen. If the crack happens within the sensing gauge of the sensor, the value of damage indicator SCEAR from the sensor will increase. Therefore, the crack will be identified with the change of the damage indicator. The effect of the proposed method is first verified by some simulations of prefabricated pavement as the cracks can be accurately identified by the proposed method. Moreover, the influence from the aircraft, such as taxiing position, aircraft load and aircraft type, is not obvious enough to mislead the identification results. Lastly the static loading tests were implemented with one small-scale model of prefabricated concrete pavement in the lab. From the experimental results the prefabricated cracks inside the pavement slab can be identified accurately with the proposes method as the parameter SCEAR is increased by about 100% at the crack position, while it is only changed by about 3% at the undamaged position.

Glioblastoma (GBL) is one of the more malignant primary brain tumors, currently treated by a multimodality strategy including surgery, radio- and chemotherapy, mainly consisting of Temozolomide(TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with a patient median survival <2 years. The identification of natural molecules having strong anti-tumor activity, led to combine these compounds with conventional chemotherapeutic agents, developing protocols of integrated anticancer therapies. Curcumin (CUR), Resveratrol (RES), and its glucoside Polydatin (PLD) are widely employed in the pharmaceutical and nutraceutical fields, and several studies demonstrated that the combination of these natural products was more cytotoxic than the single compound alone in different cancers. Some of us recently demonstrated the synergistic efficacy of the sublingual administration of a new nutraceutical formulation of CUR+PLD in reducing tumor size and improving GBL patient survival. To deepen some mechanistic aspects of these results, we investigated if the pretreatment with a combination of CUR+PLD, can improve TMZ cytotoxicity on GBL cells, by analyzing the effects on cell cycle, viability and morphology, on proteins related to cell proliferation, differentiation, apoptosis or autophagy, and on actin network. Cell viability was assessed by MTT or by the cell counter CytoSmart. CalcuSyn software was used to study the CUR+PLD synergism. Morphology was evaluated by optical and scanning electron microscopy, and protein expression was analyzed by Western Blot. Flow cytometry was used for cell cycle, autophagic flux, and apoptosis analyses. The results obtained provide evidence that CUR and PLD, acting in synergy with each other, strongly improve the efficacy of alkylating antitumor agents such as TMZ, also in drug-resistant GBL cells, through their abilities to affect survival, differentiation, and tumor invasiveness.

This paper investigates an Energy Neutral System using Micro Energy Harvesters for a Health Monitoring Wireless Sensor Node (HM-WSN). We have implemented HM-WSN consisting of a solar cell energy harvester, a Power Management Unit (PMU) and the ucontroller, sensor and transmitter acting as load. A battery extender and a switching logic circuit for sensor node is designed to evaluate the efficiency of the proposed system. The HM-WSN senses body temperature with improvement in lifetime of coincell. The HM-WSN is built using commercially available off the shelf (COTS components and consumes 47.2uW for data being updated every 134s. It can be operated for approximately 1.32 years only on a coincell. Furthermore, the HM-WSN can be operated with solar energy at 200lux, achieving 96.36 years with a combination of a coincell with an additional capacitor of 2.2mF. It attains 4.07 years to 16.87 years lifetime with the load capacitor varying from 1mF to 1.5mF at 350lux lighting condition. With the same ambient condition and a 2mF load capacitor, HM-WSN attains complete energy autonomy.

Use of probiotic lactobacilli has been proposed as a strategy to mitigate damage associated to exposure to toxic metals. Their protective effect against cationic metal ions, such as those of mercury or lead, is believed to stem from their chelating and accumulating potential. However, their retention of anionic toxic metalloids, such as inorganic arsenic, is generally lower. Through the construction of mutants in phosphate transporter genes (pst) in Lactiplantibacillus plantarum and Lacticaseibacillus paracasei strains, coupled with arsenate [As(V)] uptake and toxicity assays, we determined that the incorporation of As(V), which structurally resembles phosphate, is likely facilitated by phosphate transporters. Surprisingly, inactivation in Lc. paracasei of PhoP, the tran-scriptional regulator of the two-component system PhoPR, a signal transducer involved in phosphate sensing, led to an increased resistance to arsenite [As(III)]. In comparison to the wild type, the phoP strain exhibited no differences in the ability to retain As(III), and there were no observed changes in the oxidation of As(III) to the less toxic As(V). These results reinforce the idea that specific transport, and not unspecific cell retention plays a role in As(V) biosorption by lactobacilli, while they reveal an unexpected phenotype for the lack of the pleiotropic regulator PhoP.

Both the use of plastic and its decomposition products lead to the distribution of plastic all over the earth and finally to the uptake by all kind of living beings including humans. Still, it is widely unknown what risks harbor the widespread uptake of plastics for human health, espe-cially regarding contributing factors like size, shape and surface composition. We assessed the uptake of polymethylmethacrylate (PMMA)-nano- and microbeads for HEK293-, A549- and MRC5 cells. Via confocal microscopy, we localized multiple PMMA-beads inside the cytosol of cells. Uptake of PMMA-beads did not alter cell growth and cell division, implying no short-term toxicity towards human cells. Further, we used a cAMP response element binding protein (CREB)-mediated reporter assay to assess whether internalized PMMA-nanobeads alter cell-signaling pathways. In contrast to the in vitro transcription, where the addition of PMMA-nanobeads abolished the transcription, no changes regarding CREB-mediated cell sig-naling are given in HEK293-cells. Our data led to the assumption that PMMA-nano-and mi-crobeads are internalized via endocytosis and end up as lysosomes within the cells cytosol. Therefore, we concluded differences regarding the surface composition of the PMMA-nanobeads mainly affect its potential to alter cell signaling. These findings emphasize the key role the sur-face composition plays regarding microplastic and its risks for human health.

Background: This study introduces a novel dexamethasone (DEX) mixed micellar system (DEX-MM) using Soluplus® and Pluronic F-127 (PF127) to enhance ocular drug delivery. The enhancement of ocular application properties was achieved by creating a chitosan-coated DEX-MM (DEX-CMM), which promotes better adherence to the ocular surface, thereby improving drug absorption; Methods: Using the solvent evaporation method, a formulation was developed with a Soluplus® to drug ratio of 1:10, enhanced with 0.25% PF127. After dispersing in water, 1% chitosan (CS) was added. The stability and integrity of DEX within the micelles were verified using attenuated total reflection-fourier transform infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC). Additionally, in vitro and ex vivo drug release studies were con-ducted; Results: DEX-CMM (F6) demonstrated a particle size of 151.9±1 nm and a polydispersity index (PDI) of 0.168±0.003, suggesting uniformity and high electrostatic stability with a zeta po-tential of +35.96±2.13 mV. The non-Fickian drug release mechanism indicated prolonged drug retention. Comparative analyses showed DEX-CMM outperforming a standard DEX suspension in drug release and ocular tissue permeation, with flux measurements significantly higher than the DEX suspension; Conclusion: The study confirmed the efficacy of DEX-CMM in enhancing drug delivery to ocular tissues, evidenced by improved permeability. Safety evaluations using the HET-CAM test demonstrated that DEX-CMM was non-irritant, supporting its potential for effective ocular drug delivery.

In this review we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients.

Molecularly imprinted polymers (MIPs) were synthesized and applied for the selective extraction of oblongifolin C (OC) from fruit extracts of Garcinia yunnanensis Hu. A series of experiments and computational approaches were employed to improve the efficiency of screening for optimal MIP systems in the study. The molar ratio (1:4) was chosen at last based on the comparison of the binding energy of the complexes between the template (OC) and functional monomers using density functional theory (DFT) at the RI-PBE-D3-gCP/def2-TZVP level of theory. The binding characterization and the molecular recognition mechanism of MIPs were further explained using the molecular modeling method and NMR and IR spectra data. The reusability of this approach was demonstrated in over 20 batch rebinding experiments. 140.5 mg of OC (>95% purity) was obtained from the 5 g extracts with 2 g of MIPs with the best binding properties through gradient elution program from 35% to 70% methanol-water solution. At the same time, another structural analog, 46.5 mg of guttiferone K (GK) (>88% purity), was also obtained by the gradient elution procedure. Our results showed that the structural analogs could be separated from the crude extracts by the molecularly imprinted solid-phase extraction (MISPE) using a gradient elution procedure for the first time.

This review delves into the growing field of flexible and stretchable strain sensors utilized in human gait analysis, focusing on determining knee bending angle and muscle activities when a human subject walks. Recent advancements have enabled these sensors to accurately capture biomechanical parameters while accommodating the body's natural movements. We examine the principles underlying these sensors' design and fabrication techniques, emphasizing their flexibility, stretchability, and biocompatibility for seamless integration into wearable systems. Through critical evaluation of existing methodologies, we assess the reliability and validity of these sensors in quantifying gait parameters. Furthermore, we discuss this technology's clinical and research implications, highlighting its potential in personalized rehabilitation and sports performance optimization. We provide an overview of flexible strain sensors and their application for analyzing human walking gait, especially for observing walking gait in rehabilitation programs. First, we present the basic working principles of various flexible strain sensors. Second, by the application of flexible strain sensors as walking gait monitoring. Finally, current challenges and future opportunities in this research area are discussed. By synthesizing current knowledge and outlining future directions, this review aims to provide insights for researchers and practitioners seeking to leverage flexible and stretchable strain sensors for comprehensive human gait analysis.

The state-of-the-art smart city has been calling for an economic but efficient energy management over large-scale network, especially for the electric power system. It is a critical issue to monitor, analyze and control electric loads of all users in system. In this paper, we employ the popular computer vision techniques of AI to design a non-intrusive load monitoring method for smart electric energy management. First of all, we utilize both signal transforms (including wavelet transform and discrete Fourier transform) and Gramian Angular Field (GAF) methods to map one-dimensional current signals onto two-dimensional color feature images. Second, we propose to recognize all electric loads from color feature images using a deep neural network with multi-scale feature extraction and attention mechanism. Third, we design our method as a cloud-based, non-intrusive monitoring of all users, thereby saving energy cost during electric power system control. Experimental results on both public and our private datasets have demonstrated our method achieves superior performances than its peers, and thus supports efficient energy management over large-scale Internet of Things.

In the dynamic landscape of drug discovery, Computer-rAided Drug Design (CADD) emerges as a transformative force, bridging the realms of biology and technology. This paper overviews CADD's historical evolution, categorization into structure-based and ligand-based approaches, and its crucial role in rationalizing and expediting drug discovery. As CADD advances, incorporating diverse biological data and ensuring data privacy become paramount. Challenges persist, demanding the optimization of algorithms and robust ethical frameworks. Integrating Machine Learning and Artificial Intelligence amplifies CADD's predictive capabilities, yet ethical considerations and scalability challenges linger. Collaborative efforts and global initiatives, exemplified by platforms like Open Source Malaria, underscore the democratization of drug discovery. The convergence of CADD with personalized medicine offers tailored therapeutic solutions, though ethical dilemmas and accessibility concerns must be navigated. Emerging technologies like quantum computing, immersive technologies, and green chemistry promise to redefine the future of CADD. The trajectory of CADD, marked by rapid advancements, anticipates challenges in ensuring accuracy, addressing biases in AI, and incorporating sustainability metrics. The paper concludes by highlighting the need for proactive measures in navigating the ethical, technological, and educational frontiers of CADD to shape a healthier, brighter future in drug discovery.

This paper details the comprehensive activities conducted in a laboratory setting to assess the Structural Health Monitoring (SHM) of prefabricated building envelopes. Aimed at enhancing the structural evaluation of buildings, the focus of this research lies in employing nondestructive sensors for SHM with the objective to advance in the understanding and assessment of facade conditions. The paper outlines the methodologies employed, starting with a modal analysis to define the structural vibration's modal frequency. Subsequently, tests were defined and executed to validate building envelope compliance in case of stress typical of high-rise building. Throughout these tests, continuous monitoring of the façade was conducted using both conventional (accelerometers, extensimeter washers) and non-conventional sensors (Fiber Optic Sensing) The gathered data underwent thorough processing and analysis to provide an overall perspective on the structure's behavior during the stress test. The investigation aimed to identify whether specific physical phenomena correlate with distinct signals and to evaluate if continuous façade monitoring over the building's lifespan aids in preventing potential structural damage. Moreover, two modal analyses were conducted to compare final data and frequencies with earlier data, enabling the detection of any structural alterations. The results from compliance testing and structural analysis yielded noteworthy insights contributing to the evolving field of structural health monitoring, offering valuable findings that advance our ability to proactively manage and maintain the integrity of building structures.