Background: Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved vaccines or treatments for enterovirus infections. Methods: We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 (EV1) in human adenocarcinoma alveolar basal epithelial A549 cells. We also tested combinations of the most active compounds against EV1 in A549 and human immortalized retinal pigment epithelium RPE cells. Results: We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir-vemurafenib, vemurafenib-pleconaril and rupintrivir-pleconaril combinations against EV1 infection. Conclusions: Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their combinations may have fewer side effects in vivo and therefore should be further studied in pre- and clinical trials.

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.

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.

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.

Antimicrobial resistance (AMR) has been a serious threat to human health, and combination therapy is proved to be an economic and effective strategy to fight the resistance. However, the abuse of drug combinations would conversely accelerate the spread of AMR. In our previous work, it had been concluded that the mutant selection indexes (SIs) of one agent against a specific bacterial strain are closely related to the proportions of two agents in a drug combination. To discover probable correlations, predictors and laws for further proposing feasible principles and schemes guiding the AMR-preventing practice, here three aspects were further explored. First, the power function (y=ax^b, a > 0) correlation between the SI (y) of one agent and the ratio value (x) of two agents in a drug combination was further established based on the mathematical and statistical analyses for those experimental data, and two rules a₁ × MIC₁ = a₂ × MIC₂ and b₁ + b₂ = -1 were discovered from both equations of y=a₁x^b1 and y=a₂x^b2 respectively for two agents in drug combinations. Simultaneously, it was found that one agent with larger MPC alone for drug combinations show greater potency for narrowing itself MSW and preventing the resistance. Second, a new concept as mutation-preventing selection index (MPSI) was proposed and used for evaluating the mutation-preventing potency difference of two agents in drug combinations, and the positive correlation between the MPSI and the mutant prevention concentration (MPC) or minimal inhibitory concentration (MIC) was subsequently established. Inspired by this, the significantly positive correlation, contrary to previous reports, between the MIC and the corresponding MPC of antimicrobial agents against pathogenic bacteria was established using one hundred and eighty-one of data pairs reported. These results together of above three aspects indicate that the MPCs in alone and combination are very important indexes for drug combinations to predict the mutation-preventing effects and the trajectories of collateral sensitivity, and while the MPC of an agent can be roughly calculated from its corresponding MIC. Subsequently, the former conclusion was further verified and improved by the antibiotic exposure to forty-three groups designed as different drug concentrations and various proportions. The results further proposed that the C/MPC for the agent with larger proportion in drug combinations can be considered as a predictor and is the key to judge whether the resistance and the collateral sensitivity occur to two agents. Based on these above correlations, laws, and their verification experiments, some principles were proposed, and a diagram of the mutation-preventing effects and the resistant trajectories for drug combinations with different concentrations and ratios of two agents was presented. Simultaneously, the reciprocal of MPC alone (1/MPC), proposed as the stress factors of two agents in drug combinations, together with their SI in combination, is the key to predict the mutation-preventing potency and control the trajectories of collateral sensitivity. Finally, a preliminary scheme for antimicrobial combinations preventing the AMR was further proposed for subsequent improvement research and clinic popularization, based on the above analyses and discussion. Moreover, some similar conclusions were speculated for triple or multiple drug combinations.

Background: In the present study, cisplatin, artemisinin and oleanolic acid were evaluated alone and in combination, on human ovarian A2780, A2780ZD0473R and A2780cisR cancer cell lines with aim of overcoming cisplatin resistance and side effects. Methods: Cytotoxicity was assessed by MTT reduction assay. CI values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Results: Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism and biosynthetic processes and drug resistance and detoxification. Conclusion: Results indicate that appropriately sequenced combinations of cisplatin with ART and OA may provide a means to reduce side effects and circumvent platinum resistance.

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.

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.

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.

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.

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.

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.

Due to the extraordinary mechanical properties of ultra-high-performance concrete (UHPC), the shear stirrups in UHPC beams could potentially be removed. The aim of this study is to determine the effect of beam height and steel fiber volume content on the shear behavior of non-stirrup UHPC beams under a larger shear span-depth ratio (up to 2.8). Eight beams were designed and fabricated, including six non-stirrup UHPC beams and two comparing stirrup-reinforced normal concrete (NC) beams. The experimental results demonstrated that the volume content of steel fiber could be a crucial factor affecting the ductility, cracking strength, and shear strength of non-stirrup UHPC beams and altering their failure modes. Additionally, the height of the beam had a considerable effect on its shear resistance. This study revealed that the French standard formulae were more accurate for the UHPC beams with larger shear span-depth ratios and PCI-2021 formulae greatly overestimate the shear capacity of UHPC beams with larger shear span-depth ratios. Xu’s formulae were more accurate for the steel fiber-reinforced UHPC beams with larger shear span-depth ratios.

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.

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.

Large-span post-tensioned (PT) beams play a crucial role in maximizing the benefits of post-tensioning techniques. Bonded and unbonded systems are prevalent, with the latter being more widespread in the United States. While bonded systems are advantageous for creating long spans when multiple tendons are grouped in ducts, limited literature exists on their demolition. In a case study, this paper addresses the unique challenge of demolishing large-span bonded post-tensioned beams due to a building's functional change. Emphasizing insights for engineers, it explores the use of cutting and dismantling methods, considering the presence of prestressed cables. The demolition process is distinctive due to the presence of numerous pre-stressed cables along the beams, necessitating a specialized and cautious cutting approach. This is accomplished through the use of a drilling technique that selectively distresses the tendons, ensuring they are not all affected simultaneously. An intriguing observation discussed in this paper pertains to the occurrence of horizontal cracks accompanied by loud sounds following the drilling process, offering insights from the design perspective of PT systems. The paper details an innovative method for safely demolishing large-span bonded PT beams, using ground-penetrating radar and computer models to navigate structural complexities and ensure nearby structures' safety.

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.

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations in dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies, and 31 articles referring to case reports/clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts/essential oils, calcineurin inhibitors, peptides, disinfectant agents and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e.: azole [mainly itraconazole], terbinafine or griseofulvin) plus a topical medication (i.e.: azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful in accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available as far, it is desirable to continue the research in this field.

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.

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.

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.

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.

Although working memory (WM) is crucial for intellectual abilities, not much is known about its brain underpinnings, especially the structural connectivity. We used diffusion tensor imaging (DTI) to look across the whole brain for the white matter integrity correlates of the individual differences in the reading span (verbal WM capacity during reading) in healthy adults. Right-handed healthy native Russian speakers (N = 67) underwent DTI on a 3T Philips Ingenia scanner. Verbal WM was assessed with the Daneman-Carpenter reading span test (Russian version). Fractional anisotropy maps from each participant were entered into the group tract-based spatial statistics analysis with the reading span as a covariate; the results were TFCE-corrected. After taking into account effects of age, sex, education and handedness, reading span positively correlated with the white matter integrity in multiple sites: the body, the genu and the splenium of corpus callosum; bilateral corona radiata (anterior, posterior, and superior); bilateral superior longitudinal fasciculus; several tracts in the right hemisphere only, including the internal and external capsule; bilateral superior parietal and frontal white matter. Although the left hemisphere is central for verbal processing, we revealed the important role of the right hemisphere white matter for the verbal WM capacity. Our finding indicates that larger verbal working memory span may originate from additional processing resources of the right hemisphere.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

The present study aims to evaluate the antibacterial activity of five commercially available essential oils (EOs): Lavender (LEO), Clove (CEO), Oregano (OEO), Eucalyptus (EEO), and Peppermint (PEO) against the most-known MDR Gram-positive and Gram-negative bacteria - Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853) - alone and in various combinations. Gas Chromatography-Mass Spectrometry (GC-MS) analysis established their complex composition. Then, the antibacterial activity was investigated in vitro by diffusimetric antibiogram method, using sterile cellulose discs with Ø 6 mm impregnated with 10 µl of sample and sterile borosilicate glass cylinders loaded with 100 µl of sample; MIC (µg/mL) for each EO was calculated from IZD values (mm) measured after 24 hours. The following EO combinations were evaluated: OEO+CEO, CEO+EEO, CEO+PEO, LEO+EEO, and EEO+PEO. Then, the influence of each dual combination on 3 conventional antibacterial drugs – Neomycin (NEO), Tetracycline (TET), and Bacitracin (BAC) - activity was investigated. The most active EOs against S. aureus and E. coli were LEO and OEO (IZD = 40 mm). They were followed by the CEO and EEO (IZD = 20-27 mm); PEO exhibited the lowest antibacterial activity (IZD = 15-20 mm). EEO alone showed the highest inhibitory activity on P. aeruginosa (IZD = 25-35 mm). It was followed by the CEO, LEO, and EEO (IZD = 7-11 mm), while PEO proved no antibacterial action against it (IZD = 0 mm). Only one synergic action was recorded (OEO+CEO against P. aeruginosa); EEO+PEO revealed partial synergism against S. aureus and CEO+PEO additive behavior against E. coli. Two triple associations with TET showed partial synergism against E. coli, and the other 2 ones (with NEO and TET) evidenced the same behavior against S. aureus; all contained EEO+PEO or CEO+PEO. Most combinations reported indifference. However, numerous cases were of antagonism between constituents included in double and triple combinations, and EOs with the strongest antibacterial activities belong to the highest antagonistic combinations. A consistent statistical analysis supports our results, showing that EOs with moderate antibacterial activities could generate combinations with higher inhibitory effects based on synergistic or additive interactions.

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.

The rapid rise in research and development following the discovery of photodynamic therapy to establish novel photosensitizers and overcome the limitations of the technology soon after its clinical translation has given rise to a few significant milestones. These include several novel generations of photosensitizers, the widening of the scope of applications, leveraging of the offerings of nanotechnology for greater efficacy, selectivity for the disease over host tissue and cells, the advent of combination therapies with other similarly minimally invasive therapeutic technologies, the use of stimulus-responsive delivery and disease targeting, and greater penetration depth of the activation energy. Brought together, all these milestones have contributed to significant enhancement of what is still arguably a novel technology. Yet the major applications of photodynamic therapy still remain firmly located in neoplasms, from where most of the new innovations appear to launch to other areas, such as microbial, fungal, viral, acne, wet age-related macular degeneration, atherosclerosis, psoriasis, environmental sanitization, pest control, and dermatology. The core value proposition of combinations of photodynamic therapy is that they enhance the leading alternative and are proposed to overcome challenges of the leading clinical anticancer and antibacterial methods, mainly due to its inherent barriers against the emergence of resistance and its rapid development of targeted and high precision therapy. Combinations with chemotherapy and radiotherapy and demonstrated applications in mop-up surgery adventitiously promise to repurpose these top three clinical tools. This review will navigate the vast and increasing innovations that have been created so as to obviate novel areas of further innovation.

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.

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 purpose of the study was to provide support in the decision-making process for architects and engineers regarding large-spans structures for the presentation of archaeological sites in situ - construction of roofs, shelters, and bridges. We examined existing practice and analyzed their engineering classifications looking for a pattern in their application regarding sustainability and relation between type of cultural heritage site and type of applied large span structure. Contemporary engineering structures at built heritage sites create a sharp contrast between old and new. A presentation of cultural heritage in situ requires an understanding of heritage theory and internationally accepted doctrine which exceeds common engineering education. Nevertheless, application of large-span structures, which often take advantages of state-of-art construction-technologies nowadays, is also an aesthetical statement that affects the appearance of the site. Therefore, we gave an overview of the theoretical background of aesthetical issues and the overall ethics of the decision-making process in such sensitive cases. Within the framework of heritage-presentation, engineering and architectural issues, and selected case studies, we concluded in favor of the application of large-span structures under certain conditions.

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.

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.

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.

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.

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.

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.

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.

The recently defined and yet rather new topic of Healthy aging is gathering more attention on the global stage. With world’s population getting older - it is rapidly becoming very important to develop and maintain functional abilities in older age and develop mechanisms to protect senior population from chronic diseases. One of the most effective components, as well as, one may call - process involved in, and strongly associated with aging is recently discovered and Nobel prize awarded - nitric oxide as a signaling molecule, which followed by later discoveries showed to have a positive metabolic, immune and anti-inflammatory effects. One of the most debated topics of the last decade in the scientific community is nitrates, one of the pathways involved in nitric oxide production. Thus, the objective of this study was to evaluate effect of different potassium nitrate concentrate supplementation on Drosophila melanogaster longevity. 0,5-3% potassium nitrate medium was analyzed on the life span and motor function in different groups consisting of 100 females fruit flies each. In this assay, female fly species supplemented with potassium nitrate diet showed life span increase by 18.6% and 5.1% with 1% and 2% KNO3- respectively with a positive impact on locomotor function. In conclusion, we found that low concentration of potassium nitrate medium increased lifespan and locomotor function in Drosophila melanogaster.

This paper discusses a possible approach to validate the Goldbach conjucture which states that all even numbers can be expressed as a summation of two prime numbers. For this purpose the paper begins with the concept of successive-addition-of-digits-of-an-integer-number (SADN) and its properties in terms of basic algebraic functions like addition, multiplication and subtraction. This concept of SADN forms the basis for classifying all odd numbers into 3 series- the S1, S3 and S5 series- which comprise of odd numbers of SADN(7,4,1), SADN(3,9,6) and SADN(5,2,8) respectively and follow a cyclical order. The S1 and S5 series are of interest in the analysis since they include both prime and composite numbers while the S3 series exclusively consists of composite numbers. Furthermore, the multiplicative property of SADN shows why composites on the S1 series are derived as products of intra-series elements of the S1 and S5 series while composites on the S5 series are derived as products of inter-series elements of the S1 and S5 series. The role of SADN is also important in determining the relevant series for identifying the combination of primes for a given even number since it shows why such combinations for even numbers of SADN(1,4,7) will be found on the S5 series while those for even numbers of SADN(2,5,8) will lie on the S1 series and both the series have a role to play in identifying the prime number combinations for even numbers with SADN(3,6,9). Thereafter, the analysis moves to calculating the total number of acceptable combinations for a given even number that would include combinations in the nature of two composites (c1+c2), one prime and one composite (p+c) and two primes (p1+p2). A cyclical pattern followed by even numbers is also discussed in this context. Identifying the c1+c2 and p+c combinations and thereafter subtracting them from the total number of combinations will yield the number of p1+p2 combinations. For this purpose the paper discusses a general method to calculate the number of composites on the S1 and S5 series for a given number and provides a detailed method for deriving the number of c1+c2 combinations. The paper presents this analysis as a proof to validate the Goldbach conjecture. Since even numbers can be of SADN 1 to 9 and the relation between nTc (i.e. total number of acceptable combinations) and nc(i.e. number of composites) for all even numbers can either be of nTc > nc or nTc ≤ nc, the paper shows that the Goldbach conjecture is true for both these categories of even numbers. In this manner this analysis is totally inclusive of all even numbers in general terms and since the analysis of every even number is common in methodology but unique in compilation, apart from being totally inclusive, it is also mutually exclusive in nature. This proves that the Goldbach conjecture which states that all even numbers can be expressed as atleast one combination of two prime numbers holds true for all even numbers, across all categories possible. Additionally this approach proves that the identification of p1+p2 combinations which would validate the Goldbach conjecture lies in the identification of c1+c2 combinations.

Texture has long been considered an important attribute for food acceptance. However, which specific textural characteristics contribute to overall acceptance of a food is not well understood. It has been suggested that texture contrasts and combinations are a universal feature in giving foods a desirable texture, yet this notion is largely based upon anecdotal data. This study uses multiple survey research methods to assess the importance of texture contrast and combinations across cultures (Poland, U.S.A., and Singapore). Participants (n = 288) completed a survey that included overt measures of food texture contrast importance as well as free response questions regarding texture. The overall importance of texture for food liking was not different across the populations. However, the participants from Singapore and Poland gave more importance to a desirable food having multiple textures than the U.S.A. cohort. When looking at free responses, participants were twice as likely to mention combinations (multiple textures) with a texture contrast when describing foods they liked, in comparison to foods they disliked. This was observed across all 3 cultures. However, the type and quantity of texture terms used within combinations were different among cultures. For instance, Asians enjoyed more texturally diverse food combinations than the other two cultures. These findings highlight the importance of texture contrasts and combinations in three distinct cultures.

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.

Cisplatin is an election chemotherapeutic agent for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. In this paper we report that a combination of vitamins A, C, E and Mg++ (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in the rat. The addition of 500 mg N-acetylcysteine (NAC), which administered individually also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation, results in degradation of ACEMg otoprotection. Mg++ administered alone, as MgSO4, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection also is greatly degraded. Increasing the dose of NAC to 1000 mg, also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet to be defined “antioxidation threshold”, results in unrecoverable redox imbalance with loss of otoprotectant activity.

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.

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.

Rubber compounds based on styrene-butadiene rubber, ethylene-propylene-diene-monomer rubber and the combinations of both rubbers were cured with different sulfur and peroxide curing systems. In sulfur curing systems, two type of accelerators, namely N-cyclohexyl-2-benzothiazole sulfenamide, tetramethylthiuram disulfide and combinations of both accelerators were used. In peroxide curing systems, dicumyl peroxide, and combination of dicumyl peroxide with zinc diacrylate or zinc dimethacrylate, respectively were applied. The work was focused on investigation of the curing system composition as well as type of the rubber or rubbers combinations on curing process, cross-link density and physical-mechanical properties of vulcanizates. The dynamic-mechanical properties on the selected vulcanizates were examined, too. The result revealed correlation between the cross-link density and physical-mechanical properties. Similarly, there was recorded certain correlation between cross-linking degree and glass transition temperature. The tensile strength of vulcanizates based on rubbers combinations was higher when compared to that based on pure rubbers, which points out the fact that by rubbers combination, not only the features of both elastomers can be combined, but also improved tensile characteristics can be achieved. When compared to vulcanizates cured with dicumyl peroxide, materials cured with sulfur system exhibited higher tensile strength. By application of co-agents in peroxide vulcanization, the tensile strength overcame the tensile behavior of sulfur cured vulcanizates.

In the semi-arid region of Brazil, it is common to use saline or brackish water for crop production. However, this practice can negatively affect the soil, nutrient balance, and fruit quality and production. From this perspective, this study aimed to evaluate the effect of fertilization combinations with nitrogen (N), phosphorus (P), and potassium (K) on the production and quality of West Indian cherry grown under salt stress in the second year of production. The study was conducted in a protected environment following a randomized block design with treatments distributed in a 2 x 10 factorial arrangement referring to two levels of electrical conductivity of irrigation water (ECw) (0.6 and 4.0 dS m-1) and 10 NPK fertilization combinations (80-100-100; 100-100-100; 120-100-100; 140-100-100; 100-80-100; 100-120-100; 100-140-100; 100-100-80; 100-100-120 e 100-100-140% of the recommendation in the second year of production), with three replicates and one plant per lysimeter. The results indicate that irrigation of West Indian cherry crop irrigation at the water salinity of 4.0 dS m-1 negatively affected all fruit production variables. The interaction between the ECw of 0.6 dS m-1 and the 100-80-120 NPK fertilization combination increased the total number of fruits and the total fruit weight of West Indian cherry.

In view of the limitations of the existing optimization method of suspender cable force, in order to improve the stress of suspender under completion state and avoid frequent adjustment of cable force and grid beam elevation during construction, a new method of cable force optimization is proposed. The article takes the longest large span arch bridge in the world, Pingnan Third Bridge, a Concrete-filled steel tube (CFST) arch bridge with a span of 575m as the engineering background combined with the finite element analysis and multi-objective optimization method. One cable force optimization method that suspender “Real-time correction during construction, in the process variable optimal and results reliable” during panel girder lifting of long span CFST arch bridges is clarified. Taking the panel girder weight and displacement during the construction as parameter variables, the displacement and unevenness of the panel girder under completion state as constraint conditions, the displacement and cable force during the hoisting construction as the objective equation, through the optimization of the objective equation, the suspender cable force and dis-placement of each hoisting section are calculated. The results show that it is feasible to introduce the optimization theory into the cable force optimization when lifting the panel girder. the segment displacement variation is minimized to meet the destination. The cable force distributed evenly under completion state of the bridge that further making sure the completion state satisfies the requirements. No repeating iteration is needed, thus avoiding cumberso me calculation, getting cable force once. With higher optimization efficiency and better effects, the method provides high value for the cable force calculation of same type bridge suspender construction and for guiding construction.

Noise model selection criteria has a significant impact on identifying the stochastic noise proper-ties of any GNSS daily coordinate time series. The low-frequency random walk noise existing in these time series could lead to overestimation of the tectonic rate, so it is of great significance to accurately detect the random walk component. This study focuses on noise model estimation cri-terion (BIC_tp) derived from the AIC and the BIC by introducing 2π factors. It is more sensitive to abnormal steps (random jumps). Using observation data from 72 GNSS stations from 1992 to 2022 and simulated data, four combined noise models are used to explore the impacts of time se-ries lengths (ranging from2 to 24 years) and data loss (between 2% and 30%) on noise models and velocity estimation. The results show that as the time length increased, the selected optimal noise model, and the estimated uncertainty of the tectonic trend with different data gap, gradually con-verge. When the time length is short (less than 8 years), it could lead to the FNRWWN, FNWN, and PLWN models being mistakenly estimated as GGMWN models, thereby affecting the accura-cy of determining the station velocity parameters. When the time length is 12 years, the RW noise component is more probably detected, As the time length increases, the impact of RW on velocity uncertainty is weakened. Finally, we conclude that for a time series with a minimum time length of 12 years, both the selection of the optimal stochastic noise model and the estimation of the ve-locity parameters are reliable.

The BP neural network and PSO algorithm are applied into analyzing the reliability of long-span Concrete Filled Steel Tubular (CFST) arch bridges. Firstly, using BP neural network to fit the structural performance function. And then the PSO method was used to calculate the reliability index. A long-span Concrete Filled Steel Tubular arch bridges reliability indices were calculated whether considering the geometric nonlinearity or not. The calculation and analysis results showed that the BP neural network and PSO algorithm compensated the deficiency of the traditional reliability analysis methods, improved the calculation accuracy, provided a new thought and means for the research on the reliability of long-span bridge structure, and well applied to the reliability analysis of long-span Concrete Filled Steel Tubular arch bridges. Additionally, the reliability analysis of long-span Concrete Filled Steel Tubular arch bridges on service limit state must consider the geometric nonlinearity effect, or the results will tend to be unsafe.

During composting process, soils undergo many changes in their physical, chemical and biological properties. Composting has been widely known as an aerobic process during which organic matter is decomposed to humus like substances broken into many organic materials or compounds. The project aims to compare and analyze different combination of composting that yield different properties and nature of soils, and testing their soil physical properties. Dug three compost pits each 1.5 m in depth, labeled compost pit A consisting of potato peels – the only kitchen waste most common around the college hostels, compost pit B consisting of leaf litter and other garden trimmings and compost pit C consisting of cow dung and the other as a controlled experiment with no composting practices.

The unusual occurrence and developmental diversity of asexual eukaryotes still remain a puzzle. Despite asexual organisms have a theorized two-fold reproductive advantage over sexuals, asexual lineages are rare among multicellular eukaryotes. Justification of such disparity relies on the consequences of a lack of meiosis, which restricts genotype diversity and adaptation to novel conditions while accelerating the genetic degeneration that drives asexual lineages to an early demise. However, evidence indicates asexuals use different strategies to limit negative consequences of ameiosis, and age estimates show some asexual vertebrates and plants are much older than expected. If rapid extinction is not a factor influencing asexuals lifespan, then why asexuals are not more frequent? Here we review traditional ideas and new data and provide a novel unified evolutionary frame to understand the intriguing nature, developmental diversity and maintenance of asexual lineages. As a rule, de novo formation of a functioning asexual genome requires a unique assemblage combining particular sets of genes or gene states to disrupt cellular mechanisms of meiosis and gametogenesis, and affect discrete components of sexuality to produce clonal or hemiclonal offspring. We highlight two usually overlooked but essential conditions to understand the molecular nature of clonal organisms, i.e. a non-recombinant genomic assemblage retaining modifiers of the sexual program, and a complementation between altered reproductive components. These subtle conditions are the basis for physiologically viable and genetically balanced transitions between generations. Genomic and developmental evidence from asexual animals and plants indicates the lack of complementation of molecular changes in the sexual reproductive program is likely the main cause of asexuals' rarity, and can provide an explanatory frame for the developmental diversity and lability of developmental patterns in some asexuals as well as for the discordant time to extinction estimations.

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.

Several bio-actors are involved in the occurrence of leishmaniasis, which is made too complex for prevention and control options. Currently, all forms of leishmaniasis are being treated with chemical drugs, which have limitations and adverse effects on patients. Searching the bioactive molecules from plant sources allows the development of a novel drug. The essential oil and solvent extract of the roots of E. kebericho showed antileishmanial activity. But looking for biological activities of the isolated active ingredient from tubers of E. kebericho was scant. Thus, the isolation of the leishmanicidal compound from the roots of E. kebericho through a bioassay-guided technique was an aim of this work. Dehydrocostus lactone showed doubled potent than the standard drug miltefosine on leishmanicidal activities against L. major and L. tropica. Besides, the broad-spectrum biological activities of dehydrocostus lactone could be a potential drug candidate for co-infected patients caused by an association of leishmania and another pathogen.

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.

Rasagiline (Azilect®) is a selective monoamine oxidase B (MAO-B) inhibitor that provides symp-tomatic benefit in Parkinson’s disease (PD) treatment and found to exert preclinical neuroprotec-tive effects. Here, we investigated the neuroprotective signaling pathways of rasagiline in the PC12 neuronal cultures exposed to an ischemic-like insult. Exposure of neurons to oxy-gen-glucose deprivation for 4 h followed by 18 h of reoxygenation caused 40% aponecrotic cell death. Rasagiline induced dose-dependent neuroprotection by decreasing cell death and produc-tion of the neurotoxic reactive oxygen species, and reducing the nuclear translocation of glycer-aldehyde-3-phosphate dehydrogenase (GAPDH). Rasagiline increased protein kinase B (Akt) phosphorylation and decreased protein expression of the ischemia-induced α-synuclein protein, in correlation to the neuroprotective effect. Treatment with rasagiline induced nuclear shuttling of transcription factor Nrf2 and increased the mRNA levels of the antioxidant enzymes heme oxy-genase-1, (NAD (P) H- quinone dehydrogenase, and catalase. These results indicate that rasagiline provides neuroprotection in the ischemic neuronal cultures with inhibition of α-synuclein and GAPDH-mediated aponecrotic cell death, and via mitochondrial protection, as by increasing mi-tochondria-specific antioxidant enzymes by a mechanism involving the Akt/Nrf2 redox-signaling pathway. These findings may be exploited for neuroprotective drug development in PD and stroke therapy.

Pseudomonas aeruginosa infections are the focus of new treatment alternatives due to their frequent development of resistance to antibiotics and formation of biofilms. Recently, emphasis has been placed on combinations of antibiotics with drugs used for different indications. In this study the combined effects of metformin with imipenem, ceftazidime, cefepime, ciprofloxacin and levofloxacin has been investigated. 50 P. aeruginosa isolates isolated from patients with cystic fibrosis come to Gaziantep University Microbiology Laboratory were included in the study. The susceptibilities of the isolates to antibiotics were investigated by the liquid microdilution method and the combined effect of metformin and antibiotics by the chequerboard synergy test. In our study, as a result of the chequerboard synergy test; synergy between ceftazidime and metformin 6%, partial synergistic 22% isolates; while no synergistic effect was detected between cefepime and metformin in any isolate, partially synergy 46%; synergy between imipenem and metformin 4%, partial synergy 10%; synergy between ciprofloxacin and metformin 6%, partial synergy 6%, antagonist effect 2%; synergy was detected between levofloxacin and metformin 2% and a partial synergy was detected 12%. This study shows that metformin could be a potential antibiotic in its current form or in different chemical forms to be produced synthetically.

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.

Microneedle technology is a novel platform technology that revolutionizes ocular drug delivery and addresses critical challenges in the treatment of ocular diseases. Routine treatment methods, such as eye drops and intravitreal injections, suffer from low bioavailability and poor patient compliance. So, novel advanced platform technologies are required to overcome these challenges. Microneedle is a minimally invasive and promising alternative technique that helps precisely control drug delivery to targeted tissues and organs. This review investigates the potential impact of microneedle technology for eye care, underscoring recent advancements, underlying mechanisms, and emerging preclinical and clinical uses. Different types of microneedles, including solid, coated, dissolvable, and hollow, have demonstrated their potential and capability to bypass several barriers in the cornea and sclera. This ensures effective drug penetration and delivery. The current innovations in material science and fabrication methods have enhanced the safety and efficacy of microneedles, reducing discomfort and the chances of infections. These microneedle technologies offer sustained and controlled drug delivery, which could improve therapeutic outcomes for various disease conditions like age-related macular degeneration, glaucoma, diabetic neuropathy, etc. In the current review, recent preclinical and clinical studies emphasize microneedle-based ocular drug delivery's feasibility and potential benefits. These include improved pharmacokinetics, reduced dosing frequency, enhanced patient adherence, and, most importantly, microneedles offer versatile platforms for delivering a wide range of small and large molecules and gene therapies. Despite the exciting progress, obstacles such as regulatory barriers, scalability, and long-term biocompatibility persist. It will be essential to tackle these challenges through interdisciplinary research and partnerships to integrate microneedle technology into standard clinical use effectively. Ultimately, microneedle drug delivery offers a revolutionary method that has the potential to significantly enhance the treatment and results of ocular diseases, marking the dawn of a new era in eye care.

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric problem with a few core symptoms: weaknesses in social behavior, verbal impairments, repetitive behavior and restricted interests. Beyond the core symptoms, autism has strong association with other disorders such as intellectual disability, epilepsy, schizophrenia among many others. This paper outlines a theory of ASD with capacity to connect heterogeneous ‘core’ symptoms, medical and psychiatric comorbidities as well as other etiological theories of autism in a unifying cognitive framework rooted in neuroscience and genetics. Cognition is embedded into an ever-developing structure modified by experiences, including the outcomes of environment influencing behaviors. We introduce the hypothesis that autism is caused by deficits in component-based cognition and the internal learning reinforcing machinery. Specifically, we outline our Cartesian Factor forming autoencoder like model that supports cognition by breaking combinatorial explosion and discuss the cognitive and neural processes behind our model. The high dimensionality of sensory information poses serious problems, since the brain can handle only 7±2 relevant variables at a time making processes, such as the extraction and encoding of the relevant variables and their efficient manipulation critical. These processes are influenced by previous experiences and the internal reward system. In addition, large delays of distributed information processing should be counteracted by learned predictive models to synchronize sensory, proprioceptive, and cognitive signals and have timely and accurate model-based actions. Impairments in any of these aspects may disrupt learning and execution. Combinations of small impairments may allow the solving of low complexity tasks but may become visible if learned variables and the related metric are improper and imprecise, respectively, especially if their number is large. We claim that social interactions are amongst the most challenging cognitive tasks in terms of the number of variables involved. In turn, they are highly susceptible to combinations of small impairments. We consider impairments as the basic colors of autism, whereas the combinations of diverse impairments make the palette of autism. In turn, social processes can be spoiled in many ways and can lead to diverse comorbidities.

Chitosan (CS) nanoparticles are under investigation for a wide range of applications in nanomedicine. The structural, molecular and physicochemical properties of chitosan nanoparticles have a direct bearing on their efficacy in drug conjugation and delivery, gene delivery, and tissue engineering. Herein we report on the structural, morphological and molecular properties of chitosan nanoparticles synthesized using the ionic gelation method with the intended purpose of being used for drug delivery. The chitosan nanoparticles (CS-NPs) were prepared in the 0.25 to 1.0% w/v concentration range, whereas separate samples of the 1.0% w/v CS-NPs were also functionalized with polyethylene oxide (PEO) alone and with a diblock copolymer of PEO and polypropylene glycol (PPG). The average size of the CS-NPs was determined from TEM imaging to be in the range of 11.3 to 14.8 nm. The XRD and TEM analyses show that the CS-NPs have semi-crystalline structure with the degree of crystallinity depending upon the nature of synthesis. Our results show that functionalizing the 1.0% w/v CS-NPs with PEO increases the degree of crystallinity whereas functionalizing with the diblock copolymer PEO - PPG results in a significant increase in their degree crystallinity. The CS/TPP concentration (CS:TPP fixed at 1:1 ratio) had no apparent effect on the degree of crystallinity of the CS-NPs. The results from the FTIR analysis confirm incorporation of TPP with CS in the CS-NPs. Additionally, FTIR analysis shows an enhancement of hydrogen bonding that is consistent with the increase in the degree of crystallinity of the CS-NPs.

Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin and MMP2, enhancing drug resistance and migration in recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights to the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment.

As Chronic Non-Communicable Diseases (CNCD) increase, preventive approaches become more crucial. In this review, Calorie Restriction (CR) effects on human beings were evaluated, comparing benefits and risks of different CR diets: classic CR vs ketosis-inducing diets, including Intermittent Fasting (IF), Classic Ketogenic Diet (CKD), Fasting Mimicking Diet (FMD), Very-Low-Calorie Ketogenic Diet (VLCKD) and Spanish Ketogenic Mediterranean Diet (SKMD). Special emphasis on Insulin Resistance (IR) was placed, as it mediates Metabolic Syndrome (MS), a risk factor for CNCD, and predicts MS diagnosis. CR is the most robust intervention known to increase lifespan and health span, with high evidence and known biochemical mechanisms. CR improves cardiometabolic risk parameters, boosts exercise insulin sensitivity response, and there may be benefits of implementing moderate CR on healthy young and middle-aged individuals. However, there is insufficient evidence to support long-term CR. CKD is effective for weight and MS management, and may have additional benefits such as prevention of muscle loss and appetite control. SKMD has extreme significance benefits for all the metabolic parameters studied. Studies show inconsistent benefits of IF compared to classic CR. More studies are required to study biochemical parameters, reinforce evidence, identify risks, and seek effective and safe nutritional CR approaches.

One of the non-linear phenomena that affect high bandwidth and long reach communication systems is the non-linear phenomenon called four-wave mixing (FWM). Unfortunately, the simulation of such systems aiming to obtain their design parameter limitations require more time as the number of channels increases. In this paper, we propose a new high-performance computational model to obtain optimal design parameters in a multi san Dense Wavelength Division Multiplexing (DWDM) system, limited by FWM and the intrinsic Amplified Spontaneous Emission (ASE) noise of optical amplifiers employed in each segment. The simulation in this work provides a complete optical design characterization and compares the efficiency and speed improvement of the proposed parallelization model versus a previous sequential model. Additionally, an analysis of the computational complexity of parallel model is presented, where two parallel implementations are used. First, Open Multi−Processing (OpenMP), based on the use of a central, multi-core processing unit is used and secondly the Compute Unified Device Arquitecture (CUDA), which is based on the use of graphics processing unit. Results show that parallelism improves to up to 40 times the performance of the simulation when nested parallelization with CUDA is used, over de sequential method and up to 6 times compared with the implementation with OpenMP using 12 processors. Within our parallel implementation, it is possible to simulate with an increased number of channels, that was unpractical in the sequential simulation.

Improper lifting measures of long-span spatial steel structures during construction process may delay the construction period and even cause safety accidents. Few studies on long-span spatial steel structures considered time-varying mechanical characteristic during construction process. In order to achieve safe and efficient installation in a long-span spatial steel structure, this research presents a time-varying mechanical analysis of the synchronous and asynchronous integral lifting and a single and interlaced point’s asynchronous integral lifting analysis method of a long-span spatial steel structure. The results showed that in the case of asynchronous lifting of single point, the displacement influence on other members is related to the distance. The closer the distance from the lifting point, the greater the influence. In asynchronous integral lifting, the lifting point with large lifting force is first installed to the specified position, and the lifting point with small lifting force is installed to the specified position.

The determination of the non-loading condition of the rail cable shifting (RCS) system, which consists of main cables, hangers and rail cables, is the premise of the girder erection for the long-span suspension bridges. An analytical form-finding analysis model of shifting system is established according to the basic assumptions of flexible cable structures. Herein, the rail cable is discretized into segmental linear cable elements and the main cable is discretized into segmental catenary elements. Moreover, the calculation and analysis equation of each member and their iterative solutions are derived by taking the elastic elongation of the sling into account. In addition, by taking the girder construction of Aizhai suspension bridge as engineering background, a global scale model of the RCS system is designed and manufactured; also the test system and working conditions are established. The comparison between the test results and analytical results shows the presented analytical method is correct and effective. The process is simplified in the analytical method, and the computational results and precision can satisfy the practical engineering requirements. In addition, the proposed method is suitable to apply to the computation analysis of similar structures.

The emergence of drug-resistant mycobacteria has rendered many clinical drugs and regimens ineffective, imposing significant economic and healthcare burden on individuals and society. Repurposing drugs intended for treating other diseases is a time-saving, cost-effective, and efficient approach for identifying excellent anti-mycobacterial candidates or lead compounds. This study is the first to demonstrate that rupatadine (RTD), a drug used to treat allergic rhinitis, possesses excellent activity against mycobacteria without detectable resistance, particularly Mycobacterium tuberculosis and Mycobacterium marinum, with a minimal inhibitory concentration as low as 3.13 µg/mL. Furthermore, RTD exhibited moderate activity against nonreplicating M. tuberculosis with the minimal inhibitory concentrations lower than drugs targeting the cell wall, suggesting that RTD has the great potential to be modified and used for the treatment of nonreplicating M. tuberculosis. Additionally, RTD exhibits partial synergistic effects when combined with clofazimine, pretomanid, and TB47 against M. tuberculosis, providing the theoretical foundation for the development of treatment regimens. Transcriptomic profiling leads us to speculate that eight essential genes may be the targets of RTD or may be closely associated with the mycobacterial resistance to RTD. In summary, RTD may be a promising hit for further anti-mycobacterial drug or regimen optimization, especially in case of nonreplicating mycobacteria.

Numerous types of oligonucleotide modifications have been developed since automated synthesis of DNA/RNA became a common instrument in the creation of synthetic oligonucleotides. Despite the growing number of types of oligonucleotide modifications under development, only a few of them, and moreover, their combinations have been studied wide enough in terms of their in-fluence on the properties of corresponding NA constructions. In the present study, a number of oligonucleotides with combinations of 3′ end lipophilic (single cholesteryl or pair of dodecyl residues) and phosphate backbone modifications were synthesized. The influence of the combi-nation of used lipophilic groups with phosphate modifications of various nature and different position on the efficiency of cell penetration was evaluated. Obtained results indicate that even a couple of phosphate modifications are able to affect a set of oligonucleotide properties in a complex manner and can remarkably change cellular uptake. These data clearly show that the strategy of using different patterns of modification combinations has great potential for the ra-tional design of oligonucleotide structures with desired predefined properties.

The athletic performance and safety of racehorses is influenced by hoof-surface interactions. This intervention study assessed the effect of eight horseshoe-surface combinations on hoof acceleration patterns at impact and foot-off in 14 galloping Thoroughbred racehorses retired from racing. Aluminium, barefoot, GluShu (aluminium-rubber composite) and steel shoeing conditions were trialled on turf and artificial (Martin Collins Activ-Track) surfaces. Shod conditions were applied across all four hooves. Tri-axial accelerometers (SlamStickX, range ±500 g, sampling rate 5000 Hz) were attached to the dorsal hoof wall (x: medio-lateral, medial=positive; y: along dorsal hoof wall, proximal=positive; z: perpendicular to hoof wall, dorsal=positive). Linear mixed models assessed whether surface, shoeing condition or stride time influenced maximum (most positive) or minimum (most negative) accelerations in x, y and z directions, using ≥40,691 strides (significance at p&lt;0.05). Day and horse-rider pair were included as random factors and stride time as a covariate. Collective mean accelerations across x, y and z axes were 22–98 g at impact and 17–89 g at foot-off. Mean stride time was 0.48 ± 0.07 s (mean ± 2 s.d.). Impact accelerations were larger on turf in all directions for forelimbs and hindlimbs (p≤0.015), with the exception of forelimb z-minimum, and in absolute terms maximum values were typically double minimum values. Surface-type affected all foot-off accelerations (p≤0.022), with the exception of hindlimb x-maximum; for example, there was an average increase of 17% in z-maximum across limbs on the artificial track. Shoe-type influenced all impact and foot-off accelerations in forelimb and hindlimb datasets (p≤0.024), with the exception of hindlimb impact y-maximum. Barefoot hooves generally experienced the lowest accelerations. Stride time affected all impact and foot-off accelerations (p<0.001). Identifying factors influencing hoof vibrations on landing and hoof motion during propulsion bears implication for injury risk and racing outcomes.

Climate change is the long-term shift in global weather patterns, largely caused by anthropogenic activity of greenhouse gas emissions. Global climate temperatures have unmistakably risen and naturally-occurring climate variability alone cannot account for this trend. Human activities are estimated to have caused about 1.0 °C of global warming above the pre-industrial baseline and if left unchecked, will continue to drastically damage the Earth and its inhabitants. Globally, natural disasters and subsequent economic losses have become increasingly impactful as a result of climate change. Both wildlife ecosystems and human habitats have been negatively impacted, from rising sea levels to alarming frequency of severe weather events around the world. Attempts towards alleviating the effects of global warming have often been at odds and remain divided among a multitude of strategies, reducing the overall effectiveness of these efforts. It is evident that collaborative action is required for avoiding the most severe consequences of climate change. This paper evaluates the main strategies (industrial/energy, political, economic, agricultural, atmospheric, geological, coastal, and social) towards both mitigating and adapting to climate change. As well, it provides an optimal combination of seven solutions which can be implemented simultaneously, working in tandem to limit and otherwise accommodate the harmful effects of climate change. Previous legislation and deployment techniques are also discussed as guides for future endeavors.

Lead optimization in drug discovery is a crucial phase where initial hits are refined into compounds with improved pharmacological properties. While traditional methods rely on manual experimentation and modifications, AI-driven techniques have revolutionized this process by leveraging big data and predictive modeling. This review explores how AI-driven approaches accelerate lead optimization, showcasing examples like deep neural networks and reinforcement learning. Integration of multi-omic data and experimental validation further enhances AI-driven strategies. The future lies in refining these AI methods, democratizing tools, and interdisciplinary collaboration to streamline drug discovery and address medical needs efficiently.

Background: Despite advances in the treatment of hepatocellular carcinoma (HCC) over the last few decades, treatment opportunities for patients with HCC remain limited. HCC is the most common form of liver cancer, accounting for approximately 90% of all cases worldwide. Moreover, apart from the current pharmacological interventions, hepatic resection and liver transplantation are the mainstay curative approaches for patients with HCC. Methods: This systematic review included phase I, II, III, and IV clinical trials (CTs) and randomized controlled trials (RCTs) on current treatments for patients with HCC in an Asian population (2013–2023). A total of 427 articles were screened, and 184 non-duplicate publications were identified. After screening titles and abstracts, 96 publications were excluded, and another 28 were excluded after full-text screening. The remaining 60 eligible RCTs/CTs were finally included. Results: Sixty clinical trials fulfilled our inclusion criteria and screened 36 drugs as monotherapy or combination therapy for HCC. Most studies used sorafenib alone or in combination with any of the treatment regimens. Lenvatinib or atezolizumab with bevacizumab was used for HCC after initial sorafenib treatment. Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. Conclusion: This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicated that sorafenib alone or in combination with atezolizumab and bevacizumab has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in an Asian population

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine if additional alkaloids in the extracts contribute to Hh signaling inhibition, we replicated the concentrations of these alkaloids observed in extracts using commercially available standards and compared the inhibitory potential of the extracts to alkaloid standard mixtures using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts contribute to Hh signaling inhibition.

Chronic wounds remain a significant clinical challenge, necessitating the exploration of novel therapeutic agents. Sedum telephium L. (syn. Hylotelephium telephium (L.) H. Ohba) leaf juice, known for its traditional medicinal uses, was evaluated for its wound healing properties. This study aimed to chemically characterize the leaf juice and assess its efficacy in promoting wound healing in vitro. Fresh leaves were collected and processed to obtain the juice, which was analyzed for polyphenols, flavonoids, polysaccharides, and proteins. Key bioactive compounds, including flavonols such as kaempferol glycosides and quercetin glycosides, were identified. The juice and its polysaccharidic fraction were tested on human keratinocytes (HaCaT) and fibroblasts (HFF-1) to assess cell viability, wound closure, and the production of growth factors and pro-collagen I. Our results indicated that the whole juice significantly enhanced wound closure in both cell types, with a marked increase in fibroblast growth factor (FGF) and LAP(TGF-β1) production in keratinocytes, highlighting its potential mechanisms of action. The polysaccharidic fraction alone showed limited efficacy, emphasizing the importance of the complete phytocomplex. These findings suggest that Sedum telephium L. represents a promising candidate in the setting of skin regeneration and repair.

The regulation of cell death is a fundamental issue in cell biology and continues to be intensely investigated worldwide. The significance of research in this field persists because understanding the determinants of cell lifespan directly impacts the maintenance of multicellular organism homeostasis and, consequently, is crucial for addressing biomedical challenges associated with various diseases. It is recognized that the initiation of cell death can be prompted by both specific signals (such as cytokines or hormones) and nonspecific stimuli, including radiation, temperature increase, or oxidants. When these factors affect a cell, numerous signaling pathways are triggered in the cell, leading to neutralization of the effects of their negative effects or, in case of irreparable damage, to cell elimination. This removal of damaged cells occurs through apoptosis or programmed cell death, a highly regulated process. Numerous signaling molecules participate in orchestrating the apoptotic process, many of which also govern other essential functions within the organism. Physiological factors capable of triggering the apoptotic program in cells include nitric oxide (NO), which serves as one of the key signaling molecules regulating the functions of the cardiovascular, nervous, and immune systems of the organism. The unique chemical nature of NO, along with its numerous intracellular targets and physiologically active redox forms, raises questions about the specific mechanisms through which NO exerts its damaging effects on cells. Utilizing pharmacological preparations- such as sources (donors) of exogenous nitric oxide- represents an approach to investigating the initiation and execution of the apoptotic program in sensitive target cells. Furthermore, this approach holds promise as a direction for discovering new selective drugs.

Does cell clustering influence intrinsic and acquired multi-drug resistance (MDR) differently? To address this question, we studied cultured monolayers (representing individual cells) and cultured spheroids (representing clusters) formed by drug-naïve (intrinsic MDR) and drug-exposed (acquired MDR) lines of ovarian cancer A2780 cells by cytometry of reaction rate constant (CRRC). MDR efflux was characterized by accurate and robust “cell number vs. MDR efflux rate constant (kMDR)” histograms. Both drug-naïve and drug-exposed monolayer cells presented unimodal histograms; the histogram of drug-exposed cells was shifted towards higher kMDR value suggesting greater MDR activity. Spheroids of drug-naïve cells presented a bimodal histogram indicating the presence of two subpopulations with different MDR activity. In contrast, spheroids of drug-exposed cells presented a unimodal histogram qualitatively similar to that of the monolayers of drug-exposed cells but with a moderate shift towards greater MDR activity. The observed greater effect of cell clustering on intrinsic than on acquired MDR can help guide the development of new therapeutic strategies targeting clusters of circulating tumor cells.

Public restrooms are often a hub of microbial contamination, and the examination of bacterial contamination in these facilities can serve as an important indicator of the transmission of infectious diseases. This study was conducted to determine the prevalence of bacterial contamination in public restrooms based on the economic class of the building. Samples were collected from various spots in 32 restrooms found in 10 shopping malls, classifying them into two categories: upper-end restrooms and lower-end restrooms. The findings showed that the level of contamination was higher in the lower-end restrooms, with the seat being the most contaminated area. The most dominant Gram-positive bacteria were coagulase-negative staphylococci species, making up 86% of the identified Gram-positive isolates. The most dominant Gram-negative bacteria identified were Klebsiella pneumoniae and Pseudomonas aeruginosa. The antibiotic sensitivity test results revealed the presence of multi-drug resistant bacteria among the Gram-positive and negative isolates, including Staphylococcus haemolyticus, Staphylococcus kloosi, Acinetobacter baumanii, and Pseudomonas aeruginosa. In conclusion, the study underscores the significance of monitoring bacterial contamination in public restrooms and the need for measures to reduce the spread of infectious diseases. Further research is crucial to gain a complete understanding of the bacterial contamination in public restrooms and their resistance patterns, to ensure the safety and health of the public. The implementation of improved cleaning practices and hands-free designs in restrooms can help reduce the risk of cross-contamination and prevent the spread of diseases.

Epoxy asphalt (EA) concrete is widely used in constructing long-span steel bridge pavements (SBDPs). This study aims to derive a fatigue damage evolution law, conducting an experimental investigation of SBDP. First, a general theoretical form of the fatigue damage evolution law of materials is established based on the thermal motion of atoms. Then, fatigue experiments demonstrate that this evolution law well represents the known damage–life relationships of SBDP. Taking into account the experimental relationships between damage and fatigue life under symmetrical cyclic loadings with different overload amplitudes and temperature variations, a detailed damage evolution law is deduced. Finally, the role of damage accumulation is discussed on the basis of the proposed damage evolution law for the extreme situation of heavy overload and severe environments. The results show that both heavy loading and falling temperatures increase the fatigue damage of SBDP considerably; therefore, SBDP should avoid heavy loading combined with winter temperatures. EA shows a fatigue life two to three times longer than that of modified matrix asphalt (SMA) or guss asphalt (GA). For the same thickness, EA pavement is demonstrated to be more suitable for an anti-fatigue design of large-span SBDP under high traffic flows and low temperatures.

Phage, which is often used therapeutically, has begun to receive interest as an alternative to antibiotic growth promoters (AGPs) to enhance chicken growth. Another option that has been extensively studied as a growth promoter in chicken is probiotics. However, there are no studies using phages and probiotics as prospective feed additives for broiler chickens. Therefore, this study demonstrated the effects of phage cocktail, probiotics and their combinations on growth performance and gut microbiota of broiler chickens. A total of 288 one-day-old male Cobb 500 broilers were randomly allotted to 1 of 6 treatments in a completely randomised design. The treatments were: (i) C (basal diet (BD) only), (ii) 1ɸ (BD + 0.1% phage cocktail), (iii) 2ɸ (BD + 0.2% phage cocktail), (iv) P (BD + 0.1% probiotic), (v) 1ɸP (BD + 0.1% phage cocktail + 0.1% probiotic), (vi) 2ɸP (BD + 0.2% phage cocktail + 0.1% probiotic). The 1ɸP treatment had significantly (P < 0.05) better BW (35 d), BWG (22 – 35 d, 1 – 35d), and FCR (1-21 d. 22-35 d, 1-35 d) compared to C. Unique gut microbiota diversity was also found between the ɸP (1ɸP and 2ɸP) and non-ɸP groups (C, 1ɸ, 2ɸ and P) in ilea, particularly in the 35 d chickens. Microorganisms associated with short-chain fatty acid (SCFA) producers were significantly (P <0.05) present in the ɸP group than in the non- ɸP group. The carbohydrate and amino acid metabolism predicted genes were significantly upregulated in ɸP groups compared to non- ɸP groups. These genes were involved in the digestion and absorption of nutrients as well as the production of energy. Our findings showed that 1ɸP treatment could be a potential alternative to AGPs for poultry where growth performance was enhanced, and gut microbiota was positively modulated.

Cobalamin is an essential nutrient required for the normal functioning of cells. Its deficiency can lead to various pathological states. Hydroxocobalamin (HOCbl) and cyanocobalamin (CNCbl) are the forms of vitamin B12 that are most commonly used for supplementation. There is substantial evidence indicating that cobalamins can both suppress and promote oxidative stress; however, the mechanisms underlying these effects are poorly understood. Here, it was shown that the oxidation of thiols catalyzed by HOCbl and CNCbl is accompanied by ROS production and induces, under certain conditions, oxidative stress and cell death. The form of vitamin B12 and the structure of thiol play a decisive role in these processes. It was found that the mechanisms and kinetics of thiol oxidation catalyzed by HOCbl and CNCbl differ substantially. It was discussed how these differences may explain different levels of ROS production and cytotoxicity induced by combinations of thiols with HOCbl and CNCbl. On the whole, the data obtained provide a new insight into the redox processes in which cobalamins are involved and might be helpful in developing new approaches to the treatment of some cobalamin-responsive disorders in which oxidative stress is an important component. In addition, these data may be useful for a better understanding of mechanisms underlying induction of different types of death of cancer cells and in a search for new targets for anticancer therapy.

This review of the meaningful data from 2021 on cervical, endometrial, and ovarian cancers aims to provide an update of the most clinically relevant studies presented at important oncologic congresses during the year [the American Society of Clinical Oncology (ASCO) Annual Meeting, the European Society for Medical Oncology (ESMO) Congress and the Society of Gynecologic Oncology (SGO) Annual Meeting]. Despite the underlying existence of the COVID-19 pandemic, the last year has been notable in terms of research, with significant and promising advances in gynecologic malignancies. Several major studies reporting the effects of innovative therapies for patients with cervical, endometrial, and ovarian cancers might change the medical practice in the future.

Artificial intelligence AI or machine learning has proven to be a potential activity in the health and biomedical sciences. Previous research it has found that AI can learn new data and transform it into the useful knowledge. In the field of pharmacology, the aim is to design more efficient and novel vaccines using this method which are also cost effective. The underlying fact is to predict the molecular mechanism and structure for increased likelihood of developing new drugs. Clinical, electronic and high resolution imaging datasets can be used as inputs to aid the drug development niche. Moreover, the use of comprehensive target activity has been performed for repurposing a drug molecule by extending target profiles of drugs which also include off targets with therapeutic potential providing a new indication.

While the number of publications on wine and health is steadily increasing, ranging from molecular level to epidemiological studies, often with contradictory results, little attention has been given to an holistic approach. In this review some unusual concepts are considered, such as phytocomplex, vehicle and the Matrix effect. As an example, three mono/polyphenols present in wine, Tyrosol, Hydroxytyrosol and Resveratrol, have been selected and the consequences of respecting, disregarding or ignoring the Matrix effect are shown. Underestimation of the wine Matrix effect could lead to deceiving results, as in the case of de-alcoholized wine or wine-compound-based nutritional supplements,or in emphasizing a single component toxic activity, in this case alcohol, ignoring the specific protective action at molecular level of other compounds (polyphenols) present in the same Matrix. The dark side of Matrix effect is also discussed. It is suggested that specificity of wine should be always taken in consideration by public health Authorities.

The ingestion of ethanol presents a significant global public health challenge. Chronic alcohol consumption is associated with the development of conditions such as cancer, cirrhosis, hepatic diseases, cardiovascular diseases, and diabetes, as well as neurological impairments that may predispose individuals to dementia, schizophrenia, and behavioral disorders such as violence and suicide. Alcohol-related fatalities constitute 5.3% of worldwide deaths annually, totaling approximately 3 million. Notably, alcohol consumption is implicated in 25% of cirrhosis-related deaths and 4.1% of cancer-related deaths. Taurine (2-aminoethanesulfonic acid) is a non-protein β-amino acid essential for cellular homeostasis, possessing antioxidant, anti-inflammatory, and cytoprotective properties crucial for life maintenance. This study aimed to evaluate the effects of taurine administration on hippocampal neurogenesis, neuronal preservation or reverse damage in rats exposed to forced ethanol consumption. Results demonstrated the neuroprotective effects of taurine on ethanol-treated rats, promoting tissue regeneration and suggesting its pivotal role in this process. However, this aminoacid failed to induce neurogenesis in the tissues of healthy rats, implying that its activity may be contingent upon post-injury stimuli.

Long span cable-stayed bridge is the main bridge type with a span of more than 400 meters. It is generally designed as a double tower long-span structure with good spanning capacity and economic performance. Wind resistance safety performance is the main index to control the long-span cable-stayed bridge structure. During the operation of long-span cable-stayed bridge structure, because the service life of the cable is far less than the design life of the structure, the wind resistance performance of the structure will inevitably deteriorate significantly, which will seriously affect the structural service performance of symmetric cable-stayed bridge. Based on symmetric reliability theory, this paper takes flutter and static wind stability of long-span cable-stayed bridge structure as the main design control index, uses positive reliability theory to calculate the reliability index of symmetric cable-stayed bridge structure, uses inverse reliability theory to calculate the safety factor of symmetric cable-stayed bridge structure, and evaluates the wind resistant time-varying performance of long-span cable-stayed bridge structure by comprehensively considering the reliability index and safety factor. Taking a practical project of a long-span cable-stayed bridge as a specific case, the wind resistant time-varying reliability of the bridge during its operation for more than 30 years is analyzed, and the parameter sensitivity is analyzed. The results show that the wind resistance performance of the cable-stayed bridge structure is obviously affected by the cable, and the degradation of the cable performance will have an important impact on the wind resistance time-varying performance of the structure, especially the critical wind speed of the structure has obvious time-varying characteristics. The safety factor and reliability index can objectively evaluate the wind resistance time-varying performance of the long-span cable-stayed bridge structure.

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.

Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing the clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus with very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo to drug-drug interactions (DDI) with other concomitant therapies. Although only few clinical evidence are available, it is possible to predict clinical relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDI of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa.

It is an utmost importance to characterize drug candidates as early in the development pipeline as possible. Appropriate application of the emerging high throughput analytical techniques unlocks the opportunities to obtain experimental data for in vitro absorption, distribution, metabolism and elimination (ADME) profiling of large compound libraries which is crucial for selection of lead compounds. In an usual scenario, only one drug candidate will be selected from thousands of early compounds based on several stability and screening results. A high to medium throughput screening approaches could significantly accelerates the subsequent research and production phases. Traditionally, the analysis of metabolic stability assays heavily relies on high throughput LC-MS/MS techniques to meet with the lead profiling demands. In this study presented an innovative experimental approach that can offer a refreshing alternative. Laser Assisted Rapid Evaporative Ionization Mass Spectrometry (LA-REIMS) is a quick and efficient method for characterizing complex biological samples without laborious sample preparation and chemical separation. Therefore, using an automated LA-REIMS well plate reader as fast as 8 seconds per sample, we assessed the oxidative metabolic stability of active agents using biomimetic metalloporphyrin-based oxidative model reactions at various pH for commercially available drug substances and compared stability measurements with traditional HPLC-DAD-MS results.

Stress is a critical factor in the development of mental disorders such as addiction, underscoring the importance of stress resilience strategies. While the ketogenic diet (KD) has shown efficacy in reducing alcohol consumption in male mice without cognitive impairment, its impact on the stress response and addiction development, especially in females, remains unclear. This study examined the KD's effect on increasing ethanol intake due to vicarious social defeat (VSD) in female mice. Sixty-four female OF1 mice were divided into two dietary groups: standard diet (n=32) and KD (n=32). These were further split based on exposure to four VSD or exploration sessions, creating four groups: EXP-STD (n=16), VSD-STD (n=16), EXP-KD (n=16), and VSD-KD (n=16). KD-fed mice maintained ketosis from adolescence until the fourth VSD/EXP session, after which they switched to a standard diet. The Social Interaction Test was performed 24 hours after the last VSD session. Three weeks post-VSD, the Drinking in the Dark test and Oral Ethanol Self-Administration assessed ethanol consumption. The results showed that KD blocked the increase in ethanol consumption induced by VSD in females. Moreover, among other changes, KD increased the expression of the ADORA1 and CNR1 genes, which are associated with mechanisms modulating neurotransmission. Our results pointed to KD as a useful tool to increase resilience to social stress in female mice.

The biofilm is a conglomerate of cells surrounded by an extracellular matrix, which contributes to the persistence of infections. The difficulty in removing the biofilm drives the research for new therapeutic options. In this work, the effect of terpenes (-)-trans-Caryophyllene, (S)-cis-Verbenol, (S)-(-)-Limonene, (R)-(+)-Limonene, and linalool was evaluated, individually and in combinations on bacterial growth, by assay with resazurin; the formation of biofilm, by assay with violet crystal; and the expression of associated genes, by real-time PCR, in two clinical isolates of S. aureus, ST30-t019 and ST5-t311, responsible for more than 90% of pediatric infections by this pathogen in Paraguay. All combinations of terpenes can inhibit biofilm formation in more than 50% without affecting bacterial growth. The most effective combination was (-)-trans-Caryophyllene and linalool at a 500 μg/mL concentration for each, with an inhibition percentage of 88%. This combination decreased the expression levels of the sdrD, spa, agr, and hld genes associated with the initial cell adhesion stage and quorum sensing. At the same time, it increased the expression levels of the cap5B and cap5C genes related to the production of capsular polysaccharides. The combinations of compounds tested are promising alternatives to inhibit biofilm formation in S. aureus.

WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stem- ness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2^nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1, we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2^nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline’s efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (ra- dial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3^rd order biological hypotheses emerge some of which are con- firmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest.

This article delves into the intersection of generative AI and digital twins within drug discovery, exploring their synergistic potential to revolutionize pharmaceutical research and development. Through various instances and examples, we illuminate how generative AI algorithms, capable of simulating vast chemical spaces and predicting molecular properties, are increasingly integrated with digital twins of biological systems to expedite drug discovery. By harnessing the power of computational models and machine learning, researchers can design novel compounds tailored to specific targets, optimize drug candidates, and simulate their behavior within virtual biological environments. This paradigm shift offers unprecedented opportunities for accelerating drug development, reducing costs, and, ultimately, improving patient outcomes. As we navigate this rapidly evolving landscape, collaboration between interdisciplinary teams and continued innovation will be paramount in realizing the promise of generative AI and digital twins in advancing drug discovery.

Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Recent epidemiological studies conducted in developing countries identified Shigella species as the most predominant pathogenic bacteria responsible for diarrhea. Antimicrobial therapy is necessary for Shigella infections; however, the rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. To identify alternative antimicrobial compounds with activity against Shigella species, the pathogens responsible for bacterial diarrhea. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing benzothiazoles backbone, and their combination with certain antibiotics. In continuation to our effort in searching potent antimicrobial compounds, we have found this time around that two acetaminophen derivatives containing benzothiazoles backbone (4a and 4b) could inhibit the growth of Shigella flexneri with common MIC value of 12.5 µg/ml. These compounds were established through a time-kill kinetics’ study to be bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a & b) were found to be poorly active (MIC: 100 µg/ml) against this pathogen. Combination studies of 4a and 4b with the least susceptible antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity. The present study demonstrates that the azobenzothiazole dyes 4 (a & b) can be repurposed as potential anti-Shigella compounds, which can serve as scaffolds for the development of new agents against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.

Polysaccharides such as alginate and gellan gum are biocompatible and easily accessible biopolymers with excellent properties to produce microparticles as drug delivery systems. However, the production methods often fail in reproducibility, compromising the translational potential of such systems. In this work, microparticles made from gellan gum and alginate were optimized using the coaxial air flow method, and an inexpensive and reproducible production method. A Design of Experiments was used to identify the main parameters that affect the microparticle’s production and optimization, focusing on the diameter and dispersibility. Airflow was the most significant factor for both parameters. Pump flow affected the diameter, whilst the gellan gum/alginate ratio affected dispersibility. After optimization, microparticle swelling, drug entrapment and release profile were analyzed at two pH, 7.4 and 6.5. Using methylene blue as a model drug, higher encapsulation and swelling indexes were obtained at pH 7.4, whilst a more pronounced release occurred at pH 6.5. The microparticle release profiles were studied by resorting to well-known models, showing a Fickian type release. The developed microparticles show promising results as drug-delivery vehicles for biomedical applications.