Search

Autophagy is a critical cellular process that maintains homeostasis by recycling damaged or aberrant components. This process is orchestrated by a network of proteins that form autophagosomes, which engulf and degrade intracellular material. In cancer, autophagy plays a dual role: it suppresses tumor initiation in the early stages but supports tumor growth and survival in advanced stages. Chronic myeloid leukemia (CML), a hematological malignancy, is characterized by the Philadelphia chromosome, a chromosomal abnormality resulting from a translocation between chromosomes 9 and 22. Autophagy has emerged as a key factor in CML pathogenesis, promoting cancer cell survival and contributing to resistance against tyrosine kinase inhibitors (TKIs), the primary treatment for CML. Targeting autophagic pathways is being actively explored as a therapeutic approach to overcome drug resistance and enhance cancer cell death. Recent research highlights the intricate interplay between autophagy and CML progression, underscoring its role in disease biology and treatment outcomes. This review aims to provide a comprehensive analysis of the molecular and cellular mechanisms underlying CML, with a focus on the therapeutic potential of targeting autophagy.

The quality of Coffee arabica L. beans, particularly the aroma, is a key determinant of commercial value. Fatty acids, as precursors of volatile aroma compounds, play a crucial role in this quality. Screening and identification of their related genes are of particular significance. This study identified 21 members of the CaFAD gene family in the C. arabica genome using bioinformatics tools. Gene duplication events observed in the CaFAD gene family were likely driven by natural selection and mutation pressure, with natural selection being more prominent. Transcriptome sequencing, qRT-PCR, and fatty acid profiling across four fruit developmental stages revealed that CaFAD8 was closely associated with fatty acid synthesis regulation. Fatty acid content was initially high but decreased during the later stages, while CaFAD8 expression showed an inverse pattern. Subcellular localization indicated that CaFAD8 functions primarily on the inner membrane. CaFAD8-OE heterologous expression experiment in Arabidopsis thaliana reduced the total fatty acid content in seeds but increased unsaturated fatty acids, including oleic, linoleic, and linolenic acids. These findings suggest that CaFAD8 promotes fatty acid unsaturation and provides insights into fatty acid metabolism in C. arabica. This study offers a foundation for understanding CaFAD gene regulation and supports breeding strategies for high-oil C. arabica varieties.

Cryptosporidiosis is a zoonotic protozoan parasite-born disease, equally significant in both animals and humans, especially affecting immunocompromised individuals (e.g., AIDS patients) and neonates. The prime concerns of this review article are to demonstrate the disruption of the intestinal barrier and variations in the gut microbiome during cryptosporidiosis, and to explore host gut-parasite interactions that can lead to the development of novel therapeutics. The review concluded that the enteric barrier is particularly maintained by tight junction proteins (e.g., occludin, claudin, and ZO-1, etc.) and mucosal immunity, both of which are severely compromised during Cryptosporidium spp. infections, resulting in increased intestinal barrier permeability, inflammatory responses, diarrhea, and ultimately death in severe cases. Cryptosporidium -induced dysbiosis is characterized by reduced microbial diversity and richness, a shift from commensal to pathogenic bacteria, as evidenced by increased pro-inflammatory taxa like Proteobacteria, and reduced proportions of beneficial SCFAs producing bacteria, e.g., Firmicutes. Recent investigations have highlighted the interrelations between gut microbiota and epithelial barrier integrity, especially during cryptosporidiosis, demonstrating the modulations regarding tight junctions (TJs), immune reactions, and SCFA production, all of which are main players in alleviating this protozoal parasitic infection. This review comprehensively describes the fine details underlying these impairments, including autophagy-mediated TJs' degradation, inflammasome activation, and gut microbiome-driven alterations in metabolic pathways, providing the latest relevant, and well-organized piece of knowledge regarding intestinal barrier alterations and microbial shifts during cryptosporidiosis. This work emphasizes the future need for longitudinal studies and advanced sequencing techniques to understand host gut microbiota-parasite interactions, aiming to formulate innovative strategies to mitigate cryptosporidiosis.

Diabetic neuropathy is one of the severe complications of diabetes, which affects the quality of life in a patient and increases the risk of amputations and chronic wounds. Current therapeutic approaches are symptomatically oriented, focusing on comfort and non-inflammatory aspects without addressing the mechanism or molecular target of the disease. The present study investigates the therapeutic effects of an ethanolic polyherbal extract from Citrullus colocynthis (Bitter Apple), Curcuma longa (Turmeric), and Myristica fragrans (Nutmeg) using advanced in silico and analytical methods. According to the findings, PHE showed the presence of a total of 39 bioactive compounds in GC-MS analysis, which include alcohols, fatty acids, terpenoids, esters, neolignans, phenylpropanoids, and steroids. Three of the compounds--4-isopropyl-1,6-dimethyl-1,2,3,4-tetrahydronaphthalene (-11.4 kcal/mol), (1S,2R)-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-1-propanol (-9.8 kcal/mol) and (S)-5-Allyl-2-((1-(3,4-dimethoxyphenyl)propan-2-yl)oxy)-1,3-dimethoxybenzene (-10.3 kcal/mol)-followed the Lipinski rule and showed the binding affinity with aldol reductase. Docking experiments showed that compound 4-isopropyl-1,6-dimethyl-1,2,3,4-tetrahydronaphthalene (-11.4 kcal/mol) has high-affinity binding to aldose reductase, an enzyme involved in diabetic neuropathy pathophysiology, whereas molecular dynamics simulations show long-range persistence of the interaction of (S)-5-Allyl-2-((1-(3,4-dimethoxyphenyl)propan-2-yl)oxy)-1,3-dimethoxybenzene with aldol reductase in physiological conditions. Therefore, this combination of herbal therapy and advanced computational/analytical techniques could be leading towards innovative, multi-targeted therapies against diabetic neuropathy. Nevertheless, further studies in vivo are required to confirm the efficacy, safety, and pharmacokinetics of the PHE in biological systems.

A new aluminum complex (NSO)AlMe 2 featuring a hydrogen bond donor on the ligand backbone has been synthesized via the reaction of AlMe 3 with 1-((2-(isopropylamino)phenyl)thio)propan-2-ol (NSO-H) and spectroscopically characterized. In the complex, the aluminum atom is in a distorted tetrahedral coordination sphere determined by the anionic oxygen and neutral nitrogen atoms of the ligand and by the two carbon atoms of the alkyl groups. After proper activation, the complex (NSO)AlMe 2 was able to promote the ring-opening polymerization of L -, rac -lactide, ε -caprolactone and rac - β -butyrolactone. The polymerization of rac -lactide was faster than that of L -lactide: in a toluene solution at 80 °C, the high monomer conversion of 100 equivalents was achieved in 1.5 h, reaching a turnover frequency of 63 mol LA ·mol Al -1 ·h -1 . The experimental molecular weights of the obtained polymers were close to those calculated, assuming the growth of one polymer chain for one added alcohol equivalent and the polydispersity indexes were monomodal and narrow. The kinetic investigation of the polymerization led to the determination of the apparent propagation constants and the Gibbs free energies of activation for the reaction; the terminal groups of the polymers were also identified. The complex (NSO)AlMe 2 was active in harsh conditions such as at a very low concentration or in the melt using technical-grade rac -lactide. A relatively high level of activity was observed in the ring-opening polymerization of ε -caprolactone and rac - β -butyrolactone. DFT calculations were performed and revealed the central role of the NH function of the coordinated ligand. Acting as a hydrogen bond donor, it docks the monomer in the proximity of the metal center and activates it toward the nucleophilic attack of the growing polymer chain.

A common life-threatening hereditary disease, Cystic Fibrosis (CF), affects primarily Caucasian infants. High sweat-salt levels are observed as a result of a single autosomal mutation in chromosome 7 that affects the critical function of the cystic fibrosis transmembrane regulator (CFTR). For establishing tailored treatment strategies, it is important to understand the broad range of CFTR mutations and their impacts on disease pathophysiology. This study thoroughly investigates the six main classes of classification of CFTR mutations based on their functional effects. Each class is distinguished by distinct molecular flaws, such as poor protein synthesis, misfolding, gating defects, conduction defects, and decreased CFTR expression at the apical membrane. Furthermore, this paper focuses on the emerging field of CFTR modulators, which intend to restore CFTR function or mitigate its consequences. These modulators, which are characterized by the mode of action and targeted mutation class, have the potential to provide personalized therapy regimens in CF patients. This review provides valuable insights into the genetic basis of CF pathology, and highlights the potential for precision medicine methods in CF therapy by thoroughly investigating CFTR mutation classification and related modulators.

The antioxidant defense mechanisms play a critical role in mitigating the deleterious effects of reactive oxygen species (ROS). Catalase stands out as a paramount enzymatic antioxidant. It efficiently catalyzes the decomposition of hydrogen peroxide (H 2 O 2 ) into water and oxygen, a potentially harmful byproduct of cellular metabolism. This reaction detoxifies H 2 O 2 and prevents oxidative damage. Catalase has been extensively studied as a therapeutic antioxidant. Its applications range from direct supplementation in conditions characterized by oxidative stress to gene therapy approaches to enhance endogenous catalase activity. The enzyme's stability, bioavailability, and the specificity of its delivery to target tissues are significant hurdles. Furthermore, studies employing conventional catalase formulations often face issues related to enzyme purity, activity, and longevity in the biological milieu. Addressing these challenges necessitates rigorous scientific inquiry and well-designed clinical trials. Such trials must be underpinned by sound experimental designs, incorporating advanced catalase formulations or novel delivery systems that can overcome existing limitations. Enhancing catalase's stability, specificity, and longevity in vivo could unlock its full therapeutic potential. It is necessary to understand the role of catalase in disease-specific contexts, paving the way for precision antioxidant therapy that could significantly impact the treatment of diseases associated with oxidative stress.

Dysferlinopathies refer to a spectrum of muscular dystrophies that cause progressive muscle weakness and degeneration. They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes. This review delves into the clinical spectra of dysferlinopathies, their molecular mechanisms, and the spectrum of emerging therapeutic strategies. We examine the phenotypic heterogeneity of dysferlinopathies, highlighting the incomplete understanding of genotype-phenotype correlations and discussing the implications of various DYSF mutations. In addition, we explore the potential of symptomatic, pharmacological, molecular, and genetic therapies in mitigating the disease's progression. We also consider the roles of diet and metabolism in managing dysferlinopathies, as well as the impact of clinical trials on treatment paradigms. Furthermore, we examine the utility of animal models in elucidating disease mechanisms. By culminating the complexities inherent in dysferlinopathies, this write up emphasizes the need for multidisciplinary approaches, precision medicine, and extensive collaboration in research and clinical trial design to advance our understanding and treatment of these challenging disorders.

The surface roughness (Ra) of indirect computer-aided design/computer-aided manufacturing (CAD/CAM)-fabricated dental restorations is crucial for their long-term durability. This study intended to evaluate the Ra of five different types of contemporary indirect CAD/CAM restorative materials with varying compositions that were glazed and finished/polished. A total of 75 specimens, disc-shaped (10 mm × 2 mm), were obtained from five materials ( n = 15) (Tetric CAD, IPS e.max CAD, IPS e.max ZirCAD, CELTRA Duo, and Vita Enamic) and fabricated by CAD/CAM. One of the two surfaces for each specimen was subjected to glazing, while the other surface was subjected to finishing/polishing. The Ra of the two surfaces in micrometers (μm) was evaluated using a Profilometer, while the surface topography was examined using a scanning electron microscope. Using SPSS, the Kruskal-Wallis, post hoc Conover, and Mann-Whitney tests were used to statistically evaluate the data. A comparison of the Ra for the finished/polished surfaces of the five test materials showed significant differences ( p < 0.0001). Among the finished/polished surfaces, the mean rank values of Vita Enamic were significantly higher than the other four test materials ( p < 0.0001). A comparison of the Ra of glazed surfaces among the five study materials revealed significant differences ( p < 0.0001). The Ra for the IPS e.max ZirCAD material was significantly higher than the rest of the four materials ( p < 0.001). A comparison of the Ra for two types of surface conditioning within each of the five test materials showed a significant difference ( p < 0.05). Only for IPS e.max ZirCAD was the Ra of the glazed surface significantly higher than the finished/polished surface ( p < 0.0001). Significant variations in the surface roughness (Ra) were exhibited between the finished/polished and glazed surfaces of the five test materials. Hybrid ceramics showed the highest Ra values for the finished/polished surfaces, and zirconia exhibited the highest Ra values among the glazed surfaces among the tested materials. The Ra values of either finished/polished or glazed surfaces of the test materials were within the clinically acceptable range (0.2-0.5 μm), except for the glazed surface of the zirconia ceramics (0.84 μm)., Competing Interests: The authors declare no conflicts of interest.

Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that impede progress in the broader field of medical research into ultra-rare conditions.

Background: Health-related quality of life is rapidly becoming recognized as an important indicator of how a disease affects patient lives and for evaluating the quality of care, especially for chronic conditions such as chronic kidney disease (CKD). Objectives: This study is an attempt to assess the quality of life in patients with chronic kidney disease at MMIMSR and also identify characteristics that may be associated with their worsening quality of life. Materials and Methods: This cross-sectional investigation was conducted at the in-patient department (IPD) of the MMIMSR hospital. This study included 105 CKD patients and used a systematic random sampling method for quantitative analysis. This study utilized a 36-item short-form SF-36 (v1.3) questionnaire to assess HRQoL in CKD patients. Descriptive statistics were employed at the baseline. Chi square and ANOVA were used to draw comparisons between two groups or more than two groups, respectively. Logistic regression analysis was utilized to identify the potential QoL determinants. A p value of 0.05 or lower was used to determine statistical significance. Results: Among a total of 105 participants, the mean (±standard deviation) age was found to be 54.53 ± 13.47 years; 48 were male patients, and 57 were female patients. Diabetes Mellitus (61.9%), hypertension (56.2%), chronic glomerulonephritis (7.6%), chronic pyelonephritis (6.7%), and polycystic kidney disease (5.7%) were identified to be the most frequent disorders associated with CKD. The current study also demonstrated that the HRQoL score domains such as symptom problem list, the effect of kidney disease, and the burden of kidney disease decline significantly and progressively as the patient advances into higher stages of CKD ( p = 0.005). A similar pattern was observed in work status, sleep, and general health ( p < 0.005). Additionally, a statistically significant difference was noted for cognitive function, quality of social interaction, overall health, dialysis staff encouragement, patient satisfaction, social support, physical functioning, role of physical health, pain, emotional well-being, role of emotional health, social functioning, and energy fatigue ( p < 0.005). The mean difference for PCS and MCS based on CKD stages was found to be statistically significant ( p < 0.005). The PCS and MCS showed a positive correlation with GFR (r = 0.521), and Hb (r = 0.378), GFR (r = 0.836), and Hb (r = 0.488), respectively. Conclusions: The findings of this study demonstrated that a significant decrease in HRQoL was observed among CKD patients, with a progressive deterioration of HRQoL dimensions as the patient advances to end-stage renal disease. This study also revealed that CKD imposes various restrictions on patients' day-to-day lives, particularly in terms of their physical and mental functioning, even in the initial stages of the disease.

The critical applications of difficult-to-machine Inconel 617 (IN617) compel the process to be accurate enough that the requirement of tight tolerances can be met. Electric discharge machining (EDM) is commonly engaged in its machining. However, the intrinsic issue of over/undercut in EDM complicates the achievement of accurately machined profiles. Therefore, the proficiency of deep cryogenically treated (DCT) copper (Cu) and brass electrodes under modified dielectrics has been thoroughly investigated to address the issue. A complete factorial design was implemented to machine a 300 μm deep impression on IN617. The machining ability of DCT electrodes averagely gave better dimensional accuracy as compared to non-DCT electrodes by 13.5% in various modified dielectric mediums. The performance of DCT brass is 29.7% better overall compared to the average value of overcut (OC) given by DCT electrodes. Among the non-treated (NT) electrodes, the performance of Cu stands out when employing a Kerosene-Span-20 modified dielectric. In comparison to Kerosene-Tween-80, the value of OC is 33.3% less if Kerosene-Span-20 is used as a dielectric against the aforementioned NT electrode. Finally, OC's nonlinear and complex phenomena are effectively modeled by an artificial neural network (ANN) with good prediction accuracy, thereby eliminating the need for experiments.

Microelectronic components are used in a variety of applications that range from processing units to smart devices. These components are prone to malfunctions at high temperatures exceeding 373 K in the form of heat dissipation. To resolve this issue, in microelectronic components, a cooling system is required. This issue can be better dealt with by using a combination of metal foam, heat sinks, and nanofluids. This study investigates the effect of using a rectangular-finned heat sink integrated with metal foam between the fins, and different water-based nanofluids as the working fluid for cooling purposes. A 3D numerical model of the metal foam with a BCC-unit cell structure is used. Various parameters are analyzed: temperature, pressure drop, overall heat transfer coefficient, Nusselt number, and flow rate. Fluid flows through the metal foam in a turbulent flow with a Reynold's number ranging from 2100 to 6500. The optimum fin height, thickness, spacing, and base thickness for the heat sink are analyzed, and for the metal foam, the material, porosity, and pore density are investigated. In addition, the volume fraction, nanoparticle material, and flow rate for the nanofluid is obtained. The results showed that the use of metal foam enhanced the thermal performance of the heat sink, and nanofluids provided better thermal management than pure water. For both cases, a higher Nusselt number, overall heat transfer coefficient, and better temperature reduction is achieved. CuO nanofluid and high-porosity low-pore-density metal foam provided the optimum results, namely a base temperature of 314 K, compared to 341 K, with a pressure drop of 130 Pa. A trade-off was achieved between the temperature reduction and pumping power, as higher concentrations of nanofluid provided better thermal management and resulted in a large pressure drop.

Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that β-elemene and compound 5a showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both β-elemene and compound 5a could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose-matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that β-elemene and compound 5a combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death.

Cancer represents one of the most frequent causes of death in the world. The current therapeutic options, including radiation therapy and chemotherapy, have various adverse effects on patients' health. In this vista, the bioactive ingredient of natural products plays a vital role in disease management via the inhibition and activation of biological processes such as oxidative stress, inflammation, and cell signaling molecules. Although natural products are not a substitute for medicine, they can be effective adjuvants or a type of supporting therapy. Hesperidin, a flavonoid commonly found in citrus fruits, with its potential antioxidant, anti-inflammatory, and hepatoprotective properties, and cardio-preventive factor for disease prevention, is well-known. Furthermore, its anticancer potential has been suggested to be a promising alternative in cancer treatment or management through the modulation of signal transduction pathways, which includes apoptosis, cell cycle, angiogenesis, ERK/MAPK, signal transducer, and the activator of transcription and other cell signaling molecules. Moreover, its role in the synergistic effects with anticancer drugs and other natural compounds has been described properly. The present article describes how hesperidin affects various cancers by modulating the various cell signaling pathways.

Alzheimer's disease (AD) is a progressive neurological illness that is distinguished clinically by cognitive and memory decline and adversely affects the people of old age. The treatments for this disease gained much attention and have prompted increased interest among researchers in this field. As a springboard to explore new anti-Alzheimer's chemical prototypes, the present study was carried out for the synthesis of benzoxazole-oxadiazole analogues as effective Alzheimer's inhibitors. In this research work, we have focused our efforts to synthesize a series of benzoxazole-oxadiazole ( 1 - 19 ) and evaluating their anti-Alzheimer properties. In addition, the precise structures of synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1 H-NMR, 13 C-NMR and HREI-MS. To find the anti-Alzheimer potentials of the synthesized compounds ( 1 - 19 ), in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), inhibitory activities were performed using Donepezil as the reference standard. From structure-activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes were due to different substitution patterns of substituent(s) at the variable position of both acetophenone aryl and oxadiazole aryl rings. The results of the anti-Alzheimer assay were very encouraging and showed moderate to good inhibitory potentials with IC 50 values ranging from 5.80 ± 2.18 to 40.80 ± 5.90 µM (against AChE) and 7.20 ± 2.30 to 42.60 ± 6.10 µM (against BuChE) as compared to standard Donepezil drug (IC 50 = 33.65 ± 3.50 µM (for AChE) and 35.80 ± 4.60 µM (for BuChE), respectively. Specifically, analogues 2 , 15 and 16 were identified to be significantly active, even found to be more potent than standard inhibitors with IC 50 values of 6.40 ± 1.10, 5.80 ± 2.18 and 6.90 ± 1.20 (against AChE) and 7.50 ± 1.20, 7.20 ± 2.30 and 7.60 ± 2.10 (against BuChE). The results obtained were compared to standard drugs. These findings reveal that benzoxazole-oxadiazole analogues act as AChE and BuChE inhibitors to develop novel therapeutics for treating Alzheimer's disease and can act as lead molecules in drug discovery as potential anti-Alzheimer agents.

The superior engineering properties and excellent biocompatibility of titanium alloy (Ti6Al4V) stimulate applications in biomedical industries. Electric discharge machining, a widely used process in advanced applications, is an attractive option that simultaneously offers machining and surface modification. In this study, a comprehensive list of roughening levels of process variables such as pulse current, pulse ON time, pulse OFF time, and polarity, along with four tool electrodes of graphite, copper, brass, and aluminum are evaluated (against two experimentation phases) using a SiC powder-mixed dielectric. The process is modeled using the adaptive neural fuzzy inference system (ANFIS) to produce surfaces with relatively low roughness. A thorough parametric, microscopical, and tribological analysis campaign is established to explore the physical science of the process. For the case of the surface generated through aluminum, a minimum friction force of ~25 N is observed compared with the other surfaces. The analysis of variance shows that the electrode material (32.65%) is found to be significant for the material removal rate, and the pulse ON time (32.15%) is found to be significant for arithmetic roughness. The increase in pulse current to 14 A shows that the roughness increased to ~4.6 µm with a 33% rise using the aluminum electrode. The increase in pulse ON time from 50 µs to 125 µs using the graphite tool resulted in a rise in roughness from ~4.5 µm to ~5.3 µm, showing a 17% rise.

Oligonucleotide-based therapies are a promising approach for treating a wide range of hard-to-treat diseases, particularly genetic and rare diseases. These therapies involve the use of short synthetic sequences of DNA or RNA that can modulate gene expression or inhibit proteins through various mechanisms. Despite the potential of these therapies, a significant barrier to their widespread use is the difficulty in ensuring their uptake by target cells/tissues. Strategies to overcome this challenge include cell-penetrating peptide conjugation, chemical modification, nanoparticle formulation, and the use of endogenous vesicles, spherical nucleic acids, and smart material-based delivery vehicles. This article provides an overview of these strategies and their potential for the efficient delivery of oligonucleotide drugs, as well as the safety and toxicity considerations, regulatory requirements, and challenges in translating these therapies from the laboratory to the clinic.

This study investigates the influence of design, relative density (RD), and carbon fiber (CF) incorporation parameters on mechanical characteristics, including compressive modulus (E), strength, and specific energy absorption (SEA) of triply periodic minimum surface (TPMS) lattice structures. The TPMS lattices were 3D-printed by fused filament fabrication (FFF) using polylactic acid (PLA) and carbon fiber-reinforced PLA(CFRPLA). The mechanical properties of the TPMS lattice structures were evaluated under uniaxial compression testing based on the design of experiments (DOE) approach, namely, full factorial design. Prediction modeling was conducted and compared using mathematical and intelligent modeling, namely, adaptive neuro-fuzzy inference systems (ANFIS). ANFIS modeling allowed the 3D printing imperfections (e.g., RD variations) to be taken into account by considering the actual RDs instead of the designed ones, as in the case of mathematical modeling. In this regard, this was the first time the ANFIS modeling utilized the actual RDs. The desirability approach was applied for multi-objective optimization. The mechanical properties were found to be significantly influenced by cell type, cell size, CF incorporation, and RD, as well as their combination. The findings demonstrated a variation in the E (0.144 GPa to 0.549 GPa), compressive strength (4.583 MPa to 15.768 MPa), and SEA (3.759 J/g to 15.591 J/g) due to the effect of the studied variables. The ANFIS models outperformed mathematical models in predicting all mechanical characteristics, including E, strength, and SEA. For instance, the maximum absolute percent deviation was 7.61% for ANFIS prediction, while it was 21.11% for mathematical prediction. The accuracy of mathematical predictions is highly influenced by the degree of RD deviation: a higher deviation in RD indicates a lower accuracy of predictions. The findings of this study provide a prior prediction of the mechanical behavior of PLA and CFRPLA TPMS structures, as well as a better understanding of their potential and limitations.

Studies on using multifunctional graphene nanostructures to enhance the microfabrication processing of monolithic alumina are still rare and too limited to meet the requirements of green manufacturing criteria. Therefore, this study aims to increase the ablation depth and material removal rate and minimize the roughness of the fabricated microchannel of alumina-based nanocomposites. To achieve this, high-density alumina nanocomposites with different graphene nanoplatelet (GnP) contents (0.5 wt.%, 1 wt.%, 1.5 wt.%, and 2.5 wt.%) were fabricated. Afterward, statistical analysis based on the full factorial design was performed to study the influence of the graphene reinforcement ratio, scanning speed, and frequency on material removal rate (MRR), surface roughness, and ablation depth during low-power laser micromachining. After that, an integrated intelligent multi-objective optimization approach based on the adaptive neuro-fuzzy inference system (ANIFS) and multi-objective particle swarm optimization approach was developed to monitor and find the optimal GnP ratio and microlaser parameters. The results reveal that the GnP reinforcement ratio significantly affects the laser micromachining performance of Al 2 O 3 nanocomposites. This study also revealed that the developed ANFIS models could obtain an accurate estimation model for monitoring the surface roughness, MRR, and ablation depth with fewer errors than 52.07%, 100.15%, and 76% for surface roughness, MRR, and ablation depth, respectively, in comparison with the mathematical models. The integrated intelligent optimization approach indicated that a GnP reinforcement ratio of 2.16, scanning speed of 342 mm/s, and frequency of 20 kHz led to the fabrication of microchannels with high quality and accuracy of Al 2 O 3 nanocomposites. In contrast, the unreinforced alumina could not be machined using the same optimized parameters with low-power laser technology. Henceforth, an integrated intelligence method is a powerful tool for monitoring and optimizing the micromachining processes of ceramic nanocomposites, as demonstrated by the obtained results.

Hepatitis C virus (HCV) is a major human pathogen that requires a better understanding of its interaction with host cells. There is a close association of HCV life cycle with host lipid metabolism. Lipid droplets (LDs) have been found to be crucial organelles that support HCV replication and virion assembly. In addition to their role in replication, LDs also have protein-mediated antiviral properties that are activated during HCV infection. Studies have shown that HCV replicates well in cholesterol and sphingolipid-rich membranes, but the ways in which HCV alters host cell lipid dynamics are not yet known. In this study, we performed a kinetic study to check the enrichment of LDs at different time points of HCV infection. Based on the LD enrichment results, we selected early and later time points of HCV infection for global lipidomic study. Early infection represents the window period for HCV sensing and host immune response while later infection represents the establishment of viral RNA replication, virion assembly, and egress. We identified the dynamic profile of lipid species at early and later time points of HCV infection by global lipidomic study using mass spectrometry. At early HCV infection, phosphatidylinositol phospholipids (PIPs), lysophosphatidic acid (LPA), triacyl glycerols (TAG), phosphatidylcholine (PC), and trihexosylceramides (Hex3Cer) were observed to be enriched. Similarly, free fatty acids (FFA), phosphatidylethanolamine (PE), N-acylphosphatidylethanolamines (NAPE), and tri acylglycerols were enriched at later time points of HCV infection. Lipids enriched at early time of infection may have role in HCV sensing, viral attachment, and immune response as LPA and PIPs are important for immune response and viral attachment, respectively. Moreover, lipid species observed at later infection may contribute to HCV replication and virion assembly as PE, FFA, and triacylglycerols are known for the similar function. In conclusion, we identified lipid species that exhibited dynamic profile across early and later time points of HCV infection compared to mock cells, which could be therapeutically relevant in the design of more specific and effective anti-viral therapies.

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N -aminothiazole-hydrazineethyl-pyridines, beginning with a N '-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy ( 8a = -8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19.

The prevalent convolutional neural network (CNN)-based image denoising methods extract features of images to restore the clean ground truth, achieving high denoising accuracy. However, these methods may ignore the underlying distribution of clean images, inducing distortions or artifacts in denoising results. This paper proposes a new perspective to treat image denoising as a distribution learning and disentangling task. Since the noisy image distribution can be viewed as a joint distribution of clean images and noise, the denoised images can be obtained via manipulating the latent representations to the clean counterpart. This paper also provides a distribution-learning-based denoising framework. Following this framework, we present an invertible denoising network, FDN, without any assumptions on either clean or noise distributions, as well as a distribution disentanglement method. FDN learns the distribution of noisy images, which is different from the previous CNN-based discriminative mapping. Experimental results demonstrate FDN's capacity to remove synthetic additive white Gaussian noise (AWGN) on both category-specific and remote sensing images. Furthermore, the performance of FDN surpasses that of previously published methods in real image denoising with fewer parameters and faster speed.

Willingness to pay (WTP) for booster doses of coronavirus disease 2019 (COVID-19) vaccines is an under studied research topic. Therefore, the current study aimed to investigate the WTP for the booster doses of COVID-19 vaccines and its predictors in Indonesia using an online survey distributed all over the provinces of this low-middle-income country. The WTP was evaluated using a basic dichotomous contingent valuation approach, and its associated determinants were evaluated using a linear regression model. Out of 2935 responders, 66.2% (1942/2935) were willing to pay for a booster dose of the COVID-19 vaccine. The majority of respondents (63.5%) were willing to pay within a price range of 100,000-500,000 Indonesian rupiah (IDR), i.e., USD 6.71-33.57. Being older than 40 years, having a higher educational level, having a higher income, knowing and understanding that booster doses were important, and having a vaccine status that is certified halal (permissible in Islamic law), were all associated with a higher WTP for the booster dose of COVID-19 vaccines. The study findings imply that the WTP for a booster dose of COVID-19 vaccination in Indonesia is lower compared to acceptance of vaccines provided free of charge. This WTP data can be utilized to develop a pricing scheme for the booster doses of COVID-19 vaccination in the country with potential benefits in other low-income countries. The government may be required to provide subsidies for the herd immunity vaccination process to proceed as anticipated. Furthermore, the public community must be educated on the importance of vaccination as well as the fact that the COVID-19 epidemic is far from being over.

The burden of allergic illnesses is continuously rising, and patient diagnosis is a significant problem because of how intricately hereditary and environmental variables interact. The past three to four decades have seen an outbreak of allergies in high-income countries. According to reports on the illness, asthma affects around 300 million individuals worldwide. Identifying clinically important allergens for the accurate classification of IgE-mediated allergy respiratory disease diagnosis would be beneficial for implementing standardized allergen-associated therapy. Therefore, the current study includes an in silico analysis to identify potential IgE-mediated allergens in date palms and cockroaches. Such an immunoinformatic approach aids the prioritization of allergens with probable involvement in IgE-mediated allergic respiratory diseases. Immunoglobulin E (IgE) was used for molecular dynamic simulations, antigen-antibody docking analyses, epitope identifications, and characterizations. The potential of these allergens (Per a7, Per a 1.0102, and Bla g 1.0101) in IgE-mediated allergic respiratory diseases was explored through the evaluation of physicochemical characteristics, interaction observations, docking, and molecular dynamics simulations for drug and vaccine development.

Cancer is the leading cause of death and has remained a big challenge for the scientific community. Because of the growing concerns, new therapeutic regimens are highly demanded to decrease the global burden. Despite advancements in chemotherapy, drug resistance is still a major hurdle to successful treatment. The primary challenge should be identifying and developing appropriate therapeutics for cancer patients to improve their survival. Multiple pathways are dysregulated in cancers, including disturbance in cellular metabolism, cell cycle, apoptosis, or epigenetic alterations. Over the last two decades, natural products have been a major research interest due to their therapeutic potential in various ailments. Natural compounds seem to be an alternative option for cancer management. Natural substances derived from plants and marine sources have been shown to have anti-cancer activity in preclinical settings. They might be proved as a sword to kill cancerous cells. The present review attempted to consolidate the available information on natural compounds derived from plants and marine sources and their anti-cancer potential underlying EMT mechanisms.

Triply periodic minimum surface (TPMS)-based lattice structures have gained interest for their outstanding capacity to absorb energy, their high load-bearing capacity, and their high surface-to-volume ratio. This study considered three TPMS cell topologies, including Diamond, Gyroid, and Primitive. The FDM process was used to print the lattice structures with two materials: pure polylactic acid (PLA) and carbon fiber-reinforced PLA (PLA + CF). The influence of carbon fiber (CF) incorporation, unit cell type (topologies) and size, and relative density (RD) on mechanical properties and failure patterns were explored comprehensively under uniaxial compression testing. The results demonstrate a change in the compressive modulus (0.09 to 0.47 GPa), compressive strength (2.98 to 13.89 MPa), and specific energy absorption (SEA) (0.14 MJ/m 3 /g to 0.58 MJ/m 3 /g) due to the influence of CF incorporation, cell type and size, and RD. Results indicate that the Diamond structure outperformed both Primitive and Gyroid structures in terms of compressive modulus and strength, and SEA. All the CF-based TPMS structures showed a higher compressive modulus. Compressive strength and energy absorption capacity were both slightly enhanced in most PLA + CF-based Diamond structures. On the contrary, Gyroid and Primitive structures showed better performance for pure PLA-based structures in terms of compression strength and specific absorption energy.

One of the sustainability goals in the aeronautical industry includes developing cost-effective, high-performance engine components possessing complex curved geometries with excellent dimensional precision and surface quality. In this regard, several developments in wire electric discharge machining have been reported, but the influence of flushing attributes is not thoroughly investigated and is thus studied herein. The influence of four process variables, namely servo voltage, flushing pressure, nozzle diameter, and nozzle-workpiece distance, were analyzed on Inconel 718 in relation to geometrical errors (angular and radial deviations), spark gap formation, and arithmetic roughness. In this regard, thorough statistical and microscopical analyses are employed with mono- and multi-objective process optimization. The grey relational analysis affirms the reduction in the process's limitations, validated through confirmatory experimentation results as 0.109 mm spark gap, 0.956% angular deviation, 3.49% radial deviation, and 2.2 µm surface roughness. The novel flushing mechanism improved the spark gap by 1.92%, reducing angular and radial deviations by 8.24% and 29.11%, respectively.

Cancer is the leading cause of death worldwide. In spite of advances in the treatment of cancer, currently used treatment modules including chemotherapy, hormone therapy, radiation therapy and targeted therapy causes adverse effects and kills the normal cells. Therefore, the goal of more effective and less side effects-based cancer treatment approaches is still at the primary position of present research. Medicinal plants or their bioactive ingredients act as dynamic sources of drugs due to their having less side effects and also shows the role in reduction of resistance against cancer therapy. Apigenin is an edible plant-derived flavonoid that has received significant scientific consideration for its health-promoting potential through modulation of inflammation, oxidative stress and various other biological activities. Moreover, the anti-cancer potential of apigenin is confirmed through its ability to modulate various cell signalling pathways, including tumor suppressor genes, angiogenesis, apoptosis, cell cycle, inflammation, apoptosis, PI3K/AKT, NF-κB, MAPK/ERK and STAT3 pathways. The current review mainly emphases the potential role of apigenin in different types of cancer through the modulation of various cell signaling pathways. Further studies based on clinical trials are needed to explore the role of apigenin in cancer management and explain the possible potential mechanisms of action in this vista.

This work was undertaken to explore the phytochemical composition, antioxidant, and enzyme-inhibiting properties of Neurada procumbens L. extracts/fractions of varying polarity (methanol extract and its fractions including n -hexane, chloroform, n -butanol, and aqueous fractions). A preliminary phytochemical study of all extracts/fractions, HPLC-PDA polyphenolic quantification, and GC-MS analysis of the n -hexane fraction were used to identify the phytochemical makeup. Antioxidant (DPPH), enzyme inhibition (against xanthine oxidase, carbonic anhydrase, and urease enzymes), and antibacterial activities against seven bacterial strains were performed for biological investigation. The GC-MS analysis revealed the tentative identification of 22 distinct phytochemicals in the n -hexane fraction, the majority of which belonged to the phenol, flavonoid, sesquiterpenoid, terpene, fatty acid, sterol, and triterpenoid classes of secondary metabolites. HPLC-PDA analysis quantified syringic acid, 3-OH benzoic acid, t -ferullic acid, naringin, and epicatechin in a significant amount. All of the studied extracts/fractions displayed significant antioxidant capability, with methanol extract exhibiting the highest radical-scavenging activity, as measured by an inhibitory percentage of 81.4 ± 0.7 and an IC 50 value of 1.3 ± 0.3. For enzyme inhibition experiments, the n -hexane fraction was shown to be highly potent against xanthine oxidase and urease enzymes, with respective IC 50 values of 2.3 ± 0.5 and 1.1 ± 0.4 mg/mL. Similarly, the methanol extract demonstrated the strongest activity against the carbonic anhydrase enzyme, with an IC 50 value of 2.2 ± 0.4 mg/mL. Moreover, all the studied extracts/fractions presented moderate antibacterial potential against seven bacterial strains. Molecular docking of the five molecules β-amyrin, campesterol, ergosta-4,6,22-trien-3β-ol, stigmasterol, and caryophyllene revealed the interaction of these ligands with the investigated enzyme (xanthine oxidase). The results of the present study suggested that the N. procumbens plant may be evaluated as a possible source of bioactive compounds with multifunctional therapeutic applications.

Diabetes is emerging as an epidemic and is becoming a public health concern worldwide. Diabetic nephropathy is one of the serious complications of diabetes, and about 40% of individuals with diabetes develop diabetic nephropathy. The consistent feature of diabetes and its associated nephropathy is hyperglycemia, and in some cases, hyperamylinemia. Currently, the treatment includes the use of medication for blood pressure control, sugar control, and cholesterol control, and in the later stage requires dialysis and kidney transplantation, making the management of this complication very difficult. Bioactive compounds, herbal medicines, and extracts are extensively used in the treatment and prevention of several diseases, and some are reported to be efficacious in diabetes too. Therefore, in this study, we tried to identify the therapeutic potential of phytochemicals used in in silico docking and molecular dynamic simulation studies using a library of 5284 phytochemicals against the two potential targets of type 2 diabetes-associated nephropathy. We identified two phytochemicals (i.e., gentisic acid and michelalbine) that target human amylin peptide and dipeptidyl peptidase-4, respectively, with good binding affinity. These phytochemicals can be further evaluated using in vitro and in vivo studies for their anti-hyperglycemia and anti-hyperamylinemia effects.

Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (-10.4 kcal/mol), poncirin had the highest binding energy (-9.4 kcal/mol) with NF-κB and JNK (-9.5 kcal/mol), respectively, and icariin had the highest binding affinity (-9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin's greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood-brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.

One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance.

Pregabalin is widely used as a treatment for multiple neurological disorders; however, it has been reported to have the potential for misuse. Due to a lack of safety studies in pregnancy, pregabalin is considered the last treatment option for various neurological diseases, such as neuropathic pain. Therefore, pregabalin abuse in pregnant women, even at therapeutic doses, may impair fetal development. We used primary mouse embryonic neurons to investigate whether exposure to pregabalin can impair the morphogenesis and differentiation of ventral midbrain neurons. This study focused on ventral midbrain dopaminergic neurons, as they are responsible for cognition, movement, and behavior. The results showed that pregabalin exposure during early brain development induced upregulation of the dopaminergic progenitor genes Lmx1a and Nurr1 and the mature dopaminergic gene Pitx3 . Interestingly, pregabalin had different effects on the morphogenesis of non-dopaminergic ventral midbrain neurons. Importantly, our findings illustrated that a therapeutic dose of pregabalin (10 μM) did not affect the viability of neurons. However, it caused a decrease in ATP release in ventral midbrain neurons. We demonstrated that exposure to pregabalin during early brain development could interfere with the neurogenesis and morphogenesis of ventral midbrain dopaminergic neurons. These findings are crucial for clinical consideration of the use of pregabalin during pregnancy.

Ammonia oxidizing archaea (AOA) and bacteria (AOB) mediate a crucial step in nitrogen (N) metabolism. The effect of N fertilizer rates on AOA and AOB communities is less studied in the wheat-fallow system from semi-arid areas. Based on a 17-year wheat field experiment, we explored the effect of five N fertilizer rates (0, 52.5, 105, 157.5, and 210 kg ha -1 yr -1 ) on the AOA and AOB community composition. This study showed that the grain yield of wheat reached the maximum at 105 kg N ha -1 (49% higher than control), and no further significant increase was observed at higher N rates. With the increase of N, AOA abundance decreased in a regular trend from 4.88 × 10 7 to 1.05 × 10 7 copies g -1 dry soil, while AOB abundance increased from 3.63 × 10 7 up to a maximum of 8.24 × 10 7 copies g -1 dry soil with the N105 treatment (105 kg N ha -1 yr -1 ). Application rates of N fertilizer had a more significant impact on the AOB diversity than on AOA diversity, and the highest AOB diversity was found under the N105 treatment in this weak alkaline soil. The predominant phyla of AOA and AOB were Thaumarchaeota and Proteobacteria , respectively, and higher N treatment (N210) resulted in a significant decrease in the relative abundance of genus Nitrosospira . In addition, AOA and AOB communities were significantly associated with grain yield of wheat, soil potential nitrification activity (PNA), and some soil physicochemical parameters such as pH, NH 4 -N, and NO 3 -N. Among them, soil moisture was the most influential edaphic factor for structuring the AOA community and NH 4 -N for the AOB community. Overall, 105 kg N ha -1 yr -1 was optimum for the AOB community and wheat yield in the semi-arid area.

This study investigated the health-promoting activities of methanolic extracts of Ajwa date seed and fruit pulp extracts through in vitro studies. These studies confirmed potential antioxidant, anti-hemolytic, anti-proteolytic, and anti-bacterial activities associated with Ajwa dates. The EC 50 values of fruit pulp and seed extracts in methanol were reported to be 1580.35 ± 0.37 and 1272.68 ± 0.27 µg/mL, respectively, in the DPPH test. The maximum percentage of hydrogen peroxide-reducing activity was 71.3 and 65.38% for both extracts at 600 µg/mL. Fruit pulp and seed extracts inhibited heat-induced BSA denaturation by 68.11 and 60.308%, heat-induced hemolysis by 63.84% and 58.10%, and hypersalinity-induced hemolysis by 61.71% and 57.27%, and showed the maximum anti-proteinase potential of 56.8 and 51.31% at 600 μg/mL, respectively. Seed and fruit pulp inhibited heat-induced egg albumin denaturation at the same concentration by 44.31 and 50.84%, respectively. Ajwa seed showed minimum browning intensity by 63.2%, percent aggregation index by 64.2%, and amyloid structure by 63.8% at 600 μg/mL. At 100 mg/mL, Ajwa seed extract exhibited good antibacterial activity. Molecular docking analysis showed that ten active constituents of Ajwa seeds bind with the critical antioxidant enzymes, catalase (1DGH) and superoxide dismutase (5YTU). The functional residues involved in such interactions include Arg72, Ala357, and Leu144 in 1DGH, and Gly37, Pro13, and Asp11 in 5YTU. Hence, Ajwa dates can be used to develop a suitable alternative therapy in various diseases, including diabetes and possibly COVID-19-associated complications.

In this work, a new prototype of the eight-element MIMO antenna system for 5G communications, internet of things, and networks has been proposed. This system is based on an H-shaped monopole antenna system that offers 200 MHz bandwidth ranges between 3.4-3.6 GHz, and the isolation between any two elements is well below -12 dB without using any decoupling structure. The proposed system is designed on a commercially available 0.8 mm-thick FR4 substrate. One side of the chassis is used to place the radiating elements, while the copper from the other side is being removed to avoid short-circuiting with other components and devices. This also enables space for other systems, sub-systems, and components. A prototype is fabricated and excellent agreement is observed between the experimental and the computed results. It was found that ECC is 0.2 for any two radiating elements which is consistent with the desirable standards, and channel capacity is 38 bps/Hz which is 2.9 times higher than 4 × 4 MIMO configuration. In addition, single hand mode and dual hand mode analysis are conducted to understand the operation of the system under such operations and to identify losses and/or changes in the key performance parameters. Based on the results, the proposed antenna system will find its applications in modern 5G handheld devices and internet of things with healthcare and high rate delivery. Besides that, its design simplicity will make it applicable for mass production to be used in industrial demands.

Irisin is a clinically significant protein playing a valuable role in regulating various diseases. Irisin attenuates synaptic and memory dysfunction, highlighting its importance in Alzheimer's disease. On the other hand, Microtubule Affinity Regulating Kinase 4 (MARK4) is associated with various cancer types, uncontrolled neuronal migrations, and disrupted microtubule dynamics. In addition, MARK4 has been explored as a potential drug target for cancer and Alzheimer's disease therapy. Here, we studied the binding and subsequent inhibition of MARK4 by irisin. Irisin binds to MARK4 with an admirable affinity ( K = 0.8 × 10 7 M -1 ), subsequently inhibiting its activity (IC 50 = 2.71 µm). In vitro studies were further validated by docking and simulations. Molecular docking revealed several hydrogen bonds between irisin and MARK4, including critical residues, Lys38, Val40, and Ser134. Furthermore, the molecular dynamic simulation showed that the binding of irisin resulted in enhanced stability of MARK4. This study provides a rationale to use irisin as a therapeutic agent to treat MARK4-associated diseases.

This study evaluated the microstructure, grain size, and mechanical properties of the alloy 800H rotary friction welds in as-welded and post-weld heat-treated conditions. The standards for the alloy 800H not only specify the composition and mechanical properties but also the minimum grain sizes. This is because these alloys are mostly used in creep resisting applications. The dynamic recrystallization of the highly strained and plasticized material during friction welding resulted in the fine grain structure (20 ± 2 µm) in the weld zone. However, a small increase in grain size was observed in the heat-affected zone of the weldment with a slight decrease in hardness compared to the base metal. Post-weld solution heat treatment (PWHT) of the friction weld joints increased the grain size (42 ± 4 µm) in the weld zone. Both as-welded and post-weld solution heat-treated friction weld joints failed in the heat-affected zone during the room temperature tensile testing and showed a lower yield strength and ultimate tensile strength than the base metal. A fracture analysis of the failed tensile samples revealed ductile fracture features. However, in high-temperature tensile testing, post-weld solution heat-treated joints exhibited superior elongation and strength compared to the as-welded joints due to the increase in the grain size of the weld metal. It was demonstrated in this study that the minimum grain size requirement of the alloy 800H friction weld joints could be successfully met by PWHT with improved strength and elongation, especially at high temperatures.

Laser-powder bed fusion (L-PBF) process is a family of modern technologies, in which functional, complex (3D) parts are formed by selectively melting the metallic powders layer-by-layer based on fusion. The machining of L-PBF parts for improving their quality is a difficult task. This is because different component orientations (L-PBF-layer orientations) produce different quality of machined surface even though the same cutting parameters are applied. In this paper, stainless steel grade SS 316L parts from L-PBF were subjected to the finishing (milling) process to study the effect of part orientations. Furthermore, an attempt is made to suppress the part orientation effect by changing the layer thickness (LT) of the parts during the L-PBF process. L-PBF parts were fabricated with four different layer thicknesses of 30, 60, 80 and 100 μm to see the effect of the LT on the finish milling process. The results showed that the layer thickness of 60 μm has significantly suppressed the part orientation effect as compared to the other three-layer thicknesses of 30, 80 and 100 μm. The milling results showed that the three-layer thickness including 30, 80 and 100 μm presented up to a 34% difference in surface roughness among different part orientations while using the same milling parameters. In contrast, the layer thickness of 60 μm showed uniform surface roughness for the three-part orientations having a variation of 5-17%. Similarly, the three-layer thicknesses 30, 80 and 100 μm showed up to a 25%, 34% and 56% difference of axial force (Fa), feed force (Ff) and radial force (Fr), respectively. On the other hand, the part produced with layer thickness 60 μm showed up to 11%, 25% and 28% difference in cutting force components F a , F f and F r , respectively. The three-layer thicknesses 30, 80 and 100 μm in micro-hardness were found to vary by up to 14.7% for the three-part orientation. Negligible micro-hardness differences of 1.7% were revealed by the parts with LT 60 μm across different part orientations as compared to 6.5-14% variations for the parts with layer thickness of 30, 80 and 100 μm. Moreover, the parts with LT 60 μm showed uniform and superior surface morphology and reduced edge chipping across all the part orientations. This study revealed that the effect of part orientation during milling becomes minimum and improved machined surface integrity is achieved if the L-PBF parts are fabricated with a layer thickness of 60 μm.

Green synthesis of nanomaterials is advancing due to its ease of synthesis, inexpensiveness, nontoxicity and renewability. In the present study, an eco-friendly biogenic method was developed for the green synthesis of nickel oxide nanoparticles (NiONPs) using phytochemically rich Berberis balochistanica stem (BBS) extract. The BBS extract was rich in phenolics, flavonoids and berberine. These phytochemicals successfully reduced and stabilised the NiNO 3 (green) into NiONPs (greenish-gray). BBS-NiONPs were confirmed by using UV-visible spectroscopy (peak at 305 nm), X-ray diffraction (size of 31.44 nm), Fourier transform infrared spectroscopy (identified -OH group and Ni-O formation), energy dispersive spectroscopy (showed specified elemental nature) and scanning electron microscopy (showed rhombohedral agglomerated shape). BBS-NiONPs were exposed to multiple in vitro bioactivities to ascertain their beneficial biological applications. They exhibited strong antioxidant activities: total antioxidant capacity (64.77%) and 2, 2-diphenyl-1-picrylhydrazyl (71.48%); and cytotoxic potential: Brine shrimp cytotoxicity assay with IC 50 (10.40 µg/mL). BBS-NiONPs restricted the bacterial and fungal pathogenic growths at 1000, 500 and 100 µg/mL. Additionally, BBS-NiONPs showed stimulatory efficacy by enhancing seed germination rate and seedling growth at 31.25 and 62.5 µg/mL. In aggregate, BBS extract has a potent antioxidant activity which makes the green biosynthesis of NiONPs easy, economical and safe. The biochemical potential of BBS-NiONPs can be useful in various biomedical and agricultural fields.

In this paper, an experimental investigation into the machinability of AISI 316 alloy during finishing end milling operation under different cooling conditions and with varying process parameters is presented. Three environmental-friendly cooling strategies were utilized, namely, dry, minimal quantity lubrication (MQL) and MQL with nanoparticles (Al 2 O 3 ), and the variable process parameters were cutting speed and feed rate. Power consumption and surface quality were utilized as the machining responses to characterize the process performance. Surface quality was examined by evaluating the final surface roughness and surface integrity of the machined surface. The results revealed a reduction in power consumption when MQL and MQL + Al 2 O 3 strategies were applied compared to the dry case by averages of 4.7% and 8.6%, respectively. Besides, a considerable reduction in the surface roughness was noticed with average values of 40% and 44% for MQL and MQL + Al 2 O 3 strategies, respectively, when compared to the dry condition. At the same time, the reduction in generated surface roughness obtained by using MQL + Al 2 O 3 condition was marginal (5.9%) compared with using MQL condition. Moreover, the results showed that the improvement obtained in the surface quality when using MQL and MQL + Al 2 O 3 coolants increased at higher cutting speed and feed rate, and thus, higher productivity can be achieved without deteriorating final surface quality, compared to dry conditions. From scanning electron microscope (SEM) analysis, debris, furrows, plastic deformation irregular friction marks, and bores were found in the surface texture when machining under dry conditions. A slight smoother surface with a nano-polishing effect was found in the case of MQL + Al 2 O 3 compared to the MQL and dry cooling strategies. This proves the effectiveness of lubricant with nanoparticles in reducing the friction and thermal damages on the machined surface as the friction marks were still observed when machining with MQL comparable with the case of MQL + Al 2 O 3 .

Titanium alloys, especially Ti-6Al-4V, which is considered a difficult-to-cut material, bears numerous applications in aerospace and biomedical sectors. The criticality of the accurate formation of the machined cavity for the said applications and properties of Ti-6Al-4V accentuated the use of electric discharge machining (EDM). However, the issues of lower material removal rate (MRR) and tool wear (TWR) discouraged the use of EDM. These inherent issues hold a pivotal role regarding the sustainable machining of Ti-alloy. Therefore, in this research the potentiality of kerosene-based dielectric, having graphene nanoparticles, is comprehensively examined for the sustainable EDM of Ti-6Al-4V, which was not focused upon yet. Experimentation was performed under Taguchi's design (L18) with three types of electrodes, namely Aluminum, Brass and Copper. In total, 36 experiments were conducted, of which 18 were with graphene-mixed dielectric and the remaining were with kerosene. Experimental results reveal that the brass electrode with negative tool polarity yields higher MRR for both types of dielectrics. The maximum MRR (7.602 mm 3 /min) achieved with graphene mixed dielectric is 64.5% greater as compared to that obtained with kerosene (4.621 mm 3 /min). Moreover, the minimum TWR obtained for graphene-based dielectric, i.e., 0.17 mg/min is approximately 1.5 times less than that achieved with kerosene.

The studies about the effect of the graphene reinforcement ratio and machining parameters to improve the machining performance of Ti6Al4V alloy are still rare and incomplete to meet the Industry 4.0 manufacturing criteria. In this study, a hybrid adaptive neuro-fuzzy inference system (ANFIS) with a multi-objective particle swarm optimization method is developed to obtain the optimal combination of milling parameters and reinforcement ratio that lead to minimize the feed force, depth force, and surface roughness. For achieving this, Ti6Al4V matrix nanocomposites reinforced with 0 wt.%, 0.6 wt.%, and 1.2 wt.% graphene nanoplatelets (GNPs) are produced. Afterward, a full factorial approach was used to design experiments to investigate the effect of cutting speed, feed rate, and graphene nanoplatelets ratio on machining behaviour. After that, artificial intelligence based on ANFIS is used to develop prediction models as the fitness function of the multi-objective particle swarm optimization method. The experimental results showed that the developed models can obtain an accurate estimation of depth force, feed force, and surface roughness with a mean absolute percentage error of 3.87%, 8.56%, and 2.21%, respectively, as compared with experimentally measured outputs. In addition, the developed artificial intelligence models showed 361.24%, 35.05%, and 276.47% less errors for depth force, feed force, and surface roughness, respectively, as compared with the traditional mathematical models. The multi-objective optimization results from the new approach indicated that a cutting speed of 62 m/min, feed rate of 139 mm/min, and GNPs reinforcement ratio of 1.145 wt.% lead to the improved machining characteristics of GNPs reinforced Ti6Al4V matrix nanocomposites. Henceforth, the hybrid method as a novel artificial intelligent method can be used for optimizing the machining processes with complex relationships between the output responses.

This paper presents an experimental study into the comparative response of wiper and round-nose conventional carbide inserts coated with TiCN + AL 2 O 3 + TiN when turning an AISI 4340 steel alloy. The optimal process parameters, as identified by pre-experiments, were used for both types of inserts to determine the machined surface quality, tool wear, and specific cutting energy for different cutting lengths. The wiper inserts provided a substantial improvement in the attainable surface quality compared with the results obtained using conventional inserts under optimal cutting conditions for the entire range of the machined lengths. In addition, the conventional inserts showed a dramatic increase in roughness with an increased length of the cut, while the wiper inserts showed only a minor increase for the same length of cut. A scanning electron microscope was used to examine the wear for both types of inserts. Conventional inserts showed higher trends for both the average and maximum flank wear with cutting length compared to the wiper inserts, except for lengths of 200-400 mm, where conventional inserts showed less average flank wear. A higher accumulation of deposited chips was observed on the flank face of the wiper inserts than the conventional inserts. The experimental results demonstrated that edge chipping was the chief tool wear mechanism on the rake face for both types of insert, with more edge chipping observed in the case of the conventional inserts than the wiper inserts, with negligible evidence of crater wear in either case. The wiper inserts were shown to have a higher specific cutting energy than those detected with conventional inserts. This was attributed to (i) the irregular nose feature of the wiper inserts differing from the simpler round nose geometry of the conventional inserts and (ii) a higher tendency of chip accumulation on the wiper inserts.

The purinergic receptor P2Y6 is expressed in immune cells, including the microglia that are implicated in neurological disorders. Its ligand, UDP, is a signaling molecule that can serve as an "find-me" signal when released in significant quantities by damaged/dying cells. The binding of UDP by P2Y6R leads to the activation of different biochemical pathways, depending on the disease context and the pathological environment. Generally, P2Y6R stimulates phagocytosis. However, whether or not phagocytosis coincides with cell activation or the secretion of pro-inflammatory cytokines needs further investigation. The current review aims to discuss the various functions of P2Y6R in some CNS disorders. We present evidence that P2Y6R may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies, such as ischemic stroke, Alzheimer's disease, Parkinson's disease, radiation-induced brain injury, and neuropathic pain.

Microtubule affinity-regulating kinase (MARK4) plays a key role in Alzheimer's disease (AD) development as its overexpression is directly linked to increased tau phosphorylation. MARK4 is a potential drug target of AD and is thus its structural features are employed in the development of new therapeutic molecules. Donepezil (DP) and rivastigmine tartrate (RT) are acetylcholinesterase (AChE) inhibitors and are used to treat symptomatic patients of mild to moderate AD. In keeping with the therapeutic implications of DP and RT in AD, we performed binding studies of these drugs with the MARK4. Both DP and RT bound to MARK4 with a binding constant ( K ) of 10 7 M -1 . The temperature dependency of binding parameters revealed MARK-DP complex to be guided by static mode while MARK-RT complex to be guided by both static and dynamic quenching. Both drugs inhibited MARK4 with IC 50 values of 5.3 μM (DP) and 6.74 μM (RT). The evaluation of associated enthalpy change (Δ H ) and entropy change (Δ S ) implied the complex formation to be driven by hydrogen bonding making it seemingly strong and specific. Isothermal titration calorimetry further advocated a spontaneous binding. In vitro observations were further complemented by the calculation of binding free energy by molecular docking and interactions with the functionally-important residues of the active site pocket of MARK4. This study signifies the implications of AChE inhibitors, RT, and DP in Alzheimer's therapy targeting MARK4.

This paper presents the results of an investigation on the capacity of wire electrical discharge machining (WEDM) to produce microchannels in the Nickel-based alloy, Monel 400. The main objective of the current study is to produce microchannels with desired/target geometry and acceptable surface quality. Square cross-sectional microchannels with dimensions of 500 × 500 µm were investigated. Experiments were conducted based on the one-factor-at-a-time approach for the key input WEDM process parameters, namely pulse-on time (TON), pulse-off time (TOFF), average gap voltage (VGAP), wire feed (WF), and dielectric flow rate (FR). Dimensional accuracy, machining speed, surface roughness, surface morphology, microhardness, and microstructure were analyzed to evaluate the microchannels. The minimum errors of 6% and 3% were observed in the width and depth of the microchannels, respectively. Furthermore, microchannels with enhanced surface integrity could be produced exhibiting smooth surface morphology and shallow recast layer (~0-2.55 µm).

Titanium alloys are widely used in various applications including biomedicine, aerospace, marine, energy, and chemical industries because of their superior characteristics such as high hot strength and hardness, low density, and superior fracture toughness and corrosion resistance. However, there are different challenges when machining titanium alloys because of the high heat generated during cutting processes which adversely affects the product quality and process performance in general. Thus, optimization of the machining conditions while machining such alloys is necessary. In this work, an experimental investigation into the influence of different cutting parameters (i.e., depth of cut, cutting length, feed rate, and cutting speed) on surface roughness (Rz), flank wear (VB), power consumption as well as the material removal rate (MRR) during high-speed turning of Ti-6Al-4V alloy is presented and discussed. In addition, a backpropagation neural network (BPNN) along with the technique for order of preference by similarity to ideal solution (TOPSIS)-fuzzy integrated approach was employed to model and optimize the overall cutting performance. It should be stated that the predicted values for all machining outputs demonstrated excellent agreement with the experimental values at the selected optimal solution. In addition, the selected optimal solution did not provide the best performance for each measured output, but it achieved a balance among all studied responses.

To apply data fusion in time-domain based on Dempster-Shafer (DS) combination rule, an 8-step algorithm with novel entropy function is proposed. The 8-step algorithm is applied to time-domain to achieve the sequential combination of time-domain data. Simulation results showed that this method is successful in capturing the changes (dynamic behavior) in time-domain object classification. This method also showed better anti-disturbing ability and transition property compared to other methods available in the literature. As an example, a convolution neural network (CNN) is trained to classify three different types of weeds. Precision and recall from confusion matrix of the CNN are used to update basic probability assignment (BPA) which captures the classification uncertainty. Real data of classified weeds from a single sensor is used test time-domain data fusion. The proposed method is successful in filtering noise (reduce sudden changes-smoother curves) and fusing conflicting information from the video feed. Performance of the algorithm can be adjusted between robustness and fast-response using a tuning parameter which is number of time-steps( t s ).