Fuzzy-Based Efficient Healthcare Data Collection and Analysis Mechanism Using Edge Nodes in the IoMT.

The Internet of Things (IoT) is an advanced technology that comprises numerous devices with carrying sensors to collect, send, and receive data. Due to its vast popularity and efficiency, it is employed in collecting crucial data for the health sector. As the sensors generate huge amounts of data, it is better for the data to be aggregated before being transmitting the data further. These sensors generate redundant data frequently and transmit the same values again and again unless there is no variation in the data. The base scheme has no mechanism to comprehend duplicate data. This problem has a negative effect on the performance of heterogeneous networks.It increases energy consumption; and requires high control overhead, and additional transmission slots are required to send data. To address the above-mentioned challenges posed by duplicate data in the IoT-based health sector, this paper presents a fuzzy data aggregation system (FDAS) that aggregates data proficiently and reduces the same range of normal data sizes to increase network performance and decrease energy consumption. The appropriate parent node is selected by implementing fuzzy logic, considering important input parameters that are crucial from the parent node selection perspective and share Boolean digit 0 for the redundant values to store in a repository for future use. This increases the network lifespan by reducing the energy consumption of sensors in heterogeneous environments. Therefore, when the complexity of the environment surges, the efficiency of FDAS remains stable. The performance of the proposed scheme has been validated using the network simulator and compared with base schemes. According to the findings, the proposed technique (FDAS) dominates in terms of reducing energy consumption in both phases, achieves better aggregation, reduces control overhead, and requires the fewest transmission slots.

Stimuli-Responsive Therapeutic Metallodrugs.

The success of platinum-based anticancer agents has motivated the exploration of novel metal-based drugs for several decades, whereas problems such as drug-resistance and systemic toxicity hampered their clinical applications and efficacy. Stimuli-responsiveness of some metal complexes offers a good opportunity for designing site-specific prodrugs to maximize the therapeutic efficacy and minimize the side effect of metallodrugs. This review presents a comprehensive and up-to-date overview on the therapeutic stimuli-responsive metallodrugs that have appeared in the past two decades, where stimuli such as redox, pH, enzyme, light, temperature, and so forth were involved. The compounds are classified into three major categories based on the nature of stimuli, that is, endo-stimuli-responsive metallodrugs, exo-stimuli-responsive metallodrugs, and dual-stimuli-responsive metallodrugs. Representative examples of each type are discussed in terms of structure, response mechanism, and potential medical applications. In the end, future opportunities and challenges in this field are tentatively proposed. With diverse metal complexes being introduced, the foci of this review are pointed to platinum and ruthenium complexes.

Multiaction Platinum(IV) Prodrug Containing Thymidylate Synthase Inhibitor and Metabolic Modifier against Triple-Negative Breast Cancer.

Multifunctional platinumIV anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical problems of drug resistance and side effects of platinumII anticancer agents. Herein, we develop dual and triple action platinumIV complexes with targeted and biological active functionalities. One complex (PFL) that consists of cisplatin, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells. Cellular uptake and distribution studies reveal that PFL mainly accumulates in mitochondria. As a result, PFL disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochondrial membrane potential, which further leads to an increase in production of reactive oxygen species (ROS) and a decrease in ATP synthesis in MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thymidylate synthase, which shows the intracellular conversion of tegafur into 5-FU after its release from PFL. Furthermore, treatment with PFL impairs the mitochondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondrial pathway. The RNA-sequencing experiment shows that PFL can perturb the pathways involved in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These findings demonstrate that PFL intervenes in several cellular processes including DNA damage, thymidylate synthase inhibition, and perturbation of the mitochondrial bioenergetics to kill the cancer cells. The results highlight the significance of a triple-action prodrug for efficient anticancer therapy for TNBCs.

A double-locus scarless genome editing system in Escherichia coli.

OBJECTIVE: To develop a convenient double-locus scarless genome editing system in Escherichia coli, based on the type II Streptococcus pyogenes CRISPR/Cas9 and λ Red recombination cassette. RESULTS: A two-plasmid genome editing system was constructed. The large-sized plasmid harbors the cas9 and λ Red recombination genes (gam, bet, and exo), while the small-molecular plasmid can simultaneously express two different gRNAs (targeting genome RNAs). The recombination efficiency was tested by targeting the galK, lacZ, and dbpA genes in E. coli with ssDNA or dsDNA. Resulting concurrent double-locus recombination efficiencies were 88 ± 5.5% (point mutation), 39.7 ± 4.3% (deletion/insertion), and 57.8 ± 3.4%-58.5 ± 4.1% (mixed point and deletion/insertion mutation), depending on 30 (ssDNA) or 40 bp (dsDNA) homologous side arms employed. In addition, the curing efficiency of the guide plasmid expressing gRNAs for negative selection was higher (96 ± 3% in 4 h) than the help plasmid carrying cas9 and λ Red (92 ± 2% in 9 h). CONCLUSIONS: The new editing system is convenient and efficient for simultaneous double-locus recombination in the genome and should be favorable for high-throughput multiplex genome editing in synthetic biology and metabolic engineering.

Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX-2 and PD-L1.

Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes. Cyclooxygenase-2 (COX-2) plays a vital role in the progression of BC, correlating with the expression of programmed death-ligand 1 (PD-L1). Overexpression of PD-L1 contributes to the immune escape of cancer cells, and its blockade would stimulate anticancer immunity. Two multispecific platinum(IV) complexes DNP and NP were prepared using non-steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells. DNP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX; moreover, it displayed potent antitumor activity and almost no general toxicity in mice bearing triple-negative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX-2 and PD-L1 in vitro and vivo, inhibit the secretion of prostaglandin, reduce the expression of BC-associated protein BRD4 and phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), and block the oncogene c-Myc in BC cells. These findings demonstrate that DNP is capable of intervening in inflammatory, immune, and metastatic processes of BC, thus presenting a new mechanism of action for anticancer platinum(IV) complexes. The multispecificity offers a special superiority for DNP to treat TNBC by combining chemotherapy and immunotherapy in one molecule.

Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion-Targeted Platinum(II) Complex.

Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in a caspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphology and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As a result, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics, thus inducing cancer cells to enter a hypometabolic state.

Impact of Mitochondrion-Targeting Group on the Reactivity and Cytostatic Pathway of Platinum(IV) Complexes.

Platinum(IV) complexes are prodrugs of cisplatin with multiple potential advantages over platinum(II) drugs. Mitochondria play pivotal roles in producing energy and inducing death of cancer cells. Two platinum(IV) complexes, namely, c,c,t-[Pt(NH3)2Cl2(OH)(OCOCH2CH2CH2CH2PPh3)]Br and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2CH2CH2PPh3)2]Br2, were designed to explore the effect of mitochondrion-targeting group(s) on the bioactivity and cytotoxicity of platinum(IV) complexes. The complexes were characterized by electrospray ionization mass spectrometry, reverse-phase high-performance liquid chromatography, and multinuclear (1H, 13C, 31P, and 195Pt) NMR spectroscopy. The introduction of triphenylphosphonium targeting group(s) markedly influences the reactivity and cytotoxicity of the Pt(IV) complexes. The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin. The lipophilicity of the Pt(IV) complexes is enhanced by the targeting group(s), while their reactivity to DNA is decreased. As a result, the mitochondrial morphology and adenosine triphosphate producing ability are impaired, which constitutes an alternative pathway to inhibit cancer cells. This study shows that both the reactivity of platinum(IV) center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted Pt(IV) complexes. For targeting groups with pharmacological activities, their intrinsic function could enrich the anticancer mechanism of Pt(IV) complexes.

Complete genome sequence analysis of Edwardsiella tarda SC002 from hatchlings of Siamese crocodile.

Edwardsiella tarda is a Gram-negative, facultative anaerobic rod-shaped bacterium and the causative agent of the systemic disease "Edwardsiellosis". It is commonly prevalent in aquatic organisms with subsequent economic loss and hence has attracted increasing attention from researchers. In this study, we investigated the complete genome sequence of a highly virulent isolate Edwardsiella tarda SC002 isolated from hatchlings of the Siamese crocodile. The genome of SC002 consisted of one circular chromosome of length 3,662,469 bp with a 57.29% G+C content and four novel plasmids. A total of 3,734 protein-coding genes, 12 genomic islands (GIs), 7 prophages, 48 interspersed repeat sequences, 248 tandem repeat sequences, a CRISPR component with a total length of 175 bp, and 171 ncRNAs (tRNA = 106, sRNA = 37, and rRNA = 28) were predicted. In addition, the coding genes of assembled genome were successfully annotated against eight general databases (NR = 3,618/3,734, COG = 2,947/3,734, KEGG = 3,485/3,734, SWISS-PROT = 2,787/3,734, GO = 2,648/3,734, Pfam = 2,648/3,734, CAZy = 130/3,734, and TCDB = 637/3,734) and four pathogenicity-related databases (ARDB = 11/3,734, CARD = 142/3,734, PHI = 538/3,734, and VFDB = 315/3,734). Pan-genome and comparative genome analyses of the complete sequenced genomes confirmed their evolutionary relationships. The present study confirmed that E. tarda SC002 is a potential pathogen bearing a bulk amount of antibiotic resistance, virulence, and pathogenic genes and its open pan-genome may enhance its host range in the future.

Comparison of the Efficacy of Continuous Femoral Nerve Block With Epidural Analgesia for Postoperative Pain Relief After Unilateral Total Knee Replacement.

Introduction With recent developments in postoperative pain management after total knee replacement (TKR), the continuous femoral nerve block is becoming a common practice. The purpose of this study was to compare a femoral nerve block with time-tested epidural analgesia in a tertiary care setup in a developing country. Methodology A randomized control trial took place at Shifa International Hospital (SIH), Islamabad, Pakistan. Sixty patients, aged 40 to 90 years old, 12 males and 48 females, who were undergoing unilateral TKR for osteoarthritis in American Society of Anesthesiologists (ASA) physical status classes I and II, weighing between 50 and 99 kg, and fully able to understand and respond to the numeric rating scale (NRS) were included in the study. While patients belonging to ASA physical status class ≥3, with chronic opiate therapy, having allergies to local anesthetics or equipment material, or with neuromuscular disease, were excluded from the study. Ethical approval was obtained, and patients were divided into two groups, with group A given epidural and group B given a femoral nerve block for pain management postop. Data were collected. The pain was recorded using the NRS at six, 12, and 24 hours postop. Results The results for six hours and 12 hours were found to be significant. Patients in group A had a lower NRS rating postop as compared to group B and required a lesser amount of additional boluses for pain management.  Conclusion The femoral nerve block is inferior to epidural analgesia for pain management after unilateral TKR in the first 24 hours, with a greater need for extra boluses to relieve pain.

Recurrence Rate of Trigeminal Neuralgia With the Use of Percutaneous Stereotactic Continuous Radiofrequency Ablation at 80°C for 90 Seconds: A Single-Center Study.

Introduction With recent development in the treatment of trigeminal neuralgia (TN), percutaneous stereotactic rhizotomy is being widely used as an interventional technique. The purpose of this study was to find the recurrence rate of TN in patients who were treated with stereotactic rhizotomy at 80°C for 90 seconds, in a tertiary care set up in a developing country. Methodology A retrospective cohort study was conducted at Shifa International Hospital, Islamabad, Pakistan from September 2016 to August 31, 2021. A total of 57 patients (19 males and 38 females) aged 27-90 years old, whose MRI of the brain had ruled out organic or structural pathologies, and who fulfilled the International Classification of Headache Disorders, 3rd edition for TN were recruited for the study. Of these patients, 51 underwent radiofrequency ablation (RFA) of the trigeminal ganglion (one or more branches of the trigeminal nerve (cranial nerve V (CN V)) in the operation theater. Patients having concomitant comorbid conditions like brain tumors, vascular pathologies, or coagulopathies, those who had previously undergone trigeminal ganglion neurolysis with either alcohol or phenol, who were lost to follow-up before the completion of the six months or had not visited back after the procedure, and those on oral anticoagulants and the ones declared high risk or American Society of Anesthesiologists (ASA) 3 and above for general anesthesia were excluded. Ethical approval was obtained and data were collected from the medical records department. The pain was recorded using the Numeric Rating Scale and recurrence was recorded from the follow-up visits of the patient over at least 12 months. Results Out of 51 patients, three patients who underwent RFA reported recurrence of the same problem for which they had initially reported to the pain clinic and were treated again with RFA. Five patients came back with the neuralgia of a different but contiguous branch of the same Gasserian ganglion opted for the RFA and were treated with no subsequent recurrences. The initial pain relief rate was 84.31%. At the end of the five-year study period, 16 patients reported variable degrees of sensory deficit, and two patients experienced non-debilitating unilateral reversible motor weakness of the jaw. One patient experienced keratitis due to unintentional loss of corneal reflex and subsequent ipsilateral loss of vision. Conclusion RFA is one of the leading treatment options for TN, with lower recurrence at higher temperatures of the radiofrequency electrode, at the cost of more significant sensory and motor deficits.

Redirecting Cisplatin and Doxorubicin to Mitochondria Affords Highly Effective PlatinumIV Prodrug Against Triple Negative Breast Cancer.

A mitochondria targeting dual-action platinumIV prodrug exhibits high anticancer activity in triple negative breast cancer cells. The complex intervenes in several cellular processes including DNA damage, perturbation of mitochondrial bioenergetics and induction of necrosis to kill cancer cells.

Aerodynamic analysis of hummingbird-like hovering flight.

Flapping wing micro aerial vehicles are studied as the substitute for fixed and rotary wing micro aerial vehicles because of the advantages such as agility, maneuverability, and employability in confined environments. Hummingbird's sustainable hovering capability inspires many researchers to develop micro aerial vehicles with similar dynamics. In this research, a wing of a ruby-throated hummingbird is modeled as an insect wing using membrane and stiffeners. The effect of flexibility on the aerodynamic performance of a wing in hovering flight has been studied numerically by using a fluid-structure interaction scheme at a Reynolds number of 3000. Different wings have been developed by using different positions and thicknesses of the stiffeners. The chordwise and spanwise flexural stiffnesses of all the wings modeled in this work are comparable to insects of similar span and chord length. When the position of the stiffener is varied, the best-performing wing has an average lift coefficient of 0.51. Subsequently, the average lift coefficient is increased to 0.56 when the appropriate thickness of the stiffeners is chosen. The best flexible wing outperforms its rigid counterpart and produces lift and power economy comparable to a real hummingbird's wing. That is, the average lift coefficient and power economy of 0.56 and 0.88 for the best flexible wing as compared to 0.61 and 1.07 for the hummingbird's wing. It can be concluded that a simple manufacturable flexible wing design based on appropriate positioning and thickness of stiffeners can serve as a potential candidate for bio-inspired flapping-wing micro aerial vehicles.

Biotin-tagged platinum(iv) complexes as targeted cytostatic agents against breast cancer cells.

A biotin-guided platinumIV complex is highly cytotoxic against breast cancer cells but hypotoxic against mammary epithelial cells. The mono-biotinylated PtIV complex is superior to the di-biotinylated one and hence a promising drug candidate for the targeted therapy of breast cancer.

Dual-drug loaded nanoformulation with a galactosamine homing moiety for liver-targeted anticancer therapy.

Drug resistance and unfavorable pharmacokinetics are the major obstacles for conventional anticancer drugs. A combination of different anticancer drugs into one formulation is a common strategy to alleviate the side effects of individual drugs in clinical practice. Platinum anticancer drugs are the typical defective therapeutic agents for cancer chemotherapy and have poor selectivity for tumor cells. In this study, a nanosystem composed of poly(lactic-co-glycolic acid) (PLGA), Pt(IV) prodrug (PPD) and α-tocopheryl succinate (α-TOS) was designed to overcome these defects. The Pt(IV) prodrug, c,c,t-[Pt(NH3)2Cl2(O2CC(CH3)3)2], was prepared by the reaction of oxoplatin with trimethylacetic anhydride and its structure was characterized by X-ray crystallography. The PPD and α-TOS self-assembled with PLGA, forming a dual-drug loaded nanoparticle (DDNP). The surface of the DDNP was decorated with galactosamine (G), giving rise to a G-DDNP that can actively target the liver cancer cells through the overexpressed asialoglycoprotein receptors. The DDNPs and G-DDNPs were characterized by SEM, TEM, and DLS. They are spherical in shape with required polydispersity and suitable mean size (ca. 150 nm). The in vitro cytotoxicity of DDNPs and G-DDNPs was tested against the human SMMC-7721 liver cancer cell line. G-DDNPs are more potent than the corresponding free drugs and untargeted DDNP, showing that some synergistic and tumor-specific effects are achieved by this strategy. The results demonstrate that dual-drug loaded nanoformulations with tumor-targeting function could be effective anticancer agents for conquering the shortcomings related to single-drug chemotherapy.

Metal-based anticancer chemotherapeutic agents.

Since the discovery of the cisplatin antitumor activity, great efforts have focused on the rational design of metal-based anticancer agents that can be potentially used in cancer chemotherapy. Over the last four decades, a large number of metal complexes have been extensively investigated and evaluated in vitro and in vivo, and some of them were at different stages of clinical studies. Amongst these complexes, platinum (Pt(II) and Pt(IV)), ruthenium (Ru(II) and Ru(III)), gold (Au(I) and Au(III)) and titanium (Ti(IV)) complexes are the most studied metals. We describe here some most recent progresses on Pt(IV) prodrugs which can be activated once enter tumor cells, polynuclear Pt(II) complexes which have unique DNA binding ability and mode, anti-metastatic Ru(II)/Ru(III) complexes, and Au(I)/Au(III) and Ti(IV) antitumor active complexes. The key focuses of these studies lie in finding novel metal complexes which could potentially overcome the hurdles of current clinical drugs including toxicity, resistance and other pharmacological deficiencies.