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Abstract The quantitative determination of average roughness parameters, from the determination of height variations of the surface points, is frequently used to estimate the adhesion between an adhesive and the surface of a substrate. However, to determine the interaction between an adhesive and a surface of a heterogeneous material, such as a red ceramic, it is essential to define other roughness parameters. This work proposes a method for determining the roughness of red ceramic blocks from a three-dimensional evaluation, with the objective of estimating the contact area that the ceramic substrate can provide for a cementitious matrix. The study determines the average surface roughness from multiple planes and proposes the adoption of 2 more roughness parameters, the valley area index and the average valley area. The results demonstrate that there are advantages in using the proposed multiple plane method for roughness computation and that the valley area parameters are efficient to estimate the extent of adhesion between the materials involved.

Abstract Needle artifacts pose a major limitation for MRI-guided interventions, as they impact the visually perceived needle size and needle-to-target-distance. The objective of this agar liver phantom study was to establish an experimental basis to understand and reduce needle artifact formation during MRI-guided abdominal interventions. Using a vendor-specific prototype fluoroscopic T1-weighted gradient echo sequence with real-time multiplanar acquisition at 1.5 T, the influence of 6 parameters (flip angle, bandwidth, matrix, slice thickness, read-out direction, intervention angle relative to B0) on artifact formation of 4 different coaxial MR-compatible coaxial needles (Nitinol, 16G–22G) was investigated. As one parameter was modified, the others remained constant. For each individual parameter variation, 2 independent and blinded readers rated artifact diameters at 2 predefined positions (15 mm distance from the perceived needle tip and at 50% of the needle length). Differences between the experimental subgroups were assessed by Bonferroni-corrected non-parametric tests. Correlations between continuous variables were expressed by the Bravais–Pearson coefficient and interrater reliability was quantified using the intraclass classification coefficient. Needle artifact size increased gradually with increasing flip angles (p = 0.002) as well as increasing intervention angles (p

In most organisms, cells typically maintain genome integrity, as radical genome reorganization leads to dramatic consequences. However, certain organisms, ranging from unicellular ciliates to vertebrates, are able to selectively eliminate specific parts of their genome during certain stages of development. Moreover, partial or complete elimination of one of the parental genomes occurs in interspecies hybrids reproducing asexually. Although several examples of this phenomenon are known, the molecular and cellular processes involved in selective elimination of genetic material remain largely undescribed for the majority of such organisms. Here, we elucidate the process of selective genome elimination in water frog hybrids from the Pelophylax esculentus complex reproducing through hybridogenesis. Specifically, in the gonads of diploid and triploid hybrids, but not those of the parental species, we revealed micronuclei in the cytoplasm of germ cells. In each micronucleus, only one centromere was detected with antibodies against kinetochore proteins, suggesting that each micronucleus comprises a single chromosome. Using 3D-FISH with species-specific centromeric probe, we determined the role of micronuclei in selective genome elimination. We found that in triploid LLR hybrids, micronuclei preferentially contain P. ridibundus chromosomes, while in diploid hybrids, micronuclei preferentially contain P. lessonae chromosomes. The number of centromere signals in the nuclei suggested that germ cells were aneuploid until they eliminate the whole chromosomal set of one of the parental species. Furthermore, in diploid hybrids, misaligned P. lessonae chromosomes were observed during the metaphase stage of germ cells division, suggesting their possible elimination due to the inability to attach to the spindle and segregate properly. Additionally, we described gonocytes with an increased number of P. ridibundus centromeres, indicating duplication of the genetic material. We conclude that selective genome elimination from germ cells of diploid and triploid hybrids occurs via the gradual elimination of individual chromosomes of one of the parental genomes, which are enclosed within micronuclei. [ABSTRACT FROM AUTHOR]

Emerging bacterial antibiotic resistance draws attention to bacteriophages as a therapeutic alternative to treat bacterial infection. Examples of phage that combat bacteria abound. However, despite careful testing of antibacterial activity in vitro, failures nevertheless commonly occur. We investigated immunological response of phage antibacterial potency in vivo. Anti-phage activity of phagocytes, antibodies, and serum complement were identified by direct testing and by high-resolution fluorescent microscopy. We accommodated the experimental data into a mathematical model. We propose a universal schema of innate and adaptive immunity impact on phage pharmacokinetics, based on the results of our numerical simulations. We found that the mammalian-host response to infecting bacteria causes the concomitant removal of phage from the system. We propose the notion that this effect as an indirect pathway of phage inhibition by bacteria with significant relevance for the clinical outcome of phage therapy. [ABSTRACT FROM AUTHOR]

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) infection is one of the global healthcare concerns. Here, we report the phenotypic and genotypic characterization of a novel multi-host Staphylococcus phage RuSa1, isolated from wastewater samples derived from a spotted sambar deer (Rusa unicolor) enclosure located at Mangalore, India. Clinical MRSA strains (n = 18) susceptible to RuSa1 were genetically and phenotypically diverse as determined by DNA fingerprinting and in vitro culture assays. RuSa1 displayed a latent period and burst size of 10 min and 50 PFU, respectively, and exhibited efficient biofilm removal activities against S. aureus ATCC BAA-44. The phage exhibited moderate UV stability (3 min) and high titre at 4–37 °C and pH 5‒9. RuSa1 possessed a linear double-stranded genomic DNA with a length of 140 kb. The genome contained 30.18% GC composition and shared 82.0‒94.9% sequence similarity with eleven authentic species of Kayvirus recognized by the International Committee on Taxonomy of Viruses based on VIRIDIC analysis. RuSa1 established distinct phyletic lineage in the maximum likelihood phylogenetic analysis of DNA encoding structural proteins and lacked genes that confer lysogeny. Based on the genotypic, phylogenetic and phenotypic data, RuSa1 is proposed to be a lytic phage and a new species of Kayvirus with a potential therapeutic ability against staphylococcal infections. [ABSTRACT FROM AUTHOR]

In our ears, outer-hair-cell bundles (OHBs) convert sound-induced forces into receptor currents that drive cochlear amplification, the process responsible for the micropascal-scale threshold and million-fold dynamic range of hearing. OHBs rely on gating springs to open mechanoelectrical-transduction (MET) ion channels, through which the receptor current flows. OHBs have larger gating-spring stiffnesses than other types of hair bundles, but we have a poor understanding of how gating-spring stiffness contributes to OHB mechanics and receptor-current regulation. Using experimentally-constrained mathematical models of the OHB, we show that the increased gating-spring stiffness in an OHB increases its stiffness and damping. The OHB’s 3D morphology reduces the contribution of gating-spring stiffness to OHB stiffness, reduces the contribution of MET-channel gating to OHB stiffness and damping, but causes additional OHB damping that rises with gating-spring stiffness. Gating-spring stiffness increases the OHB’s receptor current but decreases its displacement-current dynamic range. Strikingly, the OHB’s 3D morphology causes its force-current dynamic range to decrease with gating-spring stiffness. Our results suggest a trade-off between threshold and dynamic range regulated by OHB gating-spring stiffness. [ABSTRACT FROM AUTHOR]

Polyphenols are natural biomolecules known for circumventing several diseases including cancer with little adverse effects. This study aimed to investigate the polyphenol enriched fractions from the leaf extract of Asystasia gangetica for their composition, biological activities such as antioxidant activity, haemolytic effects, and in vitro cytotoxicity against cancer cell lines. LC–MS/MS analysis of the enriched fractions identified a total of 35 distinct polyphenols with caffeic acid, luteolin, apigenin, and protocatechuic acid at higher concentrations. Fractions AG-3 and AG-4 exhibited the highest total antioxidant activity with higher concentration of phenolics and flavonoids. The AG-4 fraction had the highest levels of DPPH radical scavenging (IC50 = 32.74 µg mL-1) and ABTS radical scavenging (IC50 = 29.45 µg mL–1) activity, in addition to a modest iron chelating activity and reducing power. The fractions exhibited the least haemolytic activity. The cytotoxic potential of enriched fractions against the HCT-116, HeLa, PC-3, and HDF cell lines was further examined. While the extract showed no inhibitory effect on normal HDF cells, the cytotoxic activity of fractions on cell lines varied, with HCT-116 cells having the strongest anticancer activity with an IC50 of 43.82 µg mL–1. Additionally, fractions induced apoptotic activity in HCT-116 cells, resulting in cell cycle arrest at the G2M phase and an increase in sub-G0/G1 cells, with an IC50 of 13.54 µg mL–1 after 48 h of incubation. The in silico molecular docking of the active compounds against the TNIK receptor protein and ADMET (Absorption–Distribution–Metabolism–Excretion–Toxicity) characteristics are described. Overall, the study highlights the enhanced biological and antiproliferative activities of polyphenols in Asystasia gangetica leaf extract, which could be further utilized as a potential cancer treatment strategy. [ABSTRACT FROM AUTHOR]

Biofilms are mucilaginous-organic layers produced by microbial activity including viruses. Growing biofilms form microbial mats which enhance sediment stability by binding particles with extracellular polymeric substances and promoting growth through nutrient cycling and organic matter accumulation. They preferentially develop at the sediment-water interface of both marine and non-marine environments, and upon the growing surfaces of modern tufa and travertine. In this context, however, little is known about the factors, environmental or anthropogenic, which affect viral communities in freshwater spring settings. To explore this issue, geochemical and metagenomic data were subjected to multidimensional analyses (Principal Component Analysis, Classical Multidimensional Scaling, Partial Least Squares analysis and cluster analysis based on beta-diversity), and these show that viral composition is specific and dependent on environment. Indeed, waters precipitating tufa and travertine do vary in their geochemistry with their viruses showing distinct variability between sites. These differences between virus groups allow the formulation of a viral proxy, based on the Caudoviricetes/Megaviricetes ratio established on the most abundant groups of viruses. This ratio may be potentially used in analysing ancient DNA preserved in carbonate formations as an additional source of information on the microbiological community during sedimentation. [ABSTRACT FROM AUTHOR]

Anxiety among pregnant women can significantly impact their overall well-being. However, the development of data-driven HCI interventions for this demographic is often hindered by data scarcity and collection challenges. In this study, we leverage the Empatica E4 wristband to gather physiological data from pregnant women in both resting and relaxed states. Additionally, we collect subjective reports on their anxiety levels. We integrate features from signals including Blood Volume Pulse (BVP), Skin Temperature (SKT), and Inter-Beat Interval (IBI). Employing a Support Vector Machine (SVM) algorithm, we construct a model capable of evaluating anxiety levels in pregnant women. Our model attains an emotion recognition accuracy of 69.3%, marking achievements in HCI technology tailored for this specific user group. Furthermore, we introduce conceptual ideas for biofeedback on maternal emotions and its interactive mechanism, shedding light on improved monitoring and timely intervention strategies to enhance the emotional health of pregnant women. [ABSTRACT FROM AUTHOR]

Damage from ice and potential toxicity of ice-inhibiting cryoprotective agents (CPAs) are key issues in assisted reproduction of humans, domestic and research animals, and endangered species using cryopreserved oocytes and embryos. The nature of ice formed in bovine oocytes (similar in size to oocytes of humans and most other mammals) after rapid cooling and during rapid warming was examined using synchrotron-based time-resolved x-ray diffraction. Using cooling rates, warming rates and CPA concentrations of current practice, oocytes show no ice after cooling but always develop large ice fractions—consistent with crystallization of most free water—during warming, so most ice-related damage must occur during warming. The detailed behavior of ice at warming depended on the nature of ice formed during cooling. Increasing cooling rates allows oocytes soaked as in current practice to remain essentially ice free during both cooling and warming. Much larger convective warming rates are demonstrated and will allow routine ice-free cryopreservation with smaller CPA concentrations. These results clarify the roles of cooling, warming, and CPA concentration in generating ice in oocytes and establish the structure and grain size of ice formed. Ice formation can be eliminated as a factor affecting post-warming oocyte viability and development in many species, improving outcomes and allowing other deleterious effects of the cryopreservation cycle to be independently studied. [ABSTRACT FROM AUTHOR]

Chronic Otitis Media (COM) is defined as long term inflammation and colonization with pathogenic bacteria due to a defect or retraction of the tympanic membrane. Surgical interventions are often augmented by antibiotic resistance development and therefore, off-label treatment using the natural drug 1,8-Cineol was carried out. All COM patients underwent antibiotic therapy and middle ear surgery and developed antibiotic resistances. Microbiological investigations from the auditory canal and stool samples were performed in correlation with the clinical course. Therapy of COM patients with 1,8-Cineol revealed a clear reduction of inflammatory microbes P. aeruginosa and Proteus mirabilis in ear samples as well as intestinal Prevotella copri, which was associated with an improved clinical outcome in certain individuals. The present off-label study revealed manifold anti-inflammatory effects of the natural monoterpene 1,8-Cineol in Otitis media patients. A better understanding of the underlying mechanisms will improve the current treatment options and possible forms of application of this natural drug. [ABSTRACT FROM AUTHOR]

Low-grade chronic inflammation is associated with many age-related conditions. Non-invasive methods to monitor low-grade chronic inflammation may improve the management of older people at risk of poorer outcomes. This longitudinal cohort study has determined baseline inflammation using neopterin volatility in monthly urine samples of 45 independent older adults (aged 65–75 years). Measurement of neopterin, an inflammatory metabolite, enabled stratification of individuals into risk categories based on how often in a 12-month period their neopterin level was raised. Hearing was measured (pure-tone audiometry) at baseline, 1 year and 3 years of the study. Results show that those in the highest risk category (neopterin raised greater than 50% of the time) saw greater deterioration, particularly in high-frequency, hearing. A one-way Welch’s ANOVA showed a significant difference between the risk categories for change in high-frequency hearing (W (3, 19.6) = 9.164, p = 0.0005). Despite the study size and duration individuals in the highest risk category were more than twice as likely to have an additional age-related morbidity than those in the lowest risk category. We conclude that volatility of neopterin in urine may enable stratification of those at greatest risk of progression of hearing loss. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae releases the peptides AKTIKITQTR and FNEMQPIVDRQ, which bind the pneumococcal proteins AmiA and AliA respectively, two substrate-binding proteins of the ABC transporter Ami-AliA/AliB oligopeptide permease. Exposure to these peptides alters pneumococcal phenotypes such as growth. Using a mutant in which a permease domain of the transporter was disrupted, by growth analysis and epifluorescence microscopy, we confirmed peptide uptake via the Ami permease and intracellular location in the pneumococcus. By RNA-sequencing we found that the peptides modulated expression of genes involved in metabolism, as pathways affected were mostly associated with energy or synthesis and transport of amino acids. Both peptides downregulated expression of genes involved in branched-chain amino acid metabolism and the Ami permease; and upregulated fatty acid biosynthesis genes but differed in their regulation of genes involved in purine and pyrimidine biosynthesis. The transcriptomic changes are consistent with growth suppression by peptide treatment. The peptides inhibited growth of pneumococcal isolates of serotypes 3, 8, 9N, 12F and 19A, currently prevalent in Switzerland, and caused no detectable toxic effect to primary human airway epithelial cells. We conclude that pneumococci take up K. pneumoniae peptides from the environment via binding and transport through the Ami permease. This changes gene expression resulting in altered phenotypes, particularly reduced growth. [ABSTRACT FROM AUTHOR]

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) emphasises the urgent need for novel antimicrobial agents as alternatives to antibiotics. Bacteriophage therapy is one of the most promising antimicrobial strategies. Here, we isolated and comprehensively characterized a novel Staphylococcus phage, vB_SauM_VL10 (VL10), from urban sewage. The VL10 genome displays 141,746 bp of linear double-stranded DNA, containing 193 open reading frames and lacking tRNA, virulence, or antibiotic resistance genes. Phylogenetic analysis categorizes VL10 as a novel species within the Silviavirus genus, Twortvirinae subfamily. VL10 exhibits lytic behaviour characterized by efficient adsorption, a short latent period, and substantial burst size, with environmental stability. It demonstrates lytic activity against 79.06% of tested S. aureus strains, highlighting its species specificity. Additionally, VL10 effectively targets MRSA biofilms, reducing biomass and viable cells. In MRSA-infected G. mellonella larvae, VL10 enhances survival rates, supporting its potential for phage therapy applications. Moreover, the emergence of VL10-resistant S. aureus strains associated with fitness trade-offs, including reduced growth, biofilm formation, and virulence. Altogether, these findings emphasize VL10 as a promising candidate for developing therapeutic agents against MRSA infections, providing insights into phage biology and resistance dynamics. [ABSTRACT FROM AUTHOR]

Klebsiella aerogenes is an emergent pathogen associated with outbreaks of carbapenem-resistant strains. To date, studies focusing on K. aerogenes have been small-scale and/or geographically restricted. Here, we analyzed the epidemiology, resistome, virulome, and plasmidome of this species based on 561 genomes, spanning all continents. Furthermore, we sequenced four new strains from Brazil (mostly from the Amazon region). Dozens of STs occur worldwide, but the pandemic clones ST93 and ST4 have prevailed in several countries. Almost all genomes were clinical, however, most of them did not carry ESBL or carbapenemases, instead, they carried chromosomal alterations (omp36, ampD, ampG, ampR) associated with resistance to β-lactams. Integrons were also identified, presenting gene cassettes not yet reported in this species (blaIMP, blaVIM, blaGES). Considering the virulence loci, the yersiniabactin and colibactin operons were found in the ICEKp10 element, which is disseminated in genomes of several STs, as well as an incomplete salmochelin cluster. In contrast, the aerobactin hypervirulence trait was observed only in one ST432 genome. Plasmids were common, mainly from the ColRNAI replicon, with some carrying resistance genes (mcr, blaTEM, blaNDM, blaIMP, blaKPC, blaVIM) and virulence genes (EAST1, senB). Interestingly, 172 genomes of different STs presented putative plasmids containing the colicin gene. [ABSTRACT FROM AUTHOR]

Neonatal Jaundice is a common occurrence in neonates. High excess bilirubin would lead to hyperbilirubinemia, leading to irreversible adverse damage such as kernicterus. Therefore, it is necessary and important to monitor neonates' bilirubin levels in real-time for immediate intervention. However, current screening protocols have their inherent limitations, necessitating more convenient measurements. In this proof-of-concept study, we evaluated the feasibility of using machine learning for the screening of hyperbilirubinemia in neonates from smartphone-acquired photographs. Different machine learning models were compared and evaluated to gain a better understanding of feature selection and model performance in bilirubin determination. An in vitro study was conducted with a bilirubin-containing tissue phantom to identify potential biological and environmental confounding factors. The findings of this study present a systematic characterization of the confounding effect of various factors through separate parametric tests. These tests uncover potential techniques in image pre-processing, highlighting important biological features (light scattering property and skin thickness) and external features (ISO, lighting conditions and white balance), which together contribute to robust model approaches for accurately determining bilirubin concentrations. By obtaining an accuracy of 0.848 in classification and 0.812 in regression, these findings indicate strong potential in aiding in the design of clinical studies using patient-derived images. [ABSTRACT FROM AUTHOR]

Bacteriophage therapy is one potential strategy to treat antimicrobial resistant or persistent bacterial infections, and the year 2021 marked the centennial of Felix d'Hérelle's first publication on the clinical applications of phages. At the Center for Phage Biology & Therapy at Yale University, a preparatory modular approach has been established to offer safe and potent phages for single-patient investigational new drug applications while recognizing the time constraints imposed by infection(s). This study provides a practical walkthrough of the pipeline with an Autographiviridae phage targeting Pseudomonas aeruginosa (phage vB_PaeA_SB, abbreviated to ΦSB). Notably, a thorough phage characterization and the evolutionary selection pressure exerted on bacteria by phages, analogous to antibiotics, are incorporated into the pipeline. [ABSTRACT FROM AUTHOR]

The bio-adsorption of heavy metals (including Cu2+, Ni2+, and Zn2+) in aqueous solution and also in an industry wastewater using the ZnO-modified date pits (MDP) as the bio-adsorbent are investigated. The fresh and used bio-adsorbents were characterized by FT-IR, SEM, BET, and XRD. The bio-adsorption parameters (including the pH of solution, the particle size of MDP, the shaking speed, the initial concentration of heavy metals, the dosing of MDP, the adsorption time, and the adsorption temperature) were screened and the data were used to optimize the bio-adsorption process and to study the bio-adsorption isotherms, kinetics, and thermodynamics. Two adsorption models (Langmuir isotherm model and Freundlich isotherm model) and three kinetic models (pseudo-first-order model, pseudo-second-order model, and intra-particle diffusion model) were applied to model the experimental data. Results show that the maximum adsorption amount of Cu2+, Ni2+, and Zn2+ on a complete monolayer of MDP are 82.4, 71.9, and 66.3 mg g−1, which are over 4 times of those of date pits-based bio-adsorbents reported in literature. The bio-adsorption of heavy metals on MDP is spontaneous and exothermic, and is regulated by chemical adsorption on the homogeneous and heterogeneous adsorption sites of MDP surface. This work demonstrates an effective modification protocol for improved bio-adsorption performance of the date pits-based bio-adsorbent, which is cheap and originally from a waste. [ABSTRACT FROM AUTHOR]

Activated carbon (AC) is becoming the limelight due to its widespread application as an adsorbent for wastewater treatment, gases, and catalysis. However, its high consumption and price have drawn more attention to the sustainable use of natural resources as precursor for AC production. This study focuses on synthesising AC from two types of oil palm trunk (OPT) fibres, a significant agricultural waste products produced by Malaysia's thriving palm oil industries. The BET surface area of about 2057.9 m2 g−1 was achieved by chemical activation with phosphoric acid (H3PO4). The efficiency of the synthesised AC was critically analysed based on the adsorption experiments with methylene blue (MB) by varying several parameters (dosage of adsorbent, pH, initial dye concentration, and temperature of the solution) to elucidate the adsorption mechanism(s). A maximum adsorption capacity of 320.4 mg g−1 at 50 °C was achieved, and the Temkin (r2 = 0.98, 0.95, 0.95) and Langmuir (r2 = 0.94, 0.93, 0.95) isotherm models fitted the adsorption process better than the Freundlich (r2 = 0.95, 0.90, 0.86) model. Besides, the pseudo-second-order model (r2 > 0.90) best described the adsorption process, favouring chemisorption over physisorption. Thermodynamics showed MB adsorption on AC was spontaneous except at the highest dye concentration. It was exothermic at lower dye concentrations (50 and 100 mg L−1) and endothermic at higher ones (300, 500, and 700 mg L−1). In a nutshell, this study reveals that OPT fibre is a promising precursor for synthesising highly porous AC for the adsorption of MB dye. [ABSTRACT FROM AUTHOR]

Phthalates constitute a family of anthropogenic chemicals developed to be used in the manufacture of plastics, solvents, and personal care products. Their dispersion and accumulation in many environments can occur at all stages of their use (from synthesis to recycling). However, many phthalates together with other accumulated engineered chemicals have been shown to interfere with hormone activities. These compounds are also in close contact with microorganisms that are free-living, in biofilms or in microbiota, within multicellular organisms. Herein, the activity of several phthalates and their substitutes were investigated on the opportunistic pathogen Legionella pneumophila, an aquatic microbe that can infect humans. Beside showing the toxicity of some phthalates, data suggested that Acetyl tributyl citrate (ATBC) and DBP (Di-n-butyl phthalate) at environmental doses (i.e. 10–6 M and 10–8 M) can modulate Legionella behavior in terms of motility, biofilm formation and response to antibiotics. A dose of 10–6 M mostly induced adverse effects for the bacteria, in contrast to a dose of 10–8 M. No perturbation of virulence towards Acanthamoeba castellanii was recorded. These behavioral alterations suggest that L. pneumophila is able to sense ATBC and DBP, in a cross-talk that either mimics the response to a native ligand, or dysregulates its physiology. [ABSTRACT FROM AUTHOR]

In this work, we propose a GIS-based platform aimed at the analysis of heatwave scenarios risks produced in urbanised environments, applied to assess vulnerability and impact heatwave scenarios. Our framework implements a hierarchical model that represents a good trade-off between forecast accuracy and portability in different urban fabrics, apart from the spatial scale of the data, using topographic and remote sensing spatial data provided by institutional agencies. The framework has been applied to two study areas: the dense city of Naples (Italy) and the intermediately populated city of Avellino (Italy) in order to evaluate its accuracy performances and portability in different urban fabrics. Our framework can be used by urban planners and decision makers as a tool to locate potential risk zones where it is necessary to implement climate-resilient solutions. [ABSTRACT FROM AUTHOR]

Resveratrol, curcumin, and quercetin are the secondary metabolites from medicinal food homology plants, that have been proven their potency in cancer treatment. However, the antitumor effect of a single component is weak. So, herein, we designed an antitumor compound named RCQ composed of resveratrol, curcumin, and quercetin. This study examined the effect on tumorigenesis and development of 4T1 breast cancer-bearing mice following administering RCQ by intragastric administration. RCQ increased the recruitment of T cells and reduced the accumulation of neutrophils and macrophages in the tumor microenvironment. Meanwhile, RCQ suppressed the development of tumor-infiltrating lymphocytes into immunosuppressive cell subpopulations, including CD4+ T cells to T helper Type 2 type (Th2), tumor-associated neutrophils (TANs) to the N2 TANs, and tumor-associated macrophages (TAMs) cells to M2 TAMs. RCQ reversed the predominance of immunosuppressive infiltrating cells in the tumor microenvironment and tipped the immune balance toward an immune activation state. In vitro the study showed that RCQ significantly increased reactive oxygen species (ROS), reduce mitochondrial membrane potentials in cancer cells, and modulate pro-apoptotic Bcl-2 family members. In conclusion, RCQ can promote the ROS apoptosis mechanism of tumor cells and alleviate immunosuppression of the tumor microenvironment to enhance the anti-tumor effect. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a well-known risk factor for atrial fibrillation (AF), but the mechanism(s) by which DM affects AF prevalence remains unclear. This study aims to evaluate the impact of diabetes mellitus severity (expressed as its known duration), antihyperglycemic treatment regimen and glycaemic control on AF prevalence. From the representative sample of 3014 participants (mean age 77.5, 49.1% female) from the cross-sectional NOMED-AF study, 881 participants (mean age 77.6 ± 0.25, 46.4% female) with concomitant DM were involved in the analysis. AF was screened using a telemonitoring vest for a mean of 21.9 ± 9.1 days. The mean DM duration was 12 ± 0.35 years, but no significant impact of DM timespan on AF prevalence was observed. No differences in the treatment pattern (oral medication vs insulin vs both oral + insulin) among the study population with and without AF were shown (p = 0.106). Metabolic control reflected by HbA1c levels showed no significant association with AF and silent AF prevalence (p = 0.635; p = 0.094). On multivariate analyses, age (Odds Ratio (OR) 1.35, 95%CI: 1.18–1.53, p < 0.001), p = 0.042), body mass index (BMI; OR 1.043, 95%CI: 1.01–1.08, p = 0.027) and LDL < 100 mg/dl (OR 0.64, 95%CI: 0.42–0.97, p = 0.037) were independent risk factors for AF prevalence, while age (OR 1.45, 95%CI: 1.20–1.75, p < 0.001), LDL < 100 mg/dl (OR 0.43, 95%CI 0.23–0.82, p = 0.011), use of statins (OR 0.51, 95%CI: 0.28–0.94, p = 0.031) and HbA1c ≤ 6.5 (OR 0.46, 95%CI: 0.25–0.85, p = 0.013) were associated with silent AF prevalence. Diabetes duration, diabetic treatment pattern or metabolic control per se did not significantly impact the prevalence of AF, including silent AF detected by prospective continuous monitoring. Independent predictors of AF were age, BMI and low LDL levels, with statins and HbA1c ≤ 6.5 being additional independent predictors for silent AF. Trial registration: NCT03243474. [ABSTRACT FROM AUTHOR]

The present study explores the avenue of phage therapy as an alternative antimicrobial therapeutic approach to counter multidrug-resistant (MDR) Pseudomonas aeruginosa infection. Our study investigated two novel virulent phages PSPa and APPa, specific to P. aeruginosa, in which in vitro evaluations were carried out to assess the therapeutic potential of phages. Both the identified phages exhibited host specificity by showing antagonistic activity of about 96.43% (27/28) and 92.85% (26/28) towards the 28 MDR clinical isolates of P. aeruginosa. The PSPa phage was found to have linear dsDNA with a sequence length of 66,368 bp and 92 ORFs, of which 32 were encoded for known functions of the phage life cycle and the remaining 60 were hypothetical functions. The APPa phage was found to have linear dsDNA with 59,591 bp of genome length and 79 ORFs, of which 15 were found to have known phage functions and the remaining 64 were found to be hypothetical proteins. Notably, the genome of both the phages lacks genes coding for tRNA, rRNA, and tmRNA. The phylogenetic analysis revealed that PSPa and APPa share > 95% sequence similarity with previously sequenced Pseudomonas viruses of their respective families. Further, the in vivo efficacy evaluation using the zebrafish model revealed that the treatment with PSPa and APPa has remarkably improved the survival rate of bacterial-infected zebrafish, reinforcing the anti-infective potential of the isolated phages PSPa and APPa against P. aeruginosa infection. [ABSTRACT FROM AUTHOR]

Psoriasis is a skin disease that causes lesions of various sizes across the body and can persist for years with cyclic deterioration and improvement. During treatment, and a multiple-severity disease, with irregular severity within the observation area may be found. The current psoriasis evaluation is based on the subjective evaluation criteria of the clinician using the psoriasis area and severity index (PASI). We proposed a novel psoriasis evaluation method that detects representative regions as evaluation criteria, and extracts severity features to improve the evaluation performance of various types of psoriasis, including multiple-severity diseases. We generated multiple-severity disease images using CutMix and proposed a hierarchical multi-scale deformable attention module (MS-DAM) that can adaptively detect representative regions of irregular and complex patterns in multiple-severity disease analyses. EfficientNet B1 with MS-DAM exhibited the best classification performance with an F1-score of 0.93. Compared with the performance of the six existing self-attention methods, the proposed MS-DAM showed more than 5% higher accuracy than that of multiscale channel attention module (MS-CAM). Using the gradient-weighted activation mapping method, we confirmed that the proposed method works at par with human visual perception. We performed a more objective, effective, and accurate analysis of psoriasis severity using the proposed method. [ABSTRACT FROM AUTHOR]

Bone marrow-derived human mesenchymal stem cells (hMSCs) can differentiate into various lineages, such as chondrocytes, adipocytes, osteoblasts, and neuronal lineages. It has been shown that the high-efficiency DNA-repair capacity of hMSCs is decreased during their differentiation. However, the underlying its mechanism during adipogenesis and osteogenesis is unknown. Herein, we investigated how alkyl-damage repair is modulated during adipogenic and osteogenic differentiation, especially focusing on the base excision repair (BER) pathway. Response to an alkylation agent was assessed via quantification of the double-strand break (DSB) foci and activities of BER-related enzymes during differentiation in hMSCs. Adipocytes showed high resistance against methyl methanesulfonate (MMS)-induced alkyl damage, whereas osteoblasts were more sensitive than hMSCs. During the differentiation, activities, and protein levels of uracil-DNA glycosylase were found to be regulated. In addition, ligation-related proteins, such as X-ray repair cross-complementing protein 1 (XRCC1) and DNA polymerase β, were upregulated in adipocytes, whereas their levels and recruitment declined during osteogenesis. These modulations of BER enzyme activity during differentiation influenced DNA repair efficiency and the accumulation of DSBs as repair intermediates in the nucleus. Taken together, we suggest that BER enzymatic activity is regulated in adipogenic and osteogenic differentiation and these alterations in the BER pathway led to different responses to alkyl damage from those in hMSCs. [ABSTRACT FROM AUTHOR]

Human monkeypox is a very unusual virus that can devastate society. Early identification and diagnosis are essential to treat and manage an illness effectively. Human monkeypox disease detection using deep learning models has attracted increasing attention recently. The virus that causes monkeypox may be passed to people, making it a zoonotic illness. The latest monkeypox epidemic has hit more than 40 nations. Computer-assisted approaches using Deep Learning techniques for automatically identifying skin lesions have shown to be a viable alternative in light of the fast proliferation and ever-growing problems of supplying PCR (Polymerase Chain Reaction) Testing in places with limited availability. In this research, we introduce a deep learning model for detecting human monkeypoxes that is accurate and resilient by tuning its hyper-parameters. We employed a mixture of convolutional neural networks and transfer learning strategies to extract characteristics from medical photos and properly identify them. We also used hyperparameter optimization strategies to fine-tune the Model and get the best possible results. This paper proposes a Yolov5 model-based method for differentiating between chickenpox and Monkeypox lesions on skin pictures. The Roboflow skin lesion picture dataset was subjected to three different hyperparameter tuning strategies: the SDG optimizer, the Bayesian optimizer, and Learning without Forgetting. The proposed Model had the highest classification accuracy (98.18%) when applied to photos of monkeypox skin lesions. Our findings show that the suggested Model surpasses the current best-in-class models and may be used in clinical settings for actual Human Monkeypox disease detection and diagnosis. [ABSTRACT FROM AUTHOR]

The host-produced nodule specific cysteine-rich (NCR) peptides control the terminal differentiation of endosymbiotic rhizobia in the nodules of IRLC legumes. Although the Medicago truncatula genome encodes about 700 NCR peptides, only few of them have been proven to be crucial for nitrogen-fixing symbiosis. In this study, we applied the CRISPR/Cas9 gene editing technology to generate knockout mutants of NCR genes for which no genetic or functional data were previously available. We have developed a workflow to analyse the mutation and the symbiotic phenotype of individual nodules formed on Agrobacterium rhizogenes-mediated transgenic hairy roots. The selected NCR genes were successfully edited by the CRISPR/Cas9 system and nodules formed on knockout hairy roots showed wild type phenotype indicating that peptides NCR068, NCR089, NCR128 and NCR161 are not essential for symbiosis between M. truncatula Jemalong and Sinorhizobium medicae WSM419. We regenerated stable mutants edited for the NCR068 from hairy roots obtained by A. rhizogenes-mediated transformation. The analysis of the symbiotic phenotype of stable ncr068 mutants showed that peptide NCR068 is not required for symbiosis with S. meliloti strains 2011 and FSM-MA either. Our study reports that gene editing can help to elicit the role of certain NCRs in symbiotic nitrogen fixation. [ABSTRACT FROM AUTHOR]

To assess factors associated with galcanezumab response in a real-world study of Korean patients with migraine. Predictors of the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP(-R) mAb) have been rarely investigated in Asians. We prospectively recruited and followed up patients with migraine who received monthly galcanezumab treatment in a single university hospital from June 2020 to October 2021. We defined the treatment response with ≥ 50% reduction in moderate/severe headache days in the 3rd month of treatment compared to baseline. Responders and non-responders were compared in terms of demographics, disease characteristics and severity, and previous response to migraine prophylactic treatments. Potential predictors of anti-CGRP(-R) mAb response were tested by using the univariable and multivariable logistic regression analyses. Among 104 patients (81.7% female; mean age 42.0 ± 13.02; 76.9% chronic migraine; and 45.5% medication overuse headache) included, 58 (55.7%) were responders. Non-responders had more chronic migraine, medication overuse headache, monthly headache days, days with acute medication, and daily headaches (i.e. chronic migraine persisting everyday without remission). The multivariable logistic analysis showed chronic migraine (OR 0.05 [95% CI 0.00–0.82], p = 0.036) and the number of previously failed preventive medication classes (OR 0.55 [95% CI 0.33–0.92], p = 0.024] were independently associated with treatment response. Chronic migraine and multiple failures from preventive medication are associated with poor galcanezumab response. Further studies are needed to investigate if earlier treatment before disease chronification or multiple failures may lead to a greater therapeutic gain from anti-CGRP(-R) mAb treatment. [ABSTRACT FROM AUTHOR]

Xanthines such as caffeine and theobromine are among the most consumed psychoactive stimulants in the world, either as natural components of coffee, tea and chocolate, or as added ingredients. The present study assessed if xanthines affect liver sinusoidal endothelial cells (LSEC). Cultured primary rat LSEC were challenged with xanthines at concentrations typically obtained from normal consumption of xanthine-containing beverages, food or medicines; and at higher concentrations below the in vitro toxic limit. The fenestrated morphology of LSEC were examined with scanning electron and structured illumination microscopy. All xanthine challenges had no toxic effects on LSEC ultrastructure as judged by LSEC fenestration morphology, or function as determined by endocytosis studies. All xanthines in high concentrations (150 μg/mL) increased fenestration frequency but at physiologically relevant concentrations, only theobromine (8 μg/mL) showed an effect. LSEC porosity was influenced only by high caffeine doses which also shifted the fenestration distribution towards smaller pores. Moreover, a dose-dependent increase in fenestration number was observed after caffeine treatment. If these compounds induce similar changes in vivo, age-related reduction of LSEC porosity can be reversed by oral treatment with theobromine or with other xanthines using targeted delivery. [ABSTRACT FROM AUTHOR]

S. 4,[5],12:i:-, a monophasic variant of S. enterica serovar Typhimurium, is an important multidrug resistant serovar. Strains of colistin-resistant S. 4,[5],12:i:- have been reported in several countries with patients occasionally had recent histories of travels to Southeast Asia. In the study herein, we investigated the genomes of S. 4,[5],12:i:- carrying mobile colistin resistance (mcr) gene in Thailand. Three isolates of mcr-3.1 carrying S. 4,[5],12:i:- in Thailand were sequenced by both Illumina and Oxford Nanopore platforms and we analyzed the sequences together with the whole genome sequences of other mcr-3 carrying S. 4,[5],12:i:- isolates available in the NCBI Pathogen Detection database. Three hundred sixty-nine core genome SNVs were identified from 27 isolates, compared to the S. Typhimurium LT2 reference genome. A maximum-likelihood phylogenetic tree was constructed and revealed that the samples could be divided into three clades, which correlated with the profiles of fljAB-hin deletions and plasmids. A couple of isolates from Denmark had the genetic profiles similar to Thai isolates, and were from the patients who had traveled to Thailand. Complete genome assembly of the three isolates revealed the insertion of a copy of IS26 at the same site near iroB, suggesting that the insertion was an initial step for the deletions of fljAB-hin regions, the hallmark of the 4,[5],12:i:- serovar. Six types of plasmid replicons were identified with the majority being IncA/C. The coexistence of mcr-3.1 and blaCTX-M-55 was found in both hybrid-assembled IncA/C plasmids but not in IncHI2 plasmid. This study revealed possible transmission links between colistin resistant S. 4,[5],12:i:- isolates found in Thailand and Denmark and confirmed the important role of plasmids in transferring multidrug resistance. [ABSTRACT FROM AUTHOR]

Thymoma is the most common malignant tumor in thymic epithelial tumors (TETS). This study aimed to identify the changes in serum proteomics in patients with thymoma. Proteins were extracted from twenty patients with thymoma serum and nine healthy controls and prepared for mass spectrometry (MS) analysis. Data independent acquisition (DIA) quantitative proteomics technique was used to examine the serum proteome. Differential proteins of abundance changes in the serum were identified. Bioinformatics was used to examine the differential proteins. Functional tagging and enrichment analysis were conducted using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The string database was used to assess the interaction of different proteins. In all, 486 proteins were found in all samples. There were differences in 58 serum proteins between patients and healthy blood donors, 35 up-regulated and 23 down-regulated. These proteins are primarily exocrine and serum membrane proteins involved in controlling immunological responses and antigen binding, according to GO functional annotation. KEGG functional annotation showed that these proteins play a significant role in the complement and coagulation cascade and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signal pathway. Notably, the KEGG pathway (complement and coagulation cascade) is enriched, and three key activators were up-regulated: von willebrand factor (VWF), coagulation factor v (F5) and vitamin k-dependent protein c (PC). Protein–protein interaction (PPI) analysis showed that six proteins ((VWF, F5, thrombin reactive protein 1 (THBS1), mannose-binding lectin-associated serine protease 2 (MASP2), apolipoprotein B (APOB), and apolipoprotein (a) (LPA)) were up-regulated and two proteins (Metalloproteinase inhibitor 1(TIMP1), ferritin light chain (FTL)) were down-regulated. The results of this study showed that several proteins involved in complement and coagulation cascades were up-regulated in the serum of patients. [ABSTRACT FROM AUTHOR]

Two-dimensional materials stacked atomically at small twist angles enable the modification of electronic states, motivating twistronics. Here, we demonstrate that heterostrain can rotate the graphene flake on monolayer h-BN within a few degrees (− 4° to 4°), and the twist angle stabilizes at specific values with applied constant strains, while the temperature effect is negligible in 100–900 K. The band gaps of bilayers can be modulated from ~ 0 to 37 meV at proper heterostrain and twist angles. Further analysis shows that the heterostrain modulates the interlayer energy landscape by regulating Moiré pattern evolution. The energy variation is correlated with the dynamic instability of different stacking modes of bilayers, and arises from the fluctuation of interlayer repulsive interaction associated with p-orbit electrons. Our results provide a mechanical strategy to manipulate twist angles of graphene/h-BN bilayers, and may facilitate the design of rotatable electronic nanodevices. [ABSTRACT FROM AUTHOR]

Ascorbic acid (AA) has a pivotal role in corneal wound healing via stimulating the biosynthesis of highly organized extracellular matrix components, but its rapid degradation and low corneal permeability limits its therapeutic effects. In this paper, we present the pharmacokinetic properties of a liposomal-based formulation of AA in terms of corneal permeation. Chemical stability, shelf-life, and drug release rate of lyophilized liposome (AA-LLipo) formulation was determined in comparison to free-form of AA solution using high-performance liquid chromatography (HPLC) and rapid equilibrium dialysis. In vitro transcorneal permeability was studied using a parallel artificial membrane permeability assay (PAMPA). Ex vivo permeation was examined on AA-LLipo-treated porcine cornea by determining the AA content on the ocular surface, in the cornea as well as in the aqueous humor using HPLC, and by Raman-mapping visualizing the AA-distribution. Our results showed that the liposomal formulation improved the chemical stability of AA, while drug release was observed with the same kinetic efficiency as from the free-form of AA solution. Both corneal-PAMPA and porcine corneal permeability studies showed that AA-LLipo markedly improved the corneal absorption kinetics of AA, thus, increasing the AA content in the cornea and aqueous humor. AA-LLipo formulation could potentially increase the bioavailability of AA in corneal tissues. [ABSTRACT FROM AUTHOR]

Patellar luxation with condylar defect is a challenging situation for reconstruction in humans. Patella reluxation, cartilage damage and pain are the most common complications. This study aims to present a new patient specific method of overformed implant design and clinical implantation that prevents luxation of patella without damaging the cartilage in a dog. Design processes are Computer Tomography, Computer Assisted Design, rapid prototyping of the bone replica, creation of the implant with surgeon's haptic knowledge on the bone replica, 3D printing of the implant and clinical application. The implant was fully seated on the bone. Patella reluxation or implant-related bone problem was not observed 80 days after the operation. However, before the implant application, there were soft tissue problems due to previous surgeries. Three-point bending test and finite element analysis were performed to determine the biomechanical safety of the implant. The stress acting on the implant was below the biomechanical limits of the implant. More cases with long-term follow-up are needed to confirm the success of this method in patellar luxation. Compared with trochlear sulcoplasty and total knee replacement, there was no cartilage damage done by surgeons with this method, and the implant keeps the patella functionally in sulcus. This is a promising multidisciplinary method that can be applied to any part of the bone and can solve some orthopaedic problems with surgeon's haptic knowledge. [ABSTRACT FROM AUTHOR]

Exogenous glutathione (GSH) promotes the proliferation of embryogenic callus (EC) cells in Korean pine in the course of somatic embryogenesis, and reactive oxygen species (ROS) may play an important role in regulating the proliferation of EC cells by exogenous GSH. However, the concrete metabolic response of ROS is unclear. In this study, two cell lines of Korean pine with high proliferative potential 001#-001 (F, Fast proliferative potential cell line is abbreviated as F) and low proliferative potential 001#-010 (S, Slow proliferative potential cell line is abbreviated as S) were used as test materials. The responses of ROS-related enzymes and substances to exogenous GSH and L-Buthionine-sulfoximine (BSO) were investigated in EC cells. The results showed that the exogenous addition of GSH increased the number of early somatic embryogenesis (SEs) in EC cells of both F and S cell lines, decreased the amount of cell death in both cell lines. Exogenous addition of GSH promoted cell division in both cell lines, increased intracellular superoxide dismutase (SOD) and catalase (CAT) activities, inhibited intracellular hydrogen peroxide (H2O2), malondialdehyde (MDA) and nitric oxide (NO) production, and increased NO/ROS ratio. In conclusion, the exogenous GSH promoting the proliferation of Korean pine EC cells, the activity of intracellular antioxidant enzymes was enhanced, the ROS level was reduced, and the resistance of cells to stress was enhanced. [ABSTRACT FROM AUTHOR]

Charting the long-term trends in European wheat and maize yields and harvested areas and the relation of yields to climatic and economic drivers, two profound spatial processes become apparent. One consequence of the relatively late modernization of Eastern Europe has been to shift the focus of grain production from West to East. The warming trend prevailing over the past decades in the summer and winter seasons has been accompanied by a South to North shift in the harvested areas. The combination of these two processes has meant that the north-eastern sector of the European grain chessboard has emerged as the main beneficiary. There, the relatively low sensitivity of cereals to climatic change plus high economic growth rates have been accompanied by the most dynamic increases in cereal yields on the continent. As a result, a modern version of the 3000 year-old grain distribution system of the Ancient World is being restored before our eyes. One noteworthy finding is that increasing January–March temperatures have had a significant positive impact on wheat yields from Northern to South-Eastern Europe, and this is, at least in part, compensating for the negative impact of summer warming. [ABSTRACT FROM AUTHOR]

The essence of enterotypes is stratifying the entire human gut microbiome, which modulates the association between diet and disease risk. A study was designed at the Center of Reproductive Medicine, Shengjing Hospital of China Medical University and Jinghua Hospital of Shenyang. Prevotella and Bacteroides were analyzed in 407 samples of stool, including 178 men with enterotype B (61 normal, 117 overweight/obese) and 229 men with enterotype P (74 normal, 155 overweight/obese). The ratio between Prevotella and Bacteroides abundance, P/B, was used as a simplified way to distinguish the predominant enterotype. In enterotype P group (P/B ≥ 0.01), obesity was a risk factor for a reduced rate of forward progressive sperm motility (odds ratio [OR] 3.350; 95% confidence interval [CI] 1.881–5.966; P < 0.001), and a reduced rate of total sperm motility (OR 4.298; 95% CI 2.365–7.809; P < 0.001). Obesity was also an independent risk factor (OR 3.131; 95% CI 1.749–5.607; P < 0.001) after adjusting follicle-stimulating hormone. In enterotype P, body mass index, as a diagnostic indicator of a reduced rate of forward progressive sperm motility and a decreased rate of decreased total sperm motility, had AUC values of 0.627 (P = 0.001) and 0.675 (P < 0.0001), respectively, which were significantly higher than the predicted values in all patients. However, in enterotype B group (P < 0.01), obesity was not a risk factor for asthenospermia, where no significant difference between obesity and sperm quality parameters was observed. This study is tried to introduce enterotypes as a population-based individualized classification index to investigate the correlation between BMI and asthenospermia. In our study, overweight/obese men with enterotype P were found to have poorer sperm quality. however, sperm quality was not associated with overweight/obese in men with enterotype B. Thereof, BMI is a risk factor for asthenospermia only in men with enterotype P, but not in men with enterotype B. [ABSTRACT FROM AUTHOR]

Vibrio owensii is a widely distributed marine vibrio species that causes acute hepatopancreatic necrosis in the larvae of Panulirus ornatus and Penaeus vannamei, and is also associated with Montipora white syndrome in corals. We characterized V. owensii GRA50-12 as a potent pathogen using phenotypic, biochemical, and zebrafish models. A virulent phage, vB_VowP_phi50-12 (phi50-12), belonging to the N4-like Podoviridae, was isolated from the same habitat as that of V. owensii GRA50-12 and characterized. This phage possesses a unique sequence with no similar hits in the public databases and has a short latent time (30 min), a large burst size (106 PFU/infected cell), and a wide range of pH and temperature stabilities. Moreover, phi50-12 also demonstrated a strong lysis ability against V. owensii GRA50-12. SDS-PAGE revealed at least nine structural proteins, four of which were confirmed using LC–MS/MS analysis. The size of the phi50-12 genome was 68,059 bp, with 38.5% G + C content. A total of 101 ORFs were annotated, with 17 ORFs having closely related counterparts in the N4-like vibrio phage. Genomic sequencing confirmed the absence of antibiotic resistance genes or virulence factors. Comparative studies have shown that phi50-12 has a unique genomic arrangement, except for the well-conserved core regions of the N4-like phages. Phylogenetic analysis demonstrated that it belonged to a group of smaller genomes of N4-like vibrio phages. The therapeutic effect in the zebrafish model suggests that phi50-12 could be a potential candidate for application in the treatment of V. owensii infection or as a biocontrol agent. However, further research must be carried out to confirm the efficacy of phage50-12. [ABSTRACT FROM AUTHOR]

We present comprehensive mathematical modeling of radiopharmaceutical spatiotemporal distributions within vascularized solid tumors. The novelty of the presented model is at mathematical level. From the mathematical viewpoint, we provide a general modeling framework for the process of radiopharmaceutical distribution in the tumor microenvironment to enable an analysis of the effect of various tumor-related parameters on the distribution of different radiopharmaceuticals. We argue that partial differential equations (PDEs), beyond conventional methods, including ODE-based kinetic compartment modeling, can be used to evaluate radiopharmaceutical distribution in both time and space. In addition, we consider the spatially-variable dynamic structure of tumor microvascular networks to simulate blood flow distribution. To examine the robustness of the model, the effects of microvessel density (MVD) and tumor size, as two important factors in tumor prognosis, on the radiopharmaceutical distribution within the tumor are investigated over time (in the present work, we focus on the radiopharmaceutical [18F]FDG, yet the framework is broadly applicable to radiopharmaceuticals). Results demonstrate that the maximum total uptake of [18F]FDG at all time frames occurs in the tumor area due to the high capillary permeability and lack of a functional lymphatic system. As the MVD of networks increases, the mean total uptake in the tumor is also enhanced, where the rate of diffusion from vessel to tissue has the highest contribution and the rate of convection transport has the lowest contribution. The results of this study can be used to better investigate various phenomena and bridge a gap among cancer biology, mathematical oncology, medical physics, and radiology. [ABSTRACT FROM AUTHOR]

During hair cell development, the mechanoelectrical transduction (MET) apparatus is assembled at the stereocilia tips, where it coexists with the stereocilia actin regulatory machinery. While the myosin-based tipward transport of actin regulatory proteins is well studied, isoform complexity and built-in redundancies in the MET apparatus have limited our understanding of how MET components are transported. We used a heterologous expression system to elucidate the myosin selective transport of isoforms of protocadherin 15 (PCDH15), the protein that mechanically gates the MET apparatus. We show that MYO7A selectively transports the CD3 isoform while MYO3A and MYO3B transports the CD2 isoform. Furthermore, MYO15A showed an insignificant role in the transport of PCDH15, and none of the myosins tested transport PCDH15-CD1. Our data suggest an important role for MYO3A, MYO3B, and MYO7A in the MET apparatus formation and highlight the intricate nature of MET and actin regulation during development and functional maturation of the stereocilia bundle. [ABSTRACT FROM AUTHOR]