Finding sustainable renewable energy sources for energy conversion and management is still an obscure topic. This paper presents a model-based simulation for an energy conversion system using piezoelectric energy harvester (PEH) technology. A dynamic mathematical model of a PEH device consists of a piezoelectric transducer, a controlled PWM rectifier, and a closed-loop buck boost converter is developed. A piezoelectric transducer converts mechanical vibrations from a wind force into an oscillating train of electrical charges. The sinewave peak-to-peak level relationship describes the changeable values of these charges, which depend on the severity of the wind vibration. The controlled PWM rectifier, in conjunction with a closed-loop buck-boost converter, converts this train of sinewave cycles into DC voltages. The control blocks of the closed-loop buck-boost converter use the perturbation and observation (P&O) algorithm based on maximum power point tracking (MPPT), which adapts the operational voltage of the piezoelectric source to deliver the maximum power to load and improves the PEHS output voltage stability. A simulation program is employed to perform mathematical analysis on various wind vibration scenarios, piezoelectric sources without PWM converters, and piezoelectric vibration sources connected to a closed-loop P&O converter. The crucial results of this paper demonstrate that the proposed dynamic PEHS model effectively feeds low-power electronic loads by directly adjusting the output voltage level to the set voltage, even under different vibration severity levels. As a result, the proposed PEHS dynamic model serves as a guideline for researchers in the development of self-powered sensors, which contributes to understanding sustainable energy alternatives.

In this study, we obtained results for the computation of eigen-pairs, singular value decomposition, pseudo-inverse, and the least square problem for elliptic quaternion matrices. Moreover, we established algorithms based on these results and provided illustrative numerical experiments to substantiate the accuracy of our conclusions. In the experiments, it was observed that the p-value in the algebra of elliptic quaternions and elliptic numbers directly affects the performance of the problem under consideration. Selecting the optimal p-value for problem-solving and the elliptic behavior of many physical systems make this number system advantageous in applied sciences.

Using assembly theory, we investigate the assembly pathways of binary strings of length N formed by joining bits present in the assembly pool and the strings that entered the pool as a result of previous joining operations. We show that the string assembly index is bounded from below by the shortest addition chain for N, and we conjecture about the form of the upper bound. We define the degree of causation for the minimum assembly index and show that for certain N it features regularities that can be used to determine a shortest addition chain. We show that a string with the smallest assembly index for N can be assembled by a binary program of length equal to this index if the length of this string is expressible as a product of Fibonacci numbers. We conjecture that there is no binary program that has a length shorter than the length of the string having the largest assembly index for N that could assemble this string. The results confirm that four Planck areas provide a minimum information capacity that corresponds to a minimum thermodynamic (Bekenstein-Hawking) entropy. Knowing that the problem of determining the assembly index is at least NP-complete, we conjecture that this problem is NP-complete, while the problem of creating the string so that it would have a predetermined largest assembly index is NP-hard. The proof of this conjecture would imply P ≠ NP, since every computable problem and every computable solution can be encoded as a finite binary string.

The effect of neutron irradiation of Si-Ge/Si film structures obtained by gas-phase epitaxy on the processes of charge carrier generation and the magnitude of the dark short-circuit current and open-circuit voltage caused by it is studied, it is shown that their magnitude practically does not change with time. The results obtained indicate that all types of structural defects, both associated with dopant impurities and radiation exposure, contribute to the generation of charge carriers in heated silicon structures with the participation of deep energy levels, which indicates the applicability of neutron processing of silicon materials to create thermal energy converters, operating at high temperatures.

Inhibition of quorum sensing (QS)-dependent biofilm formation and virulence is extensively investigated as a novel approach to combat bacterial pathogens by impeding their ability to cause antibiotic-tolerant diseases. Such strategies are considered a promising alternative to conventional antibacterial therapy since interrupting the central cell-to-cell communication system imposes less selective pressure on the target pathogen. In this study, novel hybrid compounds composed of anthranilic acids substituted with halogens at different positions of the phenyl ring, and 4-(2-aminoethyl/4-aminobuthyl)amino-7-chloroquinoline linked via 1,3,4-oxadiazole were synthesized using standard procedures. Their anti-QS activities were evaluated using Chromobacterium violaceum ATCC31532 (anti-biofilm and bactericidal activities) and Pseudomonas aeruginosa PAO1 (anti-biofilm/-virulence activities). The results showed that compounds 15–19 and 23 inhibited the production of violacein, the QS-inducible pigment, in C. violaceum to a similar extent as the model QS inhibitor - quercetin (83.5–90%). Compound 15 exhibited the strongest effect on P. aeruginosa in the anti-biofilm screening, reducing its ability to form biofilm by almost 50%, while compounds 16 and 19 were able to reduce the biofilm formation by approximately 30%. However, compound 23 did not demonstrate significant anti-biofilm activity and only inhibited pyocyanin production in P. aeruginosa. In conclusion, this study suggests that 1,3,4-oxadiazoles 15, 16, and 19 are the most promising compounds for future research as novel QS inhibitors against Gram-negative bacteria equipped with different QS signaling pathways.

A simple and sensitive liquid chromatography-tandem mass spectrometry (LC– MS/MS) method has been developed for the simultaneous determination of atorvastatin (ATOR), ezetimibe (EZM) and their three metabolites including o-hydroxyl atorvastatin (o-OH ATOR), p-hydroxyl atorvastatin (p-OH ATOR), and ezetimibe-glucuronide (EZM-G) in human plasma using benzyl paraben (BP) as internal standard (IS). The analytes and IS were ionized using ESI positive ion mode (ATOR, o-OH ATOR, and p-OH ATOR), ESI negative ion mode (EZM, EZM-G, and BP), and operated in multiple reaction monitoring (MRM) mode. They were next extracted by salting-out assisted liquid–liquid extraction with acetonitrile, and then analyzed by liquid chromatography on a reversed-phase chromatographic column (50 mm × 4.6 mm; 3.5 µm), using a mixture of ac-etonitrile and an acetic acid solution (0.5%) as the mobile phase, showing high extraction effi-ciency (>70%), and a minimized matrix effect. The method was satisfactorily validated, and showed excellent linearity over wide concentration ranges of 0.06–15 ng/mL, 0.6–150 ng/mL, 0.4–100 ng/mL, 0.12–30 ng/mL, and 0.05–3 ng/mL for EZM, EZM-G, ATOR, o-OH ATOR, and p-OH ATOR, respectively.

BackgroundIt is unclear what underpins the large global variations in the prevalence of fluoroquinolone resistance in gram-negative bacteria. We tested the hypothesis that different intensities in the use of quinolones for food-animals plays a role. MethodsWe used Spearman’s correlation to assess if the country-level prevalence of fluoroquinolone resistance in human infections with Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was correlated with the use of quinolones for food producing animals. Linear regression was used to assess the relative contributions of country-level quinolone consumption for food-animals and humans on fluoroquinolone resistance in these 4 species. ResultsThe prevalence of fluoroquinolone resistance in each species was positively associated with quinolone use for food-producing animals (E. coli [ρ=0.55; P<0.001], K. pneumoniae [ρ=0.58; P<0.001]; A. baumanii [ρ=0.54; P=0.004]; P. aeruginosa [ρ=0.48; P=0.008]). Linear regression revealed that both quinolone consumption in humans and food animals were independently associated with fluoroquinolone resistance in E. coli and A. baumanii. ConclusionsReducing quinolone use in food-producing animals may help retard the spread of fluoroquinolone resistance in various gram negative bacterial species.

In this paper, the notion of θ∗-weak contraction is introduced, which is utilized to prove some fixed point results. These results are helpful to give a positive response to certain open question raised by Kannan [Amer. Math. Monthly 76:1969] and Rhoades [Contemp. Math. 72:1988] on the existence of contractive definition which does not force the mapping to be continuous at the fixed point. Some illustrative examples are also given to support our results. As applications of our result, we investigate the existence and uniqueness of a solution of non-linear matrix equations and integral equations of Volterra type as well.

Different contact materials along with optimization of the deposition techniques expand the possibilities to obtain high performance room temperature CdTe-based X/γ-ray detectors. The heterostructures with ohmic (MoOx) and Schottky (MoOx, TiOx, TiN, and In) contacts, created by DC reactive magnetron sputtering and vacuum thermal evaporation, as well as In/CdTe/Au diodes with a p-n junction, formed by laser-induced doping, were developed and investigated. Depending on the pre-treatment of the surface of semi-insulating p-CdTe crystals, deposition of a MoOx film formed an ohmic or Schottky contact. Based on the calculations and IV characteristics of the fabricated Mo-MoOx/р-CdTe/MoOx-Mo, In/CdTe/MoOx-Mo, Ti-TiOx/р-CdTe/MoOx-Mo, and Ti-TiN/р-CdTe/MoOx-Mo Schottky-diode detectors, the current transport processes were described in the models of the carrier generation-recombination within the space-charge region (SCR) at low bias voltages, and space-charge limited current at higher voltages, respectively. The energies of generation–recombination centers, density of trapping centers, and carrier lifetimes were determined. A sharp increase in the reverse current in the Mo-MoOx/р-CdTe/MoOx-Mo, Ti-TiOx/р-CdTe/MoOx-Mo, and Ti-TiN/р-CdTe/MoOx-Mo heterostructures at high bias was discussed in frames of the Poole–Frenkel emission model. Nanosecond laser irradiation of the In electrode, pre-deposited on the p-CdTe crystals, resulted in an increase in the voltage range, corresponding to the carrier generation-recombination in the SCR, in the IV characteristics of the In/CdTe/Au diodes. Such In/CdTe/Au p-n junction diodes demonstrated high energy resolutions (7%@59.5 keV, 4%@122 keV, and 1.6%@662 keV).

Arabidopsis contains eight different h-type thioredoxins (Trx) being distributed in different cell organelles. Although Trx h2 is deemed to be localized in mitochondria, its subcellular localization and function remains a matter of debate. Here, Trx h2 localization and function were investigated using cell fractionation studies and reverse genetics. Differential centrifugation and immunodetection showed the Trx h2 protein to be distributed to the microsomal fraction rather than to mitochondrial preparations. To analyze whether Trx h2 has different roles than mitochondrial Trxs, Arabidopsis mutants lacking Trx h2 were compared with mutants deficient in mitochondrial Trx o1 and double mutants with joint deficiencies in both Trxs. Under constant medium light, trxh2 grew as the wild type, while trxo1 and trxo1h2 mutants showed impaired growth. This was accompanied by differences in the metabolite profiles. The trxo1 and trxo1h2 mutants clustered differently from the wild type during the night, revealing a decrease in ascorbate and glutathione redox states. In fluctuating light intensities, genotypic differences in growth rates were attenuated. Compared to the wild type, the fluctuating-light induced decrease in the NADPH/NADP ratio was diminished in the mutants, with the trxo1h2 double mutant showing the strongest effect. This was accompanied by an increase in the photosynthetic efficiency of the trxo1h2 mutant, specifically in the high light phases of fluctuating light. Conclusively, these results support the view that Trxs o1 and h2 are localized in different subcellular compartments, and have different effects on ascorbate and glutathione redox states and growth in medium light, but cooperatively affect NADP(H) redox state and photosynthetic efficiency in fluctuating light.

Transforming growth factor beta (TGF-β) is a determinant for inflammation and fibrosis in cardiac and skeletal muscle in Chagas disease. To determine its regulatory mechanisms, we investigated the response of T. cruzi-infected cardiomyocytes (CM), cardiac fibroblasts (CF) and L6E9 skeletal myoblasts to TGF-β. Cultures of CM, CF and L6E9 were infected with T. cruzi (Y strain) and treated with TGF-β (1–10 ng/mL, 1h or 48 h). Fibronectin (FN) distribution was analyzed by immunofluorescence and Western blot (WB). Phosphorylated SMAD2 (PS2), phospho-p38 (p-p38), and phospho-c-Jun (p-c-Jun) signaling were evaluated by WB. CF and L6E9 showed an increase in FN from 1 ng/mL of TGF-β, while CM displayed FN modulation only after 10 ng/mL treatment. CF and L6E9 showed higher PS2 levels than CM, while p38 is less stimulated in CF than CM and L6E9. After T. cruzi infection, localized FN disorganization was observed in infected CF and L6E9. T. cruzi induced an increase in FN in CF cultures, mainly in uninfected cells. Infected CF cultures treated with TGF-β showed a reduction in PS2 and an increase in p-p38 and p-c-Jun levels. Our data suggest that p38 and c-Jun pathways may be participating in the fibrosis regulatory process mediated by TGF-β after T. cruzi infection.

In this paper, we investigate a new $q$-analogue of the higher order degenerate Changhee polynomials and numbers, which are called the Witt-type formula for the $q$-analogue of degenerate Changhee polynomials of order $r$. We can derive some new interesting identities related to the degenerate $(h,q)$-Changhee polynomials and numbers.

In this paper, we investigate a new $q$-analogue of the higher order degenerate Changhee polynomials and numbers, which are called the Witt-type formula for the $q$-analogue of degenerate Changhee polynomials of order $r$. We can derive some new interesting identities related to the degenerate $(h,q)$-Changhee polynomials and numbers.

In this paper, we study the p-adic integral representation on Z_p of q-Bernoulli numbers arising from two variable q-Bernstein polynomials and investigate some properties for the q-Bernoulli numbers. In addition, we give some new identities of q-Bernoulli numbers.

In the present paper, we introduce (p, q)-extension of Apostol type Frobenius-Euler polynomials and numbers and investigate some basic identities and properties for these polynomials and numbers, including addition theorems, difference equations, derivative properties, recurrence relations and so on. Then, we provide integral representations, explicit formulas and relations for these polynomials and numbers. Moreover, we discover (p, q)-extensions of Carlitz's result [L. Carlitz, Mat. Mag., 32 (1959), 247–260] and Srivastava and Pintér addition theorems in [H. M. Srivastava, A. Pinter, Appl. Math. Lett., 17 (2004), 375–380].

This perspective describes the current status and future prospects of developing long- to ultralong-acting anti-obesity peptides. First, we review the current status of lipidation, PEGylation, and Fc fusion technologies to obtain long-acting peptides administered once weekly. Next, we describe the approach and current results of using macromolecular peptide prodrugs with pre-programmed releasable linkers to achieve longer-acting peptides that can be administered weekly or monthly. Finally, we posit novel modifications of the latter technology that could provide ultralong half-lives of over one month by advantageously exploiting the clearance rates of released peptides. As examples, we posit that prodrugs of low-clearance GLP-1 agonists derived from peptides already modified by lipidation, PEGylation, and Fc fusion could produce ultralong-acting agonists with dosing intervals reaching 3 to even 6 months.

Objectives: To assess the role of soluble PD-L1 and PD-1 in combination with mRNA transcripts of PCA3, PSMA, AR genes in diagnostics of clinically significant prostate cancer (PCa). Methods: For 68 PCa patients, plasma sPD-L1 and sPD-1 were measured by ELISA method and the urinary PSMA, PCA3 and AR were tested using RT-qPCR. Results: PSMA and AR were iden-tified as the most reliable biomarkers for predicting clinically significant prostate cancer, with AUCs of 0.81 and 0.78, respectively. Additionally, the expression levels of PSMA and PCA3 were associated with the pT3 stage. Despite the diagnostic potential of mRNA transcripts alone, the ad-dition of sPD-L1 and sPD-1 significantly enhanced diagnostic accuracy. Combination doubled the specificity of PCA3 from 44.1% to 88.0%, compared to PCA3 alone. sPD-L1, sPD-1 and AR resulted in the best distinction between clinically significant and insignificant prostate cancer, achieving an AUC of 0.97, an accuracy of 0.95, a sensitivity of 100%, a specificity of 95%, revealing the potential of AR in distinguishing clinically significant PCa, more effectively than PSMA and PCA3. Our find-ings highlight the significant potential of sPD-1 in enhancing diagnostic accuracy when added to a triple gene panel, achieving an AUC of 0.90 compared to an AUC of 0.78 without sPD-1. This un-derscores the value of sPD-1, which has been less explored than sPD-L1 in cancer diagnostics. Con-clusions: sPD-L1 and sPD-1 has a potential to significantly enhance the accuracy of PCa diagnostics when added to the diagnostic panel, alongside PSMA, PCA3, and AR mRNA transcripts.

Antimicrobial peptides represent a promising alternative to traditional drugs in relation to cost, toxicity and, primarily, the growing problem of drug resistance. Here we report on the activity against HSV-1 and HSV-2 of a previously described wide-spectrum synthetic decapeptide, Killer Peptide (KP). As determined by plaque reduction assays, treatment with KP at 100 μg/mL resulted in a reduction in the viral yield titer of 3.5 Logs for HSV-1 and 4.1 Logs for HSV-2. Further evaluation of KP antiviral activity focused on the early stages of virus replicative cycle, including the determination of the residual infectivity of viral suspensions treated with KP. A direct effect of the peptide on viral particles, impairing virus absorption and penetration, was shown. The toxicity profile proved to be extremely good with a selectivity index of 29.6 for HSV-1 and 156 for HSV-2. KP was also active against an acyclovir (ACV)-resistant HSV-1 strain, while HSV-1 subcultures in the presence of sub-inhibitory doses of KP did not lead to the emergence of resistant strains. Finally, the antiviral action of KP proved to be synergistic with that of ACV. Overall, these results demonstrate that KP could represent an interesting addition/alternative to acyclovir for antiviral treatment.

Collapse calderas often experience large up and down movements, which rarely give rise to eruptions. The pattern of vertical deformation has generally an elliptical geometry, very close to a circular one. A simple and powerful method to explore second order anomalies of the volcanic caldera deformation patterns can enlighten important structural features. This method is here presented and applied to the case study of Campi Flegrei caldera ground deformation, representing a typical example of such a quasi-circular geometry, with dominant ground uplift occurring since 1950. Despite a markedly radial dependence of the vertical displacement, with a very constant shape in the time, we explore in the paper the second order anomalies, with respect to a purely radial behavior. To this aim, we have used a procedure based on the polynomial fit of the vertical displacement data, assuming they only depend on the distance from the maximum uplift point (i.e. deformation center); then, we have obtained anomalies map by subtracting from the theoretical deformation so determined the true data. We then obtain very peculiar results, which put in evidence a sharp separation between a less uplifted zone and a more uplifted one than expected, along a NE-SW alignment which approximately define the most seismically active area, in which most of the largest magnitude earthquakes occur. This very peculiar feature is likely to represent a main volcano-tectonic structure in the area, which can be of leading importance for evaluating both the highest seismic hazard area and the most likely zone of possible eruptive vent opening. The results obtained here indicate that the proposed method can be useful to analyze unrest related hazards.

Intercellular adhesion molecule 1 (ICAM-1/CD54), a transmembrane glycoprotein, has been considered as one of the most important adhesion molecules during leukocyte recruitment. It is encoded by the ICAM1 gene and plays a central role in inflammation. It’s crucial role in many inflammatory diseases such as ulcerative colitis and rheumatoid arthritis are well established. Given that neuroinflammation, underscored by microglial activation, is a key element in neurodegenerative diseases such as Parkinson’s disease (PD), we investigated whether ICAM-1 has a role in this progressive neurological condition and if so, elucidate the underpinning mechanisms. Specifically, we were interested in potential interaction between ICAM-1, glial cells and ferroptosis, an iron-dependent form of cell death that has recently been implicated in PD. We conclude that there exist direct and indirect (via glial cells and T cells) influences of ICAM-1 on ferroptosis and that further elucidation of these interactions can suggest novel intervention for this devastating disease.

During HIV-1 virus assembly the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag-Psi interactions, there is almost no information on kinetic aspects of this interaction. We have investigated the kinetics of Gag binding to different RNAs using switchSENSE DRX2 technology. We measured the association rate of Gag binding to monomeric Psi, to a “Multiple Binding Site Mutant” Psi that is inactive for genome packaging in vivo, and to a scrambled Psi. We discovered that Gag binds more rapidly to Psi RNA than to the mutant or scrambled RNAs. Furthermore, rapid Gag association kinetics are retained within sub-regions of Psi: Gag associates more rapidly with RNA containing only the 3’ two of the three Psi stem-loops than with monomeric RNA containing the 5’ two stem-loops or a scrambled RNA. No differences were detectable with individual Psi stem-loops. Interestingly, the rate of binding of Gag molecules to Psi increases with increasing Gag concentration, suggesting cooperativity in binding. The results are consistent with the hypothesis that selectivity in packaging derives from kinetic differences in initiation of particle assembly.

Sepsis, characterized by a dysregulated systemic inflammatory response to infection, remains a significant global health burden, despite substantial advancements in its treatment. An understanding of the underlying mechanisms driving sepsis is crucial for the development of targeted therapeutic strategies. Silent information regulator 1 (SIRT1), a member of the class III histone deacetylases, plays a pivotal role in regulating gene expression by catalyzing the deacetylation of lysine residues on non-histone and histone proteins. With the advancement of sepsis research, SIRT1 has been shown to exert significant anti-inflammatory, anti-oxidative, anti-apoptotic, and metabolic regulatory effects, positioning it as a potential therapeutic target for sepsis. This article reviews the latest progress on research into the signaling pathways modulated by SIRT1 in sepsis and its associated regulatory mechanisms to further elucidate the pathogenesis of sepsis and assist in guiding clinical treatment.

While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T cell responses against the transgene product upon vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8+ T cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1>MyD88 and TLR9>MyD88>IFN I>IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. We further provide evidence that CpG depletion of vector genomes and inclusion of TLR9 inhibitory sequences can have a synergistic effect. However, even low-frequency CD8+ T cell responses could eliminate transgene expression. Thus, innate immune avoidance/blockade strategies, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of redundancy of immune activating pathways.

Dent disease type 1 is a rare inherited renal disorder affecting mainly young males, generally leading to end-stage renal failure and for which there is no cure. It is caused by inactivating mutations in the gene encoding ClC-5, a 2Cl-/H+ exchanger found on endosomes in the renal proximal tubule. This transporter participates in reabsorbing all filtered plasma proteins which justifies why proteinuria is commonly observed when ClC-5 is defective. In the context of Dent disease type 1, a proximal tubule dedifferentiation was shown to be accompanied by a dysfunctional cell metabolism. However, the exact mechanisms linking such alterations to chronic kidney disease are still unclear. In this review, we gather knowledge from several Dent disease type 1 models to summarize the current hypotheses generated to understand the progression of this disorder. We also highlight some urinary biomarkers for Dent disease type 1 suggested in different studies.

The relationship between nations is largely seen as a peripheral issue in the recent history of political philosophy and in the majority of discussions of political philosophy issues today. The idea of a universal natural state were countries are seen as essentially self-sufficient, functional units, and have been proposed to represent the relative lack of moral standards guiding relationships between nations. At one extreme of the tradition, international thought has substituted raison d'état being the highest norm for any universal laws governing relations between states, a view embodied by Machiavelli, Rodin, and others and Hobbes , The lack of supranational political powers has led to the conclusion that, even in cases where the possibility of international moral relationships has been acknowledged, such as in post-Grotian publications on international law, these ties are significantly weaker than in-tranational social bonds. The justification and aversion to war—the primary mode of social in-teraction in the natural condition of the world—is the only issue in the field of global relations to have received substantial theoretical study. Even though this disregard was justified in the past, a number of recent events force us to re-consider the "recalcitrance of international affairs to being theorized about."2. The growing gap between both prosperous and impoverished nations; the emergence of centers of economic in-fluence beyond the reach of effective state regulation; the emergence of severe food and energy shortages brought on, at least in part, by national governments' pursuit of disorganized and uncontrolled growth policies; the growing sensitivity of domestic Countries to the outside eco-nomic, political, and cultural events are some of these developments , requests from third-world nations for greater equal access to international politics and economy. To put it in terms more familiar to conversations about this topic, the rise of "low politics" in negotiation and "welfare questions" within global forums corresponds with the growing influence of transnational con-nections and international agreements on human well-being. Not because "high politics"—that is, the threat and prevention of war—has lost significance; rather, it is just one issue among many for which international cooperation is now required in order to find answers.

Background: Methotrexate (MTX) displayed cytotoxic properties against some cancer cells. However, there is very limited data about the possible anti-tumoral potential of them in breast cancer (BC) cells. We aimed to determine the effects of MTX, which is widely used in clinical practice, on cell viability, Hypoxia-inducible factor (HIF) -1α, HIF-2α and prolyl 4-hydroxylase-transmembrane (P4H-TM) in BC cells (MCF-7) and health breast cell (HTERT-HME1) treated with MTX. Methods: Human healthy breast cells (HTERT-HME1) and BC cells (MCF-7) treated with MTX for 24 h, 48h, and 72 h, the effects of MTX on cell viability. Results: The cell viability and with half-maximal inhibitory concentration (IC50) values of of MTX treatment in healthy breast cells were determined to be higher than in MCF-7 cells. MTX showed higher cytotoxicity against MCF-7 cells. MTX significantly reduced cell viability values in HTERT-HME1 and MCF-7 cells. HIF-1α, HIF-2α, and P4H-TM levels was significantly higher in the MCF-7 group than the other groups. Morever, there was a moderate significant correlation between HIF-1α and HIF-2α levels and between HIF-1α and P4H-TM. Conclusions: MTX will show a further decrease in cell viability in long-term treatments of 48 and 72 hours, it is predicted that short-term use may be more appropriate. P4H-TM may be a novel regulator of hypoxia in BC cells. HIF-1α, a key protein responsible for the molecular mechanism of hypoxia in cells, is a key mediator between P4H-TM and hypoxia in MTX-treated cells. HIF-1α, HIF-2α, and P4H-TM values may be markers that can be used as a panel to differentiate BC from healthy women.

Autism has been described as a gastrointestinal and neurological condition that is represented by impairments in language and social situations. Recently reported increases in the occurrence of Autism Spectrum Disorder (ASD) have resulted in increased research into the environmental differences between areas with a high occurrence, as in the “Western” diet populations, and a more locally derived diet population, wherein the rate appears to be significantly less. Thirty autistic children (USA) ages 6 to 21, were sampled at three different intervals: prior to any intervention, post-xylitol intervention, and post-probiotic intervention. The sampling consisted of buccal swabs for MITOSWAB testing, and saliva for metatranscriptomics to determine the entire range of microorganisms and the metabolome. In addition, a “Blue Zone” subject component that included 30 Colombian children, ages 6-16, and who were healthy and within normal behavior standards, also had buccal swabbing and salivary sampling performed for comparison along with 30 healthy (no history medications, illnesses, or behavior issues) USA children matched for age and gender. Saliva samples were analyzed metatranscriptomically and artificial intelligence was utilized to discern important differences in the microbiome that included bacteria, archaea, fungi, and viruses, and microbial functions. Significant differences were noted, and seen in the temporal data, demonstrating shifts that may have been precipitated by the interventions, with both the probiotics and the polyols. Particular bacterial strains were significantly more prevalent in the autism subject group including a strain that reduces neurotransmitters by enzymatic degradation. This provided supporting evidence to the hypothesis that the occurrence of autism may also be influenced by low Gamma Amino Butyric Acid (GABA) levels during development. Also, of interest was the un-expected finding that verbal skills dramatically increased in 6 of the 30 ASD subjects following xylitol supplementation.

Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3. These galectins have been implicated in numerous diseases due to their pleiotropic nature, including cancer and fibrosis, with therapeutic inhibitors being clinically developed to block the CRD. One of the early methods developed to characterise these galectins was hemagglutination of red blood cells. Although insightful this approach has been hampered by a lack of sensitivity and accurate quantification of the agglutination observed. In this study we aimed to validate a more precise and quantitative method to enable further investigation of differences between galectins in respect to agglutination induction in different blood groups as well as characterisation of small molecule inhibitors. Quantification of hemagglutination was shown to be optimal using U-bottom plates imaged and analysed with FIJI ImageJ rather than flat bottom plates read for absorbance on an optical density plate reader. Galectin-3-induced red blood cell agglutination efficacy increased significantly from blood group O to A to B. However, for both the galectin-1 monomer and concatemer a more comparable effect was observed between blood group B and O but with more potent effects than in blood group A. Inhibition assays for both galectin-3 and galectin-1 induced-hemagglutination were able to demonstrate clear concentration-responses and expected selectivity profiles for a set of small molecule glycomimetics, confirming historical profiles obtained in biochemical binding and functional cellular assays.

The beta-galactoside-binding mammalian lectin galectin-1 can bind, via its carbohydrate recognition domain (CRD), various cell surface glycoproteins and has been implicated in a range of cancers. As a consequence of binding to sugar residues on cell surface receptors it has been shown to have a pleiotropic effect across many cell types and mechanisms resulting in immune system modulation and cancer progression. As a result, it has started to become a therapeutic target for both small and large molecules. In previous studies, we have used fluorescence polarisation (FP) assays to determine KD values to screen and triage small molecule glycomimetics that bind to the galectin-1 CRD. In this study surface plasmon resonance (SPR) was used to compare human and mouse galectin-1 affinity measures with FP as SPR has not been applied for compound screening against this galectin. Binding affinities for a selection of mono- and di-saccharides covering a 1,000-fold range correlated well between FP and SPR assay formats for both human and mouse galectin-1. It was shown that slower dissociation drove the increased affinity at human galectin-1 whilst faster association was responsible for the effects at mouse galectin-1. This study demonstrates that SPR is a sound alternative to FP for early drug discovery screening and determining affinity estimates. Consequently, it also allows association and dissociation constants to be measured in a high throughput manner for small molecule galectin-1 inhibitors.

Angiostrongylus cantonensis, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with A. cantonensis show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood-brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by A. cantonensis infection. We investigate pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after A. cantonensis. The study evaluates the critical role of Cav-1 regulation through the TLR4 / MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in A. cantonensis-induced meningoencephalitis.

The NP method was used to elucidate the contributions of vehicles and coal combustion to seasonal and long-term atmospheric PM-bound Pyr and 1-NP concentrations in Kanazawa, Kitakyushu, Shenyang, and Shanghai in the Western Pacific region from 1997 to 2021. Among the four cities, Kanazawa demonstrated the lowest Pyr concentration. The contribution of vehicles to Pyr before and after 2010 were 35% and 5%, respectively. The 1-NP concentration reduced by a factor of more than 1/10. These changes can be attributed to the emission control from vehicles. Kitakyushu revealed the second lowest Pyr and the lowest 1-NP concentrations. Coal combustion was found to be the main contributor to Pyr, while its contribution to 1-NP increased from 9% to 19%. The large contribution of coal combustion is attributed to iron manufactures. Shenyang demonstrated the highest atmospheric Pyr concentration with its largest seasonal change. Vehicles are the largest contributors to 1-NP. However, coal combustion, including winter coal heating, contributed 97% or more to Pyr and more than 14% to 1-NP. Shanghai revealed the second highest Pyr and 1-NP concentrations, but the former was substantially lower than in Shenyang. Coal combustion was the major contributor, but the contribution of vehicles to Pyr was larger before 2010 similar to Kanazawa.

Since 2019, the SARS-CoV-2 virus has caused a global pandemic, resulting in widespread infections and ongoing mutations. Analysing these mutations is essential for predicting future impacts. Unlike influenza mutations, SARS-CoV-2 mutations displayed distinct selective patterns that were concentrated in the spike protein and small ORFs. In contrast to the gradual accumulation seen in influenza mutations, SARS-CoV-2 mutations lead to the abrupt emergence of new variants and subsequent outbreaks. This phenomenon may be attributed to their targeted cellular substances; unlike the influenza virus, which has mutated to evade acquired immunity, SARS-CoV-2 appeared to mutate to target individuals who have not been previously infected. The Omicron variant, which emerged in late 2021, demonstrates significant mutations that set it apart from previous variants. The rapid mutation rate of SARS-CoV-2 has now reached a level comparable to 30 years of influenza variation. The most recent variant, JN.1, exhibits a discernible trajectory of change distinct from previous Omicron variants.

: AliCPT-1 is the first Cosmic Microwave Background (CMB) experiment in China, dedicated to achieve accurate measurements of B-mode polarization. Situated in Ali of Tibet, China, this telescope is currently undergoing deployment and will operate in two frequency bands centered at 90 and 150 GHz. The Far-Field Flat Mirror（FFF）is a calibration device of AliCPT-1 telescope for far-field beam mapping. The design of FFF is optimized for easy assembly and adjustment. Meteorological station data reveals that the maximum wind speed near FFF is 17.5 m/s, while the maximum wind speed on the windward side is 8 m/s. The wind pressure on FFF was analysed using a maximum wind speed of 17.5m/s as the input condition, based on the fluid-structure coupling method in ANSYS. The results demonstrate that it is safe and reliable when withstanding combined gravity and wind pressure loads. The torque on the mount is within the motor rated torque. The flatness of the FFF reflective surface can be adjusted to an RMS value of 0.05 mm when taken into account the effect of gravity and assembly accuracy. The deformation caused by the maximum wind loads is approximately 0.0587 mm under the protection of wind-proof wall. The combined deformation is 0.077 mm in RMS value combining the two influences, which is less than 1/20 of wavelength. The FFF mirror assembly is stable and precisely for telescope calibration.

Mangifera indica (mango), a member of the Anacardiaceae family, is renowned for its diverse pharmacological properties, encompassing antidiabetic, antioxidant, antiviral, cardiotonic, hypotensive, and anti-inflammatory effects. The present study delves the insulin-releasing and glucose-lowering potential of the ethanolic extract of Mangifera indica (EEMI) leaves in streptozotocin (STZ)-induced type 2 diabetic rats, concurrently investigating its phytoconstituents. EEMI's effects on insulin secretion were measured using BRIN BD11 β-cells and isolated mouse islets. It’s enzymatic inhibitory properties on carbohydrate digestion, glucose absorption, and free radicals were investigated using starch digestion, glucose diffusion and DPPH assay methods. In-vivo parameters including lipid profile and liver glycogen content were assessed on streptozotocin-induced type 2 diabetic rats. EEMI exhibited a dose-dependent increase in insulin secretion from clonal pancreatic BRIN BD11 β-cells and isolated mouse islets. EEMI inhibited starch digestion, glucose diffusion over time and DPPH activity in vitro. In acute in vivo studies, EEMI improved food intake, oral glucose tolerance. Moreover, following 28 days of treatment with EEMI, a remarkable amelioration in body weight, fasting blood glucose, plasma insulin, liver glycogen content, total cholesterol, triglyceride, LDL, VLDL and HDL levels were observed. Further phytochemical analysis with EEMI identified the presence of alkaloids, tannins, saponins, steroids, glycosides, flavonoids, and reducing sugar. The synergistic effects of EEMI, potentially attributable to naturally occurring phytoconstituents, hold promise for the development of enriched antidiabetic therapies, offering a promising avenue for the management of type 2 diabetes.

Cell junction that is usually associated with dynamic cytoskeletons is essential for a wide range of cellular activities such as cell migration, cell communication, barrier function and signal transduction. Real-time observation of cell junction facilitates understanding of the mechanisms by which cell junction regulate relevant cellular activities. In this study, we examined the binding capacity of a modified tridecapeptide from Cx43 to cell junction protein ZO-1 and sought to create a fluorescent peptide that could be used to label cell junction. To introduce the fluorescent peptide into the cells, a cell-penetrating peptide was linked to the modified tridecapeptide and synthesized. The binding of the modified tridecapeptide was tested using pull down and immunoprecipitation assay. The ability of the peptide to label cell junction was assessed by adding it to fixed or cultured Caco-2 cells. Testing assay revealed that the Cx43-derived peptide can bind to ZO-1. Besides, the peptide was able to label cell junction of fixed cell, although no obvious cell junction labeling was observed clearly in living cells, probably due to the inadequate affinity. These results indicate that a peptide-based strategy for labeling cell junction may be feasible, and efforts to improve its affinity are warranted in the future.

The COVID-19 pandemic, declared in early 2020, is an unprecedented global health crisis, causing over 7.0 million deaths and ongoing challenges. While the pharmaceutical industry expedited vaccine development, mutant SARS-CoV-2 strains remain a major fear. Moreover, concerns regarding the long-term health repercussions of COVID-19-affected individuals persist since individuals affected by mild and moderate to severe SARS-CoV-2 infection experience long-term cardiovascular complications, liver dysfunction, pulmonary afflictions, kidney impairments, and most importantly neurocognitive deficits. In recent studies, we documented pathophysiological changes in various organs following the post-acute infection of mice with murine hepatitis virus-1 (MHV-1), a coronavirus, at both 7 days and 12 months after infection. One part of the body that can be drastically affected by SARS-CoV-2 is the skin. Studies have shown major changes in the skin post-acute SARS CoV-2 infection in humans. However, long-term dermatologic changes post-COVID have never been explored. For the first time, we show several cutaneous findings both at the acute stages and long-term post-infection of mice with MHV-1 coronavirus (a promising experimental model to study acute and long-COVID). Precisely, we found destruction of the epidermal layer, an increase in the number of hair follicles, extensive collagen deposition in the dermal layer, and hyperplasticity of the sebaceous glands at the acute stages, along with thinning of the panniculus carnosus, as well as the adventitial layer, which corresponds well with studies in humans. In contrast, the cutaneous investigation in the long-COVID phase shows the absence of hair follicles from both the epidermal and dermal layers, the destruction of adipose tissues, and the devastation of the epidermal layer. Further, treatment of these mice with a 15 amino acid synthetic peptide, SPIKENET (SPK), which was effective in preventing Spike glycoprotein-1 binding with host receptors, as well as has a potent anti-inflammatory response to severe inflammatory stimulus) restored the loss of hair follicles and re-architected the epidermal and dermal layers. Additionally, destruction in fatty tissue in the infected mice was successfully restored post-treatment with SPK. These findings suggest that SARS-CoV-2 initiates the changes early post-infection, leading to devastating skin alterations in the long term which can be prevented by our newly identified peptide drug SPK.

Hepatic carboxylesterase 1(CES1) metabolizes many prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aim to develop a semi-physiologically based pharmacokinetic model(Semi-PBPK model) to simultaneously predict pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis(LC) patients. Six prodrugs(enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. The parameters including organ blood flows, plasma binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate(GFR) and gastrointestinal transit rate were introduced into the simulation. Pharmacokinetic profiles of these drugs and their active metabolites were simulated in 100 virtual subjects. The developed semi-PBPK model, following validation in healthy subjects, was extrapolated to LC patients. Most of the observations are within the 5% and 95% quantile of simulations from 100 virtual patients. The estimated AUC and Cmax are within 0.5-2-fold of observation. The sensitivity analysis showed that the decreased plasma exposure of active metabolite due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model has successfully predicted pharmacokinetics of CES1 substrates and their metabolites in healthy subjects and LC patients, which assists in tailoring dosages of CES1 substrates in LC patients.

Understanding the molecular factors involved in the development of uterine myomas may result in the use of pharmacological drugs instead of aggressive surgical treatment. ANGPT1, CASR, and PTK2 were examined in myoma and peripheral tissues samples taken from women after myoma surgery and in normal uterine muscle tissue samples in the control group. Tests were performed using tissue microarray immunohistochemistry. No statistically significant differences in ANGPT1 expression between the tissue of the myoma, the periphery, and the normal uterine muscle tissue of the control group were recorded. The CASR value was reduced in the myoma and peripheral tissue and normal in the group of women without myomas. PTK2 expression was also lower in the myoma and periphery com-pared to healthy uterine myometrium. Calcium supplementation could have an effect on stop-ping the growth of myomas.

Visceral leishmaniasis (VL) is a chronic systemic disease. In Brazil this infection is caused by Leishmania (Leishmania) infantum. Extracellular vesicles (EVs) released by Leishmania species have different functions like modulation of host immune system, inflammatory response, among others. This study evaluated the participation of EVs from L. (L.) infantum (Leish-EVs) in stimulation of the humoral and cellular immune responses of hosts with VL. Promastigotes were cultivated in 199 medium and, in the log phase of growth, they were centrifuged, washed, resuspended in RPMI medium and incubated for 2 to 24h, at 25ºC or 37°C to release Leish-EVs. This dynamic was evaluated by transmission (TEM) and scanning (SEM) electron microscopies, as well as nanoparticle tracking analysis (NTA). The results suggested that parasite penetration in mammal macrophages requires more Leish-EVs than those living in insect vectors, since promastigotes incubated at 37°C released more Leish-EVs than those incubated at 25ºC. In comparison to the control group, infected THP-1 cells produced a significantly higher concentration of EVs (THP-1 cells-EVs). Similar results were obtained when THP-1 cells were treated with Leish-EVs or a crude Leishmania antigen. These data suggest that the concentration of host-EVs-Can distinguish between infected and uninfected cells. THP-1 cells treated with Leish-EVs expressed more IL-12 than control THP-1 cells, but were unable to produce IFN-γ. These same cells produced IL-10, which inhibited TNF and IL-6. Equally, THP-1 cells treated with Leish-EVs up-expressed miR-21-5p and miR-146a-5p. These findings indicate that the increased levels of miR-21-5p and miR-146a-5p observed in Leish-EVs-treated-THP-1 cells lead to immunosuppression and the secretion of pro-inflammatory cytokines.

Ipomoea batatas L. (IBL) has gained significant popularity as a complementary therapy or herbal medicine in the treatment of anti-diabetes. The objective of this review is to examine the mechanism of action of flavonoid compounds found in IBL that can activate GLP-1 as an anti-diabetic agent. The review article refers to PRISMA guidelines. The literature search was conducted using electronic databases such as Crossref, Pubmed, Scopus, and Science Direct. The search query was based on specific keywords, including Ipomoea batatas OR sweet potato AND anti-diabetic OR hypoglycemic. A total of 1055 articles were found, but only 32 articles were selected for further review based on inclusion and exclusion criteria. IBL contains various compounds, including phenolic acid, flavonols, flavanols, flavones, and anthocyanins, which exhibit activity against anti-diabetes. Flavonols, flavonols, and flavones belong to a group of flavonoids that possess the ability to form complexes with AlCl3 and Ca2+. Retention of Ca2+ within intracellular L cells, resulting in the release of GLP-1. Flavonols, flavones, and flavone groups have been found to strongly interact with DPP-IV, which inhibits the degradation of GLP-1. This mechanism effectively prolongs the half-life of GLP-1 in the systemic system, thereby contributing to the anti-diabetic activity of IBL

Bacteria are engaged in a constant battle against preying viruses, called bacteriophages (or phag-es). These remarkable nano-machines pack and store their genomes in a capsid and inject it into the cytoplasm of their bacterial prey following specific adhesion to the host cell surface. Tailed phages possessing dsDNA genomes are the most abundant phages in the bacterial virosphere, particularly those with long, non-contractile tails. All tailed phages possess a nano-device at their tail tip that specifically recognizes and adheres to a suitable host cell surface receptor, being pro-teinaceous and/or saccharidic. Adhesion devices of tailed phages infecting Gram-positive bacte-ria are highly diverse and, for the majority, remain poorly understood. Their long, flexible and multi-domain encompassing tail limits experimental approaches to determine their complete structure. We have previously shown that the recently developed protein structure prediction program AlphaFold2 can overcome this limitation by predicting the structures of phage adhesion devices with confidence. Here, we extend this approach and employ AlphaFold2 to determine the structure of a complete phage, the lactococcal P335 phage TP901-1. Herein we report the structures of its capsid and neck, its extended tail, and the complete adhesion device, the baseplate, which was previously partially determined by X-ray crystallography.

HIV-1 infection can activate the expression of human endogenous retroviruses (HERVs), particularly HERV-K (HML-2). HIV controllers (HICs) are rare people living with HIV (PLWH) who naturally control HIV-1 replication. The ability of HICs to control the expression of endogenous retroviruses has not been previously addressed. In this study, we measured ERVK-6 RNA expression in PBMCs of HICs (n = 23), antiretroviral (ART)-suppressed subjects (n = 8), and HIV-1-negative (NEG) individuals (n = 10) and correlated the transcript expression of ERVK-6 with multiple HIV-1 restriction factors. Our study reveals that ERVK-6 RNA expression in PBMCs from HICs was significantly downregulated compared with both ART and NEG control groups. Moreover, we detected that ERVK-6 RNA levels in PBMCs across all groups were negatively correlated with the expression levels of p21 and MCPIP1. In our previous study, these two cellular restriction factors were upregulated in HICs compared with control groups. Interestingly, p21 and MCPIP1 limit the activation of macrophages and T cells by downregulating the activity of NF-kB, a transcription factor that stimulates the LTR-driven transcription of HIV-1 and HERV-K proviruses. These findings support that HICs activate innate antiviral mechanisms that may simultaneously downregulate the transcription of both HIV-1 and endogenous retroviruses.

A relevant aspect in the epidemiology of Tegumentary Leishmaniasis (TL) is the Leishmania parasites carrying a viral endosymbiont Leishmania RNA Virus 1 (LRV1), a dsRNA virus. Leishmania parasites carrying LRV1 are prone to causing more severe TL symptoms, increasing the likelihood of unfavorable clinical outcomes. LRV1 has been observed in cultured strains of five L. (Viannia) species, and host specificity was suggested when studying LRV1 from L. braziliensis and L. guyanensis strains. The coevolution hypothesis of LRV1 and Leishmania was based on phylogenetic analyses, implying an association between LRV1 genotypes, Leishmania species, and their geographic origins. This study aimed to investigate LRV1 specificity to Leishmania (Viannia) species hosts by analyzing LRV1 from L. (Viannia) species. To this end, LRV1 was screened in L. (Viannia) species other than L. braziliensis or L. guyanensis, and it was detected in 11 out of 15 L. naiffi and in 2 out of 4 L. shawi. Phylogenetic analyses based on partial LRV1 genomic sequencing supported the hypothesis of host specificity, as LRV1 clustered according to their respective Leishmania species hosts. These findings underscore the importance of investigating Leishmania and LRV1 coevolution and its impact on Leishmania (Viannia) species dispersion and pathogenesis in the American Continent.

This study aimed to identify and differentiate the factors that may affect the incidence of temporomandibular joint (TMJ) dysfunction in children with type 1 diabetes. We analyzed the TMJ symptoms, clinical and laboratory parameters of type 1 diabetes in a cohort of 101 consecutive patients. The participants were evaluated regarding the presence of pain in the masticatory muscles, TMJ sounds, mouth opening, maximum mouth opening, lateral and protrusive excursions, and Fonseca scores. The overall cohort showed a mean Fonseca score of 20 ± 13.89, referred to mild TMJ dysfunction. Of patients, 34.65% presented at least one clinical symptom and were defined as having dysfunction. The most frequently recorded symptom was TMJ sounds, presented in 16.8% of children. In subjects with dysfunction compared to those without dysfunction, a significant difference was found at height standard deviation scores, Fonseca scores and maximum mouth opening (p&lt;0.001). HbA1c levels, diabetes duration, age and gender did not reveal any significant differences between the patients with and without dysfunction. Type 1 diabetes is often associated with limited mouth opening and mild TMJ dysfunction. This dysfunction may reflect a more chronic condition and possibly exceeds the prevalence of cheiroartropathy. This study could be a starting point towards enhancing our understanding of clinically evident TMJ involvement in type 1 diabetes.

Small molecule modulators of neurotensin receptor 1 (NTSR1), a class A G protein-coupled receptor (GPCR), has been emerging as promising therapeutics for psychiatric disorders and cancer. Interestingly, a chemical group substitution of NTSR1 modulators can launch different downstream regulation, highlighting the significance of deciphering the internal fine-tuning mechanism. Here, we conducted synergistic application of Gaussian accelerated molecular dynamics simulation, conventional molecular dynamics simulation, and Markov state models (MSM) to investigate the underpinning mechanism of ‘driver chemical groups’ of modulators triggering inverse signaling. The result indicated that the flexibility of leucine moiety in NTSR1 agonists contributes to the inward displacement of TM7 through a loosely coupled allosteric pathway, while the rigidity of adamantane moiety in NTSR1 antagonists leads to unfavorable downward transduction of agonistic signaling. Furthermore, we found that R3226.54, Y3196.51, F3537.42, R1483.32, S3567.45 and S3577.46 may play a key role in inducing the activation of NTSR1. Together, our findings not only highlight the ingenious signal transduction within class A GPCRs, but also lay a foundation for the development of targeted drugs harboring different regulatory function of NTSR1.

DKA represents an acute, severe complication of relative insulin deficiency and a common presentation of Type 1 Diabetes Mellitus (T1DM) primarily and, occasionally, T2DM in children and adolescents. It is characterized by the biochemical triad of hyperglycaemia, ketonaemia and/or ketonuria, and acidaemia. Clinical symptoms include dehydration, tachypnoea, gastrointestinal symptoms, and reduced level of consciousness, precipitated by a variably long period of polyuria, polydipsia and weight loss. The present review aims to summarize potential pitfalls in the diagnosis and management of DKA. A literature review was conducted using the Pubmed/Medline databases including articles published from 2000 onwards. Diagnostic challenges include differentiating between T1DM and T2DM, DKA and hyperosmolar hyperglycaemic state (HHS), or between DKA and alternative diagnoses presenting with overlapping symptoms, such as pneumonia, asthma exacerbation, urinary tract infection, gastroenteritis, acute abdomen and central nervous system infection. The mainstays of DKA management include careful fluid resuscitation, timely intravenous insulin administration and restoration of shifting electrolyte disorders and underlying precipitating factors. However, evidence suggests that optimal treatment remains a therapeutic challenge. Accurate and rapid diagnosis, prompt intervention and meticulous monitoring are of major importance to break the vicious cycle of life-threatening events and prevent severe complications during this potentially fatal medical emergency.

Ostreid herpesvirus 1 (OsHV-1) is one of the most economically important pathogens of Pacific oysters. Understanding the pathogenesis of this virus is critical to developing tools to control outbreaks on shellfish farms. OsHV-1 is genetically related to vertebrate herpesviruses, which have a lytic and a latent stage, with the latent stage capable of being reactivated to the lytic stage. Here, OsHV-1 latency in Pacific oysters was investigated in experimentally and naturally infected oysters. Lytic infection in one-year-old oysters injected with the Tomales Bay strain of OsHV-1 was detectable between 1 and 4 days post-infection (dpi) but was not detectable after 5 dpi. The infected oysters shed 1102 to 1104 DNA copies/ml during the 4-day acute phase. At 21 dpi, the recovered oysters were temperature and chemically stressed and were found to shed 1104 to 1105 DNA copies/ml over a period of 48 h. Lytic shedding was not detectable in two-year-old oysters injected similarly with the same strain of OsHV-1; however, the OsHV-1 genome was detectable by qPCR in the adductor muscle, gill, mantle, and hemocytes within the first 3 dpi, after which it became undetectable. No OsHV-1 was detectable in the adductor muscle, gill, or mantle from experimentally infected oysters on days 15 and 21 post-infection or from oysters sampled 9 months after surviving an OsHV-1 mortality event; however, OsHV-1 DNA could be detected in hemocytes of both experimentally infected oysters at 21 dpi and naturally infected oysters. In addition, lytic viral gene transcription was detectable in hemocytes of experimentally infected oysters between 1 and 21 dpi and in hemocytes of naturally infected oysters.

Objectives: Carbapenem-resistant Acinetobacter baumannii (CRAB) isolates are one of the most difficult pathogens to treat. Cefiderocol, a chlorocatechol-substituted siderophore antibiotic, was approved by the U.S. Food and Drug Administration (FDA) in 2019 indicated for the treatment of infections due to CRAB infections. Despite the initial positive treatment outcomes with this antimicrobial, recent studies reported higher than all-cause mortality rate in patients treated with cefiderocol. The cause(s) behind these outcomes remains unconfirmed. A plausible hypothesis is heteroresistance, a phenotype characterized by the survival of a small proportion of cells in a population seemingly isogenic. Recent results have shown that the addition of human fluids to CRAB cultures leads to cefiderocol heteroresistance. Here we describe molecular and phenotypic analyses of CRAB heteroresistant bacterial subpopulations to better understand the nature of the less-than-expected successful outcomes after cefiderocol treatment. Methods: Isolation of heteroresistant variants of the CRAB strain AMA40 was carried out in cultures supplemented with cefiderocol and human pleural fluid (HPF). Two AMA40 variants, AMA40 IHC1 and IHC2, were subjected to whole genome sequencing and transcriptional analysis to identify mutations and expression changes associated with cefiderocol heteroresistance. The impact of these mutations on the pharmacodynamic activity of cefiderocol was assessed via susceptibility testing, EDTA and boronic acid inhibition analysis, biofilm formation, and static time-kill assays. Results: Heteroresistant variants AMA40 IHC1 and AMA40 IHC2 have 53 chromosomal mutations, of which 40 are common to both strains. None of the mutations occurred in genes associated with high affinity iron-uptake systems or β-lactam resistance. However, transcriptional analyses showed significant modifications in levels of expression of genes associated with these functions. The blaNDM-1 and blaADC-2, as well as various iron-uptake system genes, were expressed at higher levels than the parental strain. On the other hand, the carO and ompA genes’ expression was reduced. One of the mutations common to both heteroresistant strains mapped within pipA, a gene associated with iron homeostasis in other species. Static time-kill assays showed that supplementing cation-adjusted Mueller-Hinton broth with human serum albumin, the main protein component of HPF, considerably reduced cefiderocol killing activity for all three strains tested. Notably, collateral resistance to amikacin was observed in both variants. Conclusions: We conclude that exposing CRAB to fluids containing high HSA facilitates the rise of heteroresistance associated with point mutations and upregulation of genes coding for β-lactamases and biofilm formation.

Background The main aim of reconstructive surgery (RS) is to restore the integrity of soft tissues damaged by trauma, surgery, congenital deformity, burns or infection. Microsurgical techniques consist of harvesting tissues that are separated from the vascular sources of the donor site and anastomosed to the vessels of the recipient site. In these procedures, there are some preoperative modifiable factors that have the potential to influence the outcome of the flap transfer and its anastomosis. Methods Chronic inflammatory anaemia (ACD) is a constant condition in patients who have undergone RS and correlates with the perfusion of the free flap. In RS, it is important to maintain good tissue oxyporesis, avoiding blood hyperviscosity. From January 2017 to September 2019, we studied 16 patients (16 males, mean age 38 years) who underwent microsurgical procedures for RS. Haemoglobin (Hb) levels, Corpuscular Indexes, Transferring saturation (TSAT) ferritin concentrations and creatinine clearance have been measured the first day after surgery (T0), after the first week (T1) and after five weeks (T2). At T0 all patients showed low hemoglobin levels (average 7.4 g/dl, STD 0,71range 6,2-7,4 g dL-1), with an MCV of 72, MCH 28, MCHC 33, RDW 16, Sideremy 35, Ferritin 28, Ret% 1,36, TRF 277 and Creatinine Clearance 119. . We assessed all patients for clinical status, medical history and comorbidities before starting therapy. Results. In collaboration between the two departments, we started a therapeutic protocol with erythropoietic stimulating agents (ESAs) (Binocrit 6000 UI/week) and intravenous iron every other day, on the second day after surgery. Thirteen patients received ESAs and FCM (500-1000 mg per session), three patients received ESAs and iron gluconate (1 vial every other day). No patients received blood transfusions. No side effects were observed and, most importantly, no limb or flap rejection. Conclusions Preliminary data from our protocol show an optimal therapeutic response in a surgical setting with limited data in the scientific literature. The enrolment of further patients will allow us to validate this therapeutic protocol with statistically significant data.

Despite the numerous advances in target therapy for the treatment of colorectal cancer, aggressive colorectal cancer remains an incurable disease whose negative modulation of the immune system in the tumor microenvironment is still critical for improving the patient's prognosis. Extracellular vesicles (EVs) have received attention for their use as cell-membrane-camouflaged nanoparticles and drug delivery systems in nanomedicine derived by nearly all cell types for intercellular communication and regulation in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), or combined together with retinoic acid and Libidibia ferrea (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines, as well as their capacity to prevent metastases in mouse models of colorectal cancer such as allographic and peritoneal. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or especially combined (M1EV4) downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastases in peritoneum, liver and lungs. STAT3, NF-kB and AKT were the major genes downregulated by systems of M1EVs. Tumor-associated macrophages (TAM) switched M2 phenotype (CD163) towards M1 (CD68) reducing levels of IL-10, TGF-β and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR-1, survivin, vimentin, CXCR4, and PD-L1 after treatment with systems of M1EVs. The results obtained in this study provided evidence that EVs from M1 antitumor macrophages can transport drugs and increase their immunomodulatory and antitumor activity by stimulating activation or blockage of pathways involved in cell proliferation, migration, cell survival, and drug resistance processes.

PG16 is a broadly neutralizing antibody that binds to the gp120 subunit of the HIV-1 Env protein. The major interaction site is formed by the unusually long complementarity determining region (CDR) H3. The CDRH3 residue Tyr100H is known to represent a tyrosine sulfation site; however, this modification is not present in the experimental complex structure of PG16 with full-length HIV-1 Env. To investigate the role of sulfation for this complex, we modeled the sulfation of Tyr100H and compared the dynamics and energetics of the modified and unmodified complex by atomistic molecular dynamics simulations. Our results show that sulfation does not affect the overall conformation of CDRH3, but still enhances gp120 interactions both at the site of mutation and for the neighboring residues. This stabilization affects not only protein-protein contacts, but also the interactions between PG16 and the gp120 glycan shield. Further, we also investigated whether PG16-CDRH3 is a suitable template for the development of peptide mimetics. For a peptide spanning residues 93-105 of PG16 we obtained an experimental EC50 value of 3nM for the binding of gp120 to the peptide. This affinity can be enhanced by almost one order of magnitude by artificial disulfide bonding between residues 99 and 100F. In contrast, any truncation results in significantly lower affinity, suggesting that the entire peptide segment is involved in gp120 recognition. Their high affinity makes PG16-derived peptides useful building blocks for further optimization to obtain a potent inhibitor that efficiently blocks HIV-1 infection.

Background: Endotheliopathy is common pathologic findings in patients with acute and long COVID-19. It may be associated with disease severity and predispose to long-term complications. Plasma levels of a proteoglycan syndecan-1 are found to be significantly elevated in patients with COVID-19, but its roles in assessing the disease severity and predicting long-term outcome are not fully understood. Methods: 124 consecutive hospitalized patients with SARS-CoV2 infection were prospectively enrolled and blood samples were collected on admission (T1), 3-4 days following treatment (T2), and 1-2 days prior to discharge or death (T3). Plasma levels of syndecan-1 were determined using an immunosorbent assay; various statistical analyses were performed to determine the association between plasma syndecan-1 levels and disease severity or the 60-day mortality rate. Results: Compared with those in the healthy controls, plasma levels of syndecan-1 in patients with critical COVID-19 were significantly higher (p<0.0001). However, there was no statistically significant difference among patients with different disease severity (p>0.05), resulting from large individual variability. Longitudinal analysis demonstrated that while the levels fluctuated during hospitalization in all patients, plasma syndecan-1 levels were persistently elevated from baseline in critical COVID19 patients. Cox proportional hazard regression analyses revealed that elevated plasma levels of syndecan-1 (>260 ng/mL at T1, >1018 ng/mL at T2, and >461 ng/mL at T3) were significantly associated with the 60-day mortality rate. Conclusions: Endotheliopathy, marked by glycocalyx degradation and elevated plasma syndecan-1, occurs in nearly all hospitalized patients with SARS-CoV2 infection; the elevated plasma syndecan-1 is associated with increased mortality in COVID-19 patients.

The glucose-insulin regulatory system and its glucose oscillations is a recurring theme in the literature because of its impact on human lives, mostly the ones affected by diabetes mellitus. Several approaches were proposed, from mathematical to data-based models, with the aim of modeling the glucose oscillation curve. Having such a curve, it is possible to predict, when injecting insulin in type 1 diabetes (T1D) individuals. However, the literature presents prediction horizons no longer than 6 hours, which could be a problem considering their sleeping time. This work presents Tesseratus, a model that adopts a multi-agent approach to combine machine learning and mathematical modeling to predict the glucose oscillation up to 8 hours. Tesseratus uses the pharmacokinetics of insulins and data collected from T1D individuals. Its outcome can support endocrinologists while prescripting daily treatment for T1D individuals, and provide personalized recommendations for such individuals, to keep their glucose concentration in the ideal range. Tesseratus brings pioneering results for prediction horizons of 8 hours for nighttime, in an experiment with seven real T1D individuals. It is our claim that Tesseratus will be a reference for classification of glucose prediction model, supporting the mitigation of short- and long-term complications in the T1D individuals.

Microglia activation causes neuroinflammation, which is a hallmark of neurodegenerative disorders, brain injury, and aging. Ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, reduced microglial activation and enhanced brain functioning in elderly rats. In this study, we studied SH-SY5Y, a human neuroblastoma cell line, and tested viability in the presence of hydrogen peroxide and Sin1 (3-morpholinosydnonimine), which generates reactive oxygen and nitrogen species (ROS/RNS). Both stressors caused significant apoptosis and necrotic cell death that was attenuated by ladostigil. Our results from RNA-seq experiments show that long non-coding RNAs (lncRNAs) account for 30% of all transcripts in SH-SY5Y cells treated with Sin1 for 24 hours. Altogether, we identify 94 differently expressed lncRNAs in the presence of Sin1, including MALAT1, a highly expressed lncRNA with anti-inflammatory and anti-apoptotic functions. Additional activities of Sin-1 upregulated lncRNAs include redox homeostasis (e.g., MIAT, GABPB1-AS1), energy metabolism (HAND2-AS1), and neurodegeneration (e.g., MIAT, GABPB1-AS1, NEAT1). Four lncRNAs implicated as enhancers were significantly upregulated in cells exposed to Sin1 and ladostigil. Finally, we show that H2O2 and Sin1 increased the expression of DJ-1, a redox sensor and modulator of Nrf2 (nuclear factor erythroid 2–related factor 2). Nrf2 (NFE2L2 gene) is a major transcription factor regulating antioxidant genes. In the presence of ladostigil, DJ-1 expression is restored to its baseline. The mechanisms governing SH-SY5Y cell survival and homeostasis are highlighted by the beneficial role of ladostigil in the crosstalk involving Nrf2, antioxidant transcription factor DJ-1, and lncRNAs. Stress-dependent induction of lncRNAs represents an underappreciated regulatory level that contributes to cellular homeostasis and the capacity of SH-SY5Y to cope with oxidative stress.

Fungal spores are universal atmospheric components associated to allergic reactions. Alternaria (Ascomycota) is considered the most allergenic spore taxa. Alt a 1 is the major allergen of Alternaria and is present also in other Pleosporales. In this study, standard Hirst-based sampling and analyzing methods for measuring spore daily concentrations of Alternaria, Curvularia, Drechslera-Helminthosporium, Epicoccum, Leptosphaeria, Pithomyces, Pleospora and Stemphyllium (all included in the taxon Pleosporales) have been used besides two high-volume samplers, Burkard Cyclone (2017) and MCV CAV-A/mb (2019-2020), and ELISA Kits for measuring the allergen. The detection and quantification of Alt a 1 was only possible in the samples from the MCV sampler. Although Alt a 1 was better correlated with Alternaria spores than with Pleosporales spores, the three of them showed high correlations. It is shown, for the first time, a high and significant correlation of Alt a 1 with temperature, a negative one with relative humidity and no correlation with precipitation. The aerobiological monitoring of these three elements ensures the best information for understanding the affectation to allergy sufferers but, if not possible, as a minimum public health service aiming at the detection, treatment and prevention of allergy, the study of the airborne Alternaria spores should be ensured.

Carnivore protoparvovirus 1 (CPPV-1) is a DNA virus causing gastrointestinal disease and immunosuppression in various terrestrial carnivores. Domestic dogs and cats are considered the primary CPPV-1 reservoirs. The habitat overlaps of wild carnivores and free-roaming dogs increases the threat of CPPV-1 transmission between them. This study explored the CPPV-1 distribution among wild carnivores through PCR screening and compared the DNA sequences of the partial capsid protein (VP2) between wild and domestic carnivores. In total, 181 samples were screened for the CPPV-1 VP2 gene, including 32 masked palm civets (Paguma larvata), 63 Chinese ferret badgers (Melogale moschata), and 86 crab-eating mongooses (Herpestes urva), from 2015 to 2019 in Taiwan. The average prevalence of CPPV-1 was 17.7% (32/181), with the highest prevalence in masked palm civets (37.5%). In addition, a masked palm civet was coinfected with two CPPV-1 strains. Among the 33 partial VP2 gene sequences, 23 were identical to sequences amplified from domestic dogs and cats in Asia and the remaining 10 were identified for the first time. This study demonstrated that CPPV-1 has circulated between domestic and wild carnivores in rural Taiwan. Therefore, further population control and health management of free-roaming domestic carnivores are recommended.

Liver receptor homolog-1 (LRH-1) has emerged as a regulator of hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect of LRH-1 on lipid mobilization has not been addressed. This study investigated the regulatory function of LRH-1 in lipid metabolism during fasting. The wild-type (WT) and LRH-1 liver-specific knockout (LKO) mice were either fed or fasted for 24 h, and the liver and serum were isolated. During fasting, the LRH-1 LKO mice showed greater accumulation of triglycerides in the liver compared to that in WT mice. Interestingly, LRH-1 LKO liver decreased the perilipin 5 (PLIN5) expression and genes involved in β-oxidation. Additionally, the LRH-1 agonist dialauroylphosphatidylcholine also enhanced PLIN5 expression in human cultured HepG2 cells. To identify new target genes of LRH-1, these findings directed to analyze the PLIN5 promoter sequence, which revealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immuno-precipitation assays. Moreover, fasted WT primary hepatocytes showed increased co-localization of PLIN5 in lipid droplets (LDs) compared to that in fasted LRH-1 LKO primary hepatocytes. Overall, these findings suggest that PLIN5 might be a novel target of LRH-1 to mobilize LDs and manage the cellular needs.

Cytochrome-c-oxidase (COX) subunit 4 (COX4) plays important roles in the function, assembly and regulation of COX (mitochondrial respiratory complex 4), the terminal electron acceptor of the oxidative phosphorylation (OXPHOS) system. The principal COX4 isoform, COX4-1, is expressed in all tissues, whereas COX4-2 is mainly expressed in the lungs, or under hypoxia and other stress conditions. We have previously described a patient with a COX4-1 defect with a relatively mild presentation compared to other primary COX deficiencies, and hypothesized that this could be the result of compensatory upregulation of COX4-2. To this end, COX4-1 was downregulated by shRNAs in human foreskin fibroblasts (HFF), and compared to patient's cells. COX4-1, COX4-2 and HIF-1α were detected by immunocytochemistry. The mRNA transcripts of both COX4 isoforms and HIF-1 target genes were carried out by RT-qPCR. COX activity and OXPHOS function were measured by enzymatic and oxygen consumption assays, respectively. Pathways were analyzed by CEL-Seq2 and by RT-qPCR. We demonstrate elevated COX4-2 levels in the COX4-1-deficient cells with a concomitant HIF-1α stabilization, nuclear localization and upregulated hypoxia and glycolysis pathways. We suggest that COX4-2 and HIF-1α has the are upregulated, also in normoxia as a compensatory mechanism in COX4-1 deficiency.

Aim: To establish, through molecular modelling, safe and clinically acceptable putative antagonists of E571K-mutated exportin-1 among the bioactive compounds in various parts of Juglans mandshurica. Methods: The bioactive compounds were subjected to compendium of druglikeness and lead-likeness filter workflows prior to docking of the resultant compounds into E571K exportin-1 active site using PyRx AutoDock vina to establish their binding affinity and interaction profile. The evolutionary algorithm of Osiris property explorer DataWarrior software as well as lead-likeness filter were employed for generation of novel non-promiscuous analogues of the lead compound with better putative selectivity and clinical acceptability as E571K Exportin-1 antagonists.Results: The findings of this study present taxifolin as the putatively effective and lead-like E571K Exportin-1 inhibitor with high potential of qualifying for clinical evaluation but is associated with high promiscuity tendency in high throughput screening. The evolutionary derivation of novel analogues of the compound, however, results in the generation of putatively non-promiscuous, non-toxic, and lead-like E571K Exportin-1 antagonists with high synthetic accessibility and clinical developability for evaluation in the strategy for treatment of drug-resistant KRAS-mutant lung adenocarcinoma condition.

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding have been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.

Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pretransplant serum concentrations of Cav-1 and the occurrence of rejection during follow up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute rejection episodes. Moreover, Cav-1 could be therapeutically useful for attenuating graft rejection.

Exportin-1, the ubiquitous nuclear protein transporter, is widely confirmed as an active chemotherapeutic target in non-small cell lung cancer condition while Juglans mandshurica is a well-studied anticancer plant in some lung cancer cell lines. We intend to find novel exportin-1 inhibitor from Juglans mandshurica with better potential tolerability and pharmaco-dynamo-kinetic properties than the current selective inhibitors of nuclear export in non-small cell lung cancer treatment. Osiris property explorer DataWarrior, Glide standard precision docking, quantum mechanics polarized ligand docking, MMGBSA binding free energy calculations, Jaguar density functional theory analysis, and the online web-based SwissADME were employed respectively in this study to filter the retrieved compounds based on tolerability, toxicity, and Lipinsky’s rule of five violation potential, determine their druggability, establish relative stability of the lead compound in water solvation model, and evaluates druglikeness, lead-likeness, as well as synthetic accessibility of the lead compound. This study reveals eriodictyol as having higher binding free energy (-40 kcal/mol) than that of standard (-39.56 kcal/mol) in exportin-1 active site, better synthetic accessibility score (3.15 versus 3.29), high GI absorption, non-blood brain barrier permeant, lacks Brenk and PAINS alert, obeying Lipinski’s, Ghose’s, Veber’s, Egan’s, and Muegge’s rule of druglikeness and lead-likeness as well as non-cytotoxic to HepG2 cells. We therefore found eriodictyol as a lead-like, non-toxic exportin-1 inhibitor with good predictive stability and pharmacokinetic potential and thus provided data for further validation of eriodictyol as a candidate exportin-1 inhibitor in both preclinical and clinical studies involving lung cancer therapy.

Background: In France, no previous studies had addressed the acquisition of multidrug resistant (MDR) bacteria and colistin resistance genes by medical students when undertaking internships abroad. Methods: Nasopharyngeal, rectal, and vaginal swabs samples were collected from 382 French medical students before and after travel to investigate the acquisition of MDR bacteria. The bacterial diversity in the samples was assessed by culture on selective media. We also genetically characterised the isolates of MDR bacteria including Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E), methicillin-resistant Staphylococcus aureus (MRSA), and Carbapenemase-producing Enterobacteriacae (CPE) using the real-time polymerase chain reaction method. The samples were collected from 293 students and were investigated for mcr colistin-resistance genes using RT-PCR directly on the samples, followed by conventional PCR and sequencing. Results: A proportion of 29.3% of the participants had acquired ESBL-E and 2.6% had acquired CPE. The most common species and ESBL-E encoding gene were Escherichia coli (98.4%) and bla_CTX-M-A (95.3%), respectively. A proportion of 6.8% of the participants had acquired mcr-1 genes, followed by mcr-3 (0.3%) and mcr-8 (0.3%). We found that taking part in humanitarian missions to orphanages, being in contact with children during travel, the primary destination of travel being Vietnam and north India, using antibiotics during travel, and studying in 2017 were associated with the acquisition of ESBL-E. When the primary destination of travel was Vietnam and the year of study was 2018, this was associated with acquisition of colistin resistance genes. Conclusion: Medical students are at a potential risk of acquiring ESBL-E, CPE and colistin resistance genes. A number of risk factors have been identified, which may be used to develop targeted preventive measures.

VNREDSat-1 is the first Vietnamese satellite allowing the survey of environmental parameters such as vegetation and water coverages, or surface water quality at medium spatial resolution (from 2.5 to 10 meters depending on the considered channel). The NAOMI sensor on board VNREDSat-1 has the required spectral bands to assess the suspended particulate matter concentration, SPM. Because recent studies have shown that the remote sensing reflectance, Rrs(), at the blue (450 – 520 nm), green (530 – 600 nm), and red (620 – 690 nm) spectral bands can be assessed from NAOMI with a good accuracy, the present study is dedicated to the development and validation of an algorithm (hereafter referred to as V1SPM) to assess SPM from Rrs() over inland and coastal waters of Vietnam. For that purpose, an in situ data set of hyper-spectral Rrs() and SPM (from 0.47 to 240.14 g.m-3) measurements collected at 205 coastal and inland stations has been gathered. Among the different approaches, including 4 historical algorithms, the polynomial algorithms involving the red-to-green reflectance ratio presents the best performance on the validation data set (MAPD of 18,7%). Compared to the use of a single spectral band, the band ratio allows to reduce the scatter around the polynomial fit as well as the impact of imperfect atmospheric corrections. Due to the lack of matchup data points with VNREDSat-1, the full VNREDSat-1 processing chain (RED-NIR and V1SPM) aiming at estimate SPM from the top-of-atmosphere signal has been applied to the Landsat-8/OLI match-up data points with relatively low to moderate SPM concentration (3.33-15.25 g.m-3) showing a MAPD of 15,8%. An illustration of the use of this VNREDSat-1 processing chain during a flooding event occurring in Vietnam is provided.

It has been demonstrated that a decrease in cellular adenosine triphosphate (c-ATP) causes cellular dysfunction. T-cells are not an exception. One of their roles is to properly detect and eliminate cancer cells. These processes occur at the expense of ATP. Therefore, it can be concluded that a decrease in c-ATP can defect T-cell function and promote cancer evolution. In this article, we provide a hypothesis to describe the correlation between the expression of PD-1 protein on T-cells and their c-ATP levels. Moreover, we present the possible predictive factors of Anti–PD(L)-1 therapy which has not yet been determined definitely.

Space-borne Synthetic Aperture Radar (SAR) Interferometry (InSAR) is now a key geophysical tool for surface deformation studies. The European Commission’s Sentinel-1 Constellation began acquiring data systematically in late 2014. The data, which are free and open access, have global coverage at moderate resolution with a 6 or 12-day revisit, enabling researchers to investigate large-scale surface deformation systematically through time. However, full exploitation of the potential of Sentinel-1 requires specific processing approaches as well as the efficient use of modern computing and data storage facilities. Here we present LiCSAR, an operational system built for large-scale interferometric processing of Sentinel-1 data. LiCSAR is designed to automatically produce geocoded wrapped and unwrapped interferograms and coherence estimates, for large regions, at 0.001° resolution (WGS-84 system). The products are continuously updated in a frequency depending on prioritised regions (monthly, weekly or live update strategy). The products are open and freely accessible and downloadable through an online portal. We describe the algorithms, processing, and storage solutions implemented in LiCSAR, and show several case studies that use LiCSAR products to measure tectonic and volcanic deformation. We aim to accelerate the uptake of InSAR data by researchers as well as non-expert users by mass producing interferograms and derived products.

The HIV-1 nef gene terminates in a 3’-UGA stop codon, which is highly conserved in the main group of HIV-1 subtypes, along with a downstream potential coding region that could extend the nef protein by 33 amino acids, if readthrough of the stop codon occurs. Antisense tethering interactions (ATIs) between a viral mRNA and a host selenoprotein mRNA are a potential viral strategy for the capture of a host selenocysteine insertion sequence (SECIS) element (Taylor et al, 2016) [1]. This mRNA hijacking mechanism could enable the expression of virally encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine (SeC). Here we show that readthrough of the 3’-terminal UGA codon of nef occurs during translation of HIV-1 nef expression constructs in transfected cells. This was accomplished via fluorescence microscopy image analysis and flow cytometry of HEK 293 cells, transfected with engineered GFP reporter gene plasmid constructs, in which GFP can only be expressed by translational recoding of the UGA codon. SiRNA knockdown of thioredoxin reductase 1 (TR1) mRNA resulted in a 67% decrease in GFP expression, presumably due to reduced availability of the components involved in selenocysteine incorporation for the stop codon readthrough, thus supporting the proposed ATI. Addition of 20 nM sodium selenite to the media significantly enhanced stop codon readthrough in the pNefATI1 plasmid construct, by >100%, supporting the hypothesis that selenium is involved in the UGA readthrough mechanism.

In present study, the effect of Inonotus Obliquus extracts used in traditional medicine was investigated on the expression of matrix metalloproteinases-1 (MMP-1) in the normal human dermal fibroblasts. As shown our results, extracts of Inonotus Obliquus decreased MMP1 expression in oxidative stress-exposed normal human dermal fibroblasts. Additionally, Inonotus Obliquus extracts decreased AP-1 transcriptional activity and phospho-JNK in oxidative stress exposed normal human dermal fibroblasts. The results suggest that Inonotus Obliquus extracts decreased MMP1 expression using decreasing AP-1 transcriptional activity and phospho-JNK. Therefore, Inonotus Obliquus extracts has potential to reduce formation of wrinkle and to use as a cosmetic ingredient.

The high mutation rate of human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance from the development of vaccines to long-lasting drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10-5 - 10-3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the location of these mutations can be further analyzed for their potential allosteric effects to reveal potentially new inhibitors with different pharmacodynamics that can be used to circumvent fast occurring HIV drug resistance. Given that HIV is one of the fastest mutating viruses, it is a good model for comprehensive study of its mutations that can give rise to much horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.

An experiment was carried out at Nabogram Khamarbari, near the Manannogor, Sadar Upazila, Noakhali District, Noakhali-3814, Bangladesh during the period from 12th January 2018 to 17th April 2018, with two varieties of tomatillo (Physalis ixocarpa Brot.) SAU tomatillo-1 and SAU tomatillo-2. It was laid out in RCBD method having three replications and was conducted to observe the influence of staking and non-staking on tomatillo cultivation in coastal areas. For the study, growth indicating characters like no. of leaves plant^-1, size of leaf plant^-1, height of each plant, no. of branches plant^-1 and yield attributing parameters such as days to first flowering, days to 50% flowering, no. of fruits branch^-1, fruit weight and yield were obtained from the plants with the treatments of staking and non-staking. A wide variation was observed between two varieties of tomatillo with the effect of these treatments. According to the results highest no. of leaves branch^-1, maximum size of leaves branch^-1, tallest height of each plant, uppermost no. of branches plant^-1, highest no. of fruits branch^-1, maximum weight of each fruit and yield were obtained in the staking treatment over the non-staking treatment of SAU tomatillo-1 and in case of SAU tomatillo-2, with the same parameters the result indicated significantly upper in the staking treatment over non-staking treatment. Considering the two varieties of tomatillo, the outcome were significantly superior with staking treatment for the similar parameters. The findings of the experiment indicated that the best yield (21 tha¹) and highest financial benefit could be obtained by SAU tomatillo-1 and the best tomatillo production in saline soil of coastal areas is possible by cultivating SAU tomatillo-1.

Honey is a complex sweet food stuff with well-established antimicrobial and antioxidant properties. It has been used for millennia in a variety of applications, but those most noteworthy include treatment of surface wounds, burns and inflammation. A variety of substances in honey have been suggested as the key component to its antimicrobial potential; polyphenolic compounds, hydrogen peroxide, methylglyoxal and bee-defensin 1. These components vary greatly across honey samples due to botanical origin, geographical location and the individual bee. The use of medical grade honey, Medihoney and Revamil, in the treatment of surface wounds and burns has been seen to improve the healing process, reduce healing time, reduce scarring and prevent microbial contamination. Therefore, medical grade honeys should be used for these treatments and reduce the demand for antibiotic usage. In this review, we aim to outline the constituents of honey and how they affect the antibiotic potential of honeys in a clinical setting.

Growing resistance is reported to carbamate insecticides in malaria vectors in Cameroon. However, the contribution of acetylcholinesterase (Ace-1) to this resistance remains uncharacterised. Here, we established that the G119S mutation is driving resistance to carbamates in Anopheles gambiae populations from Cameroon. Insecticide bioassay on field collected mosquitoes from Bankeng, a locality in southern Cameroon, showed high resistance to the carbamates bendiocarb (64.8 ± 3.5 % mortality) and propoxur (55.71 ± 2.9 %) but a full susceptibility to the organophosphate fenithrothion. The TaqMan genotyping of the G119S mutation in field-collected adults revealed the presence of this resistance allele (39%). A significant correlation was observed between the Ace-1^R and carbamate resistance at allelic [(bendiocarb; OR = 75.9; P<0.0001) and (propoxur; OR= 1514; P<0.0001)] and genotypic [RR vs SS (bendiocarb; OR = 120.8; P<0.0001) and (propoxur; OR= 3277; P<0.0001) levels. Furthermore, the presence of the mutation was confirmed by sequencing an Ace-1 portion flanking codon 119. The cloning of this fragment revealed a likely duplication of Ace-1 in Cameroon as mosquitoes exhibited at least three distinct haplotypes. Phylogenetic analyses showed that the predominant Ace-1^R allele is identical to that from West Africa suggesting a recent introduction of this allele in Central Africa from the West. The spread of this Ace-1^R represents a serious challenge to future implementation of IRS-based interventions using carbamates or organophosphates in Cameroon

DNA vaccines are stable, safe, cost effective to produce and relatively quick and easy to manufacture. However, to date DNA vaccines have shown relatively poor immunogenicity in humans despite promising preclinical results. Consequently, a number of different approaches have been investigated to improve the immunogenicity of DNA vaccines. These include the use of improved delivery methods, adjuvants, stronger promoters and enhancer elements to increase antigen expression, and codon optimization of the gene of interest. This review describes the creation and use of a DNA vaccine vector containing a porcine circovirus (PCV-1) enhancer element that significantly increases recombinant antigen expression and immunogenicity and allows for dose sparing. A 172bp region containing the PCV-1 capsid protein promoter (Pcap) and a smaller element (PC; 70 bp) within this were found to be equally effective. DNA vaccines containing the Pcap region expressing various HIV-1 antigens were found to be highly immunogenic in mice, rabbits and macaques, at 4 to 10-fold lower doses than normally used and to be highly effective in heterologous prime-boost regimens. By lowering the amount of DNA used for immunization, safety concerns over injecting large amounts of DNA into humans can be overcome.

Based on a modified dice-and-fill technique, a PIN-PMN-PT single crystal 1-3 composite with the kerf of 12 μm and pitch of 50 μm was prepared. The as-made piezoelectric composite material behaved with high piezoelectric constant (d33 = 1500 pC/N), high electromechanical coefficient (kt = 0.81), and low acoustic impedance (16.2 Mrayls). Using lithography and flexible circuit method, a 48-element phased array was successfully fabricated from such a piezoelectric composite. The array element was measured to have a central frequency of 20 MHz and a fractional bandwidth of approximately 77% at −6 dB. Of particular significance was that this PIN-PMN-PT single crystal 1-3 composite-based phased array exhibits a superior insertion loss compared with PMN-PT single crystal and PZT-5H-based 20 MHz phased arrays. The focusing and steering capabilities of the obtained phased array were demonstrated theoretically and experimentally. These promising results indicate that the PIN-PMN-PT single crystal 1-3 composite-based high frequency phased array is a good candidate for ultrasound imaging applications.

Contrary to optical images, Synthetic Aperture Radar (SAR) images are in different electromagnetic spectrum where the human visual system is not accustomed to. Thus, with more and more SAR applications, the demand for enhanced high-quality SAR images has increased considerably. However, high-quality SAR images entail high costs due to the limitations of current SAR devices and their image processing resources. To improve the quality of SAR images and to reduce the costs of their generation, we propose a Dialectical Generative Adversarial Network (Dialectical GAN) to generate high-quality SAR images. This method is based on the analysis of hierarchical SAR information and the “dialectical” structure of GAN frameworks. As a demonstration, a typical example will be shown where a low-resolution SAR image (e.g., a Sentinel-1 image) with large ground coverage is translated into a high-resolution SAR image (e.g., a TerraSAR-X image). Three traditional algorithms are compared, and a new algorithm is proposed based on a network framework by combining conditional WGAN-GP (Wasserstein Generative Adversarial Network - Gradient Penalty) loss functions and Spatial Gram matrices under the rule of dialectics. Experimental results show that the SAR image translation works very well when we compare the results of our proposed method with the selected traditional methods.

Epstein–Barr virus (EBV) has been recently shown to be co-present with high-risk human papillomaviruses (HPVs) in human cervical cancer; thus, these oncoviruses play an important role in the initiation and/or progression of this cancer. Accordingly, our group has recently viewed the presence and genotyping distribution of high-risk HPVs in cervical cancer in Syrian women; our data pointed out that HPVs are present in 95.45% of our samples. Herein, we aim to explore the co-prevalence of EBV and high-risk HPVs in 44 cervical cancer tissues from Syrian women using polymerase chain reaction (PCR), immunohistochemistry (IHC) and tissue microarray (TMA) analyses. We found that EBV and high-risk HPVs are co-present in 15/44 (34%) of the samples. Additionally, we report that the co-expression of LMP1 and E6 genes of EBV and high-risk HPVs, respectively, is associated with poorly differentiated squamous cell carcinomas phenotype; this is accompanied by a strong and diffused Id-1 overexpression, which is an important regulator of cell invasion and metastasis. These data imply that EBV and HPVs are co-present in cervical cancer in the Middle East area including Syria and their co-presence is associated with a more aggressive cancer phenotype. Future investigations are needed to elucidate the exact role of EBV and HPVs cooperation in cervical carcinogenesis.

The Chinese drug Bombyx Batryticatus mori.L which also named as the white stiff silkworm is widely used in clinics, due to the significant antispasmodic and promotional blood circulation effects. In addition, its hypoglycemic effect is also recognized in recent years. From a pathological point of view, the enzymatic glycosylation and non-enzymatic glycation both have important roles in regulating properties of proteins and are associated with Diabetes. With the db/db mouse model, we examined the alterations of N-glycosylation of diabetic myocardium at primary stage and clarify the differences in glycosylation of myocardium before and after with 1-DNJ treatment. Hydrophilic chromatography solid phase extraction enrichment and LC-MS/MS identification was applied to profile the alternations in protein glycosylation. Meanwhile, N-glycan α1, 6-fucosylation alterations were profiled with LCA lectin blot and FITC-labelled lectin affinity histochemistry. Our results showed that AGES, hydroxyproline, CTGF and other serum indicators and fibrosis related cytokines expressional levels were reduced significantly by 1-DNJ in a dose-dependent manner. In order to verify this result, the well-known pathway of TGF-β/smad2/3 was picked out and α1, 6-core fucosylated TGFR-βⅡwas semi-quantified with western blot method. The result sustained the conclusion from LCA lectin affinity histochemistry and lectin blot analysis. The expressional level of α1, 6-fucosyltransferase mRNA was increased in the myocardium of db/db mice, however, the 1-DNJ administration did not show obvious inhibitory effect on FU8 expression. This unexpected result can be interpreted as 1-DNJ plays the roles by reducing the concentration of substrate rather than inhibiting α1，6-fucose glycosyltransferase expression. Meanwhile, 1-DNJ crude extract from BBm with some flavonoids accompany can also play the roles of anti-oxidant, and all the chemicals protect the diabetic myocardium from hyperglycemia damage commonly.

Aims: To study the effects of pyridoxal phosphate (PLP) on oxidative stress in isolated pancreatic acinar cells. We have previously shown that PLP has cytoprotective and insulinotropic effects on mice islet cells in vivo and in vitro studies. Main methods: Acinar cells were isolated from three months old WNIN male rats and were cultured in vitro for a period of 24 h in CO₂ incubator. Later the cells were divided into four groups as untreated (group 1), H₂O₂ treatment (group 2)_, PLP treatment (group 3) and PLP followed by H₂O₂ treatment (group 4). Cell viability was confirmed using MTT assays, oxidative stress levels were measured with ROS assay, change in different protein levels were recorded by flow cytometry. The acinar cells insulin secretion assay was performed with ELISA. The amylase protein expression was assessed using confocal microscopy. Key findings: The cell viability of acinar cell in group 1 was considered as 100%, while in group 2 it was reduced to 82% due to H₂O₂ effect, and in group 3 (99.8%) and group 4 (99.5%) were near to group 1 due to the cytoprotective effect of PLP. The ROS levels were increased by 1.47 folds in group 2, while PLP decreased to 1.02 fold in group 4, which was comparable with the changes in group 1. Beneficial effects of PLP were also observed from the increased expression levels of acinar cells are amylase -2.01, neurogenin-3-9.51, PDX-1- 23.6 and insulin-13.5 in group 3 compared to group 1. The specificity of PLP’s response was confirmed by amino oxy acetic acid (AOAA), a specific PLP inhibitor. The increased amylase protein localization with PLP was confirmed by confocal microscopy. Insulin secretion efficiency of acinar cells was observed to be 6.13 folds higher at basal and 24.63 fold higher at stimulated levels in group3 compared to group1. Significance: Our results advocate the antioxidant and cytoprotective effects of PLP on the pancreatic acinar cell along with increased pancreatic marker expressions of amylase,PDX-1, neurogenin-3 and insulin proteins.

Background: The prognostic and predictive role of stromal tumor-infiltrating lymphocytes (sTILs) is undetermined in pleomorphic invasive lobular cancer (pILC). The same applies for the expression of PD-1/PD-L1 in this rare breast cancer subtype. Here, we aimed to investigate the expression of sTILs, and analyze the PD-L1 expression levels in pILC. Methods: Archival tissues from sixty-six patients with pILC were collected. The sTIL density was scored as a percentage of tumor area, using the following cut-offs: 0%; <5%; 5-9%; and 10-50%. PD-L1 expression was analyzed using IHC on formalin-fixed, paraffin-embedded tissue sections, using the SP142 and 22C3 antibodies. Results: 82% of the sixty-six patients were hormone receptor-positive; 8% of cases were triple negative (TN), while 10% showed human epidermal growth factor receptor 2 (HER2) amplification. sTILs were present in 64% (1%) of the study population. Using the SP142 antibody, 36% of tumors demonstrated a positive PD-L1 score of 1%, and 28% had a positive PD-L1 score of 1 using the 22C3 antibody. There was no correlation of sTILs or PD-L1 expression with tumor size, tumor grade, nodal status, expression of estrogen receptor (ER) or amplification of HER2. Our data did not show any difference in survival between the three molecular subtypes of pILC with respect to sTILs and PD-L1 expression. Conclusion: This study shows that pILCs show some degree of sTILs and PD-L1 expression, however this was not associated with survival benefit. Additional large trials are needed to understand the immune infiltration in lobular cancer, even more in the pleomorphic subtype.

Bovine respiratory disease (BRD) is a major health problem within the global cattle industry. This disease has a complex aetiology, with viruses playing an integral role. In this study, metagenomics was used to sequence viral nucleic acids in the nasal swabs of BRD affected cattle. Viruses detected included those well known for their association with BRD in Australia (bovine viral diarrhea virus 1), as well as viruses known to be present but not fully characterised (bovine coronavirus) and viruses that have not been reported in BRD affect cattle in Australia (bovine rhinitis, bovine influenza D, and bovine nidovirus). Nasal swabs from a case control study were subsequently tested for 10 viruses and the presence of at least one virus was found to be significantly associated with BRD. Some of the more recently detected viruses had inconsistent association with BRD. Full genome sequences for bovine coronavirus, a virus increasingly associated with BRD, and bovine nidovirus were complete. Both viruses belong to the Coronaviridae family, which are frequently associated with disease in mammals. This study has provided greater insights into the viral pathogens associated with BRD and highlighted the need for further studies to elucidate more precisely the roles viruses play in BRD.

The endocannabinoid signalling system (ECS) plays a critical role from the very beginning of embryogenesis. Accordingly, the ECS is engaged early-on in nervous system development, starting from neurulation, supported by the identification of ECS components - both receptors and enzymes controlling endocannabinoid metabolism – at these early stages. In particular, regarding the brain, the ECS is involved in the tightly regulated sequence of events that comprise brain development, from neurogenesis to neuronal migration, morphological guidance for neuronal connectivity, and synaptic circuitry refinement. The importance of this broad role of the ECS across various brain development processes is further underscored by the growing understanding of the consequences of cannabis exposure at different developmental stages. Despite the considerable knowledge we have on the role of the ECS in brain development, significant gaps in our understanding remain, particularly regarding the long-term impact and underlying mechanisms of cannabis exposure at different developmental stages. This review provides an overview of the current state of knowledge on the role of the ECS throughout brain development, from embryogenesis to adulthood, and discusses the impact of cannabis exposure, especially during adolescence—a critical period of circuitry maturation and refinement coinciding with an increased risk of cannabis use.

Looking for effective synthetic methods for 1H-pyrazolo[3,4-b]quinolines preparation, we came across a procedure where in a three component reaction catalyzed by L-proline, 4-aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines are formed. These compounds can be easily oxidized to a fully aromatic system, which gave hope for a synthetic method that could replace e.g. Friedländer condensation, often used for this purpose, although severely limited by the availability of suitable substrates. However, after careful repetition of the procedures described in the publication, it turned out that the compounds described therein do not form at all. The actual compounds turned out to be 4,4-(phenylmethylene)-bis-(3-methyl-1-phenylpyrazol-5-oles). 4-Aryl-4,9-dihydro-1H-pyrazolo[3,4-b]quinolines were prepared by another method and used as standards to compare the products formed in the original procedure.

In 1937,German mathematician L.Collatz proposed a conjeture:for any positive integer,if it is even,divide it by 2;if it is odd,multiply it by 3 and 1 to get an even number;keep going on and on, the final result is 1.This paper gives a sequence classification of odd numbers,and gives 1-1 mapping of odd numbers and odd number sequences,and uses these results to give a proof of this conjecture.

Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as therapeutic sources in several degenerative diseases. Recently, microRNAs (miRNAs) were mediated one of the therapeutic mechanisms of PD-MSCs in regenerative medicine. To enhance the therapeutic effects of PD-MSCs, we established functionally enhanced PD-MSCs with phosphatase of regenerating liver-1 overexpression (PRL-1(+)). However, the profile and functions of miRNAs induced by PRL-1(+) PD-MSCs in a rat model with hepatic failure prepared by bile duct ligation (BDL) remained unclear. Hence, the objectives of the present study were to analyze the expression of miRNAs and investigate their therapeutic mechanisms for hepatic regeneration via PRL-1(+) in a rat model with BDL. We selected candidate miRNAs based on microarray analysis. Under hypoxic conditions, compared with invaded naïve PD-MSCs, invaded PRL-1(+) PD-MSCs showed improved integrin-dependent migration ability through RHO family-targeted miRNA expression (e.g., hsa-miR-30a-5p, 340-5p, and 146a-3p). Moreover, rno-miR-30a-5p and 340-5p regulated engraftment into injured rat liver by transplanted PRL-1(+) PD-MSCs through the integrin family. Additionally, an increase in PDGFRA by suppressing rno-miR-27a-3p improved vascular structure in rat liver tissues after PRL-1(+) PD-MSCs transplantation. Furthermore, decreased rno-miR-122-5p was significantly correlated with increased proliferation of hepatocytes in liver tissues by PRL-1(+) PD-MSCs by activating IL-6 signaling pathway through the repression of rno-miR-21-5p. Taken together, these findings improve the understanding of therapeutic mechanisms based on miRNA-mediated stem cell therapy in liver diseases.

C-C motif chemokine ligand 2 (CCL2), also called monocyte chemoattractant protein-1 (MCP-1) is a key β-chemokine involved in the migration of monocytes and macrophages, playing a significant role in the inflammatory responses in the airways. We aimed to assess the serum levels of MCP-1/CCL2 in a pilot cross-sectional study of Bulgarian children with bronchial asthma (BA) and cystic fibrosis (CF). Forty-two children were recruited to the study as follows: twenty with BA, twelve with CF and ten healthy children. Serum MCP-1/CCL2 levels were measured using ELISA. We found higher serum level of MCP-1/CCL2 in children with BA (191.09±64.96 pg/ml) and CF (258.51±76.45 pg/ml) compared to healthy children (70.30±64.30 pg/ml, p=0.022, and p=0.068, respectively). Younger patients with BA had higher levels of MCP-1/CCL2, as well as children with CF, with levels decreasing gradually with age. We observed also higher levels of MCP-1/CCL2 in children with moderate to severe BA compared to mild BA. We documented the significantly higher level of MCP-1/CCL2 in children with these chronic pulmonary diseases than in healthy controls, which suggesting that investigation of serum MCP-1/CCL2 levels could turn out to be beneficial for the severity of the disease.

Soil water balance (SWB) in woody crops is sometimes difficult to estimate with one-dimensional models because these crops do not completely cover the soil and usually have a deep root system, particularly when cropped under rainfed conditions in a Mediterranean climate. In this study, the actual crop evapotranspiration (ETc act) is estimated with the soil water balance model SIMDualKc which uses the dual-Kc approach (relating the fraction of soil cover with the crop coefficients) to improve the estimation of the water requirements of a rainfed vineyard, using data from a deep soil profile. The actual basal crop coefficient (Kcb act) obtained using the SIMDualKc model was compared with the Kcb act estimated using the A&amp;P approach, which is a simplified approach based on measurements of the fraction of ground cover and crop height. Spectral vegetation indices derived from Landsat-5 satellite data were used to determine the fraction of ground cover (fc VI) and thus, the density coefficient (Kd). The SIMDualKc model was calibrated using soil water content (SWC) measurements down to a depth of 1.85 meters, which significantly improved the conditions for using a SWB estimation model. The test of the model was performed using a different SWC dataset. A good agreement between simulated and field measured SWC was observed for both data sets along the crop season, with RMSE&lt;12.0 mm, NRMSE &lt;13%. The calibrated Kcb values were 0.15, 0.60 and 0.52 for the initial, mid-season, and end season, respectively. The ratio between actual (ETc act) and crop evapotranspiration (ETc) was quite low between veraison and maturity (mid-season), corresponding to 36%, indicating that the rainfall was not sufficient to satisfy the vineyards water requirements. Spectral vegetation indices used to compute fc VI were unable to fully track the plants’ conditions when water stress. However, ingestion of data from remote sensing showed promising results that could be used to support decisions making in irrigation scheduling. Further studies on the use of the A&amp;P approach using remote sensing data are required.

Photovoltaic materials convert light into electrical voltages. So far, most research in the field are focused on how to refine/improve the existing or standard photovoltaic cells to yield more efficient electricity, to reduce weight, to make more flexible shape, or to minimize costs under standard and uniform sunlight illuminations. In this project, we explore and demonstrate a hypothesis that non-uniform light illumination photovoltages can also be generated due to photo doping induced mobile charge carrier density gradient between light and dark areas in either p-type or n-type photo doping semiconductors. The term non-uniform light illumination was coined to refer to subjecting our photo sensing thin film devices to areas of high and low intensities of light illumination simultaneously, with an intention of creating a charge density gradient and therefore a voltage. Specifically, a polymeric composite thin film composed of P3HT (p-type photo doping semiconductor) and PCBM (photo doping electron acceptor and trap) at varying p-doping levels were studied. We observed that the fabricated photovoltaic cells with about 80% PCBM doped P3HT thin film devices exhibited 0.5-1.2 volts photovoltages under non-uniform light illuminations.

Background. ADHD is a neurodevelopmental disorder that is accompanied by executive deficits. Objectives. To obtain evidence of the usefulness of the BRIEF-P and to analyse the possible ceiling and floor effect of its scores in the assessment of executive function in preschoolers with signs compatible with a possible diagnosis of ADHD. Methods. Seven articles were selected from 2538 potentially eligible articles from different databases. We included studies assessing samples of individuals with symptoms compatible with ADHD, with age range 2-6 years, published in English or Spanish, during the period 2012-2022. References published in: Science Direct, NCBI (PubMed), ProQuest Education Journals in the last decade. Risk of bias was assessed using the QUADAS-2 questionnaire. The main variables were: age and executive functioning. Conclusions. Executive deficits in early-life individuals with ADHD-compatible symptoms are more extensive than deficits in working memory. BRIEF-P is an instrument that facilitates obtaining a sensitive and discriminative executive profile. It should be used in combination with other neuropsychological performance tests, finding a floor effect in tests associated with warm executive functions and a ceiling effect in cold executive functions. This requires using a variety of tests to assess executive performance in preschoolers with symptoms compatible with ADHD and designing intervention proposals in line with them...

Neuroinflammation is considered to be a significant component in a range of neuropathologies. Unfortunately, whilst its role is well recognized, the options for therapeutic intervention are limited. As such, there is a need to identify novel targets in order to increase treatment options. Given its role as both a neurotransmitter and an immune modulator, substance P and its NK1 receptor have been widely studied as a potential therapeutic target. There is evidence that NK1 receptor antagonists may exert beneficial effects in a range of conditions, including traumatic brain injury and stroke. Blocking the NK1 receptor has been shown to reduce blood-brain barrier dysfunction, reduce cerebral oedema, and reduce the levels of pro-inflammatory cytokines. These actions are associated with improved survival and functional outcomes. The NK1 receptor has also been shown to be involved in the inflammatory reaction to CNS infection, and hence antagonist may have some benefit in reducing infection-driven inflammation. However, the NK1 receptor may also play a role in the host immune response to infection, and so here, the potential beneficial and detrimental effects need to be carefully balanced. As such, the purpose of this review is to provide a summary of the involvement of substance P in acute inflammation, particularly in the context of traumatic brain injury and stroke.

Films prepared from poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymers produced by Aneurinibacillus sp. H1 using an automatic film applicator were homogeneous and had a defined thickness, which allowed a detailed study of physicochemical properties. Their properties were compared with a poly (3-hydroxybutyrate) homopolymer film prepared by the same procedure, which proved to be significantly more crystalline by DSC and XRD. Structural differences between samples had a major impact on their properties. With increasing 4-hydroxybutyrate content, the ductility and release rate of the model hydrophilic active ingredient increased significantly. Other observed properties, such as the release of the hydrophobic active substance, the contact angle with water and ethylene glycol, or the surface morphology and roughness, were also affected by the composition. The identified properties predetermine these copolymers for wide use in areas such as biomedicine or smart biodegradable packaging for food or cosmetics. The big advantage is the possibility of fine-tuning properties simply by changing the fermentation conditions.

It is unclear how important it is to reduce fluoroquinolone consumption in the general population to prevent the spread of fluoroquinolone resistance in Neisseria gonorrhoeae (bystander selection). Methods We assessed bystander selection by using Spearman’s correlation to assess if the country-level prevalence of fluoroquinolone resistance in N. gonorrhoeae was correlated with the prevalence of fluoroquinolone resistance in four other gram-negative species - Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Results Fluoroquinolone resistance in N. gonorrhoeae was positively associated with homologous resistance in all 4 species - A. baumanii. (ρ=0.61, P=0.0003, E. coli (ρ=0.67, P<0.0001), K. pneumoniae (ρ=0.52, P=0.0004) and P. aeruginosa (ρ=0.40, P=0.0206). Positive associations were also found between the national prevalence of fluoroquinolone resistance and fluoroquinolone consumption in the general population in the preceding year for 4 of the 5 species. Conclusions Gonococcal fluoroquinolone resistance can be productively viewed as being part of a syndemic of fluoroquinolone resistance. Strengthening antimicrobial stewardship programs may help retard the spread of fluoroquinolone resistance in N. gonorrhoeae.

Dendrobium okinawense is an endangered epiphytic orchid, and there has been no scientific report so far on its propagation. Protocorm is mass of cell, and protocorm-like bodies (PLBs) look alike protocorm produced by vegetative explants in vitro. Regeneration of PLBs is the most efficient technique for the orchids micro-propagation. We used different light emitting diodes (LEDs) for the efficient PLB organogenesis of D. okinawense. PLBs regenartion under green and red LED surpassed respectively 81.1% and 71.6% in numbers, and respectively 80.8% and 57.8% in fresh weight over white fluorescent light. We manipulated the culture media by different concentrations of PCIB and HMI. PLBs organogenesis promoted by low concentration, it increased respectively 35.9% and 19.3% over control by 0.01 mg/L PCIB and 0.01 ml/L HMI in numbers. Green LED and PCIB independently produced mostly similar numbers of new PLBs. Interestingly, culture media with 0.01 mg/L of PCIB further increased 8.5% of the numbers of PLBs under green LED, whereas the culture media with 0.01 mg/L HMI reduced the number of PLBs under green LED. PLBs culture under green LED with very low concentrations of PCIB manipulated culture media can significantly increase their organogenesis of D. okinawense.

The circuitry of the summarized "floating" differential stages (FDS) based on complementary field-effect transistors with a control p-n junction (CJFET), intended for use in low-noise analog microcircuits, for example, operational amplifiers. The results of modeling the flow characteristics of one of the CJFET FDSs in the LTSpice XVII environment at low temperatures (down to -197 ⁰С) and exposure to a neutron flux in the range of 1e13 ÷ 1e15 n / cm² are presented.

The article introduces a new solution approach to grid-connected single-stage three-phase PV inverter whereby a dc-link voltage can successfully achieve the desired performance. As a single-stage, the variable output of perturb and observe maximum power point tracking (P&O based-MPPT) is fully utilized as dc-link voltage reference in inverter control scheme. As a result, it is challenging for the dc-link voltage to preserve energy balance by tracking its variable dc-link voltage reference under unpredictable environmental changes. To overcome this challenge, an adaptive reference proportional-integral (ARPI) controller, self-tuning, is designed and implemented to compel the dc-link voltage tracking its voltage reference to be equal as closely as possible; hence, the capability of the dc-link under abnormal events substantially guarantees the best energy balance and transient performance enhancement. To verify the validity of the method, simulation results for multiple events scenarios on 250 KW single-stage grid-connected PV systems show the effectiveness of the ARPI controller compared with PI controller.

Quorum Sensing (QS) and Machine Learning (ML) hybrid systems represent a groundbreaking innovation in synthetic biology, offering unprecedented control and adaptability in microbial gene regulation and metabolic processes. QS, a microbial communication mechanism, is crucial for coordinating gene expression in response to population density, impacting behaviors such as biofilm formation, virulence, and resource optimization. However, traditional QS systems are constrained by their reliance on static, pre-programmed feedback loops, limiting their flexibility in dynamic, complex environments. This review highlights how integrating advanced ML algorithms—such as reinforcement learning and deep learning—into QS systems can overcome these limitations by enabling real-time data processing, predictive modeling, and dynamic feedback control. Through these innovations, QS-ML systems can autonomously adjust gene expression and metabolic outputs, making them more efficient and scalable in applications ranging from pathogen control to precision medicine and industrial biomanufacturing. Key case studies illustrate the successful deployment of QS-ML systems to combat antimicrobial resistance, optimize bio-production, and enhance therapeutic precision in cancer and immune modulation. Despite the clear advantages, challenges remain in data integration, system robustness, and regulatory oversight. Addressing these hurdles through interdisciplinary collaboration and developing scalable, multi-omics data platforms will be critical for advancing QS-ML systems from experimental settings to real-world applications. This review underscores the transformative potential of QS-ML systems in revolutionizing synthetic biology, with profound implications for personalized medicine, sustainable biomanufacturing, and environmental health.Quorum Sensing (QS) and Machine Learning (ML) hybrid systems represent a groundbreaking innovation in synthetic biology, offering unprecedented control and adaptability in microbial gene regulation and metabolic processes. QS, a microbial communication mechanism, is crucial for coordinating gene expression in response to population density, impacting behaviors such as biofilm formation, virulence, and resource optimization. However, traditional QS systems are constrained by their reliance on static, pre-programmed feedback loops, limiting their flexibility in dynamic, complex environments. This review highlights how integrating advanced ML algorithms—such as reinforcement learning and deep learning—into QS systems can overcome these limitations by enabling real-time data processing, predictive modeling, and dynamic feedback control. Through these innovations, QS-ML systems can autonomously adjust gene expression and metabolic outputs, making them more efficient and scalable in applications ranging from pathogen control to precision medicine and industrial biomanufacturing. Key case studies illustrate the successful deployment of QS-ML systems to combat antimicrobial resistance, optimize bio-production, and enhance therapeutic precision in cancer and immune modulation. Despite the clear advantages, challenges remain in data integration, system robustness, and regulatory oversight. Addressing these hurdles through interdisciplinary collaboration and developing scalable, multi-omics data platforms will be critical for advancing QS-ML systems from experimental settings to real-world applications. This review underscores the transformative potential of QS-ML systems in revolutionizing synthetic biology, with profound implications for personalized medicine, sustainable biomanufacturing, and environmental health.

Background and Objectives: To evaluate the diagnostic accuracy of widely available biomarkers longitudinally measured throughout pregnancy to predict all and term (delivery at ≥ 37 weeks) preeclampsia (PE). Materials and Methods: This is a retrospective study performed at Hospital Universitario de Torrejón (Madrid, Spain) and Shterev Hospital (Sofia, Bulgaria) between August 2017 and December 2022. All pregnant women with singleton pregnancies and non-malformed live fetuses attending their routine ultrasound examination and first-trimester screening for preterm PE at 11+0 to 13+6 weeks' gestation at the participating centers were invited to participate in a larger study for the prediction of pregnancy complications. The dataset was divided into two subsets to develop and validate a joint model of time-to-event outcome and longitudinal data, and to evaluate how the area under the receiving operating characteristic curve (AUROC) evolved with time. Results: 4056 pregnancies were included in the training set (59 all PE, 40 term PE) and 944 in the validation set (23 all PE, 20 term PE). For the joint model and all PE, the AUROC was 0.84 (95% CI 0.73 to 0.94) and the detection rate (DR) for a 10% screening positive rate (SPR) was 56.5 (95% CI 34.5 to 76.8). For term PE, AUROC was 0.80 (95% CI 0.69 to 0.91), and DR for a 10% SPR was 55.0 (95% CI 31.5 to 76.9). The AUROC using only information from the first trimester was 0.50 (95% CI 0.37 to 0.64) and it increased up to 0.84 (0.73 to 0.94) when using all information available. Conclusions: Routinely measuring MAP and UtA-PI throughout pregnancy may improve the predictive prediction power for all and term-PE.

Background/Objectives: Type 1 Diabetes Mellitus (T1DM) is the reduction or non-production of insulin. As T1DM increases cardiovascular risk, in addition to glycemic control, the monitoring of other risk factors, such as lipid profile, has gained attention. Vitamin D deficiency has been associated with the pathophysiology of T1DM, metabolic syndrome, and cardiovascular diseases. This study investigated the relationship between vitamin D, glycemic control, and lipid profiles in children and adolescents with T1DM. Methods: This observational study consisted of 81 patients with T1DM. Laboratory test data were collected to determine the lipid profile. Glycated hemoglobin (HbA1c) and fasting glucose levels assessed glycemic control. Results: A significant association was observed between serum vitamin D levels and a pubertal stage and a moderate negative correlation between vitamin D, age, and HbA1c. There is a negative correlation between vitamin D levels and age, as well as with HbA1c, and a positive correlation of HbA1c with glucose, total cholesterol, triglycerides, Low-density lipoprotein (LDL-c), non-HDL cholesterol (non-HDL cholesterol), apolipoprotein B (apoB), and the apolipoprotein B/apolipoprotein A ratio. Finally, the study indicated that vitamin D levels, insulin administration method, and total cholesterol, when considered together, explained approximately 43.6% of the observed variation in HbA1c, highlighting the complex interdependence of these factors in regulating glycemia. Conclusions: Our results show that Vitamin D levels are associated with glycemic control and other biochemical parameters and its control can bring benefits to the patient with T1DM.

Water mapping for satellite imagery has been an active research field for many applications, 1 in particular natural disaster such as flood. Synthetic Aperture Radar (SAR) provides high-resolution 2 imagery without constraint on weather conditions. Single-date SAR approach is less accurate than 3 multi-temporal but can produce results more promptly. This paper proposes novel segmentation 4 schemes that are designed to process both a target superpixel and its surrounding ones for the 5 input for machine learning. We devise MISP-SDT/XGB schemes to generate, annotate, and classify 6 superpixels, and perform land/water segmentation of SAR imagery. These schemes are applied to 7 Sentinel-1 SAR data to examine segmentation performances. Introducing single/mask/neighborhood 8 models in the MISP-SDT scheme and single/neighborhood models in the MISP-XGB, we assess the 9 effects of the contextual information about target and its neighbor superpixels on its segmentation 10 performances. As to polarization, it is shown that the VH mode produces more encouraging results 11 than the VV, which is consistent with previous studies. Also, under our MISP-SDT/XGP schemes 12 the neighborhood models show better performances than FCNN models. Overall, the neighborhood 13 model gives better performances than the single model. Results from attention maps and feature 14 importance scores show that neighbor regions are looked at or used by the algorithms in the neighbor- 15 hood models. Our findings suggest that under our schemes the contextual information has positive 16 effects on land/water segmentation.

This study presents an optimized design for a Segmented Sinusoidal Parameter Winding with Magnetic Wedge Variable Reluctance Resolver (SSPWMW-VRR), addressing challenges like winding asymmetry and harmonic distortion in conventional designs. By integrating Particle Swarm Optimization (PSO) for winding design, Magnetic Equivalent Circuit (MEC) analysis for leakage flux, and machine learning techniques (XGBoost and Multi-Layer Perceptron), the stator slot shape was fine-tuned for improved accuracy. XGBoost outperformed MLP in prediction accuracy with a Mean Absolute Error (MAE) of 0.1172. Finite Element Analysis (FEA) simulations and experimental validation demonstrated a reduction in position errors from ±30’ in conventional VRRs to ±5’ in the optimized design, along with significant harmonic reduction.

Background: Adverse pregnancy outcomes correlate with blood glucose levels in women with type 1 diabetes. There is a gap between glycaemic targets and blood glucose control achieved in pregnancy. Aims: To investigate the impact of an intensive weekly service on glycaemic control compared with our previous care model in pregnancies affected by type 1 diabetes. Materials and Methods: This is a retrospective cross-sectional pre / post study comparing measures of glycaemic control in women with type 1 diabetes at each trimester of pregnancy, in the 12 months before and the 8 months after the commencement of an intensive weekly insulin stabilisation service (ISS). Results: The study utilised data from Dexcom continuous glucose monitoring (CGM) reports for analysis of pregnancy-specific glycaemic data (incorporating time in range 3.5-7.8 mmol/L). 16 women provided data for 35 trimesters pre ISS and 17 women provided data for 38 trimesters post ISS. There was an improvement in pregnancy-specific time-in-range for trimester 3 following the commencement of an intensive weekly insulin stabilization service (mean pre 49.6%, post 61.4%, p=0.042). Similar results were seen when women using hybrid closed loop technology were excluded, albeit not then reaching statistical significance. It was not possible to assess the effect of the intervention on the first trimester. There were no statistically significant changes in glycaemia for trimester 2. Conclusions: In a small group of pregnant women with type 1 diabetes, improvement in pregnancy specific time-in-range occurred in trimester 3, but not in trimester 1 or 2, following the introduction of intensive weekly clinical support.