The inaugural AIDS Program in Brazil was established in São Paulo in 1983, with the Instituto Adolfo Lutz appointed for laboratory assistance. Subsequently, research on HIV infections and HIV/HTLV (HIV/HTLV-1 and HIV/HTLV-2) co-infections were conducted. This narrative review focuses on studies from the Immunology Department (1983–2017) that significantly influenced AIDS diagnosis or provided epidemiological data such as prevalence rates, sex, age, and risk factors. Ten studies, encompassing over 8,000 individuals, are discussed. During 1983–1985, nearly all AIDS cases were attributed to homosexual/bisexual men aged 31 years old. Subsequently, heterosexual men and women emerged as risk groups owing to intravenous drug use (IDU) and/or unprotected sexual intercourse with AIDS patients or multiple partners per year. From 1985 onwards, vertical transmission led to child infections. HIV/HTLV co-infection rates decreased over time, initially associated with male IDU, and in the 2010s, with females, IDU, and individuals aged >40 years. Trends in HIV and HIV/HTLV co-infections among younger men and women (<30 years of age) were observed from 2015–2017. The changing characteristics and risk groups for HIV and HIV/HTLV co-infections over the years underscore the necessity for ongoing public policies to prevent retrovirus transmission, particularly among adolescents and young adults.

Foxtail millet (Setaria italica (L.) P. Beauv) is an important food and forage crop that is well adapted to nutrient-poor soils. However, little is known about how foxtail millet adapts to low nitrogen (LN) at the physiological and molecular levels. In the present study, two foxtail millet varieties with contrasting low nitrogen (LN) tolerance properties were investigated through integrative analyses of physiological featureparameters and transcriptomics. The physiological results showed that JG20 (high tolerance to LN) had higher biomass accumulation, nitrogen content and nitrogen use efficiency compared with JG22 (low tolerancesensitive to LN) under LN. JG20 had higher soluble sugar and soluble protein concentration in shoots compared with JG22 under LN, while contcentrations of soluble sugar and soluble protein contents were higher in the roots of JG22. Higher levels of CTK contentzeatin concentration were found in the shoots of JG20 com-pared with JG22, and a higher ABA contcentration was found in both the shoots and roots of JG22 compared with JG20 under LN. In the transcriptomics results, JG20 had more differentially ex-pressed genes (DEGs) than JG22 both in shoots and roots in response to LN. These LN-responsive genes were enriched in glycolysis, starch and sucrose metabolism, photosynthesis, biosynthesis of amino acids, hormone metabolism and nitrogen metabolism. Furthermore, the high-affinity nitrate transporter gene, SiNRT2.1, and glutamine synthetase gene, SiGS5, chlorophyll apoprotein of photosystem II gene, SiPsbQ, ATP synthase subunit gene, b, auxin-responsive protein gene, SiIAA25, and aldose 1-epimerase gene, SiAEP, in shoots, and high-affinity nitrate transporter gene, SiNRT2.3, SiNRT2.4, and glutamate synthase gene, SiGOGAT2, auxin-responsive protein gene, SiIAA4, fructose-bisphosphate aldolase gene, SiAEP5, in root, were important genes in-volved in the LN tolerance of foxtail millet. These results provide a detailed description of the physiological and transcriptome response of foxtail millet under LN condition.

Wetlands benefits can be summarized but are not limited to their ability to store floodwaters and improve water quality, providing habitats for wildlife and supporting biodiversity, as well as aesthetic values. Over the past few decades, remote sensing and geographical information technologies has proven to be a useful and frequent applications in monitoring and mapping wetlands. Combining both optical and microwave satellite data can give significant information about the biophysical characteristics of wetlands and wetlands` vegetation. Also, fusing data from different sensors, such as radar and optical remote sensing data, can increase the wetland classification accuracy. In this paper we investigate the ability of fusion two fine spatial resolution satellite data, Sentinel-2 and the Synthetic Aperture Radar Satellite, Sentinel-1, for mapping wetlands. As a study area in this paper, Balikdami wetland located in the Anatolian part of Turkey has been selected. Both Sentinel-1 and Sentinel-2 images require pre-processing before their use. After the pre-processing, several vegetation indices calculated from the Sentinel-2 bands were included in the data set. Furthermore, an object-based classification was performed. For the accuracy assessment of the obtained results, number of random points were added over the study area. In addition, the results were compared with data from Unmanned Aerial Vehicle collected on the same data of the overpass of the Sentinel-2, and three days before the overpass of Sentinel-1 satellite. The accuracy assessment showed that the results significant and satisfying in the wetland classification using both multispectral and microwave data. The statistical results of the fusion of the optical and radar data showed high wetland mapping accuracy, with an overall classification accuracy of approximately 90% in the object-based classification. Compared with the high resolution UAV data, the classification results give promising results for mapping and monitoring not just wetlands, but also the sub-classes of the study area. For future research, multi-temporal image use and terrain data collection are recommended.

Japanese pepper (sansho, Zanthoxylum piperitum) contains several types of sanshools belonging to N-alkylamides. Because of long-chain unsaturated fatty acids present in their structure, sanshools are prone to oxidative deterioration, which poses problems in processing. Here, we evaluated the effects of antioxidants from the genus Zanthoxylum in preventing sanshool degradation using accelerated tests. An ethanolic extract of segment membranes of the sansho fruit pericarp was incubated at 70 °C for 7 days with different antioxidants to determine the residual amount of hydroxy-α-sanshool (HαS) in the extract. α-Tocopherol (α-Toc) showed excellent HαS-stabilizing activity at low concentrations. Among phenolic acids, we noted that the HαS-stabilizing activity increased with the number of hydroxy groups per molecule. For example, gallic acid and its derivatives exhibited excellent sanshool-stabilizing activity. Quercetin was found to be a superior HαS stabilizer compared with hesperetin and naringenin. However, the effective concentration was much higher for phenolic compounds than for α-Toc. These substances are believed to play a role in preventing the decomposition of sanshools in the pericarp of sansho. These sanshool stabilizers should be useful in the development of new beverages, foods, cosmetics, and pharmaceuticals that take advantage of the taste and flavor of sansho.

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, and vacuolar ATPases. We hypothesized that additional and yet undiscovered molecular targets might be associated with Manzamine A (MZA) reported pharmacological properties. We report herein for the first time to our knowledge that MZA inhibited a 90kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases. Furthermore in vitro RSK kinase assays demonstrated a 10-fold selectivity in potency of MZA against RSK1 versus RSK2. MZA’s differential binding and selectivity toward the two isoforms is also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes including growth, survival and proliferation. Consequently, our findings have lead us to hypothesize that MZA and the 80 currently known manzamine-type alkaloids isolated from several sponge genera, may have novel pharmacological properties.

Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2. This study investigated the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. We used cell-to-cell fusion assays in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increases cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduces cell-to-cell fusion by promoting the cellular degradation of ACE2. Metalloprotease activation is sensitive to enhanced cholesterol levels resulting from SKI-1-activated SREBP-2 that leads to enhanced S2’ formation. However, high metalloprotease activity results in S2’ shedding into a new C-terminal fragment (S2”), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2’’ formation, abolish S2’ and cell-to-cell fusion, as well as pseudoparticles entry, indicating that the formation of S2’’ prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested binding of ACE2 to the Pro/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms.

This paper outlines the evolution of a learning technology interface from a Beta version to launch with educators and its alignment to pedagogical theory, designed to maximise collaboration between teacher and student. It explores how the “co-creation” of curricula via textual sources that underpin teaching and learning can be enhanced through interactive e-books and outlines the challenges involved in this praxis. With a number of stakeholders involved in the live use of the platform (including teachers, students, HE educators, course instructors, curriculum designers and software developers), iterative feedback loops informed real-time design improvements to both the interface and the-ory. This collaboration utilised a design-based research (DBR) approach (Wang and Hannafin, 2005), which is outlined here as explanation of how the tool developed and how iterative feedback helped to reconsider the challenges educators face in implementing pedagogical innovation across differing contexts. We propose how speculative design (Lukens and DiSalvo, 2012) and Activity Theory (Engeström, 1987) workshops can methodologically enhance the planning and evaluation phases inherent to DBR approaches, which involve students to prepare for educators’ innovation. Finally, we conclude with how educators can utilise these design principles using stratified approaches to help prepare organisational approaches for innovation.

The extensive use of carrier-aided smoothing code (CSC) filter has led to reduce the noise level of raw code measurements in GNSS positioning and navigation applications. However, the existing CSC technique is sensitive to the changes of the integer ambiguity and then the smoothing proce-dure needs to be restarted in the presence of cycle-slips. As the Doppler shift is instantaneous ob-servation and immune to cycle-slips, Doppler-aided smoothing code (DSC) algorithm would be more promising in challenged environment. Based on the Hatch-filter, an optimal DSC approach is proposed with the principle of minimum variance. Meanwhile, to inhibit the effect of integral cumulative error of Doppler, a balance factor is adopted to adjust the contributions of raw code and DSC. The noise level of code observable is not only affected by thermal noise, but also limited by systematic bias. Satellite code bias (SCB) has been identified in the raw code observable on each frequency for each BDS-2 satellite. By minimizing the sum of absolute value of residuals, polyno-mial segment fitting algorithm as a function of elevation-angles is applied to establish the SCB cor-rection model based on epoch-differenced Multipath (MP) deviations. Finally, numerical experi-ments demonstrate the validity and efficiency of the refined DSC filter with SCB corrections on each available frequency for BDS-2 un-GEO satellites.

The 32CA reactions of a series of pairs of bent three-atom-components (B-TACs) and linear TACs (L-TACs) towards electrophilic dicyanoethylene (DCE) have been studied within the Molecular Electron Density Theory in order to understand their different reactivity. ELF analysis indicates that while pseudodiradical B-TACs change their electronic structure to pseudoradical or carbenoid L-TACs upon dehydrogenation, zwitterionic B-TACs experience no remarkable change. Analysis of the CDFT indices indicates that five of the nine studied TACs have a strong nucleophilic character, thus participating in polar reactions towards electrophilic ethylenes. The activation energies of the 32CA reactions of the nine TACs towards electrophilic DCE range from 0.6 to 22.0 kcal·mol-1, which are by between 2.0 and 10.1 kcal·mol-1 lower than those involved in the non-polar 32CA reactions with ethylene. In general, B-TACs are more reactive than their L-TAC counterparts. A change of the regioselectivity is found in these polar 32CA reactions; in general, while B-TACs are meta regioselective, L-TACs are ortho regioselective. Analysis of the geometrical parameters indicates that at all TSs, the formation of the single bond involving the most electrophilic C4 carbon of DCE is more advanced than that involving the C5 one. A change of the asynchronicity in the reactions involving B-TACs and L-TACs is also found.

Li₂TiO₃ nanopowders were synthesized by hydrothermal process using anatase TiO₂ and LiOH H₂O as raw materials. Li₂TiO₃ crystallizes in the layered monoclinic structure (space group C2/c) with average crystallite size of 34 nm. Morphology, elemental composition and local structure of products were carried out using HRTEM, FESEM, EDS, Raman and FTIR spectroscopy. Transport properties investigated by d.c. (4-probe measurements) and a.c. (complex impedance spectroscopy) show the activation energy of 0.71 and 0.65 eV, respectively. The ionic transport properties of Li⁺ ions in nanocrystalline Li₂TiO₃ characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) validate the good electrochemical properties of this anode material for lithium-ion batteries.

The enhancement of Fusarium head blight (FHB) resistance is one of the best options to reduce mycotoxin contamination in wheat. This study has aimed to verify that the genotypes with high tolerance to deoxynivalenol could guarantee an overall minimization of the sanitary risk, by evaluating the contamination of regulated, modified and emerging mycotoxins on durum wheat cvs with different degrees of FHB susceptibility, grown under different meteorological condi-tions, in 8 growing seasons in North-West Italy. The years which were characterized by frequent and heavy rainfall in spring, were also those with the highest contamination of deoxynivalenol, zearalenone, moniliformin and enniatins. The most FHB resistant genotypes resulted in the lowest contamination of all the mycotoxins but showed the highest deoxyniva-lenol-3-glucoside/deoxynivalenol ratio and moniliformin/deoxynivalenol ratio. An inverse re-lationship between the amount of deoxynivalenol and the deoxyniva-lenol-3-glucoside/deoxynivalenol ratio was recorded for all the cvs and all the years. Converse-ly, the enniatins/deoxynivalenol ratio had a less intense relationship with cv tolerance to FHB. In conclusion, even though the more tolerant cvs, showed higher relative relationships between modified/emerging mycotoxins and native/target mycotoxins than the susceptible ones, they showed lower absolute levels of contamination of both emerging and modified mycotoxins.

Previous studies found high but very variable levels of tetranor-PGEM and PGD-M (urine metabolites of prostaglandin (PG) E2 and PGD2, respectively) in persons with cystic fibrosis (pwCF), which correlated with the severity of the CF transmembrane receptor (CFTR) genetic alteration. This study aims to assess the potential role of cyclooxygenase (COX)-1 and COX-2 genetic polymorphisms in the variability of PG production, and determine the potential role of PG metabolites as markers of symptoms severity and imaging findings. Thirty healthy subjects and 103 pwCF were included in the study. Clinical and radiological CF severity was evaluated using clinical scoring methods and the extent of bronchiectasis and air trapping were assessed by chest computed tomography (CT). Urine metabolites were measured using liquid chromatography/tandem mass spectrometry. The presence of variants in the COX-1 gen (PTGS1 639 C>A, PTGS1 762+14delA, and COX-2 gen: PTGS2-899G>C (-765G>C) and PTGS2 (8473T>C) were analysed. PGE-M and PGD-M urine concentrations were significantly higher in pwCF than in healthy controls. There were also statistically significant differences between clinically mild and moderate disease and severe disease. Patients with bronchiectasis and/or air trapping had higher PGE-M levels than patients without these complications. The four polymorphisms did not associate with clinical severity, air trapping, bronchiectasis, or urinary PG levels. Taken together, the present study suggests that urinary PG level testing can be used as a biomarker of CF severity. We found no relationship between COX-1 and COX-2 genetic polymorphisms in the variability of PG production.

When it is in the template RNA, the naturally occurring m¹A epitranscriptomic RNA modification was recently reported to be able to stop the RNA polymerization reaction catalyzed by the RNA dependent RNA polymerase (RdRp) of SARS-CoV-2. In this report, we report that m¹A via its triphosphate form (m¹ATP) can be incorporated into RNA by the same RdRp. These two findings point a new direction for antiviral drug development based on m¹A for combatting COVID-19. More broadly, it is possible that the large pool of epigenetic RNA as well as DNA modifications could serve as a treasury for drug discovery aimed at combating various infectious and other diseases.

Digital Elevation Model (DEM) is a representation of elevation data that represent terrain with or without overlaying objects of the Earth. It is the ideal and most widely used method for determining topography. DEMs are generated from various techniques such as traditional Surveying, Photogrammetry, InSAR, LiDAR, Clinometry and radargrammetry. It has been observed that mostly LiDAR-generated DEMs provide the best accuracy. The unavailability of LiDAR data in most of the region restricts global researchers from high-resolution and accurate DEMs. The recent launch of ICESat-2 with a 13m beam footprint and 0.7m pulse interval, promises elevations at high orbital precision. Its accuracy is of the order of few centimeters in complex topography, because of this ICESat-2 proves to be a good source to generate high-accuracy DEMs. ICESat-2 provides discrete photon data with elevations of points on the Earth’s surface. Traditional interpolation techniques tend to over-smooth the estimated space and still are unable to justify the complicated continuity in the topographical data. Machine learning algorithms are widely being used to extract patterns and spatial extent in geographic data. To estimate a DEM from ICESat-2 LiDAR point data, machine learning regression algorithms are implemented in this study. The present study has been performed for a plain region of Ghaziabad, Uttar Pradesh, India. Studies have shown that Cartosat-1 DEM V3 R1 product provides an accuracy of the order of 2m in predominantly plain regions, hence taken for this region. Current work focuses on comparing various regression-based machine-learning techniques to interpolate DEM from ICESat-2 data The RMSE of the interpolated DEM resulted from the Gradient Boosting Regressor, Random Forest Regressor, Decision Tree Regressor, and Multi-Layer Perceptron Regressor was 7.13m, 7.01m, 7.15m, and 3.76m, respectively when evaluated against the TANDEM-X DEM of the same region. The MLP Regressor is found to perform the best among the four algorithms tested.

Recent reports suggest that the clinical course of coronavirus disease 2019 (COVID-19) in previously healthy children is usually milder as compared to adults. However, children with comorbid conditions such as diabetes are at increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as morbidity and mortality due to COVID-19. Experience in adults with diabetes shows that they are prone to faster metabolic decompensation, develop diabetes-related complications, and have a poor prognosis when hospitalized with COVID-19. Data on children are limited. The aim of this mini-review is to discuss the possible risks to children and adolescents with diabetes during the current pandemic and the special considerations in management in those affected with COVID-19. The challenges for children who develop new-onset type 1 diabetes during the COVID-19 lockdown, especially in accessing healthcare, are also discussed.

The epithelial cell tight junction structure is the site of the transepithelial movement of solutes and water between epithelial cells (paracellular permeability). Paracellular permeability can be divided into two distinct pathways, the Pore Pathway mediating the movement of small ions and solutes and the Leak Pathway mediating the movement of large solutes. Claudin proteins form the basic paracellular permeability barrier and mediate the movement of small ions and solutes via the Pore Pathway. The Leak Pathway remains less understood. Several proteins have been implicated in mediating the Leak Pathway, including occludin, ZO proteins, tricellulin, and actin filaments, but the proteins comprising the Leak Pathway remain unresolved. The properties of the Leak Pathway, such as its molecular mechanism, its regulation, and whether or not it has a size limit, remain controversial. This review will trace the evolution of the Leak Pathway concept from its origins, will discuss the current information about the properties of the Leak Pathway, and will discuss recent research suggesting a possible molecular basis for the Leak Pathway. Based on these findings, we propose a model for the molecular mechanism underlying the Leak Pathway and its regulation.

A timely inventory of agricultural areas and crop types is an essential requirement for ensuring global food security. Satellite remote sensing has proven to be an increasingly more reliable tool to identify crop types. With the Copernicus program and its Sentinel satellites, a growing source of satellite remote sensing data is publicly available at no charge. Here we use joint Sentinel-1 radar and Sentinel-2 optical imagery to create a crop map for Belgium. To ensure homogenous radar and optical input across the country, Sentinel-1 12-day backscatter composites were created after incidence angle normalization, and Sentinel-2 NDVI images were smoothed to yield dekadal cloud-free composites. An optimized random forest classifier predicted the 8 crop types with a maximum accuracy of 82% and a kappa coefficient of 0.77. We found that a combination of radar and optical imagery always outperformed a classification based on single-sensor inputs, and that classification performance increased throughout the season until July, when differences between crop types are largest. Furthermore we showed that the concept of classification confidence derived from the random forest classifier provided insight in the reliability of the predicted class for each pixel, clearly showing that parcel borders have a lower classification confidence. We concluded that the synergistic use of radar and optical data for crop classification led to richer information increasing classification accuracies compared to optical-only classification. Further work should focus on object-level classification and crop monitoring to exploit the rich potential of combined radar and optical observations.

Immune checkpoint receptors play a crucial role in steering tumor progression, prompting a focused investigation into the role of TIM3 in breast cancer. Analysis of TCGA BRCA data unveiled diverse correlations between TIM-3 expression and immune cell infiltration across subtypes. In our in-house cohort studied through IHC, significant changes in TIM3 expression with tumor grades were observed. Higher TIM3 expression correlated with increased disease-free survival in pan breast cancer, marking the first revelation of TIM3's positive role in pan BC prognosis. The study indicates that alluring TIM3 response, rather than suppression, may enhance breast cancer prognosis.

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics (GLP-1ra and SGLT2-in). Despite new guidelines, clinical inertia, that can be caused by physicians, patients or healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient's overall situation in decision-making. We looked for the possible reasons of clinical inertia and poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiative in diabetes aims to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings.

Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular (CV) disease. Contributing pathophysiologic factors include endothelial dysfunction caused by excessive production of reactive oxygen species (ROS), increased activity of nuclear factor kB (NFkB), altered macrophage polarization, and reduced synthesis of endothelial progenitor cells (EPC). Consequently, there can be a potentially rapid progression of the atherosclerotic disease with a higher propensity to unstable plaque, leading to increased cardiovascular mortality. Management is aimed at prevention, early diagnosis, and treatment of hyperglycemia and vascular complications. Innovative therapeutic approaches for T2DM seek to customize the antidiabetic treatment to each patient in order to optimize glucose-lowering effects, minimize hypoglycemia and adverse effects, and prevent cardiovascular events. The newer drugs (Glucagon Like Peptide-1 Receptor Agonists, GLP-1 RAs; Sodium GLucose coTransporter-2 inhibitors, SGLT2is; DiPeptidyl Peptidase-4 inhibitors, DPP4is) impact body weight, lipid parameters, and blood pressure, as well as endothelial function, inflammatory markers, markers of oxidative stress, and subclinical atherosclerosis. The present review summarizes the results of trials that evaluated the cardiovascular safety of these drugs and found them to be safe from the CV standpoint.

Galectins are β-galactosyl-binding proteins that fulfill essential physiological functions. Recently, we introduced galectin-1 (Gal-1) and galectin-3 (Gal-3) as fusion proteins of a His6-tag, a SNAP-tag, and a fluorescent protein. We characterized their binding in ELISA-type assays and their application in cell-surface binding. In the present study, we have constructed further fusion proteins of galectins with fluorescent protein color code. The fusion proteins of Gal-1, Gal-3, and Gal-8 were purified by affinity chromatography. For this, we have prepared glycoprotein affinity resins based on asialofetuin (ASF) and fetuin and combined this in a two-step purification with Immobilized Metal Affinity chromatography (IMAC) to get pure and active galectins. Purified galectin fractions were analyzed by size-exclusion chromatography. The binding characteristics to ASF of solely His6-tagged galectins and galectin fusion proteins were compared. As an example, we demonstrate a 1.6-3-fold increase in binding efficiency for HSYGal-3 (His6-SNAP-yellow fluorescent protein-Gal-3) compared to the HGal-3 (His6-Gal-3). Our results reveal an apparent higher binding efficiency for galectin SNAP-tag fusion proteins compared to His6-tagged galectins which are independent of the purification mode. This is also demonstrated by the binding of galectin fusion proteins to extracellular glycoconjugates laminin, fibronectin, and collagen IV. Our results indicate the probable involvement of the SNAP-tag in apparently higher binding signals, which we discuss in this study.

One method of creating a brass coating is through electrodeposition, which is most often completed in cyanide galvanic baths. Because of the toxicity of cyanides, many are working on the development of cyanide-free baths, which are promising but not satisfactory to replace the classic methods. The purpose of the study was to explore a new generation of non-aqueous cyanide-free baths based on 1-ethyl-3-methylimidazolium acetate ionic liquids. The study involved the formation of copper, zinc, and brass coatings. The influence of the bath composition, cathodic current density, and temperature was determined. The obtained coatings were characterized by their morphology, chemical composition, roughness, and corrosion resistance. It was found that the structure of the obtained coatings is strongly dependent on the process parameters. The three main structures observed were fine-grained, porous, and olive-like. To the best knowledge of the authors, it is the first time the olive-like structure was observed in the case of an electrodeposited coating. The Cu-Zn coatings consisted of 19–96 at.% copper and exhibited relatively strong corrosion resistance. High improvement of corrosion properties was found in the case of copper and brass coatings with an olive-like structure.

The three dimensional conformable time fractional Kadomtsev-Petviashvili and the conformable time fractional modified Kawahara equations are solved by implementing the Kudryashov's procedure. The corresponding wave transformation reduces both equations to some ODEs. Balancing the nonlinear and the highest order derivative terms gives the structure of the solutions in the finite series form. The useful symbolic tools are used to solve the resultant algebraic systems. The solutions are expressed in explicit forms.

Our environment has been significantly impacted by man-made pollutants, primarily due to industries make substantial use of synthetic chemicals, resulting in significant environmental consequences. In this research investigation, the co-precipitation approach was employed for the synthesis of cellulose-based ferric oxide (Fe₂O₃/cellulose) and copper oxide nanoparticles (CuOx-NPs). Scanning electron microscopy (SEM) analyses were conducted to determine the properties of the newly synthesised nanoparticles. Furthermore, the synthesized nanoparticles were employed for eliminating chromium from aqueous media under various conditions, including temperature, contact time, adsorbent concentration, adsorbate concentration, and pH. Additionally, the synthesised materials were used to recover Cr(VI) ions from real samples, including tap water, seawater, and industrial water, and the adsorptive capacity of both materials evaluated under optimal conditions. The synthesis of Fe₂O₃/cellulose and CuOx-NPs proved to be effective, as indicated by the outcomes of the study.

Good hand hygiene has proven to be essential in reducing the uncontrolled spread of human pathogens. Cold atmospheric plasma (CAP) may provide an alternative to disinfecting hands with ethanol-based handrubs when hand washing facilities are unavailable. CAP can be safely applied to the skin if the energy is well controlled. In this study, RF and DC plasma sources was built with a pin-to-mesh electrodes configuration inside a fused silica tube of 5 mm of inner diameter. Microbiological assays based on EN 13697:2015+A1:2019 using Escherichia coli DSM 682 or Staphylococcus epidermidis DSM 20044 were used to examine the antimicrobial effect of various plasma conditions. Metal and silicone disks that model skin were used as inoculation matrices. The prototype air radio frequency (RF) CAP achieved significant disinfection in the MHz range on stainless steel and silicone substrates. This is equivalent to half the performance of direct current CAP, which is only effective on conductive substrates. Using only electricity and air CAP could, with further optimization, replace or complement current hand disinfection methods, and mitigate the economic burden of public health crises in the future.

Evidence suggests that COVID-19 infection increases the risk of type 1 (T1D) and type 2 diabetes (T2D). Diabetes, in turn, increases COVID-19 susceptibility and contributes to increased COVID-19 morbidity and mortality. Oxidative stress (OxS) has emerged as a common factor driving the pathogenesis of diabetes and COVID-19 caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). The mechanistic links between OxS, T2D, and COVID-19 have primarily been studied in adults and will be summarized in this review. However, we suggest that studying these interconnections in children and young adults is critical since early intervention is optimal for improving outcomes. At the height of the pandemic, COVID-19 was a leading cause of death in children and young people, and people in this age group are as susceptible to COVID-19 as adults and the elderly. Glutathione (GSH) is the primary water-soluble intracellular antioxidant and can be deficient in both diabetes and COVID-19. GSH is a tripeptide containing cysteine (CYS), glutamic acid (GLU), and glycine (GLY). Strategies to increase GSH levels may be beneficial in helping to manage COVID-19-induced diabetes as well as diabetes-induced COVID-19 risk. Dietary supplementation with GlyNAC may be optimal since it contains two metabolic GSH precursors, i.e., n-acetyl-l-cysteine (NAC) and GLY.

Cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus, is significantly underreported in Mongolia due to geographical remoteness, lack of early diagnostics, and poor clinical management. This study aimed to provide a more accurate estimate of CE in Mongolia by comparing data of surgical (reported) and diagnosed (unreported) cases, and assessing the challenges faced by rural doctors in disease management and surveillance. We collected data on surgical cases hospitalized between 2006-2016 and newly diagnosed CE cases in 2016 from eight provinces. Using a quasi-Poisson regression model of the collected data, we used extrapolation to estimate the number of diagnosed cases for the entire country. Additionally, fourty health professionals from all 21 provinces rated local clinical management for CE through a questionnaire. Results reveal that surgical cases (2.2 per year) represent only one-eighth of diagnosed cases (15.9 per year). The laboratory facilities, disease reporting, and cyst classification usage scored below 2. These results highlight the significant underreporting of CE in Mongolia and urges human and animal health experts, along with policymakers, to invest into combating CE, particularly in remote provincial areas. It also emphasizes the need for standard clinical management involving cyst classification according to WHO-IWGE, seamless integration of CE reporting and monitoring mechanisms, which can significantly contribute to the national and global burden estimation of CE.

The sheer number of gene variants and the extent of the observed clinical and molecular heterogeneity recorded in neuropsychiatric disorders (NPDs), could be due to the magnified downstream effects initiated by a smaller group of genomic higher order alterations in response to endogenous or environmental stress. Chromosomal common fragile sites (CFS) are functionally linked with microRNA’s, gene copy number variants (CNVs), sub-microscopic deletions and duplications of DNA, rare single-nucleotide variants (SNVs/SNPs) and small insertions/deletions (indels), as well as chromosomal translocations, gene duplications, altered methylation, microRNA and L1 transposon activity and 3-D chromosomal topology characteristics. These genomic structural features have been linked with various NPDs in mostly isolated reports, and have usually only been viewed as areas harboring potential candidate genes of interest. The suggestion to use a higher level entry point, (the ‘fragilome’ and associated features), activated by a central mechanism (‘stress’) for studying NPD genetics, has the potential to unify the existing vast number of different observations in this field. This approach may explain the continuum of gene findings distributed between affected and unaffected individuals, the clustering of NPD phenotypes and overlapping comorbidities, the extensive clinical and molecular heterogeneity and the association with certain other medical disorders.

The uneven immunogenicity of the attenuated tetravalent dengue vaccine has created the diffi-culty to achieve a balanced protection against all four serotypes of dengue virus (DENV). To overcome this problem, non-replicative-based vaccines have come into focus as their immuno-genicity is adjustable. This approach is excellent for multivalent vaccines but commonly faces the issue of low immunogenicity. In this present study, we developed a non-replicating dengue vaccine composing of UV-inactivated dengue-2 virus (UV-DENV2) and DENV-2 NS1-279 protein encapsidated within nanoparticles. This vaccine candidate was administered in the presence of BCG cell wall cytoskeleton (BCG-CWS) as an adjuvant. We revealed, here, that encapsidated immunogens with BCG-CWS exerted potent activities on both B and T cells and elicited Th-1/Th-2 responses in mice. This was evidenced by strong neutralizing antibody activity with an unde-tectable antibody enhancing activity in a group of mice receiving encapsidated immunogens with BCG-CWS. Importantly, BCG-CWS significantly augmented antibody-mediated comple-ment-fixing activity, strongly stimulated the antigen-specific polyfunctional T cell responses as well as activated mixed Th-1/Th-2 responses specific to DENV2- and NS1-279 antigens. In conclu-sion, BCG-CWS potently adjuvanted the inactivated DENV-2 and subunit DENV immunogens. The mechanism of adjuvanticity remains unclear. This study revealed the potential use of BCG-CWS in vaccine development.

Satellite Crop Detection technologies are focused on detection of different types of crops on the field in the early stage before harvesting. Crop detection is usually done on a time series of satellite data by classification of the desired fields. Currently, data obtained from Remote Sensing (RS) are used to solve tasks related to the identification of the type of agricultural crops, also modern technologies using AI methods are desired in the postprocessing part. In this challenge Sentinel-1 and Sentinel-2 time series data were used due to their periodic availability. Our focus was to develop methodology for classification of time series of Sentinel 2 and Sentinel 1 data and compare how accuracy of classification can be increased, but also how to guarantee availability of data. We analyse phenology of single crops and on the basis of this analysis we started to provide crop classification. Original crop classifications were made from Enhanced Vegetation Index (EVI) layers made from Sentinel-2 time-series data and then we added also . To increase accuracy we also integrate into the process parcel borders and provide classification of fields..

Abstract: Several publications have raised the issue that the development of diabetes is preceded by alteration of the microbiome (dysbiosis) and hence, the role of environmental factors, triggering dysbiosis, should be considered. Antibiotics are powerful agents inducing dysbiosis and the authors wanted to explore the possible relationship between the consumption of different major classes of antibiotics and the prevalence of diabetes (type-1, /T1D/, type-2 /T2D/) in thirty European countries. According to our hypothesis, if such association exists, the dominant use of certain major antibiotic classes might be reflected in the prevalence of T1D and T2D in different countries. Comparisons were performed between the prevalence of diabetes (T1D and T2D) estimated for 2019 and featured in the Diabetes Atlas with the average yearly consumption of major antibiotic classes of the previous 10 years (2010-19) extracted from the ECDC yearly reports on antibiotic consumption in Europe. Pearson correlation and variance analysis were used to estimate the possible relationship. Strong, positive (enhancer) associations were found between the prevalence of T1D and the consumption of tetracycline (J01A /p: 0.001/) and the narrow spectrum penicillin (J01CE /p: 0,006/, CF /p: 0.018/). Strong negative (inhibitor) association was observed with broad-spectrum, beta-lactamase resistant penicillin (J01CR /p: 0.003/), macrolide (J01F /p: 0.008/) and quinolone (J01M /p: 0.001/). T2D showed significant positive associations with cephalosporin (J01D /p: 0.048/) and quinolone (J01M /p: 0.025/), and a non-significant negative association was detected with broad-spectrum, beta-lactamase-sensitive penicillin (J01CA /p: 0.67/). Countries with the highest prevalence of diabetes (first 10 positions) showed concordance with the higher consumption of “enhancer” and the lower consumption of “inhibitor” antibiotics (first 10 positions) as indicated by variance analysis. Countries with high prevalence of T1D showed high consumption of tetracycline (p: 0.015), and narrow spectrum, beta-lactamase sensitive penicillin (p: 0.008), and low consumption of “inhibitor” antibiotics (broad-spectrum, beta-lactamase resistant, combination penicillin (p: 0.005), cephalosporin (p: 0.036), and quinolone (p: 0.003). Countries with a high prevalence of T2D consumed more cephalosporin (p: 0.084), quinolone (p: 0.54), and less broad-spectrum, beta-lactamase sensitive penicillin (p: 0.012) than other countries. Conclusion/Interpretation: The development of diabetes-related dysbiosis might be attached to higher consumption of specific classes of antibiotics, showing positive (enhancer) associations with the prevalence of diabetes, and the low consumption of other classes of antibiotics shoving negative (inhibitory) associations. Those groups of antibiotics are different in T1D and T2D

This research aims to find out whether the synthetic 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a We are interested in using molecular docking and molecular dynamics modelling to investigate the interaction between the derivatives of 1, 2, 4-triazine and the resulting lanosterol 14 - demethylase (CYP51) of Candida albicans The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identifying the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by “priming” and/or “activation” steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusiogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.

Diagnosis of kidney diseases has recently become more comprehensive and accurate by using new renal markers. Despite the fact that creatinine and cystatin c have been sufficient in determining kidney function, they did not indicate the exact site of the damage and they were often insufficient in predicting the course of the disease. Aim of the study was to evaluate the potential correlations and differences in levels of six factors related to kidney function and injury: kidney injury molecule-1 (KIM-1), ncalbindin (CALB), glutathione S-transferase Pi (GST-Pi), calbindin and monocyte chemoattractant protein-1 (MCP-1), between renal patients with diabetic nephropathy (DM), congenital defects (CD) of the kidney and glomerulonephritis (GN). Study involved 75 patients: 49 with diabetic nephropathy, 12 with congenital defects and 14 with glomerulonephritis. Levels of renalase was measured using immunoenzymatic tests. Levels of other markers: calbindin, glutathione-S-transferase (GST-pi), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1) and monocyte chemoattractant protein-1 (MCP-1), were analyzed using Kidney Toxicity-1 Panel and BioPlex system, designed for analyses in urine and optimized by us for serum.From all analyzed markers, only levels of KIM-1 differed significantly between any subgroups, and that was for CD and DM. Renalase correlated significantly negatively with creatinine and positively with all other markers, apart from MCP-1. Obtained results indicate, that serum renalase, KIM-1, calbindin and GST-pi are related to kidney function, with KIM-1 being the most exact, while MCP-1 levels are unrelated to creatinine and glucose levels, does not differ between patients with diabetic nephropathy and other subgroups, and therefore seem to be independent of diabetes. Also, serum-optimized Kidney Toxicity Panel 1 kit for determination of selected markers gave results similar to previous ones and therefore the method can be valuable in determination of analyzed factors.

Exact solutions to conformable time fractional (3+1)- dimensional equations are derived by using the modified form of the Kudryashov method. The compatible wave transformation reduces the equations to an ODE with integer orders. The predicted solution of the finite series of a rational exponential function is substituted into this ODE. The resultant polynomial equation is solved by using algebraic operations. The method works for the Jimbo-Miwa, the Zakharov-Kuznetsov and the modified Zakharov-Kuznetsov equations in conformable time fractional forms. All the solutions are expressed in explicit forms.

The emotion of disgust protects individuals against pathogens, and it has been found that during pregnancy, it is elevated. Physiological mechanisms discussed in relation to these changes include immune markers and progesterone levels. The aim of this study is to assess the association between steroids and disgust in pregnancy. In a sample of 179 pregnant women, we have analyzed blood serum steroid concentrations and measured disgust sensitivity by text-based questionnaires in the first and third trimester. We found positive correlations between disgust sensitivity and the levels of C19 steroids, including testosterone, but also its precursors in the Δ5 pathway (androstenediol, DHEA, and their sulfates) and the Δ4 pathway (androstenedione). Furthermore, positive correlations between disgust sensitivity and 5α/β-reduced C19 steroid metabolites were consistently present in both trimesters. In the first trimester, we found a positive association between disgust sensitivity and 17-hydroxypregnanolone as well as some estrogens. In the third trimester, we have observed positive associations between disgust sensitivity and cortisol as well as immunoprotective Δ5 C19 7α/β-hydroxy-steroids. Our study has thus shown that disgust sensitivity is positively correlated with immunomodulatory steroids, and in the third trimester, steroids may reflect potential maternal anxiety-related symptoms.

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.

The endocannabinoid system has been found to be pervasive in mammalian species. It has also been described in invertebrate species primitive as the Hydra. Insects apparently are devoid of this otherwise ubiquitous system that provides homeostatic balance to the nervous and immune systems, as well as many other organ systems. The endocannabinoid system (ECS) has been defined to consist of three parts: 1. Endogenous ligands, 2. G-protein coupled receptors (GPCRs), and 3. Enzymes to degrade and recycle the ligands. Two endogenous molecules have been identified as ligands in the ECS to date. These are the endocannabinoids: Anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol). Two G-coupled protein receptors have been described as part of this system, with other putative GPC being considered. Coincidentally, the phytochemicals produced in large quantities by the Cannabis sativa L plant, and in lesser amounts by other plants, can interact with this system as ligands. These plant-based cannabinoids are termed, phytocannabinoids. The precise determination of the distribution of cannabinoid receptors in animal species is an ongoing project, with the canine cannabinoid receptor distribution currently receiving the most interest in non-human animals.

In order for the body to function properly, it needs not only food, but also nutrients and non-nutritive bioactive compounds that have an immunomodulating effect. This applies not only to healthy people, but especially to people with accompanying chronic diseases, including type 2 diabetes. Unfortunately, the current food industry and the use of highly processed food promote nutritional deficiencies. Many studies confirm their occurrence in patients with type 2 diabetes. The article presents the influence of selected nutrients on the functioning of the immune system, which ensures homeostasis of the body, with particular emphasis on type 2 diabetes. The role of macroelements, microelements, vitamins and selected substances, such as omega-3 acids, coenzyme Q10 and alpha-lipoic acid. The minimum scope of tests that should be performed in patients to directly or indirectly determine the degree of malnutrition in this group of patients is presented.

This paper presents a proposal for a non-isolated bidirectional converter (NIBC) controlled by a deep neural network (DNN) to enable vehicle-to-vehicle (V2V) and vehicle-to-grid (V2G) charging, which contributes to the development of more efficient and sustainable transportation and energy systems. The DNN controller manages power flow in both directions, making it possible to charge electric vehicles (EVs) and discharge power from EVs to the grid with improved efficiency and performance compared to traditional control methods. The non-isolated topology used in this proposal offers several benefits, including reduced cost, smaller size, and higher efficiency. To train the DNN controller, a large dataset of simulations was used, and the results were validated with a hardware setup. The real-time performance of the DNN controller was compared to a proportional-integral (PI) based controller through simulated results. The findings of the study show that the DNN controller outperforms traditional PI controllers.

Background: SARS-CoV-2 Omicron JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used RT-qPCR SGTF as the proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing for diagnosis of JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed Q229K, usually associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: The CDC should consider Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.

Background: Maternal diabetes mellitus (MDM) is associated with increased risks for adverse neonatal outcomes. However, the impact of MDM on neonatal outcomes in Bisha, a city in Saudi Arabia, is not well-documented. This study aims to investigate the impact of MDM on neonatal outcomes in the Maternity and Children’s Hospital (MCH), Bisha, Saudi Arabia. Methods: A retrospective cohort study was conducted on 181 pregnant women with diabetes and their neonates diagnosed at Maternity and Children’s Hospital (MCH), Bisha, Saudi Arabia, between October 5, 2020, and November 5, 2022. The primary outcome was a composite of adverse neonatal outcomes, including stillbirth, neonatal death, macrosomia, preterm birth, respiratory distress syndrome, hypoglycemia, and congenital anomalies. Logistic regression analyses were used to adjust for potential confounders. Results: The total sample size was 181. The average age of patients was 34 years (SD=6.45). The majority of the patients were diagnosed with GDM, 147 (81.2%), and pre-GDM, 34 (18.8%). Neonates born to mothers with MDM had a higher risk of adverse neonatal outcomes compared to those born to mothers without MDM (adjusted odds ratio [aOR] = 1.46, 95% confidence interval [CI]: 1.25-1.70). The risks of macrosomia (aOR = 1.74, 95% CI: 1.38-2.19), LBW (aOR = 1.32, 95% CI: 1.06-1.66), and RDS (aOR = 1.57, 95% CI: 1.28-1.93) were significantly higher among neonates born to mothers with MDM. Types of DM were statistically significant with some neonatal outcomes: hypoglycemia (p-value = 0.017), macrosomia (p-value = 0.050), and neonatal death (p-value = 0.017). Conclusion: MDM is associated with an increased risk of adverse neonatal outcomes in Bisha. Early identification and management of MDM may improve neonatal outcomes and reduce the burden of neonatal morbidity and mortality in this population.

Background. Waning of neutralizing and cell-mediated immune response after the primary vac-cine cycle (PVC) and the first booster dose (BD) is of concern, especially for PLWH with a CD4 count ≤200 cells/ mm3.Methods.Neutralizing antibodies (nAbs) titers by microneutralization assay against WD614G /Omicron BA.1 and IFNγ production by ELISA assay were measured in samples of PLWH at 4 time points [2 and 4 months post-PVC (T1 and T2), 2 weeks and 5 months after the BD (T3 and T4)]. Participants were stratified by CD4 count after PVC (LCD4, <200/mm3; ICD4, 201-500/mm3 and HCD4, >500/mm3). Mixed models were used to compare mean responses over T1-T4 across CD4 groups. Results. 314 PLWH on ART (LCD4=56; ICD4=120; HCD4=138) were enrolled. At T2, levels of nAbs were significantly lower in LCD4 vs ICD4/HCD4 (p=0.04). BD was crucial for increasing nAbs titres above 1:40 at T3 and up to T4 for WD614G. A positive T cell response after PVC was observed in all groups, regardless of CD4 (p=0.31). Conclusions. Waning of nAbs after PVC was more important in LCD4 group. BD managed to re-establish higher levels of nAbs against WD614G which were retained for 5 months. The level of T-cellular response was significantly higher in HCD4 and ICD4 compared to the LCD4 group although it remained above detectable levels over the entire study period regardless of CD4 count. Keywords: HIV-1 infection; SARS-CoV-2 infection;

Tdp1 and Tdp2 are DNA repair enzymes that repair DNA damages caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reasons of resistance to such widely used drugs as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (-)-usnic acid. Both (+)- and (-)-enantiomers of compounds act equally effectively against Tdp1, and only (-)-enantiomers inhibited Tdp2. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide but potentiate it against Tdp2 knockout cells. We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with effective inhibition of Tdp1, which could take over the functions of Tdp2.

Regulation (EU) No 305/2011 lays down harmonized conditions for marketing construction products in the European Union. One of its consequences has been the introduction of the product standard EN 50575 and standard EN 130501-6, concerning power, control, and communication cables permanently installed in buildings to prevent the risk of a fire and its consequences. EN 13501-6 provides the reaction to fire classifications for cables, the test methods to be performed, the requirements to meet a specific reaction to fire, and additional classifications for smoke production, flaming droplets, and acidity. EN 60754-2 is the technical standard used to assess acidity, and it defines three classes: a1, a2, and a3 (the less performant), based on pH and conductivity measurements. Due to the release of hydrogen chloride during the combustion, acidity is the weak point of PVC cables, which are not yet capable of achieving the a1 or a2 classes required in specific locations according to a fire risk assessment. EN 13501-6 does not include EN 60754-1. Both EN 60754-1 and EN 60754-2 are common standards for determining halogen gas content, acidity, and conductivity, respectively. They involve the same type of tube furnace but with different heating regimes, final temperatures, and detection methods. EN 60754-2 must be performed at temperatures between 935 – 965 °C. The paper demonstrates that, when EN 60754-2 is carried out with the thermal profile of EN 60754-1 or at 500 °C in isothermal conditions, the evolution of hydrogen chloride changes significantly if potent acid scavengers are utilized in the PVC compounds. The reason lies behind the kinetic of hydrogen chloride release during the combustion of PVC compounds: the higher the temperature or faster the heat release, the quicker hydrogen chloride evolution and the lower the probability for the acid scavenger to trap it. That further highlights the "fragility" of EN 60754-2 as a tool for assessing the risks associated with the release of hydrogen chloride in case of fire

We study the μ-μ45-T phase diagram of the 2+1-dimensional Gross-Neveu model, where μ denotes the ordinary chemical potential, μ45 the chiral chemical potential and T the temperature. We use the mean-field approximation and two different lattice regularizations with naive chiral fermions. An inhomogeneous phase at finite lattice spacing is found for one of the two regularizations. Our results suggest that there is no inhomogeneous phase in the continuum limit. We show that a chiral chemical potential is equivalent to an isospin chemical potential. Thus, all results presented in this work can also be interpreted in the context of isospin imbalance.

The premise regarding COVID-19 disease is that it is a spectrum which begins with infection with viral SARS-CoV-2 exposure via airborne or oral virus particles. The individual response to it depends on many factors including co-morbid conditions. An important aspect of SARS-CoV-2 virus infection is the cytokine storm that develops after the infection. The immuno-chemical chaos created in this cytokine storm is to the benefit of the virus. In this meta analysis the authors explore ways to let the cytokine storm die down by looking into the role of histamine. Histamine is a metabolic product of the essential aminoacid histidine. Histamine has 4 known receptors: H1, H2, H3 and H4. The immunoglobulines IgE and IgM are indicative for a COVID-19 infection. This immune response is related to inflammation. Inflammation, in turn, runs mainly via histamine after e.g. virus inoculation. The goal of the meta-study is to gather evidence to primarily block the H4 receptor (H4R) in gastrointestinal cells to diminish the cytokine overproduction in the $\approx$ 30\% of the patients suffering from gastrointestinal problems caused by SARS-CoV-2. Our concept is as follows. If we can strike a careful balance between hampering the gastrointestinal spreading of the virus and histamine antagonists to tackle the cytokine storm, then the natural immunity can later on come on line again and attack the virus without being led astray by cytokine chaos. We will concentrate on H4R but also look at H1R and H2R related effects. The proposed substances in our systemic approach can be balanced for an effective early treatment. The nature of our work is by its method and results theoretical. In that respect we also may note the structural chemistry indol skeleton resemblance among a number of different drugs.

This work addresses the problem of automatic head pose estimation and its application in 3D gaze estimation using low quality RGB--D sensors without any subject cooperation or manual intervention. The previous works on 3D head pose estimation using RGB--D sensors require either an offline step for supervised learning or 3D head model construction which may require manual intervention or subject cooperation for complete head model reconstruction. In this paper, we propose a 3D pose estimator based on low quality depth data, which is not limited by any of the aforementioned steps. Instead, the proposed technique relies on modeling the subject's face in 3--D rather than the complete head, which in turn, relaxes all of the constraints with the previous works. The proposed method is robust, highly accurate and fully automatic. Moreover, it does not need any offline step. Unlike some of the previous works, the method only uses depth data for pose estimation. The experimental results on the Biwi head pose database confirm the efficiency of our algorithm in handling large pose variations and partial occlusion. We also evaluate the performance of our algorithm on IDIAP database for 3D head pose and eye gaze estimation.

As variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, assessment of vaccine immunogenicity remains a critical factor to support continued vaccination. To this end, an in vitro microneutralization (MN50) assay was validated to quantitate SARS-CoV-2 neutralizing antibodies against ancestral and variant strains (Beta, Delta, Omicron BA.1, Omicron BA.5 and XBB.1.5) in human serum. For ancestral strain, the MN50 assay met acceptance criteria for inter-/intra-assay precision, specificity, linearity, and selectivity. The assay was robust against changes to virus/serum incubation time, cell seeding density, virus content per well, cell passage number, and serum interference. Analyte in serum samples was stable up to 5 freeze/thaw cycles and for up to 12 months of storage at –80 ± 10 °C. Similar results were observed for the variant-adapted MN50 assays. The conversion factor to convert assay result units to WHO international standard units (IU/mL) was determined to be 0.62 for the ancestral prototype strain. This MN50 assay will be useful for vaccine immunogenicity analyses in clinical trial samples, enabling assessment of vaccine immunogenicity for ancestral and variant strains as variant-adapted vaccines are developed.

Forest degradation is known to be widespread in the tropics, but is currently very poorly mapped, in part because there is little quantitative data on which satellite sensor characteristics and analysis methods are best at detecting it. To improve this, we used data from the Tropical Forest Degradation Experiment (FODEX) plots in the southern Peruvian Amazon, where different numbers of trees had been removed from four 1 ha forest plots, carefully inventoried by hand and Terrestrial Laser Scanning before and after the logging to give a range of biomass change (ΔAGB) values. We conducted a comparative study of six multispectral optical satellite sensors (WorldView-3, SkySat, SPOT-7, PlanetScope, Sentinel-2 and Landsat 8) at 0.3 – 30 m spatial resolution, to find the best combination of sensor and remote sensing indicator for change detection. Spectral reflectance, the Normalized Difference Vegetation Index (NDVI) and texture parameters were extracted after radiometric calibration and image preprocessing. The strength of the relationships between the change in these values and field-measured ΔAGB (computed in % ha−1) was analysed. The results demonstrate that: (a) texture measures correlates more with ΔAGB than simple spectral parameters; (b) the strongest correlations are achieved for those sensors with spatial resolutions in the intermediate range (1.5 - 10 m), with finer or coarser resolutions producing worse results, and (c) when texture is computed using a moving square window ranging between 9 - 14 m in length. Maps predicting ΔAGB showed very promising results using a NIR-derived texture parameter for 3 m resolution PlanetScope (R2 = 0.97 and RMSE = 1.80 % ha−1), followed by 1.5 m SPOT-7 (R2 = 0.74 and RMSE = 5.25 % ha−1) and 10 m Sentinel-2 (R2 = 0.71 and RMSE = 5.55 % ha−1). Texture models derived from 0.3 m WorldView-3 improved with increasing window size, with highest R2 of 0.62 and RMSE = 6.35 % ha−1 for a window of 14 m in length. The degradation in our field plots is invisible to the 30 m resolution Landsat data. Our findings imply that, at least for lowland Peru, low-medium intensity disturbance can be detected best in optical wavelengths using a texture measure derived from 3 m PlanetScope data. That such data are being collected daily, and currently released free as monthly mosaics over tropical forests as part of the Norway’s International Climate and Forest Initiative (NICFI), is excellent news for monitoring such degradation.

Gene expression variations of plant leaf are investigated by irradiating seed and leaf with oxygen or air plasmas. Enhancement of leaf growth is induced by oxygen plasma irradiation on seeds, which is supported by increased gene expression for protein synthesis, oxidative-reduction reactions and decreased gene expression concerning DNA methylation and histone modification. Suppression of leaf growth is observed by the oxygen plasma, which would be owing to increased gene expression concerning heat shock protein and redox reaction, and decreased expression of photosynthesis and glycoprotein. Also, gene expression variation due to air plasma irradiation is almost same as that of oxygen plasma. Active oxygen species are major factors in both oxygen and air plasmas for the variation of gene expressions in plant.

Porcine circovirus type 2 (PCV2) is a small non-enveloped DNA virus that causes swine immunosuppression by inducing apoptosis in lymphocytes. The ORF3 protein plays a major role in PCV2-induced apoptosis in porcine kidney cells, but there is little information regarding this protein in PCV2-infected lymphocytes. In this study, hybridoma screening and epitope mapping were determined by using an indirect ELISA. The mAb 7D3 against ORF3 peptide (residues 35–65) of PCV2 were generated in this study. In vivo situation, the mAb 7D3 recognized ORF3 protein existed in PCV2-infected apoptotic porcine PBMCs. It is noteworthy that thimerosal interfered with the binding of mAb 7D3 to epitope and it was diminished by adding cysteine. Additionally, thimerosal interacting with cysteine-containing peptide was demonstrated by the PTI assay. Furthermore, thimerosal specifically interacted with the antigen-binding sites of mAb 7D3. This study suggested that thimerosal blockade the occlusion of the antigen-binding sites of mAb 7D3 to bind ORF3 peptide (residues 35–65) via thimerosal interacting with cysteine residues which should be located within the antigen-binding sites of mAb 7D3. Overall, the mAb 7D3 has been characterized and it will be a valuables tool in future studies of ORF3 function and the wider mechanism of cell apoptosis caused by PCV2 infection. Similarly, these techniques will be useful for applications in detecting thimerosal too.

Astronauts at are risk of losing 1.0 – 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs designed to preserve the musculoskeletal system. This article reviews the basics of bone formation and resorption and details how exposure to microgravity or simulated microgravity affects the structure and function of osteoblasts, osteocytes, osteoclasts, and their mesenchymal and hematologic stem cell precursors. It details the critical roles that insulin-like growth facor-1 and its receptor IGFR1 play in maintaining bone homeostasis and how exposure of bone cells to microgravity affects the function of these growth factors. Lastly, it discusses the potential of tumor necrosis factor-related apoptosis-inducing ligand, syncytin-A, and sclerostin inhibitors and recombinant IGF-1 as a bone-saving treatment for astronauts in space and during their colonization of the Moon.

Expression of Krüppel–like factor 15 (KLF15), a stress induced transcription factor, is induced during bovine herpesvirus 1 (BoHV-1) reactivation from latency, and KLF15 stimulates BoHV-1 replication. Transient transfection studies revealed KLF15 and glucocorticoid receptor (GR) cooperatively transactivate the BoHV-1 immediate early transcription unit 1 (IEtu1), herpes sim-plex virus type 1 (HSV-1) infected cell protein 0 (ICP0), and ICP4 promoter. The IEtu1 promoter drives expression of bICP0 and bICP4, two key BoHV-1 transcriptional regulatory proteins. Based on these studies, we hypothesized infection is a stressful stimulus that increases KLF15 ex-pression and enhances productive infection. New studies demonstrated that silencing KLF15 impaired HSV-1 productive infection and KLF15 steady state protein levels were increased at late stages of productive infection. KLF15 was primarily localized to the nucleus following in-fection of cultured cells with HSV-1, but not BoHV-1. When cells were transfected with a KLF15 promoter construct and then infected with HSV-1, promoter activity was significantly increased. The ICP0 gene and to a lesser extent bICP0 transactivated the KLF15 promoter in the absence of other viral proteins. In contrast, BoHV-1 or HSV-1 encoded VP16 had no effect on KLF15 pro-moter activity. Collectively, these studies revealed HSV-1 and BoHV-1 productive infection in-creased KLF15 steady state protein levels, which correlated with increased virus production.

We report neutralization titer data against contemporary SARS-CoV-2 sublineages from an ongoing, open-label, phase 2/3 trial of a single 30-μg dose of monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine. Healthy participants had previously received ≥3 doses of a US-authorized mRNA vaccine, with the most recent being a bivalent Omicron BA.4/BA.5-adapted vaccine administered ≥150 days before study vaccination. In this analysis, Omicron XBB.1.5, BA.2.86, and JN.1 serum neutralizing titers were assessed at baseline and 1 month after vaccination in a subset of ≥18-year-olds (N = 40) with evidence of previous SARS-CoV-2 infection. Immunogenicity was also evaluated in a demographically matched group of participants who received bivalent BA.4/BA.5-adapted BNT162b2 in another study (ClinicalTrials.gov Identifier: NCT05472038). The XBB.1.5-adapted BNT162b2 vaccine elicited higher XBB.1.5, BA.2.86, and JN.1 neutralizing titers than those elicited by bivalent BA.4/BA.5-adapted BNT162b2. Overall geometric mean fold rises in neutralizing titers from baseline to 1 month after vaccination were higher among participants who received XBB.1.5-adapted BNT162b2 than those who received bivalent BA.4/BA.5-adapted BNT162b2 for XBB.1.5 (7.6 vs 5.6), slightly higher for JN.1 (3.9 vs 3.5), and similar for BA.2.86 (4.8 vs 4.9). ClinicalTrials.gov Identifier: NCT05997290.

This study investigates the potential of natural compounds against HIV-1 protease, a critical enzyme in the replication cycle of human immunodeficiency virus type 1 (HIV-1). HIV-1 protease is essential for cleaving large precursor proteins into smaller functional proteins necessary for viral maturation and infectivity. Protease inhibitors, specifically targeting HIV-1 protease, effectively suppress viral replication, aiding in the management of HIV infection. Using the SWISS DOCK Server, several natural compounds were investigated for their potential as inhibitors of HIV-1 protease. Docking results revealed that Amentoflavone showed excellent binding affinity with high Estimated ΔG values, suggesting its potential as an inhibitor of HIV-1 protease. Additionally, Amentoflavone exhibited similar promising results when tested against Roussarcoma virus protease. These findings indicate the potential of Amentoflavone as a natural compound against HIV and warrant further investigation into its therapeutic applications.

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is a key hormone involved in the regulation of calcium/phosphorous balance and it has been implicated in the pathogenesis of inflammation, insulin resistance and obesity. Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are the main form of vitamin D: the active form (1,25-dihydroxyvitamin D) is the result of two hydroxylations that take place in liver, kidney, pancreas and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity and cardiovascular disease. It's interesting to note that several long-term studies also revealed an inverse correlation between vitamin D level and the occurrence of diabetes mellitus. Vitamin D supplementation in people has controversial effects, in fact while some studies demonstrated improvements in insulin sensitivity, glucose and lipid metabolism, others revealed no significant effect on glycemic control and inflammation. The aim of this review is to provide insight into the molecular basis of the relationship between vitamin D, insulin-resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases.

Early-season crop-type data are required for a variety of agricultural monitoring and decision-making applications. The early season in this study referred to the prophase and middle of a growth season. Early-season detection of crop types remains challenging because of limited discriminative features, especially for landscapes that are characterized by complex cropping patterns. In fact, different remote-sensing satellites can increase the frequency of data acquisition, which can provide more information in the early season. Moreover, optical and radar sensors have different degrees of sensitivity to crop parameters. Therefore, the integration and application of two types of multitemporal data are of great significance to improve the accuracy and timeliness of crop type detection.In deep learning (DL), convolutional neural network (CNN) and recurrent neural network (RNN) models have great potential for temporal feature extraction. Compared with RNNs, CNNs usually have fewer parameters and are more conducive to determining early-season detection dates of different crop types, which requires a lot of training because of the need to model on different dates. Nevertheless, revisit dates and temporal intervals of different satellites are usually different, resulting in different data acquisition time series; these data cannot be directly used as input for the same convolutional layer. To address this challenge, a Dual-1DCNN was bulit based on the CNN model in this study. Moreover, an incremental training method was used to attain the network on each data acquisition date and obtained the best detection date for each crop type in the early season. A case study for Hengshui City in China was conducted using time series of Sentinel-1A (S1A) and Sentinel-2 (S2). To verify this method, classical methods support vector machine (SVM) and random forest (RF) were implemented. The results demonstrated the following: (1) the Dual-1DCNN extracted discriminative features from S1A and S2 time series at the early season by producing the highest overall accuracy (OA: 87.23%); (2) for summer maize, cotton, and common yam rhizome, the Dual-1DCNN achieved F1 values of 92.39%, 87.71%, and 84.38%, respectively, at the early season (moreover, the early seasons were almost 40, 70, and 80 days before the end of the growth seasons, respectively). These findings suggested that the Dual-1DCNN is promising for the accurate and timely detection of crop types.

Landslide risk mitigation is limited by data scarcity. This could be improved using continuous landslide detection systems. In order to investigate which image types and machine learning (ML) models are most useful for landslide detection in a Norwegian setting, we compared the performance of five different ML models, for the Jølster case study (30-July-2019), in Western Norway. These included three globally pre-trained models; i) the Continuous Change Detection and Classification (CCDC) algorithm, ii) a combined k-means clustering and Random Forest classification model, and iii) a convolutional neural network (CNN), and two locally-trained models, including; iv) Classification and Regression Trees and v) a U-net CNN model. Images used included Sentinel-1, Sentinel-2, digital elevation model (DEM) and slope. The globally-trained models performed poorly in shadowed areas, and were all outperformed by the locally-trained models. A maximum Matthew’s correlation coefficient (MCC) score of 89% was achieved with model v, using combined Sentinel-1 and -2 images as input. This is one of the first attempts to apply deep-learning to detect landslides with both Sentinel-1 and -2 images. Using Sentinel-1 images only, the locally-trained deep-learning model significantly outperformed the conventional ML model. These findings contribute towards developing a national continuous monitoring system for landslides.

Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that was implicated in multiple diseases including cancer, aging and heart failure as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β oxidation. In this study, we investigated the association of LRG1 with obesity markers including leptin and other adipokines in adolescents (11-14 years; n=425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese [30 (25, 38) µg/mL] and overweight [30 (24, 39) µg/mL] adolescents, compared to normal-weight participants [27 (22, 35) µg/mL]. The highest tertile of LRG1 had an OR [95%CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of HsCRP (R=0.2), Leptin (R=0.2) and Chemerin (R=0.24) with p<0.001. Additionally, it was positively associated with plasma level of IL6 (R=0.17) and IL10 (R=0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese kids and associate with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.

Surface soil moisture (SSM) is a significant factor affecting crop growth. This paper presents a method for retrieving SSM over wheat-covered areas using synergy dual-polarization C-band Sentinel-1 synthetic aperture radar and Sentinel-2 optical data. Firstly, a modified water cloud model (WCM) was proposed to remove the influence of vegetation from the backscattering coefficient of the radar data. The vegetation fraction was then introduced in this WCM, and the vegetation water content (VWC) was calculated using multiple linear regression model. Subsequently, the support vector regression technique was used to retrieve the SSM. This approach was validated using in-situ measurements of the wheat field in Hebi, in the north of Henan Province. The key findings of this study are as follows: (1) Based on vegetation indices obtained from Sentinel-2; the proposed VWC estimation model can effectively eliminate the influence of vegetation; (2) compared with vertical transmit and horizontal receive polarization, vertical transmit and vertical receive polarization is better for detecting changes in SSM at different growth stages of wheat; and, (3) the validation results indicated that the proposed approach, based on Sentinel-1 and Sentinel-2 data, successfully retrieved SSM in the study area.

Infectious as well as most non-infectious diseases share certain common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors, produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, they produce metabolic alterations that influence the pathogenesis of the disease. In this review we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, which induces migration and infiltration of immune cells in target tissues, and is involved in disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets.

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. This suggests a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents.

Notwithstanding the advances achieved in the last decades in the field of synthetic bone substitutes, the development of biodegradable 3D scaffolds with ideal mechanical and biological properties remains an unattained challenge. In this work, a novel approach is explored to produce synthetic bone grafts mimicking the complex bone structure using additive manufacturing. For the first time, scaffolds were produced, using an extrusion technique, composed of a thermoplastic polymer, polycaprolactone (PCL), hydroxyapatite nanoparticles (HANp), and polyethylene glycol diacrylate (PEGDA). These scaffolds were further compared with two groups of scaffolds: one composed of PCL and another of PCL and HANp. After production, optimisation and characterisation of these scaffolds, an in vitro evaluation was performed using human dental pulp stem/stromal cells (hDPSCs). Through the findings it was possible to conclude that PEGDA scaffolds were successfully produced presenting networks of interconnected channels, presenting hydrophilic properties (15.15 4.06°), adequate mechanical performance (10.41MPa 0.934), and allowing a cell viability significantly superior to the other groups analysed. To conclude, findings in this study demonstrated that PCL, HANp and PEGDA scaffolds may have promising effects on bone regeneration and might open new insights for 3D tissue substitutes.

Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for the brain glucose and neurotransmitter metabolism, dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (Ac-PMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. Comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but the secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in RMSSD of ECG and freezing time are most pronounced after administration of me-thyl acetylphosphinate and dimethyl acetylphosphonate. The levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation are not significantly changed by the PDHC inhibitors that affect the brain protein succinylation and glutarylation. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compen-sated by increased degradation of amino acids through the cycle with activated OGDHC, increas-ing total protein succinylation and decreasing anxiety indicators.

Ageing is associated with a decline in both Nrf2 activity and DNA repair efficiency, leading to the accumulation of DNA damage and an increased risk of cancer. Understanding the mechanisms behind the increased level of damaged DNA during ageing is crucial for developing interventions to mitigate age-related cancer risk and improve overall health in older individuals. (Poly)phenols are plant-derived bioactive compounds that undergo metabolism into simpler phenolic catabolites following ingestion. While these compounds have been associated with various health benefits, further analysis of their bioavailable catabolites is necessary. To this end, four phenolic catabolites derived from colonic microbiota were investigated for their ability to reduce DNA damage in response to oxidative challenge and modulate the Nrf2-Antixoidant Response Element pathway. Normal and adenocarcinoma colonocyte cell lines (CCD 841 CoN, & HT29 respectively) were exposed to sub cytotoxic concentrations (>10 µM,) of hydroxylated (4-hydroxybenzoic acid, 3-(3’-hydroxyphenyl) propionic acid) and non-hydroxylated (benzoic acid or 3-phenylpropionic acid) phenolic acids. Using the COMET assay, each catabolite demonstrated significant (p<0.001) geno-protective activity, albeit with varying potency. They also significantly modulated expression of key genes in the Nrf2-ARE pathway, including Nrf2, Heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone 1 (NQO1). Hydroxylation of the phenolic acids appeared to have a limited effect with respect to bioactivity. Overall, the colon derived phenolic metabolites, when assessed at physiologically relevant concentrations, reduced DNA damage in both normal and adenocarcinoma colonic cells in response to oxidative challenge, mediated – at least in part via upregulation of the Nrf2-ARE pathway.

This paper presents a) the novel hybrid learning method to train the type-1 non-singleton interval type-3 (IT3) fuzzy logic systems (IT3 NSFLS-1) and b) the novel method named enhanced Wagner-Hagras (EWH) IT3 NSFLS-1 fuzzy systems which includes the level alpha 0 output to calculate the output y alpha using the average of the outputs y alpha k instead of their weighted average. The development of the proposed methodology uses the orthogonal least square (OLS) method to train the consequent parameters and the back propagation (BP) method to train the antecedent parameters. This proposal dynamically changes the parameters of only the level alpha 0 minimizing some criterion function as new information becomes available to each level alpha k. The antecedent sets are type-2 fuzzy sets, the consequent sets are fuzzy centroids, the inputs are type-1 non-singleton fuzzy numbers with uncertain standard deviations, and the secondary membership functions are modeled as two Gaussians with uncertain standard deviation and the same mean. Based on the firing set of the level alpha 0, the proposed methodology calculates each firing set of each level alpha k to dynamically construct and update the EWH IT3 NSFLS-1 (OLS-BP) system. The algorithm was tested in a hot strip mill facility to predict the transfer bar surface temperature showing its superior capability to obtain the industrial pyrometer’s knowledge uncertainty for tuning and its better performance when compared with IT2 SFLS, IT2 NSFLS-1, GT2 SFLS, GT2 NSFLS-1, IT3 SFLS, and IT3 NSFLS-1 trained with the BP-BP algorithm.

Bovine Respiratory Disease Complex, a complex respiratory ailment in cattle, results from a combination of viral and bacterial factors, compounded by environmental stressors such as overcrowding, transportation, and adverse weather conditions. Its impact extends beyond mere health concerns, posing significant economic threats to the cattle industry. This study presents an extensive investigation into viral pathogens associated with BRDC in Serbian cattle, utilizing serum samples and nasal swabs. A cross-sectional study was conducted in 2024 across 65 randomly selected dairy farms in Serbia, excluding vaccinated farms. Farms were categorized by livestock count: small (≤50 animals), medium-sized (51-200 animals), and large (&gt;200 animals). Serum samples from adult cattle older than 24 months were tested for antibodies against BVDV, BHV-1, BRSV, and BPIV3. Nasal swab samples from animals with respiratory signs were tested using PCR for viral genome detection. Results showed seropositivity for all four viruses across all farms, with BPIV3 exhibiting universal seropositivity. Medium-sized and large farms demonstrated higher seropositivity for BRSV and BHV-1 compared to small farms (p&lt;.05). True seroprevalence estimates at the animal level were 84.29% for BRSV, 54.08% for BVDV, 90.61% for BHV-1, and 84.59% for BPIV3. PCR analysis of nasal swabs revealed positive detections for BRSV (20%), BHV-1 (1.7%), BVDV (8%), and BPIV3 (10.9%). Influenza D virus was not found in any of samples. This study provides critical insights into the prevalence and circulation of viral pathogens associated with BRDC in Serbian cattle, emphasizing the importance of surveillance and control measures to mitigate the impact of respiratory diseases in cattle populations.

A novel effective vibrational mode was discovered in the conventional transducer with an array of orthogonal (square) regular piezoelectric rods in 1-3 piezocomposite, containing the damping backing and front matching layers. The operational resonance in the structure was determined as the Surface Acoustic Wave (SAW) on the backing boundary excited by the adjacent piezo-rods, with its frequency typically near 3 times lower the fundamental half-lambda conventional piezocomposite resonance. Pulse-echo sensitivity and transmitting sound-pressure-level (SPL) in air showed that the signal strength is roughly comparable to the industrial similar air transducers at the frequency range 100…700 kHz, where at these frequencies the lateral and longitudinal piezoelement dimensions in the conventional transducer design are typically close to each other causing interference with unwanted coupling modes. As was determined theoretically and proved in experiments, the backing SAW resonance effect in the transducer performance is inherent just to the regular periodic 1-3 piezocomposite structure, and does occur neither with randomly located/oriented piezo-rods, nor in the homogeneous piezo-plate at least with the same lateral cross-section as the connected to it backing. The purpose of the article is to investigate a newly discovered operational vibrational mode of a SAW type in 1-3 regular piezocomposite, other than piezoelectric resonance. The investigated phenomena can improve the transceiver sensitivity, bandwidth, providing lower drive voltage, and smaller and lighter weight ultrasonic transducers. Based on the piezocomposites with thickness’ 1…1.5 mm (rod resonance near 2…3 MHz), pillar width 0.2…0.8 mm, kerf width 0.1…0.4 mm, the transceivers with an operating frequency from 140 kHz to 650 kHz were designed and fabricated with a conventional backing of a mixture of high-density tungsten powder and epoxy, and a matching layer of a mixture of low-density glass bubbles and epoxy. Experimental evaluation of their acoustical performance showed expected characteristics suitable for practical applications.

Incretin effect helps in regulating glucose homeostasis and maintaining glycaemic control within the human body. This effect is achieved by the two naturally occurring incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Such hormones released by specialized entero-endocrine cells of the gastrointestinal tract cause insulin augmentation after food consumption. However, incretin effects are impaired in type 2 diabetic, primarily attributed to the deterioration of GLP-1 function along with decreased GLP-1 receptor expression. Targeting this hormone has, therefore, become an important therapeutic approach to treat this diabetic condition. Native GLP-1’s brief half-life and rapid proteolytic degradation have generated significant enthusiasm in uncovering the long-acting GLP-1 receptor (GLP-1R) agonists to manage type 2 diabetes. These synthetic peptides mimic the natural GLP-1 to activate GLP-1R and effectively exert various physiological benefits in terms of weight management, blood pressure, lipid profile, obesity and major adverse cardiovascular event. This review paper provides insights into the structure, function and expression of GLP-1 and its receptor. It also summarizes existing literature regarding different types of GLP-1 receptor agonists, their effects on blood pressure and how they exert their actions. While animal models have contributed significantly to this area of study, the scarcity of human studies is noted, indicating a need for more investigation in this domain. Expanding research in humans will help in comprehending the impact of GLP-1 receptor agonists on blood pressure regulation and their underlying mechanisms.

The development of potent antiviral agents is of utmost importance to combat the global burden of viral infections. Traditional antiviral drug development involves targeting specific viral proteins, which may lead to the emergence of resistant strains. To explore alternative strategies, we investigated the antiviral potential of antimicrobial peptidomimetic compounds. In this study, we evaluated the antiviral potential of short anthranilamide-based peptidomimetic compounds 1-17 against two viruses: Murine Hepatitis Virus 1 (MHV-1-single stranded RNA virus) which is a surrogate of human coronaviruses and Herpes Simplex Virus 1 (HSV-1-double stranded DNA virus). The half-maximal inhibitory concentration (IC50) values of these compounds were determined in vitro to assess their potency as antiviral agents. Compounds 11 and 14 displayed the most potent inhibitory effect with IC50 values of 2.38μM, and 6.3μM against MHV-1 while compounds 9 and 14 showed IC50 values of 14.8μM and 13μM, against HSV-1. Multiple antiviral assessments and microscopic images obtained through transmission electron microscopy (TEM) collectively demonstrated that these compounds exert a direct influence on the viral envelope. Based on this outcome, it can be concluded that peptidomimetic compounds could offer a new approach for the development of potent antiviral agents.

Bovine coronavirus (BCoV) is one of the most common pathogens affecting cattle of all ages. BCoV possesses multiple tissue tropism in cattle, particularly in the respiratory and enteric tracts of the affected animals. Viral entry is a crucial step in the replication cycle of all viruses, including BCoV. The process of viral entry requires the orchestration between several proteins from the virus and the host side. The coronavirus spike glycoproteins contributed substantially to other viral infections and the molecular pathogenesis of coronaviruses, including BCoV. Meanwhile, among all corona-viruses, the hemagglutinin esterase enzyme is found in only BCoV and the human corona-virus-OC43 (HCoV-OC43). The viral receptors are among the key players in the viral entry and could explain the viral tropism, at least in part. The presence of some host cell proteases also en-hances the virus replication from the entry until the release of the virus from the host cells. Previous studies have shown that the 9- O-acetylated sialic acids could potentially act as receptors for the BCoV. However, little is known about the BCoV receptors and if other co/receptors might be needed to ensure viral entry to the host cells. In addition to that, the roles of other host cell proteases, such as Furin and TMPRSS2, in BCoV infection have not yet been well studied. The main objectives of the current study are to identify some novel receptors for BCoV and some host cell proteases that might enhance virus replication. We used some in silico docking tools to predict some new BCoV receptors out of some known other coronavirus receptors (ACE-2, NRP1, DPP4, APN, and CEACAM1). Our results postulated the potential actions of the host Furin and TMPRRS2 enzymes in the activation of BCoV-S glycoprotein, which potentially enhances BCoV replication. Our modeling confirms the high binding affinities of both the 9- O-acetylated sialic and the NRP1 with the BCoV-S and BCoV-HE compared to the ACE-2, DPP4, and CEACAM-1, suggesting their roles as receptors for BCoV. Our prediction models show the potential bindings of the Furin and TMPRSS2 to the BCoV-S polybasic cleavage site (RRSRR|A). To our knowledge, this is the first study to investigate the bovine coronavirus interaction with some other potential host receptors, particularly ACE-2, NRP1, DPP4, APN and CEACAM1, TMPRSS2, and the bovine Furin protease.

Many studies have demonstrated hydrogen's therapeutic and preventive effects on various diseases. Its selective antioxidant properties against hydroxyl radicals, which are responsible for the indirect effects of ionizing radiation, may make it worthy of attention as a new radio-protector. We recently developed new hydrogen water that is more stable and has higher antioxidant activity by using ultra-fine bubbles. In this study, female C57BL/6J mice given ad libitum access to ultra-fine bubble hydrogen water (UBHW) were subjected to whole-body irradiation (WBI) with X-rays, and the radio-protective effect of UBHW was evaluated. Sub-lethal WBI resulted in a 30-day survival rate of 100% in UBHW-fed mice, compared with 37% in control mice. In the case of lethal WBI, while the control mice died out in about 3 weeks, the 30-day survival rate improved to 40% by UBHW due to the high scavenging activity of hydroxy radicals. Twenty-six serum proteins involved in inflammatory and immune responses were significantly identified in UBHW-fed mice by proteomics, and UBHW may enhance and regulate these functions, resulting in reduced damage in mice exposed to WBI. We conclude that UBHW has good potential in radio-protection, with evidence that warrants further research efforts in this field.

Alkyl moieties—open chain or cyclic—are common in drug molecules and can be internal or terminal. The open-chain alkyls can be linear or branched; the cyclic alkyls may be substituted. Usually, the branches in open-chain alkyls and substituents in cycloalkyls influence both the pharmacokinetics and pharmacodynamics of a drug molecule. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some parent-drug equiactive hydroxy metabolites have been developed into metabolite ester prodrugs, while some of the parent-drug carboxy metabolites have been developed into metabolite drugs. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. Some subtexts found to manifest from the hydroxy and carboxy functionalization of alkyl moieties in drug molecules are presented and discussed. The review provides basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules; and (ii) whether the resulting metabolites will possess pharmacologic activity or be devoid of it.

Let an odd integer be represented as $\sum \limits_{n > m} 2^n + 2^m - 1$ for $m \geq 1$. To transform $2^m - 1$ according to the Collatz rules, the $3x + 1$ step is applied, resulting in the even integer $2^{m + 1} + 2^m - 2$. This even integer, being exactly once divisible by 2, becomes the next odd integer $2^m + 2^{m - 1} - 1$. This represents the growth phase, as exactly one even step follows an odd step. However, while the overall value of the integer increases, terms with decreasing indices are generated after each odd-even cycle. After $m$ such cycles, a term $2^{m - m}$ (which equals 1) is generated, canceling the negative 1. Additional even steps are then performed until the integer becomes odd again, which occurs when the next smallest index becomes zero. The positive 1 thus obtained is written as $2^1 - 1$. If uninterrupted, the term $2^1 - 1$ has the trivial cycle $2^1 - 1 \rightarrow 2^2 \rightarrow 2^1 \rightarrow 2^1 - 1$. This represents the shrinkage phase, as two even steps follow an odd step. To interrupt the trivial cycle, a sequence such as $2^1 + 2^2 + \cdots$ must be available to combine with $2^1 - 1$ and produce $2^{\mathcal{M}} - 1$. This starts another growth phase that lasts for $\mathcal{M}$ odd-even cycles. Finally, there is an attempt to craft an integer that can escape the shrinkage phase in the Collatz dynamics.

It has been discovered that representing odd integers as modified binary expressions of the form $\sum \limits_{n > m}2^n + 2^m - 1$ for $m \geq 1$ helps in understanding the dynamics of Collatz-type sequences. Starting with the original Collatz sequence $3x + 1$, it is found that when the odd step is applied to an odd integer $\sum \limits_{n > m}2^n + 2^m - 1$, an even integer $3\left(\sum \limits_{n > m}2^{n}\right) + 2^{m + 1} + 2^m - 2$ is obtained, which is exactly once divisible by 2, unless the lowest index reduces to zero. This implies that the sequence alternates between odd and even steps $m$ times. This governs the dynamics of the Collatz-type sequences because the value of $m$ determines the number of times the integer can be divided by 2 in each even step. A shortcut method is developed based on this dynamics that states that the even integer after $m$ odd-even steps are completed is $\left(\left(\frac{3}{2}\right)^m \sum \limits_{n > m}2^n\right) + 3^m - 1$. A shortcut method of this magnitude has never been utilized anywhere. The shortcut method for the modified Collatz sequence $5x + 1$ is also presented.

Cationised hemp cellulose was prepared by etherification with two quaternary ammonium salts: 3-chloro-2-hydroxypropyl trimethyl ammonium chloride (CHPTAC) and glycidyltrimethylammonium chloride (GTMAC) and examined for (i) the efficiency of Cr(VI) removal under acid mine-drainage (AMD) conditions, and (ii) antibacterial activity. Adsorbents were characterised by electron microscopy, Fourier transform infrared (FTIR), CP-MAS ¹³C nuclear magnetic resonance (NMR) spectroscopy, elemental composition and surface charge. FTIR and solid state ¹³C NMR confirmed the introduction of quaternary ammonium moieties on cellulose. ¹³C NMR also showed that cationisation decreased the degree of crystallisation and lateral dimensions of cellulose fibrils. Nevertheless, 47 % - 72% of Cr(VI) ions were removed from solutions at pH 4, by 0.1 g of CHPTAC and GTMAC-cationised cellulose, respectively. Adsorption kinetics followed the pseudo-second order model and isotherms were best described by the Freundlich and Dubinin-Radushkevich models. When GTMAC-modified cellulose was applied to AMD contaminated water (pH 2.7), however, Cr(VI) uptake removal decreased to 22% likely due to competition from Al and Fe ions. Nevertheless, cationised materials displayed considerable antibacterial effects, reducing the viability of Escherichia coli by up to 45 % after just 3 hours of exposure. Together, these results suggest that cationised cellulose can be applied in the treatment of Cr(VI)-contaminated mine water particularly if pre-treatments to reduce Fe and Al concentrations are applied.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a human DNA repair protein. It is a member of the phospholipase D family based on the structure similarity. TDP1 is a key enzyme involved in repairing stalled topoisomerase 1 (TOP1)-DNA complexes. Previously we obtained with the CRISPR/Cas9 method HEK293A cells with the homozygous knockout of the Tdp1 gene and used knockout cells as a cellular model for studying the mechanisms of anticancer therapy. In this work we studied for the first time by transcriptomic analysis the effect of Tdp1 gene knockout on genes expression changes in human HEK293A cell line. We received original data that may indicate a role of TDP1 in other process besides repair of DNA-TOP1 complex. The differentially expressed genes (DEGs) analysis revealed that TDP1 could be involved in different processes such as cell adhesion and communication, spermatogenesis, mitochondrial function, neurodegeneration, cytokine response, and MAPK pathway signaling.

To understand the biological relevance and mode of action of artificial protein ligands, crystal structures with their protein targets are essential. Here, we describe and investigate all known crystal structures that contain a so-called “molecular tweezer” or one of its derivatives with an attached natural ligand on the respective target protein. The aromatic ring system of these compounds is able to include lysine and arginine side chains, supported by one or two phosphate groups that are attached to the half-moon shaped molecule. We analyse the corresponding crystal structures with 14-3-3 proteins in complex with mono- and diphosphate tweezers. Furthermore, we solved crystal structures of two different tweezer variants in complex with the enzyme 1-Pyrroline-5-carboxyl-dehydrogenase (P5CDH), and found that the tweezers are bound to a lysine and methionine side chain, respectively. The different binding modes and their implications for affinity and specificity are discussed, as well as the general problems in crystallizing protein complexes with artificial ligands.

For Interferometry Synthetic Aperture Radar (InSAR), the normal baseline is one of the main factors that affect the accuracy of the ground elevation. For Gaofen-3 (GF-3) InSAR processing, the poor accuracy of the real-time orbit determination resulting in a large baseline error, leads to the modulation error in azimuth and the slope error in range for timely Digital Elevation Model (DEM) generation. In order to address this problem, a baseline estimation method based on external DEM is proposed in this paper. Firstly, according to the characteristic of the real-time orbit of GF-3 images, orbit fitting is executed to remove the non-linear error factor. Secondly, the height errors are obtained in slant-range plane between Shuttle Radar Topography Mission (SRTM) DEM and the GF-3 generated DEM after orbit fitting. At the same time, the height errors are used to estimate the baseline error which has a linear variation. In this way, the orbit error can be calibrated by the estimated baseline error. Finally, DEM generation is performed by using the modified baseline and orbit. This procedure is implemented iteratively to achieve a higher accuracy DEM. Based on the results of GF-3 interferometric SAR data for Hebei, the effectiveness of the proposed algorithm is verified and the accuracy of GF-3 real-time DEM products can be improved extensively.

Neurofibromatosis type 2 (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2-deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2-deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

Vascular calcification (VC) is associated with increased cardiovascular risks in patients with chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors, like empagliflozin, can improve cardiovascular and renal outcomes. We assessed the expression of Runt-related transcription factor 2 (Runx2), interleukin (IL)-1β, IL-6, AMP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor (Nrf2), and heme oxygenase 1 (HO-1) in inorganic phosphate–induced VC in mouse VSMCs to investigate the mechanisms underlying empagliflozin’s therapeutic effects. We evaluated biochemical parameters, mean artery pressure (MAP), pulse wave velocity (PWV), transcutaneous glomerular filtration rate (GFR), and histology in an in vivo mouse model with VC induced by an oral high-phosphorus diet following a 5/6 nephrectomy in ApoE−/− mice. Compared to the control group, empagliflozin-treated mice showed significant reductions in blood glucose, MAP, PWV, and calcification, as well as increased calcium and GFR levels. Empagliflozin inhibited osteogenic trans-differentiation by decreasing inflammatory cytokine expression and increasing AMPK, Nrf2, and HO-1 levels. Empagliflozin mitigates high phosphate–induced calcification in mouse VSMCs through the Nrf2/HO-1 anti-inflammatory pathway by activating AMPK. Animal experiments suggested that empagliflozin reduces VC in CKD ApoE−/− mice on a high-phosphate diet.

This study is the first report of the successful cultivation of Dinophysis norvegica isolated from Japanese coastal waters (7 of 48 isolated cells were established as the clonal cultures, 14.5%) and their toxin content and production. The strains were maintained at relatively high abundance (>2,000 cells mL-1) for more than one year when fed on Mesodinium rubrum with the addition of Teleaulax amphioxeia. At the end of the one-month incubation, the total amounts of pectenotoxin-2 (PTX2), dinophysistoxin-1 (DTX1) and okadaic acid (OA) were 132.0-375.0 ng mL-1 (n = 7), 0.7-3.6 ng mL-1 (n = 3) and trace level OA (n = 1), respectively. Similarly, the cell quota of PTX2 and DTX1 were 60.6-152.4 pg cell-1 (n = 7) and 0.5-1.2 pg cell-1 (n = 3), respectively. These data indicated that toxin production varies depending on the strains in this species. In the growth experiment, D. norvegica grew, but it was very slow first 12 days. However, after that they grew exponentially with the maximum growth rate of 0.56 divisions day-1 (during Day 24-27), reaching a maximum concentration of 3,000 cells mL-1 at the end of incubation (Day 36), suggesting that they have a long lag phase. In the toxin production, OA was not at a detectable level (≤ 0.010 ng mL-1) during the 36 days of incubation except for Day 6. The concentration of DTX1 and PTX2 showed similar patterns as described for vegetative growth, but the toxin production still increased on Day 36 (1.3 ng mL-1 and 154.7 ng mL-1 in DTX1 and PTX2, respectively). The findings of this study provide novel information on the toxin content and production in D. norvegica as well as details on the culturing and maintenance of the species.

In an era of rapid technological improvements, state-of-the-art methodologies and tools dedicated to protecting and promoting our cultural heritage should be developed and extensively employed in the contemporary built environment and lifestyle. At the same time, sustainability principles underline the importance of the continuous use of historic or vernacular buildings as part of the building stock of our society. Adopting a holistic, integrated, multi-disciplinary strategy can bridge technological innovation with conserving and restoring heritage buildings. The paper presents ongoing research and results of the application of Machine Learning methods for the remote monitoring of the built environment of the historic cluster in Cypriot cities. This study is part of an integrated, multi-scale, and multi-discipline study of heritage buildings towards the creation of an online HBIM platform for urban monitoring.

Lung cancer is a common malignant tumor of the lung and the leading cause of cancer mortality worldwide. Non-small-cell lung cancer (NSCLC) accounts for 80%–85% of lung cancer, 40% of NSCLCs will have spread beyond the lungs by the time it is diagnosed. Long non-coding RNA (LncRNA) prostate androgen-regulated transcript 1 (PART-1) was reported that promote the development of several cancers. In the current study, we conducted experiments to investigate the role of PART-1 in the proliferation, invasion, and migration of NSCLC. The expression level of the PART-1 gene increased significantly in the NSCLC cell lines, including A549, H1229, H1650, H1975, and PC9. Knocking down of PART-1 inhibited the proliferation, invasion, and migration of A549 cells, moreover, decreased the tumor proliferation in nude mice. We confirmed that PART-1 targeted miR-204-3p directly, and miR-204-3p targeted the insulin-like growth factor binding protein 2 (IGFBP-2) directly. Furthermore, we discovered that PART-1 involved the NSCLC progression by regulating the miR-204-3p-targeted IGFBP-2 pathway. LncRNA PART-1 might be a target for treating NSCLC, and a warning sign of diagnosis of early lung cancer.

This study presents a vibration control using actively tunable vibration absorbers (ATVA) to suppress vibration of a thin plate. The ATVA’s is made of a sandwich hollow structure embedded with the electrorheological fluid (ERF). ERF is considered to be one of the most important smart fluids and it is suitable to be embedded in a smart structure due to its controllable viscosity property. ERF’s apparent viscosity can be controlled in response to the electric field and the change is reversible in 10 microseconds. Therefore, the physical properties of the ERF-embedded smart structure, such as the stiffness and damping coefficients, can be changed in response to the applied electric field. A mathematical model is difficult to be obtained to describe the exact characteristics of the ERF embedded ATVA because of the nonlinearity of ERF’s viscosity. Therefore, a fuzzy modeling and experimental validations of ERF-based ATVA from stationary random vibrations of thin plates are presented in this study. Because Type-2 fuzzy sets generalize Type-1 fuzzy sets so that more modelling uncertainties can be handled, a semi-active vibration controller is proposed based on Type-2 fuzzy sets. To investigate the different performances by using different types of fuzzy controllers, the experimental measurements employing type-1 fuzzy and interval type-2 fuzzy controllers are implemented by the Compact RIO embedded system. The fuzzy modeling framework and solution methods presented in this work can be used for design, performance analysis, and optimization of ATVA from stationary random vibration of thin plates.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases including oral cancer. Cancer cells usually escape from immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα in the tumor microenvironment of oral squamous cell carcinoma (OSCC), and performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating seven immune-related factors and several clinicopathological statuses. However, the immune-checkpoint related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference of the tumor immunity in the originating-epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC might be different in the originating-epithelium, keratinized or non-keratinized.

Breast cancer develops upon sequential acquisition of driver mutations in mammary epithelial cells; however how these mutations collaborate to transform normal cells remains unclear in most cases. We aimed to reconstitute this process in a particular case. To this end, we combined the activated form of the PI 3-kinase harboring the H1047R mutation with the inactivation of the histone lysine methyl-transferase KMT2D in the non-tumorigenic human mammary epithelial cell line MCF10A. We found that PI 3-kinase activation promoted cell cycle progression, especially when growth signals were limiting, as well as cell migration, both in a collective monolayer and as single cells. Furthermore, we showed that KMT2D inactivation had relatively little influence on these processes, except for single cell migration that KMT2D inactivation promoted in synergy with PI 3-kinase activation. Combination of these two genetic alterations induced expression of the ARPC5L gene that encodes a subunit of the Arp2/3 complex. ARPC5L depletion fully abolished the enhanced migration persistence exhibited by double-mutant cells. Our reconstitution approach in MCF10A has thus revealed both the cell function, single cell migration, and the underlying Arp2/3-dependent mechanism, which are synergistically regulated when KMT2D inactivation is combined with the activation of the PI 3-kinase.

Cellulose nanocrystals (CNCs) are a kind of nano-inclusions that have experienced tremendous expansion in the material industry due to their outstanding mechanical qualities, sizable surface area, and capacity for functional tuning. Due to their vast potential, however, present practises fall short of fully using them. For example, employing CNCs in various matrices with various surface chemistries can be challenging; this problem tends to get worse if the focus is furthered on bio-based applications. This paper reviews the use of CNCs as fillers in natural and man-made polymers; we have explored in depth the production, characterisation, and of CNCs from various sources and their inclusion into various matrices. Surface alterations and the introduction of CNCs in biodegradable polymer can have a significant impact on several industrial behemoths such as tissue engineering and biomedical applications; therefore, pursue of current manuscript is extremely warranted. Throughout the manuscript various assembly techniques that involves alteration and adjustment of polymer network in building up a hydrogel with higher fracture energy and mechanical properties are also included. From rheological perspective the hydrogel processing is also discussed with some models routinely used in the literature to describe these hydrogels. Finally, bio-based hydrogels mechanically reinforced with CNCs such as Xanthan Gum, Alginate, protein, and polysaccharides were discussed.

Background: Monoclonal antibodies against PD-1 or PD-L1 are established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4) additional ICPs such as lymphocyte activation gene-3 (LAG-3) are subject of current research. In the present retrospective gene ex-pression analysis, we evaluated the prognostic significance of LAG-3 in 461 patients with early breast cancer. In addition, we examined whether there was a correlation between the different ICPs and CD8 expression. Methods: Using microarray-based gene expression analysis, we examined the prognostic signif-icance for metastasis-free survival (MFS) of LAG-3 mRNA expression in the whole cohort of 461 breast cancer patients and among different molecular subtypes. Correlations were analyzed us-ing Spearman-Rho correlation coefficient. Results: In the whole cohort, LAG-3 expression had no significant impact on MFS (p = 0.712, Log Rank). In the subgroup analyses, there was a trend, that higher LAG-3 expression was associated with favorable outcome in the luminal B (p = 0.217), basal-like (p = 0.370) and HER2 (p = 0.089) subtypes, although significance was not reached. In contrast, in multivariate Cox regression analysis adjusted for age, tumor size, axillary nodal status, histological grade of differentiation and the proliferation marker Ki-67, LAG-3 showed a significant influence on MFS (HR 0.574; 95% CI 0.369–0.894; p = 0.014). High LAG-3 significantly correlated with CD8 ( = 0.571; p < 0.001). Conclusion: LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints such as LAG-3 could serve as therapeutic targets in breast cancer.

Salivarian trypanosomes are extracellular parasites causing anthroponotic and zoonotic infections. Anti-parasite vaccination in considered the only sustainable method for global trypanosomosis control. Unfortunately, not a single field applicable vaccine solution has been successful so far. Active destruction of the host’s adaptive immune system by trypanosomes is believed to contribute to this problem. Here we show Trypanosome brucei brucei infection results in the lasting obliteration of immunological memory, including vaccine-induced memory against non-related pathogens. Using the well-established DTPa vaccine model in combination with a T. b. brucei infection and diminazene diaceturate anti-parasite treatment scheme, our result demonstrate that while the latter ensured the full recovery from the T. b. brucei infection, it failed to restore an efficacious anti-pertussis vaccine recall response. DTPa vaccine failure coincided with a shift in the IgG1/IgG2a anti-pertussis antibody ratio in favor of the latter, and a striking impact on all spleen immune cell populations. Interestingly, an increased plasma IFNy level in DTPa vaccinated trypanosome infected mice did result in a temporary antibody-independent improvement of early-stage trypanosomosis control. In conclusion, our results are the first to show that trypanosome inflicted immune damage is permanent, and is not restored by successful anti-parasite treatment.

NS-3 is one of the most used Network Simulators because it includes different modules, applications and protocols to simulate a wide range of network. Since new proposals usually involve a large number of simulations, a procedure to automatize the simulation process and extract statistics is very useful. "Statistical Framework" (SF) is an important module of NS-3 because it fulfills this need. SF allows us to collect simulation data and obtain statistical reports for NS-3. In this report, we present a detailed description of statistical framework module and two useful examples of its configuration.

Network Simulators is typically used to study services and applications in complex scenarios due to the infeasibility of deploying real testbeds. Many problems can be solved by using network simulators such as NS-3. With this in mind, the aim of this article is to introduce new NS-3 users through detailed information. It is sometimes difficult to handle by new users the traditional manuals developed by NS-3 project official website. In this article, NS-3 for communication network and Eclipse Integrated Development Environment (IDE) for powerful programming language are integrated step-by-step, explaining the main features of these open source software packages and concluding with an example simulation. Our effort is to make it easy for a beginner to be part of the NS-3 research community and to maintain an open environment of knowledge.

Dietary intake of omega-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA) exerts antiarrhythmic effects, although the mechanisms are poorly understood. Here we investigated the possible beneficial actions of EPA on saturated fatty acid-induced changes of the L-type Ca2+ channel in cardiomyocytes. Cardiomyocytes were cultured with oleic acid/palmitic acid mixture (OAPA) in the presence or absence of EPA. Beating rate reduction of cardiomyocytes caused by OAPA were reversed by EPA. EPA also retrieved a reduction of Cav1.2-L-type Ca2+ current, mRNA and protein caused by OAPA. Immunocytochemical analysis revealed a distinct downregulation of the Cav1.2 channel caused by OAPA with a concomitant decrease in the phosphorylated component of a transcription factor adenosine-3’, 5’-cyclic monophosphate (cAMP) response element binding protein (CREB) in the nucleus, which were rescued by EPA. A free fatty acid receptor 4 (FFAR4) agonist TUG-891 reversed expression of Cav1.2- and CREB-mRNA caused by OAPA, whereas an FFAR4 antagonist AH-7614 abolished the effects of EPA. Excessive reactive oxygen species (ROS) accumulation caused by OAPA decreased Cav1.2- and CREB-mRNA expressions, which were reversed by an ROS scavenger. Our data suggest that EPA rescues cellular remodeling caused by OAPA lipotoxicity and oxidative stresses via both free fatty acid receptor 4-dependent and -independent pathways.

Cathepsin B (CatB) is thought to be essential for the induction of Porphyromonas gingivalis lipopolysaccharide (Pg LPS)-induced Alzheimer’s disease- like pathologies in mice, including interleukin-1β (IL-1β) production and cognitive decline. However, little is known about the role of CatB in Pg virulence factor-induced IL-1β production by microglia. We first subjected IL-1β-luciferase reporter BV-2 microglia to inhibitors of Toll-like receptors (TLRs), IκB kinase, and the NLRP3 inflammasome following stimulation with Pg LPS and outer membrane vesicles (OMVs). To clarify the involvement of CatB, we used several known CatB inhibitors, including CA-074Me, ZRLR, and human β-defensin 3 (hBD3). IL-1β production in BV-2 microglia induced by Pg LPS and OMVs was significantly inhibited by the TLR2 inhibitor C29 and the IκB kinase inhibitor wedelolactonne, but not by the NLRPs inhibitor MCC950. Both hBD3 and CA-074Me significantly inhibited Pg LPS-induced IL-1β production in BV-2 microglia. Although CA-074Me also suppressed OMV-induced IL-1β production, hBD3 did not inhibit it. Furthermore, both hBD3 and CA-074Me significantly blocked Pg LPS-induced nuclear NF-κB p65 translocation and IκBα degradation. In contrast, hBD3 and CA-074Me did not block OMV-induced nuclear NF-κB p65 translocation or IκBα degradation. Furthermore, neither ZRLR, a specific CatB inhibitor, nor shRNA-mediated knockdown of CatB expression had any effect on Pg virulence factor-induced IL-1β production. Interestingly, phagocytosis of OMVs by BV-2 microglia induced IL-1β production. Finally, the structural models generated by AlphaFold indicated that hBD3 can bind to the substrate-binding pocket of CatB, and possibly CatL as well. These results suggest that Pg LPS induces CatB/CatL-dependent synthesis and processing of pro-IL-1β without activation of the NLRP3 inflammasome. In contrast, OMVs promote the synthesis and processing of pro-IL-1β through CatB/CatL-independent phagocytic mechanisms. Thus, hBD3 can improve the IL-1β-associated vicious inflammatory cycle induced by microglia through inhibition of CatB/CatL.

The compound, C27H23N3 (1), crystallizes in the triclinic system of the P-1 space group. The unit cell comprises a dimer of 1, in which the monomers are linked by two complementary hydrogen bonds between N1 and H1-C1 of another molecule. The dimers form chains along the a-axis through intermolecular interactions between the N2 acceptor atoms and C17 donors from molecules in the nearest neighbouring dimer. These interactions form extended sheets of the dimers of 1, along the ab plane. The quinolinylmeth-2-yl groups of 1 lie in almost orthogonal planes and their N1/2(q) donor atoms being away from the apical amino N3 atom.

The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression's development. Given that obesity and depression mutually increase each other's risk of development by 50-60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines, and C-reactive protein (CRP). As pharmacotherapy fails in at least 30-40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further effort directed to implement these strategies in clinical practice could contribute to improved outcomes in patients with depression and comorbid obesity and/or metabolic dysregulation.

Rationale: The 14-3-3 protein family is known to interact with many proteins in non-cardiac cell types to regulate multiple signaling pathways, particularly those relating to energy and protein homeostasis; and the 14-3-3 network is a therapeutic target of critical metabolic and proteostatic signaling in cancer and neurological diseases. Although the heart is critically sensitive to nutrient and energy alterations, and multiple signaling pathways coordinate to maintain the cardiac cell homeostasis, neither the structure of cardiac 14-3-3 protein interactome, nor potential functional roles of 14-3-3 protein-protein interactions (PPIs) in heart has been explored. Objective: To establish the comprehensive landscape and characterize the functional role of cardiac 14-3-3 PPIs. Methods and Results: We evaluated both RNA expression and protein abundance of 14-3-3 isoforms in mouse heart, followed by co-immunoprecipitation of 14-3-3 proteins and mass spectrometry in left ventricle. We identified 52 proteins comprising the cardiac 14-3-3 interactome. Multiple bioinformatic analyses indicated that more than half of the proteins bound to 14-3-3 are related to mitochondria; and the deduced functions of the mitochondrial 14-3-3 network are to regulate cardiac ATP production via interactions with mitochondrial inner membrane proteins, especially those in mitochondrial complex I. Binding to ribosomal proteins, 14-3-3 proteins likely coordinate protein synthesis and protein quality control. Localizations of 14-3-3 proteins to mitochondria and ribosome were validated via immunofluorescence assays. The deduced function of cardiac 14-3-3 PPIs is to regulate cardiac metabolic homeostasis and proteostasis. Conclusions: Thus, the cardiac 14-3-3 interactome may be a potential therapeutic target in cardiovascular metabolic and proteostatic disease states, as it already is in cancer therapy.

Herpes simplex virus 1 (HSV-1) expresses a large number of miRNAs, and their function is still not completely understood. In addition, HSV-1 has been found to deregulate host miRNAs, which adds to the complexity of regulation of efficient virus replication. In this study, we comprehen-sively addressed the deregulation of host miRNAs by massive-parallel sequencing. We found that only miRNAs expressed from a single cluster, miR-183/96/182 are reproducibly deregulated dur-ing productive infection. These miRNAs are predicted to regulate a great number of potential tar-gets involved in different cellular processes and have only 33 shared targets. Among these, mem-bers of the FoxO family of proteins were identified as potential targets for all three miRNAs. However, our study shows that the upregulated miRNAs do not affect the expression of FoxO proteins, moreover these proteins were upregulated in HSV-1 infection. Furthermore, we show that the individual FoxO proteins are not required for efficient HSV-1 replication. Taken together, our results indicate a complex and redundant response of infected cells to the virus infection that is efficiently inhibited by the virus.

HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of TAR RNA with acetylpromazine bound to the bulge of TAR RNA, to dock compounds from Enamine database containing 1.6 million individual compounds. Docking identified 173 compounds that were analyzed for the inhibition of HIV-1 infection. Top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50=2.97 μM), T0516-4834 (IC50=0.2 μM) and T5628834 (IC50=3.46 μM), were further tested for HIV-1 transcription inhibition. Only T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas T6780107 compound inhibited equally basal and Tat-induced transcription and T5628834 compound only inhibited basal HIV-1 transcription. The T0516-4834 compound also showed strongest inhibition of HIV-1 gag RNA expression and p24 production in CEM T cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound disrupted Tat-TAR RNA interaction indicating that it might target TAR RNA. Also, of the three tested compounds, T5628834 but not T6780107 or T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. Taken together, our study identified novel compound T0516-4834 that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.