Since its initial characterization in 2016, the interferon stimulated gene Shiftless (SHFL) has proven to be a critical piece of the innate immune response to viral infection. SHFL expression stringently restricts the replication of multiple DNA, RNA, and retroviruses with an extraordinary diversity of mechanisms that differ from one virus to the next. These inhibitory strategies include the negative regulation of viral RNA stability, translation, and even the manipulation of RNA granule formation during viral infection. Even more surprisingly, SHFL is the first human protein found to directly inhibit the activity of the -1 programmed ribosomal frameshift, a translation recoding strategy utilized across nearly all domains of life and a several human viruses. Recent literature has shown that SHFL expression also significantly impacts viral pathogenesis in mouse models, highlighting its in-vivo efficacy. To help reconcile the many mechanisms by which SHFL restricts viral replication, we provide here a comprehensive review of this complex ISG, its influence over viral RNA fate, and the implications of its functions on the virus-host arms race for control of the cell.

Background and Objectives: Ischemic and idiopathic heart failure are two different etiologies, however reactive cardiac fibrosis together with impaired vasculogenesis has been described in both of them. Implication of main proangiogenic factors as: angiogenin, agiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) has been described mainly in experimental models of heart failure. However, differences in molecular pathways between these cardiomyopathies are still under investigation. In this short communication we aimed to evaluate and compare the expression of pro-angiogenic molecules in the heart tissue of patients with advanced chronic heart failure (CHF) of ischemic and idiopathic etiology. Methods and Results: Heart tissue from left ventricular walls was obtained at transplantation from ischemic heart disease (IHD), idiopathic cardiomyopathy (ICM) patients. Tissue samples were examined using immunohistochemistry for angiogenic molecules. Immunopositivity (I-pos) for angiopoietin-1 was mainly observed in the cardiomyocytes, while I-pos for Ang-2 and Tie-2 receptor mainly in endothelial cells. Procollagen-I (PICP), angiogenin, Ang-1, Tie-2 receptor, were similarly expressed in IHD and ICM patients. In contrast, endothelial immunopositivity for Ang-2 was higher in IHD samples compared to ICM (p=0.03). Conclusions: Ang-2 expression is different in heart tissue of ICM and ICM patients and distribution of Ang-1 and angiogenin is higher in cardiomyocytes, whereas Ang-2 higher in endothelial cells, suggesting a different pattern of angiogenic stimulation, or at least of altered endothelial integrity. This data may serve for further studies investigating angiogenesis signaling pathways and in HF of different etiology.

The strategy of any organization is based on the growth of its customer base, and one of 5 its principles is that selling a product to an existing customer is much more profitable than acquiring 6 a new customer. However, this approach has several opportunities for improvement, since it usu- 7 ally has a totally reactive approach, which does not give opportunity to the areas specialized in 8 customer experience and recovery, to give an effective response for that moment, since the customer 9 is gone at the time of the intervention. This happens because usually a diagnostic analysis of cus- 10 tomers who have stopped buying products or services in a defined period, commonly three (3) pe- 11 riods or months, is performed. This thesis work challenges the way to face this problem, and pro- 12 poses the development of a complete solution, which does not focus exclusively on the prediction 13 of churn, as is usually done in the state of the art research, but to intervene in different interactions 14 that can be carried out with customers. The above focused not only to prevent customer churn, but 15 to generate an added value of continuous improvement in sales processes, increase customer pene- 16 tration, leading to an improvement in customer experience and consequently, an increase in cus- 17 tomer loyalty.

Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we present the transcriptional regulation of inflammasome genes from sensors (e.g NLRP3) to substrates (e.g. IL-1β). Lineage-determining transcription factors shape inflammasome responses in different cell types with profound consequences on the responsiveness to inflammasome-activating stimuli. Pro-inflammatory signals (sterile or microbial) have a key transcriptional impact on inflammasome genes, which is largely mediated by NF-κB and, that translates into higher antimicrobial immune responses. Furthermore, diverse intrinsic (e.g. circadian clock, metabolites) or extrinsic (e.g. xenobiotics) signals are integrated by signal-dependent transcription factors and chromatin structure changes to modulate transcriptionally inflammasome responses. Finally, anti-inflammatory signals (e.g. IL-10) counterbalance inflammasome genes induction to limit deleterious inflammation. Transcriptional regulations thus appear as the first line of inflammasome regulation to raise the defense level in front of stress and infections but also to limit excessive or chronic inflammation.

For voltage-gated Ca2+ channel (VGCC), its α2δ subunits are traditionally considered to be auxiliary subunits that regulates VGCC trafficking to the plasma membrane. The antiepileptic, antinociceptive and anxiolytic gabapentin (GBP) has previously been shown to bind the VGCC α2δ subunits with high affinity to disrupt VGCC trafficking. Yet, the interaction between GBP and α2δ still remains poorly understood from a structural point of view. For instance, it is not clear yet what the structural implication is of α2δ-1-bound GBP against VGCC trafficking. With a set of experimental data-driven structural analysis of the VGCC α2δ-1 and its ligand GBP, this article postulates for the first time that: 1), α2δ-1 bound GBP stabilizes the α2δ-1-GBP complex structure; 2), α2δ-1 bound GBP restrains the conformational flexibility of α2δ-1; 3), α2δ-1-bound GBP establishes an electrostatic axis consisting of Q535 (Gln535)-R241 (Arg241)-GBP (gabapentin)-D452 (Asp452), which constitutes an energetically favourable contribution towards the structural stability of the α2δ-1-GBP complex and helps restrains the conformational flexibility and local structural rigidification of α2δ-1; and 4), GBP-induced local conformational inflexibility and structural rigidification of α2δ-1 is one key step in the pharmacological disruption of VGCC trafficking by GBP.

We construct families of ground state representations of the U(1)-current net and of the Virasoro nets Vir_c with central charge c ≥ 1. We show that these representations are not covariant with respect to the original dilations, and those on the U(1)-current net are not solitonic. Furthermore, by going to the dual net of with respect to the ground state representations of Vir_c, one obtains possibly new family of Möbius covariant nets on S¹.

Targeted radioisotope-guided sentinel lymph node dissection (sLND) has shown high diagnostic accuracy in prostate cancer (PCa). To overcome the downsides of the radioactive tracers, magnetometer-guided sLND using superparamagnetic iron oxide nanoparticles (SPIONs) was successfully applied in PCa. This prospective study (SentiMag Pro II, DRKS00007671) determined the diagnostic accuracy of magnetometer-guided sLND in intermediate- and high-risk PCa. Fifty intermediate- or high-risk PCa patients (PSA≥10 ng/ml and/or Gleason score ≥7; median PSA 10.8 ng/ml, IQR 7.4–19.2 ng/ml) were enrolled. After intraprostatic SPIONs injection a day earlier, patients underwent magnetometer-guided sLND and eLND, followed by radical prostatectomy. SLNs were detected in vivo and in ex vivo samples. Diagnostic accuracy of sLND was assessed using eLND as the reference. SLNs were detected in all patients (detection rate 100%), with 447 SLNs (median 9, IQR 6–12) being identified and 966 LNs (median 18, IQR 15-23) being removed. Thirty-six percent (18/50) of patients had LN metastases (median 2, IQR 1–3). Magnetometer-guided sLND had 100% sensitivity, 97.0% specificity, 94.4% positive predictive value, 100% negative predictive value, 0.0% false negative rate, and 3.0% additional diagnostic value (LN metastases only in SLNs outside the eLND template). In vivo, one positive SLN/LN-positive patient was missed, resulting in a sensitivity of 94.4%. In conclusion, this new magnetic sentinel procedure has high accuracy for nodal staging in intermediate- and high-risk PCa. The reliability of intraoperative SLN detection using this magnetometer system requires verification in further multicentric studies.

Oncogenic protein E6 from Human Papilloma Virus 16 (HPV-16) mediates the degradation of Membrane-associated guanylate kinase with inverted domain structure-1 (MAGI-1), throughout the interaction of its protein binding motif (PBM) with the Discs-large homologous regions 1 (PDZ1) domain of MAG1-1. Generic variation in the E6 gene that translates to changes in the protein’s amino acidic sequence modifies the interaction of E6 with the cellular protein MAGI-1. MAGI-1 is a scaffolding protein found at tight junctions of epithelial cells, where it interacts with a variety of proteins regulating signaling pathways. MAGI-1 is a multidomain protein containing two WW (rsp-domain-9), one guanylate kinase-like, and six PDZ domains. PDZ domains played an important role in the function of MAGI-1 and served as targets for several viral proteins including the HPV-16 E6. The aim of this work was to evaluate, with an in silico approach, employing molecular dynamics simulation and protein-protein docking, the interaction of the intragenic variants E-G350 (L83V), E-C188/G350 (E29Q/L83V), E-A176/G350 (D25N/L83V), E6-AAa (Q14H/H78Y/83V) y E6-AAc (Q14H/I27RH78Y/L83V) and E6-reference of HPV-16 with MAGI-1. We found that variants E-G350, E-C188/G350, E-A176/G350, AAa and AAc increase their affinity to our two models of MAGI-1 compared to E6-reference.

This paper presents ensemble learning of multi-source satellite sensors dataset to obtain better predictive performance of the forest biomass. Spectral, spectral-indices, and spectral-textural features were generated from two optical satellite sensors, Landsat 8 Operational Land Imager (OLI) and Sentinel-2 Multispectral Instrument (MSI). In addition, two radar satellite sensors, Sentinel-1 C-band Synthetic Aperture Radar (CSAR), and Advanced Land Observing Satellite (ALOS-2) Phased Array type L-band Synthetic Aperture Radar (PALSAR-2) were utilized to generate backscattering and backscattering-textural features. The plot-wise above ground biomass data available from five forests in New England region were utilized. Ensemble learning of multi-source satellite sensors dataset was carried out by employing four machine learning regressors namely, Support Vector Machines (SVM), Random Forests (RF), Gradient Boosting (GB), and Multilayer Perceptron (MLP). A five-fold cross-validation method was used to evaluate predictive performance of the multi-source satellite sensors. The integration of multi-source satellite features, comprising of spectral, spectral-indices, backscattering, spectral-textural, and backscattering-textural information, through ensemble learning and cross-validation approach implemented in the research showed promising results (R² = 0.81, RMSE = 46.2 Mg/ha) for the estimation of plots-level forest biomass in New England region.

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.

Breast cancer (BC) is the most common type of cancer in both men and women alike, but it is more prevalent in women. Natural compounds that can modulate the oncogenic process can be considered a significant anti-cancer agent for treating BC. These natural compounds are more effective than synthetic drugs, which have profound side effects on the normal cell and resistance to cancer cells. Genistein is a type of dietary phytoestrogen included in the flavonoid group with a similar structure of estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutics drugs. Several research studies demonstrated that it can target the estrogen receptor (ER), Human epidermal growth factor receptor-2 (HER2), and Breast cancer gene-1 (BRCA-1) in multiple BC cell lines, as well as sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. Genistein effectively showed anti-cancer activities through apoptosis induction, arresting cell cycle, inhibiting angiogenesis with metastasis, reducing inflammation, mammosphere formation, tumor growth, up-regulating tumor suppressor gene, and downregulating oncogene in suppressing cancer progression in vitro and animal model study. In addition, research studies have also suggested that these phytochemicals synergistically reverse the resistance mechanism of chemotherapeutic drugs, increasing the efficacy of some chemoinformatics drugs. Our review article aims to unbox and validate the molecular pharmacology in breast tissue, cell-specific anti-cancer mechanism with synergistic activity, and possible pharmacokinetic parameters of Genistein as a potential alternative therapeutic option for the treatment of BC.

Coronavirus disease 2019 (COVID-19) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in tremendous morbidity and mortality worldwide. A major underlying cause of COVID-19 mortality is a hyperinflammatory cytokine storm in severe/critically ill patients. Although many clinical trials are testing the efficacy of targeting inflammatory cytokines/chemokines in COVID-19 patients, the critical inflammatory mediator initiating COVID-19 patient death is undefined. Here we suggest that the immunopathological pathway leading to COVID-19 mortality can be divided into three stages with distinct clinical features that can be used to guide therapeutic strategies. Our interpretation of the recently published clinical trials from COVID-19 patients suggests that the clinical efficacy in preventing COVID-19 mortality using IL-1 blockade is subjected to notable caveats, while that for IL-6 blockade is suboptimal. We discuss critical factors in determining appropriate inflammatory cytokine/chemokine targets, timing, and combination of treatments to prevent COVID-19 mortality.

Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4⁺ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.

Antisense oligonucleotide (ASO)-mediated exon skipping has become a valuable tool for investigating gene function and developing gene therapy. Machine learning-based computational methods such as eSkip-Finder have been developed to predict the efficacy of ASOs via exon skipping. However, these methods are computationally demanding, and the accuracy of predictions remains suboptimal. In this study, we propose a new approach to reduce computational burden and improve prediction performance by using feature selection within machine learning algorithms and ensemble learning techniques. We evaluated our approach using a dataset of experimentally validated exon skipping events, dividing it into training and testing sets. Our results demonstrate that using a 3-way voting approach with random forest, gradient boosting, and XGBoost can significantly reduce computation time to under ten seconds while improving prediction performance, as measured by R2 for both 2’-O-methyl nucleotides (2OMe) and phosphorodiamidate morpholino oligomers (PMOs). Additionally, the feature importance ranking derived from our approach is in good agreement with previously published results. Our findings suggest that our approach has the potential to enhance the accuracy and efficiency of predicting ASO efficacy via exon skipping. It could also facilitate the development of novel therapeutic strategies. This study could contribute to the ongoing efforts to improve ASO design and optimize gene therapy approaches.

Circadian rhythms misalignment is associated with hypertension. The aim of the study was to evaluate the concentration of selected clock proteins- cryptochrome 1 (CRY1) and circadian locomotor output cycles kaput (CLOCK) and to determine their relationships with biochemical and anthropometric parameters and lifestyle elements (diet, physical activity, quality of sleep) in hypertensive patients. In 25 female with hypertension (HT) and 49 non-hypertensive women (NHT), the CRY1 and CLOCK concentrations, total antioxidant status (TAS), lipid profile and glycemia were conducted. Blood pressure and anthropometric measurements, nutritional, exercise and sleep analyses were performed. In HT the CRY1 level was 40.2% lower than in the NHT. No differences were noted in CLOCK concentration between groups. The study showed no relationship between CRY1 or CLOCK concentrations and glucose or lipids profile, amount of physical activity and sleep quality, although CRY1 was associated with some anthropometric parameters. There was a negative correlation between the CLOCK concentration and the amount of saturated fatty acids consumed (24h) in HT. That indicates the possible influence of the diet on the CLOCK level. In a detailed prognosis of the risk of hypertension, it is worth considering the measurement of the level of CRY1 in populations with abnormal anthropometric indices.

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1β mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

Seeds represent the major source of food protein, impacting on both human nutrition and animal feeding. Therefore, seed quality needs to be appropriately addressed in the context of viability and food safety. Indeed, long-term and inappropriate storage of seeds might result in enhancement of protein glycation, which might affect their quality and longevity. Glycation of seed proteins can be probed by exhaustive acid hydrolysis and quantification of the glycation adduct N^ɛ-(carboxymethyl)lysine (CML) by liquid chromatography-mass spectrometry (LC-MS). This approach, however, does not allow analysis of thermally and chemically labile glycation adducts, like glyoxal-, methylglyoxal- and 3-deoxyglucosone-derived hydroimidazolones. Although enzymatic hydrolysis might be a good solution in this context, it requires aqueous conditions, which cannot ensure reconstitution of seed protein isolates. Because of this, the complete profiles of seed AGEs are not characterized so far. Therefore, here we propose the approach, giving access to quantitative solubilization of seed proteins in presence of sodium dodecyl sulfate (SDS) and their quantitative enzymatic hydrolysis prior to removal of SDS by reversed phase solid phase extraction (RP-SPE). Using MG-H1 as a case example, we demonstrate the applicability of this method for reliable and sensitive LC-MS-based quantification of chemically labile AGEs and its compatibility with bioassays.

E-commerce businesses employ recommender models to assist in identifying a personalized set of products for each visitor. To accurately assess the recommendations’ influence on customer clicks and buys, three target areas—customer behavior, data collection, user-interface —will be explored for possible sources of erroneous data. Varied customer behavior misrepresents the recommendations’ true influence on a customer due to the presence of B2B interactions and outlier customers. Non-parametric statistical procedures for outlier removal are delineated and other strategies are investigated to account for the effect of a large percentage of new customers or high bounce rates. Subsequently, in data collection we identify probable misleading interactions in the raw data, propose a robust method of tracking unique visitors, and accurately attributing the buy influence for combo products. Lastly, user-interface issues discuss the possible problems caused due to the recommendation widget’s positioning on the e-commerce website and the stringent conditions that should be imposed when utilizing data from the product listing page. This collective methodology results in an exact and valid estimation of the customer’s interactions influenced by the recommendation model in the context of standard industry metrics such as Click-through rates, Buy-through rates, and Conversion revenue.

We describe an efficient approach to radiometrically flatten geocoded stacks of calibrated synthetic aperture radar (SAR) data for terrain-related effects. We use simulation to demonstrate that, for the Sentinel-1 mission, one static radiometric terrain flattening factor derived from actual SAR imaging metadata per imaging geometry is sufficient for flattening interferometrically compliant stacks of SAR data. We quantify the loss of precision due to application of static flattening factors, and show that these are well below stated requirements of change detection algorithms. Finally, we discuss the implications of applying radiometric terrain flattening to geocoded SAR data instead of the traditional approach of flattening data provided in the original SAR image geometry. The proposed approach allows for efficient and consistent generation of five different Committee of Earth Observation Satellites (CEOS) Analysis Ready Dataset (ARD) families - Geocoded Single Look Complex (GSLC), Interferometric Radar (InSAR), Normalized Radar Backscatter (NRB), Polarimetric Radar (POL) and Ocean Radar Backscatter (ORB) from SAR missions in a common framework.

Foot-and-mouth disease virus (FMDV) causes the highly contagious foot-and-mouth disease, which is characterized by the appearance of vesicles in and around the mouth and feet of cloven-hoofed animals. BHK21 cells are the cell line of choice for the propagation of FMDV for vaccine production world-wide but vary in their susceptibility for different FMDV strains. Previous studies showed that the FMDV resistance of a certain BHK cell line can be overcome by using a closely related but permissive cell line for the pre-adaptation of the virus, but the adapted strains were found to harbor several capsid mutations. In this study, these adaptive mutations were introduced into the original Asia-1 Shamir isolate individually or in combination to create a panel of 17 Asia-1 mutants by reverse genetics and examine the effects of the mutations on receptor usage, viral growth, immunogenicity and stability. A single amino acid exchange from glutamic acid to lysine at position 202 in VP1 turned out to be of major importance for productive infection of the suspension cell line BHK-2P. In consequence, two traditionally passage-derived strains and two recombinant viruses with a minimum set of mutations were tested in vivo. While the passaged-derived viruses showed a reduced particle stability, the genetically modified viruses were more stable but did not confer a protective immune response against the original virus isolate.

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.

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

The objective of this study was to identify circulating miRNAs affected by disease duration in newly diagnosed children with type 1 diabetes. Forty children and adolescents from The Danish Remission Phase Cohort were followed with blood samples drawn at 1, 3, 6, 12 and 60 months after diagnosis. Pancreatic autoantibodies were measured at each visit. Cytokines were measured only the first year. miRNA expression profiling was performed by RT-qPCR and quantified for 179 human plasma miRNAs. The effect of disease duration was analyzed by mixed models for repeated measurements, adjusted for sex and age. Eight miRNAs (hsa-miR-10b-5p, hsa-miR-17-5p, hsa-miR-30e-5p, hsa-miR-93-5p, hsa-miR-99a-5p, hsa-miR-125b-5p, hsa-miR-423-3p and hsa-miR-497-5p) were found to significantly change expression (adjusted p-value < 0.05) with disease progression. Three pancreatic autoantibodies ICA, IA-2A, GADA65 and 4 cytokines IL-4, IL-10, IL-21, IL-22 were associated with the miRNAs at different time points. Pathway analysis revealed association with various immune-mediated signaling pathways. Eight miRNAs, involved in immunological pathways changed expression levels during the first five years after diagnosis in children with type 1 diabetes, and were associated with variations in cytokine and pancreatic antibodies, suggesting a possible effect on the immunological processes in the early phase of the disease.

Embryo stage of oxidation of an epi Ge(001)-2×1 by atomic oxygen and molecular O₂ is studied via synchrotron radiation photoemission. The topmost surface buckled with the up- and down-dimer atoms and the first subsurface layer behave distinctly from the bulk by exhibiting surface core-level shifts in the Ge 3d core-level spectrum. The O₂ molecules become dissociated upon reaching the epi Ge(001)-2×1 surface. One of the O atom removes off the up-dimer atom, and the other bonds with the underneath Ge atom in the subsurface layer. Atomic oxygen adsorbed on the epi Ge(001)-2×1 preferentially in between the up-dimer atoms and the underneath subsurface atoms without affecting the down-dimer atoms. The electronic environment of the O-affiliated Ge up-dimer atoms becomes similar to that of the down-dimer atoms. Both exhibit an enrichment in charge, where the subsurface of the Ge layer is maintained in a charge-deficient state. The dipole moment originally generated in the buckled reconstruction no longer exists, thereby resulting in a decrease in the ionization potential. The down-dimer Ge atoms and the back-bonded subsurface atoms remain inert to atomic O and molecular O₂, a possible cause of low reliability in Ge-related metal-oxide-semiconductor (MOS) devices.

The switch from intermittently scanned continuous glucose monitoring (isCGM) to real-time (rt) CGM could improve glycemic management in suboptimal controlled type 1 diabetes patients, but long-term study is lacking. We evaluated retrospectively the ambulatory glucose profile (AGP) in such patients after switching from Free Style libre 1 (FSL1) to Dexcom G4 (DG4) over 1 year. Patients (n=21, 43±15 years, BMI 25±5, HbA1c 8.1±1.0%) had severe hypoglycemia and/or HbA1c≥8%. AGP metrics (time-in-range (TIR) 70-180 mg/dL, time-below-range (TBR)<70 mg/dL or <54 mg/dL, glucose coefficient of variation (%CV), time-above-range (TAR) >180 mg/dL or >250 mg/dL, glucose management indicator (GMI), average glucose) were collected the last 3 months of FSL1 use (M0) and of DG4 for 3, 6 (M6) and 12 (M12) months of use. Values were means ± standard deviation or medians [Q1;Q3]. At M12 versus M0, the higher TIR (50±17 vs. 45±16, P=0.036), and lower TBR<70 mg/dL (2.5 [1.6;5.5] vs. 7.0 [4.5;12.5], P=0.0007), TBR<54 mg/dL (0.7 [0.4;0.8] vs. 2.3 [0.8;7.0], P=0.007) and %CV (39±5 vs. 45±8, P=0.0009), evidenced a long-term effectiveness of the switch. Compared to M6, TBR<70mg/dL decreased, %CV remained stable, while the improvement on hyperglycemia exposure decreased (higher GMI, TAR and average glucose). This switch was a relevant therapeutic option, though a loss of benefit on hyperglycemia stressed the need for optimized management of threshold alarms. Nevertheless, few patients attained the recommended values for AGP metrics, and the reasons why some patients are “responders” vs “non-responders” warrant to be investigated.

Glucose is the primary energy fuel used by the brain and is transported across the blood-brain barrier (BBB) by the glucose transporter type 1 and 2.[1] A GLUT1 genetic defect is responsible for glucose transporter type 1 deficiency syndrome (GLUT1DS). Patients with GLUT1DS may present with pharmaco-resistant epilepsy, developmental delay, microcephaly, and/or abnormal movements, with tremendous phenotypic variability. Diagnosis is made by the presence of specific clinical features, hypoglycorrhachia and an SLC2A1 gene mutation. Treatment with a ketogenic diet therapy (KDT) is the standard of care as it results in production of ketone bodies which can readily cross the BBB and provide an alternate energy source to the brain in the absence of glucose. KDTs have been shown to reduce seizures and abnormal movements in children diagnosed with GLUT1DS. However, little is known about the impact of KDT on cognitive function, seizures and movement disorders in adults newly diagnosed with GLUT1DS and started on a KDT in adulthood, or the appropriate ketogenic diet therapy to administer. This case report demonstrates the potential benefits of using a modified Atkins diet (MAD), a less restrictive ketogenic diet therapy on cognition, seizure control and motor function in an adult with newly-diagnosed GLUT1SD.

A double-stranded RNA (dsRNA) virus was isolated and characterized from a strain EW220 of the phytopathogenic fungus Botryosphaeria dothidea. The full-length cDNAs of dsRNAs were 6,434 bp and 5,986 bp in size, respectively. The largest dsRNA of BdBRV1 encodes a cap-pol fusion protein that contains part coat protein gene and a RNA-dependent RNA polymerase (RdRp) domain, and the second dsRNA encodes a hypothetical protein. The dsRNA virus was named Botryosphaeria dothidea botybirnavirus 1 (BdBRV1). BdBRV1 contains spherical virions that are 37 nm in diameter consisting of two segments. The structural proteins of BdBRV1 virus particles were 110 kDa, 90 kDa, and 80 kDa, which encoded by dsRNA1 and 2-ORFs. The analysis of genome sequences revealed that the sequences of BdBRV1 shared 99% identity with Bipolaris maydis botybirnavirus 1(BmBRV1). Phylogenetic reconstruction indicated that BdBRV1 and BmBRV1 are phylogenetically related to the genus Botybirnavirus. Importantly, BdBRV1 influences the growth of B. dothidea and confers hypovirulence to the fungal host. BdBRV1 and BmBRV1 were two strains of the same virus. To our knowledge, this is the first report of a botybirnavirus in B. dothidea and our result might be the first funding in the different fungi infected by the same virus.

Background: Lung cancer (LC) is a major leading cause of death worldwide. Immunomodulators that target several immune mechanisms have proven to reduce tumor burden in experimental models through induction of the immune microenvironment. We hypothesized that other biological mechanisms may also favor tumor burden reduction in lung cancer-bearing mice treated with immunomodulators. Methods: Tumor weight, area, and immune cells (T, B, macrophages, and TNF-alpha levels, immunohistochemistry) and tumor growth, oxidative stress, apoptosis, autophagy, and sirtuin-1 markers were analyzed (immunoblotting) in subcutaneous tumor of BALB/c mice injected with LP07 adenocarcinoma cells treated with monoclonal antibodies (CD-137, CTLA-4, PD-1, and CD-19, N=9/group) and non-treated control animals. Results: Compared to non-treated cancer mice, in tumors of monoclonal-treated animals, tumor area and weight and ki-67 significantly reduced, while T cell counts, oxidative stress, apoptosis, autophagy, and sirtuin-1 marker increased. Conclusion: Immunomodulators elicited a reduction in tumor burden (reduced tumor size and weight) through decreased tumor proliferation and increased oxidative stress, apoptosis, autophagy, and sirtuin-1 levels, which may have interfered with the immune profile of the tumor microenvironment. Future research should be devoted to the elucidation of the specific contribution of each biological mechanism to the reduced tumor burden.

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.

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are a diverse and evolutionarily conserved family of cytidine deaminases that provide a variety of functions from tissue-specific gene expression and immunoglobulin diversity to control of viruses and retrotransposons. APOBEC family expansion has been documented among mammalian species, suggesting a powerful selection for their activity. Enzymes with a duplicated zinc-binding domain often have catalytically active and inactive domains, yet both have antiviral function. Although APOBEC antiviral function was discovered through hypermutation of HIV-1 genomes lacking an active Vif protein, much evidence indicates that APOBECs also inhibit virus replication through mechanisms other than mutagenesis. Multiple steps of the viral replication cycle may be affected, although nucleic acid replication is a primary target. Packaging of APOBECs into virions was first noted with HIV-1, yet is not a prerequisite for viral inhibition. APOBEC antagonism may occur in viral producer and recipient cells. Signatures of APOBEC activity include G-to-A and C-to-T mutations in a particular sequence context. The importance of APOBEC activity for viral inhibition is reflected in the identification of numerous viral factors, including Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to selection for viral variants.

Neurokinin-1 receptor (NK-1R) antagonists exert an antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exerted multiple actions against cancer: antiproliferative and anti-Warburg effects, apoptosis, anti-angiogenic and antimetastatic. These multiple effects have been shown in a broad-spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed as well as the possible link, through the SP/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent.

Plants offer a simpler and cheaper alternative to mammalian animal models for the study of Endoplasmic Reticulum glycoprotein folding Quality Control (ERQC). In particular, the Arabidopsis thaliana (At) innate immune response to bacterial peptides provides an easy means of assaying ERQC function in vivo. A number of mutants that are useful to study ERQC in planta have been described in the literature, but only for a subset of these mutants the innate immune response to bacterial elicitors has been measured beyond monitoring plant weight and some physio-pathological parameters related to the plant immune response. In order to probe deeper into the role of ERQC in the plant immune response, we monitored expression levels of the PHI-1 and RET-OX genes in the At ER α-Glu II rsw3 and the At UGGT uggt1-1 mutant plants, in response to bacterial peptides elf18 and flg22. The elf18 response was impaired in the rsw3 but not completely abrogated in the uggt1-1 mutant plants, raising the possibility that the latter enzyme is partly dispensable for ERF signalling. In the rsw3 mutant, seedling growth was impaired only by concomitant application of the At ER α-Glu II NB-DNJ inhibitor at concentrations above 500 nM, suggesting residual activity in this mutant. The study highlights the need for extending plant innate immune response studies to assays sampling EFR signalling at the molecular level.

Ulcerative colitis (UC) is a relatively frequent, chronic disease that impacts significantly the patient’s quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) is a cytokine with potent cytoprotective, anti-inflammatory, and antiapoptotic properties. The purpose of this study was to assess if the administration of CT-1 could reduce colon damage in mice with experimental UC. UC was induced with 5% dextran sulfate sodium (DSS) in the drinking water. Some mice received i.v. dose of CT-1 (200 µg/kg) 2 hours before and 2 and 4 days after DSS administration. Animals were followed during 7 days after DSS. The severity of UC was measured by standard scores. Colon damage was assessed by histology and immunohistochemistry. Inflammatory mediators were measured by Western blot and PCR. CT-1 administration to DSS-treated mice ameliorated both the clinical course (disease activity index), histological damage, inflammation (colon expression of TNF-α, IL-17, IL-10, INF-γ, and iNOS), and apoptosis. Our results suggest that CT-1 administration before UC induction improves the clinical course, tissue damage and inflammation degree in DSS-induced UC in mice.

Before the adaptive immune response is established, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defence mechanisms are debated. Among these mechanisms, we focused on a RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as it has been recently demonstrated. NMD is a cotranslational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition. HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the most fit clones despite genome instability; however, its direct long-term impact remains to be investigated.

A new variant of the SARS-CoV-2 Omicron BA.5 virus has displaced all previous variants of the virus around the world. Preliminary assessment of the effectiveness of drugs for the prevention and treatment of COVID-19 requires the availability of infection models in animals. In this study, we characterize the infection model SARS-CoV-2 Omicron BA.5 and its progeny sublineage BE.1 in hACE2-transgenic mice and in Syrian hamsters. Both sublineages turned out to be pathogenic for animals – the challenged animals showed weight loss, a high level of viral load and acute inflammation in the lungs. Part of BA.5-infected mice died after virus challenge, indicating that this virus variant is more pathogenic than the previous BA.1 variant but less pathogenic than Wuhan variant.

This study investigates the spatial signatures of seasonal snow in Synthetic Aperture Radar (SAR) observations at different spatial scales and for different physiographic regions. Sentinel-1 C-band (SAR) backscattering coefficients (BSC) were analyzed in the Swiss Alps (SA), in high elevation forest and grasslands in Grand Mesa (GM), Colorado, and in North Dakota (ND) croplands. GM BSC exhibit 10dB sensitivity to wetness at small scales (~100 m) over homogeneous grassland. Sensitivity decreases to 5 dB in the presence of trees, and it is demonstrated that VH BSC sensitivity enables wet snow mapping below the tree-line. Area-variance scaling relationships show minima at ~100 m and 150-250 m respectively in barren and grasslands in SA and GM, increasing up to 1 km and longer in GM forests and ND agricultural fields. The spatial organization of BSC (as described by 1D-directional BSC wavelength spectra) exhibits multi-scaling behavior in the 100 -1,000 m range with a break at (180-360 m) that is also present in UAVSAR L-band measurements in GM. Spectral slopes in GM forested areas steepen during accumulation and flatten in the melting season with mirror behavior for grasslands reflecting changes in scattering mechanisms with snow depth and wetness, and vegetation mass and structure. Overall, this study reveals persistent patterns of SAR scattering variability spatially organized by land-cover, topography and regional winds with large inter-annual variability tied to precipitation. This dynamic scaling behavior emerges as an integral physical expression of snowpack variability that can be used to model sub-km scales and for downscaling applications.

Bone marrow derived adult human mesenchymal stem cells (hMSCs) possess therapeutic qualities that enable them to enhance wound repair. However, the mechanisms by which this occurs remains poorly understood. Basic mechanisms may include the directed migration of delivered cells to target sites and/or the production and release of soluble factors that act at a distance. Allogeneic and even xenogeneic cells may effectively participate in wound repair. Labeled hMSCs were delivered to full-thickness skin wounds that were created in immunologically competent mice. The delivery occurred on day 3 post-wounding using two different carriers; one which released cells and one which retained cells. The fates of the delivered cells were tracked for up to 25 days. During this period, released cells migrated as a tight cohort deep into the wound to reach the subdermal vascular plexus. Simultaneously, enhanced formation of granulation tissue was evident. This migration of hMSCs was not essential in that enhanced granulation tissue formation and wound contraction occurred when cells were retained in the carrier matrix. This provided further evidence for the release of therapeutic factors by hMSCs to sites of injury.

Studies have previously described the occurrence of multidrug-resistant (MDR) Escherichia coli in human and veterinary medical settings, livestock, and, to a lesser extent, in the environment and food. While they mostly analyzed foodborne E. coli regarding phenotypic and sometimes genotypic antibiotic resistance and basic phylogenetic classification, we have limited understanding of the in vitro and in vivo virulence characteristics and global phylogenetic contexts of these bacteria. Here, we investigated an E. coli strain (PBIO3502) isolated from a pork sausage in Germany in 2021 in-depth. Whole-genome sequence analysis revealed sequence type (ST)58, which is an emerging international high-risk clonal lineage. In addition to its MDR phenotype that mostly matched the genotype, PBIO3502 demonstrated pronounced virulence features, including in vitro biofilm formation, siderophore secretion, serum resilience, and in vivo mortality in Galleria mellonella larvae. Along with the genomic analysis indicating close phylogenetic relatedness of our strain with publicly available, clinically relevant representatives of the same ST, these results suggest the zoonotic and pathogenic character of PBIO3502 with the potential to cause infection in humans and animals. Also, our study highlights the necessity of the One Health approach while integrating human, animal, and environmental health, as well as the role of meat products and food chains in the putative transmission of MDR pathogens.

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.

The incidence of Type 1 Diabetes (T1D) in the Arab world, particularly, oil and gas rich Gulf Cooperative Council (GCC) countries has more than doubled in the last twenty years. Therefore, there is a dire need for careful systematic familial cohort studies, especially in high-risk populations. Several immunogenetic factors affect the pathogenesis of the disease. Genes in the human leukocyte antigen (HLA) account for the major genetic susceptibility to the disease. The triggering agents initiate disease onset by destruction of pancreatic β-cells. The autoantibodies against glutamic acid decarboxylase (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA), and zinc transporter-8 (ZnT-8A) comprise the most reliable biomarkers for T1D in both children and adults. Although three of the GCC countries, namely Kuwait, Saudi Arabia and Qatar are among the top 10 countries with high incidence rate of T1D, no proper diagnostic and prediction tools were applied in the region. Understanding the disease sequelae in a homogenous gene pool with high consanguinity in the GCC could help solve the challenges in understanding pathogenesis, as well as hasten the prevention of T1D. Arab states must incorporate T1D predictive and intervention policies on a war-footing basis to minimize the burden of this serious disease.

Developed countries have shown a time trend towards a younger age at menarche (AAM), which is associated with increased risk of later obesity and non-communicable diseases. We aimed to assess whether a time trend in AAM with associated disease risk is also present in Mexico. For this, we used data of 30,826 women from the Mexican National Health Survey (2000). Linear and log binomial regression was used for nutritional and disease outcomes, whereas Welch-ANOVA was used to test for a time trend. AAM decreased over time (p < 0.001), with a maximal difference of 0.99 years between the 1920s (13.6 years) and 1980s (12.6 years). AAM (in years) was negatively associated with weight (β = -1.01 kg; 95 % CI -1.006, -1,004) and BMI (β = -1.01 kg/m2; -1.007, -1.006), and positively with height (β = 0.18 cm; 0.112, 0.231). AAM was associated with diabetes (RR = 0.95; 0.93, 0.98) and hypercholesterolemia (RR = 0.93; 0.90, 0.95), but not with hypertension, breast cancer or arthritis. In Mexico, AAM decreased significantly during the 20th century. AAM was inversely associated with adult weight and BMI, and positively with height. Women with a later AAM had a lower risk of diabetes and hypercholesterolemia.

Since the spread of the deadly virus SARS-CoV2 in late 2019, researchers have restlessly been seeking for unraveling how the virus factually enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: 1- the nano-machine Spike protein on behalf of the virus, 2- angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, 3- some host proteases and proteins exploited by SARS-CoV2, In this review, the complex process of SARS-CoV2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the Spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Besides, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.

The emergence of cloud computing, big data analytics, and machine learning has catalysed the use of remote sensing technologies to enable more timely land management of sustainability indicators such as ground cover and grassland biomass, given the uncertainty of future climate and drought conditions. Here, we examine the potential of “regenerative agriculture”, as an adaptive grazing management strategy to minimise bare ground exposure while maximising pasture biomass productivity. High-intensity sheep grazing treatments were conducted in small fields (less than 1 hectare) for short durations (typically less than 1 day). Paddocks were subsequently spelled to allow pasture biomass recovery (treatments comprising 3, 6, 9, 12, and 15 months) with each compared with control treatments with lighter stocking rates for longer periods (2,000 DSE). Pastures were composed of wallaby grass (Austrodanthonia species), kangaroo grass (Themeda triandra), Phalaris (Phalaris aquatica, and cocksfoot (Dactylis glomerata) were destructively sampled to estimate total standing dry matter (TSDM), standing green biomass, standing dry biomass and trampled biomass. We then invoked a machine learning model using Sentinel-2 imagery to quantify TSDM, standing green biomass and standing dry biomass. Faced with La Nina conditions, regenerative grazing did not significantly impact pasture productivity, with all treatments showing similar TSDM and green biomass. However, regenerative treatments significantly impacted litter fall and trampled material, with the high intensity grazing treatments causing more dry matter trampling, increasing litter, enhancing decomposition rates and surface organic matter. Pasture digestibility was greatest for treatments with minimal spelling (3 months), whereas both standing senescent and trampled material were significantly greater for the treatment with 15-month spell periods. Estimates of TSDM using machine learning with Sentinel-2 imagery underestimated TSDM in treatment plots but explained spatiotemporal variability associated within and across treatments. The root mean square error between the measured and modelled TSDM was 903 kg DM/ha, which was less than the variability measured in the field. We conclude that regenerative grazing with short recovery periods (3-6 months) are most conducive to increasing pasture production under high rainfall conditions, and we speculate that high intensity grazing is likely to positively impact on soil organic carbon through increased litterfall and trampling. Our study paves the way forward for using machine learning with satellite imagery to quantify pasture biomass at small scales, enabling management of pastures from afar.

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

Abstract5′,8-Cyclo-2′-deoxyadenosine (cdA), in the 5′R and 5′Sdiastereomeric forms, are typical non strand-break oxidative DNA lesions, induced by hydroxyl radicals, with emerging importance as a molecular marker. These lesions are exclusively repaired by nucleotide excision repair (NER) mechanism with a low efficiency, thus readily accumulating in the genome. Poly(ADP-ribose) polymerase1 (PARP1) acts as an early responder to DNA damage and plays a key role as a nick sensor in the maintenance of the integrity of the genome by recognizing nicked DNA. So far, it was unknown whether the diastereomeric cdA lesions could induce specific PARP1 binding. Here we provide the first evidence of PARP1 to selectively recognize the diastereomeric lesions 5′S-cdA and 5′R-cdA in vitro as compared to deoxyadenosine in model DNA substrates (23-mers) by using circular dichroism,fluorescence spectroscopy, immunoblotting analysis and gel mobility shift assay. Several features of the recognition of the damaged and undamaged oligonucleotides by PARP1were characterized. Remarkably, PARP1 efficiently binds to both cdA lesions in the double stranded (ds)-oligonucleotides. In particular, PARP1 proved to bind 5′S-cdAwith a higher affinity constant for the 5'S lesion in a model of ds DNA than 5′R-cdA, showing different recognition patterns, also compared with undamaged dA. This new finding highlights the ability of PARP1 to recognize and differentiate the distorted DNA backbone in a biomimetic system caused by different diastereomeric forms of a cdA lesion.

BA.2, a sublineage of Omicron BA.1, is now prominent in many parts of the world. Early reports indicate that BA.2 is more infectious than BA.1. To gain insight into BA.2 mutation profile and the resulting impact of mutations on interaction with receptor and/or monoclonal antibodies, we analyzed available se-quences, structures of Spike/receptor, and Spike/antibody complexes, and conducted molecular dynamics simulations. The results showed that BA.2 has 50 high-prevalent mutations compared to 48 in BA.1. Seventeen BA.1 mutations are not present in BA.2. Instead, BA.2 has 19 unique mutations and a signature Delta variant mutation (G142D). Intriguingly, the BA.2 has 28 signature mutations in Spike, compared to 30 in BA.1. This is due to two revertant mutations S446G and S496G in the receptor-binding domain (RBD), making BA.2 somewhat similar to Wuhan-Hu-1 (WT), which has G446 and G496. The molecular dynamics simulations showed that the RBD consisting of G446/G496 is more stable than S446/S496 containing RBD. Thus, our analyses suggest that BA.2 has evolved with novel mutations (i) to maintain receptor binding similar to WT, (ii) evade the antibody binding greater than BA.1, and (iii) acquire mutation of the Delta variant that may be associated with the high infectivity.

Postharvest 1-MCP treatment can inhibit lignification of fruit and vegetables. It has been suggested that the mode of action of 1-MCP is through inhibiting ethylene production, but the effect of 1-MCP and ethylene on lignification of common bean remain unknown. This work compared the effect of 0.5 μL L-1 1-MCP and 100 μL L-1 ethylene on lignification of common bean during storage. Postharvest 1-MCP significantly inhibited the increase of lignified cell group, sclerenchyma became thicker, vascular bundles thickened and lignified cells grew during storage, while ethylene is the opposite. 1-MCP inhibited the increase in respiration rate, sucrose phosphate synthase (SPS), sucrose synthase (SuSy), phenylalanine ammonialyase (PAL), cinnamyl-alcohol dehydrogenase (CAD), and peroxidase (POD) activities, whereas ethylene hastened all. Ethylene treatment can be stimulated and 1-MCP inhibited the decline of reducing sugar and cellulose content. Expression of genes, including PvACO1, PvAOG1, PvSuSy, PvPAL3, and Pv4CL1, PvCOMT1 together with lignin content were significantly increased in common bean during storage. 1-MCP treatment markedly inhibited expression of PvACO1, PvSuSy2, PvPAL3, Pv4CL1 and PvCOMT1 genes, while strengthened expression of PvETR1 and PvAOG1, while ethylene was opposite. This work provides evidence that ethylene plays a key role in regulating the lignin biosynthesis of common bean, and also provides strategies for the maintenance of fruit quality during storage.

Forest fires are part of a set of natural disasters that have always affected regions of the world typically characterized by a tropical climate with long periods of drought. However, due to climate change in recent years, other regions of our planet have also been affected by this phenomenon, never seen before. One of them is certainly the Italian peninsula, and especially the regions of southern Italy. For this reason, the scientific community, as well as remote sensing one, is highly concerned in developing reliable techniques to provide useful support to the competent authorities. In particular, three specific tasks have been carried out in this work: (i) fire risk prevention, (ii) active fire detection, and (iii) post-fire area assessment. To accomplish these analyses, the capability of a set of spectral indices, derived from spaceborne remote sensing (RS) data, is assessed to monitor the forest fires. The spectral indices are obtained from Sentinel-2 multispectral images of the European Space Agency (ESA), which are free of charge and openly accessible. Moreover, the twin Sentinel-2 sensors allow to overcome some restrictions on time delivery and observation repeat time. The performance of the proposed analyses were assessed experimentally to monitor the forest fires occurred in two specific study areas during the summer of 2017: the volcano Vesuvius, near Naples, and the Lattari mountains, near Sorrento (both in Campania, Italy).

The 3x+1 problem is a problem of continuous iteration for integers. According to the basic theorem of arithmetic and the way of iteration, we derive a general formula for continuous iteration for odd integers. Through this formula, we can construct a loop iteration equation and obtain the result of the equation: the equation has only one positive integer solution. In addition, this general formula can be converted into a linear indeterminate equation. The process of solving this equation shows that the relationship between the iteration result and the odd number being iterated is linear. Extending this result to all positive even numbers, we get the answer to the 3x + 1 question.

Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell’s invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+ BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

We show that the Einstein field equations for a five-dimensional warped spacetime, where only gravity can propagate into the bulk, determine the dynamical evolution of the warp factor of the four-dimensional brane spacetime. This can be explained as a holographic manifestation. The warped 5D model can be reformulated by considering the warp factor as a dilaton field ($\omega$) conformally coupled to gravity and embedded in a smooth $M_4 \otimes R$ manifold. On the brane, where the U(1) scalar-gauge fields live, the dilaton field manifests itself classically as a warp factor and enters the evolution equations for the metric components and matter fields. We write the Lagrangian for the Einstein-scalar-gauge fields in a conformal invariant setting. However, as expected, the conformal invariance is broken (trace-anomaly) by the appearance of a mass term and a quadratic term in the energy-momentum tensor of the scalar-gauge field, arising from the extrinsic curvature terms of the projected Einstein tensor. These terms can be interpreted as a constraint in order to maintain conformal invariance. By considering the dilaton field and Higgs field on equal footing on small scales, there will be no singular behavior, when $\omega\rightarrow 0$ and one can deduce constraints to maintain regularity of the action. Our conjecture is that $\omega$, alias warp factor, has a dual meaning. At very early times, when $\omega \rightarrow 0$, it describes the small-distance limit, while at later times it is a warp (or scale) factor that determines the dynamical evolution of the universe. We also present a numerical solution of the model and calculate the (time-dependent) trace-anomaly. The solution depends on the mass ratio of the scalar and gauge fields, the parameters of the model and the vortex charge $n$.

Cutaneous T cell lymphomas (CTCLs) are caused by malignant clonal proliferation of skin-tropic T cells. Most patients have an indolent disease course managed with skin-directed therapies, while some entities, or in advanced stages of disease, have aggressive progression and poor survival. To efficiently treat CTCL consistent entity markers are needed to prevent the delay in diagnosis and to provide disease specific treatment to patients. Recently, the introduction of high throughput parallel sequencing methods resulted in identification of numerous genetic and ep-igenetic alterations affecting the transcriptome of CTCL cells. In this review, most relevant genes, including TOX, CADM1, PLS3, DNM3, CXCL13, PD-1, BCL11B and TMEM244 are reported that are specifically expressed in CTCL. Upon verification their specificity and sensitivity in larger studies, their altered expression will be able to be recognized as novel biomarkers, that can im-prove the early diagnosis of CTCL.

In this study, a structural profiling of equid alphaherpesvirus 1 (EHV-1) transcriptome was carried out using next-generation (Illumina) and third-generation (Oxford Nanopore Technologies) sequencing platforms. We annotated the canonical mRNA molecules and their isoforms, including transcript start and end site isoforms, and splice variants. Additionally, a number of putative 5′-truncated mRNAs containing shorter in-frame ORFs were detected. We also demonstrated that EHV-1 produces a high number of non-coding transcripts, including antisense and intergenic RNAs. One of the most remarkable features of the EHV-1 is the generation of abundant fusion transcripts some of which encoding chimeric polypeptides. We observed a higher number of splicing and transcriptional overlaps than in related viruses. Additionally, we found that many upstream genes of tandem gene clusters have their own transcript end sites (TESs) besides the co-terminal TESs, which is rare in other alphaherpesviruses. We show here that the replication origins (OriS and OriL) of the virus are co-localized with promoter sequences and overlap with specific RNA molecules. Furthermore, we discovered a novel non-coding RNA (designated as NOIR) that overlaps the 5′-ends of the longer transcript variants encoded by the two main transactivator genes ORF64 and 65 bracketing the OriL. These all suggest the existence of a central regulatory system which controls the genome-wide transcription and the replication through a mechanism based on the interference between the machineries carrying out the synthesis of DNA and RNA.

Let {$\Gamma(k)$} denote {$(k-1)!$}, and let {$\Gamma_{n}(k)$} denote {$(k-1)!$}, where {$n \in \{3,\ldots,16\}$} and {$k \in \{2\} \cup [2^{\textstyle 2^{n-3}}+1,\infty) \cap \mathbb N$}. For an integer {$n \in \{3,\ldots,16\}$}, let $\Sigma_n$ denote the following statement: if a system of equations {${\mathcal S} \subseteq \{\Gamma_{n}(x_i)=x_k:~i,k \in \{1,\ldots,n\}\} \cup \{x_i \cdot x_j=x_k:~i,j,k \in \{1,\ldots,n\}\}$} with $\Gamma$ instead of $\Gamma_{n}$ has only finitely many solutions in positive integers {$x_1,\ldots,x_n$}, then every tuple {$(x_1,\ldots,x_n) \in (\mathbb N \setminus \{0\})^n$} that solves the original system ${\mathcal S}$ satisfies {$x_1,\ldots,x_n \leqslant 2^{\textstyle 2^{n-2}}$}. Our hypothesis claims that the statements {$\Sigma_{3},\ldots,\Sigma_{16}$} are true. The statement {$\Sigma_6$} proves the following implication: if the equation {$x(x+1)=y!$} has only finitely many solutions in positive integers $x$ and $y$, then each such solution {$(x,y)$} belongs to the set {$\{(1,2),(2,3)\}$}. The statement {$\Sigma_6$} proves the following implication: if the equation {$x!+1=y^2$} has only finitely many solutions in positive integers $x$ and $y$, then each such solution {$(x,y)$} belongs to the set {$\{(4,5),(5,11),(7,71)\}$}. The statement {$\Sigma_9$} implies the infinitude of primes of the form {$n^2+1$}. The statement {$\Sigma_9$} implies that any prime of the form {$n!+1$} with {$n \geqslant 2^{\textstyle 2^{9-3}}$} proves the infinitude of primes of the form {$n!+1$}. The statement {$\Sigma_{14}$} implies the infinitude of twin primes. The statement {$\Sigma_{16}$} implies the infinitude of Sophie Germain primes.

HIV treatment strategies against viral enzymes are continuously hampered by viral drug resistance. Recent findings show that viral substrate Gag contributes to HIV-1 Protease Inhibitor (PI) resistance, leading to demands for new strategies in HIV treatment where Gag is recognized as a drug target. To successfully target Gag, there is a need of in-depth understanding of the Gag polyprotein and the effects of Gag mutations. Here, we propose new strategies in designing novel Gag inhibitors against existing and novel emerging Gag mutations via a structural understanding of the Gag-Protease relationship in PI resistance. In this review, we discuss the role of both novel and previously reported mutations, revealing insights to how they aid in PI resistance, and how new Gag inhibitors can be designed.

Despite the publication in 2009 of a paper on ‘terms and definitions of immune thrombocytopenia’, (ITP) some unresolved issues remain and are reflected by the disagreement in the treatment suggested for primary ITP in adults. Considering that these disagreements could be ascribed to non-shared goals, a ‘consensus’ to classify the different lines of treatment for primary ITP in adults according to their indications and goals was proposed in October 2018 to the XIX annual meeting of the Italian Gruppo di Studio delle Piastrine (GSP), a non-profit platelet study group of scientists and physicians. Having approved the project, 60 potential co-authors and experts in the world were invited to take part to a consensus through e-Delphy method and nine of the 12 who initially accepted the invitation completed the work. Agreement was reached on a classification of four lines of treatment for primary ITP in adults based on their indications and goals. The consensus obtained regarded also the criteria, ‘timing’ included, to consider practicable elective splenectomy in these patients. In our opinion, the classification of the lines of treatment for primary ITP in adults here proposed could facilitate the realization of better shared evidence-based guidelines for the treatment of the disease.

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared 15 SCs and their derivatives (tetrahydrocannabinol [THC], naphthoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

PD-1/PD-L1 axis is one key therapeutic target against tumor cell immune escape. Structurally essential to the PD-1/PD-L1-linked immune escape is the binding interface of the PD-1/PD-L1 complex structure. Incorporating currently available PD-1/PD-L1-related experimental structures, this article unveils two sets of experimentally observed inter-molecular electrostatic interactions which stabilize the binding interface of the PD-1/PD-L1 complex structure. For the first time, this article proposes an evolutionary structural hypothesis that, as a result of natural selection, PD-1 is able to genetically mutate itself to structurally disrupt the PD-1/PD-L1 axis towards the restoration of T cell-mediated anti-tumor immunity.

2-(Adamantan-1-yl)-2H-isoindole-1-carbonitrile (1) has been identified as a neurobiological fluorescent ligand that may be used to develop receptor and enzyme binding affinity assays. Compound 1 was synthesised using an optimised microwave irradiation reaction and crystallised from ethanol. Crystallization occurred in the orthorhombic space group P212121 with unit cell parameters: a = 6.4487(12) Å, b = 13.648(3) Å, c = 16.571(3) Å, V = 1458(5) Å3, Z = 4. Density functional theory (DFT) (B3LYP/6-311++G (d,p)) calculations of 1 were carried out. Results showed that the optimised geometry is similar to the crystal structure parameters with a root-mean-squared deviation of 0.143 Å. Frontier molecular orbital energies and net atomic charges are discussed with a focus on potential biological interactions. Docking experiments within the active site of the neuronal nitric oxide synthase (nNOS) protein crystal structure were carried out and analysed. Important binding interactions between the DFT optimised structure and amino acids within the nNOS active site were identified that explain the strong NOS binding affinity reported. Fluorescent properties of 1 were studied using aprotic solvents of different polarities. Compound 1 showed the highest fluorescence intensity in polar solvents with excitation and emission values of 336 nm and 380 nm, respectively.

Observing cultivated crops and other forms of land use is an important environmental and economic concern for agricultural land management and crop classification. Crop categorization offers significant crop management data, ensuring food security, and developing agricultural policies. Remote sensing data, especially publicly available Sentinel 1 and 2 data, has effectively been used in crop mapping and classification in cloudy places because of their high spatial and temporal resolution. This study aimed to improve crop type classification by combining Sentinel-1 (Synthetic Aperture Rader (SAR)) data and the Sentinel-2 Multispectral Instrument (MSI) data. In the study, Random Forest (RF) and Classification and Regression Trees (CART) classier were used to classify grain crops (Barley and Wheat). The classification results based on the combination of Sentinel-2 and Sentinel-1 data indicated an overall accuracy (OA) of 93 % and a kappa coefficient (K) of 0.896 for RF and (89.15%, 0.84) for the CART classifier. It is suggested to employ a mix of radar and optical data to attain the highest level of classification accuracy since doing so improves the likelihood that the details will be observed in comparison to the single-sensor classification technique and yields more accurate results.

Type 1 diabetes (T1D) is an autoimmune condition where the body’s immune cells destroy their insulin-producing pancreatic beta-cells leading to dysregulated glycaemia. Individuals with T1D control their blood glucose through exogenous insulin replacement therapy, often using multiple daily injections or pumps. However, failure to accurately mimic intrinsic glucose regulation results in glucose fluctuations and long-term complications impacting key organs such as the heart, kidneys, and/or the eyes. It is well-established that genetic and environmental factors contribute to the initiation and progression of type 1 diabetes, but recent studies show that epigenetic modifications are also important. Here, we discuss key epigenetic modifications associated with type 1 diabetes pathogenesis and discuss how recent research is finding ways to harness epigenetic mechanisms to prevent, reverse, or manage type 1 diabetes.

Only two percent of Glioblastoma multiforme (GBM) patients respond to standard care and survive beyond 36 months (long-term survivors, LTS) while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the GO-categories “epithelial to mesenchymal transition” and “response to hypoxia”. In this paper we applied upstream analysis approach which involves state-of-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators – IGFBP2, VEGFA, VEGF165, PDGFA, AEBP1 and OSMR which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. Critical analysis of this gene regulatory network gives insights on mechanism of gene regulation by IGFBP2 via several transcription factors including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations are validated in independent cohorts and their impact on overall survival is studied.

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.

Rheumatoid arthritis (RA) is an autoimmune disease in which joints are gradually de-stroyed, and early diagnosis and treatment before joint deformation or destruction is im-portant. The detection of novel RA biomarkers in saliva may facilitate the early detection of RA before the onset of disease. In this study, we conducted a comprehensive proteomic analysis of salivary proteins from RA model mice. Proteins were identified by Western blotting and enzyme-linked immunosorbent assay in serum, saliva, and ankle joints from DBA/1JJmsSlc mice, a model of rheumatoid arthritis. Ankle joints and submandibular glands were hematoxylin and eosin stained and immunostained, and the results were compared with those of control mice. Citrullinated α1 antitrypsin (A1AT, 46 kDa) was commonly detected in saliva, serum, and ankle joints of severe RA model mice, and was confirmed by proteome analysis. Western blotting detected a band corresponding to 46 kDa in serum, saliva and ankle joints, and immunostaining of ankle joints with A1AT an-tibody showed a strong positive signal in the synovium. In DBA/1JJmsSlc mice, not only cyclic citrullinated peptide antibodies but also A1AT may be involved in protein citrulli-nation and contribute to the development and severity of RA.

The detection of waste plastics in the marine and terrestrial environment using satellite Earth Observation data offers the possibility of large-scale mapping, and reducing on-the-ground manual investigation. In addition, costs are kept to a minimum by utilizing free-to-access Copernicus data. A Machine Learning based classifier was developed to run on Sentinel-1 and -2 data. In support of the training and validation, a dataset was created with terrestrial and aquatic cases by manually digitizing varying landcover classes alongside plastics under the sub-categories of greenhouses, plastic, tyres and waste sites. The trained classifier, including an Artificial Neural Network and post-processing decision tree, was verified using five locations encompassing these different forms of plastic. Although exact matchups are challenging to digitize, the performance has generated high accuracy statistics, and the resulting land cover classifications have been used to map the occurrence of plastic waste in aquatic and terrestrial environments.

Endothelial disorders are related to various diseases. An initial endothelial injury is characterized by endothelial glycocalyx injury. We aimed to evaluate endothelial glycocalyx injury by measuring serum syndecan-1 concentrations in patients during comprehensive medical examinations. A single-center, prospective, observational study was conducted at Asahi University Hospital. The participants enrolled in this study were 1313 patients who underwent comprehensive medical examinations at Asahi University Hospital from January 2018, to June 2018. One patient undergoing hemodialysis was excluded from the study. At enrollment, blood samples were obtained, and study personnel collected demographic and clinical data. No treatments or exposures were conducted except for standard medical examinations and blood sample collection. Laboratory data were obtained by collection of blood samples at the time of study enrolment. According to nonlinear regression, the concentrations of serum syndecan-1 were significantly related to age (p = 0.016), aspartic aminotransferase concentration (AST, p = 0.020), blood urea nitrogen concentration (BUN, p = 0.013), triglyceride concentration (p < 0.001), and hematocrit (p = 0.006). These relationships were independent associations. Endothelial glycocalyx injury, which is reflected by serum syndecan-1 concentrations, is related to age, hematocrit, AST concentration, BUN concentration, and triglyceride concentration.

Aim of this study was to evaluate the accuracy and usability of a novel continuous glucose moni-toring (CGM) system designed for needle-free insertion and reduced environmental impact. We assessed sensor performance of two GlucoMen® Day CGM systems worn simultaneously in eight participants with type 1 diabetes. Self-monitoring of blood glucose (SMBG) was performed reg-ularly over 14 days at home. Participants underwent two standardized 5-hour meal challenges with frequent plasma glucose (PG) measurements using a laboratory reference instrument at the research center. When comparing CGM to PG the overall mean absolute relative difference (MARD) was 9.7 [2.6-14.6]%. The overall MARD of CGM vs SMBG was 13.1 [3.5-18.6]%. In the consensus error grid (CEG) analysis, 98% of both CGM/PG and CGM/SMBG pairs were in the clinically acceptable zones A and B. The analysis confirms that GlucoMen® Day CGM meets the clinical requirements for state-of-the-art CGM. The needle-free insertion technology is well toler-ated by users and reduces medical waste compared to conventional CGM systems.

SARS-CoV-2 infection produces a response of the innate immune system causing oxidative stress and a strong inflammatory reaction termed ‘cytokine storm’ that is one of the leading causes of death. Paraoxonase-1 (PON1) protects against oxidative stress by hydrolyzing lipoperoxides. Alterations in PON1 activity have been associated with pro-inflammatory mediators such as the chemokine (C-C motif) ligand 2 (CCL2) and the glycoprotein galectin-3. We aimed to investigate the alterations in the circulating levels of PON1, CCL2 and galectin-3 in 126 patients with COVID-19 and their interactions with clinical variables and analytical parameters. A machine learning approach was used to identify predictive markers of the disease. For comparisons, we recruited 45 COVID-19 negative patients and 50 healthy individuals. Our approach identified a synergy between oxidative stress, inflammation and fibrogenesis in positive patients that is not observed in negative patients. PON1 activity was the parameter with the greatest power to discriminate between patients who were either positive or negative for COVID-19, while their levels of CCL2 and galectin-3 were similar. We suggest that the measurement of serum PON1 activity may be a useful marker for the diagnosis of COVID-19.

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

Dominance hierarchies are ubiquitous in invertebrates and vertebrates, but little is known on how genes influence dominance rank. Our gaps in knowledge are specifically significant concerning female hierarchies and in insects. To start filling these gaps we studied the social bumble bee Bombus terrestris, in which social hierarchies among females are common and functionally significant. Dominance rank in this bee is influenced by multiple factors, including juvenile hormone (JH) that is a major gonadotropin in this species. We tested the hypothesis that the JH responsive transcription factor Krüppel homologue 1 (Kr-h1) mediates hormonal influence on dominance behavior in the bumble bee. We first developed and validated a perfluorocarbon nanoparticles-based RNA interference protocol for knocking down Kr-h1 expression. We then used this procedure to show that Kr-h1 mediates the influence of JH not only on oogenesis and wax production, but also on aggression and dominance rank. To the best of our knowledge, this is the first study causally linking a gene to dominance rank in social insects, and one of only a few such studies in insects or in female hierarchies. These findings are important for determining whether there are general molecular principles governing dominance rank across gender and taxa.

Atrial fibrillation (AF) is a form of sustained cardiac arrhythmia and microRNAs (miRs) play crucial roles in pathophysiology of AF. To identify novel miR-mRNA pairs, we performed RNAseq from atrial biopsies of AF and non-AF patients. Differentially expressed miRs (11-down and 9-up) and mRNAs (95-up and 82-down) were identified and hierarchically clustered in a heat-map. Subsequently, GO, KEGG, and GSEA analyses were run to identify deregulated pathways. Then, miR targets were predicted in miRDB database, and a regulatory network of negatively correlated miR-mRNA pairs was constructed using Cytoscape. To select potential candidate genes from GSEA analysis, top-50 enriched genes in GSEA were overlaid with predicted targets of differentially deregulated miRs. Besides, protein-protein-interaction (PPI) network of enriched genes in GSEA was constructed, and subsequently GO and canonical pathway analyses were run for genes in PPI network. Our analyses showed that TNF-α, p53, EMT, and SYDECAN1 signaling were among the highly affected pathways in AF samples. SDC-1 (syndecan-1) was the top-enriched gene in p53, EMT, and SYDECAN1 signaling. Consistently, SDC-1 mRNA and protein levels were significantly higher in atrial samples of AF patients. Among negatively correlated miRs, miR-302b-3p was experimentally validated to suppress SDC-1 transcript levels. Overall, our results suggested that miR-302b-3p/SDC-1 axis may involve in pathogenesis of AF.

Tissue resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8 TRM, there has been recently an increased interest in defining the phenotype and the role of CD4 TRM in diseases. Circulating CD4 T cells seed tissue CD4 TRM, but there also appears to be an equilibrium between CD4 TRM and blood CD4 T cells. CD4 TRM are more mobile than CD8 TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8 TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4 and CD8 TRM persisting between lesions may control asymptomatic shedding through interferon gamma secretion, although this has been more clearly shown for CD8 T cells. The exact role of the CD4/CD8 TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4 TRM have now been shown to be a major target for productive and latent infection in cervix. In HSV and HIV co-infections, CD4 TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4 TRM and their induction by vaccines may help control sexual transmission by both viruses.

Microbial production is a promising method that can overcome major limitations in conventional methods of lycopene production, such as low yields and variations in product quality. Significant efforts have been made to improve lycopene production by engineering either the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway or mevalonate (MVA) pathway in microorganisms. To further improve lycopene production, it is critical to utilize metabolic enzymes with high specific activities. Two enzymes, 1-deoxy-D-xylulose-5-phosphate synthase (Dxs) and farnesyl diphosphate synthase (IspA), are required in lycopene production using MEP pathway. Here, we evaluated the activities of Dxs and IspA of Vibrio sp. dhg, a newly isolated and fast-growing microorganism. Considering that the MEP pathway is closely related to the cell membrane and electron transport chain, the activities of the two enzymes of Vibrio sp. dhg were expected to be higher than the enzymes of E. coli. We found that Dxs and IspA in Vibrio sp. dhg exhibited 1.08-fold and 1.38-fold higher catalytic efficiencies, respectively. Consequently, the heterologous overexpression improved the specific lycopene production by 1.88-fold. Our findings could be widely utilized to enhance production of lycopene and other carotenoids.

For more than ten years, Central Chile faces drought conditions, which impact crop production and quality, increasing food security risk. Under this scenario, implementing management practices that allow increasing water use efficiency is urgent. The study was carried out in kiwifruit trees, located in the O’Higgins region, Chile; for season 2018-2019 and 2019-2020. We evaluate nine vegetation indices in the VNIR and SWIR regions derived from Sentinel-2 (A/B) satellites to know how much variability in the canopy water status could explain. Over the study's site were installed sensors that continuously measure the leaf's turgor pressure (Yara Water-Sensor). A strong correlation between turgor pressure and vegetation indices was obtained with the Spearman's rho coefficient ($\rho$). However, the NIR range's indices were influenced by the vegetative development of the crop rather than its water status. Red-edge showed better performance as the vegetative growth did not affect it. It is necessary to expand the study to consider higher variability in kiwifruit's water conditions and incorporate the sensitivity of different wavelengths.

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.

Background: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory response is of particular importance. Methods: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 hours. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. Results &amp; conclusion: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in ROS homeostasis. Low and high concentrations of AFDs have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both a “prooxidant” and “antioxidant” effect, but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced “prooxidant” properties.

Within the scope of observed materialistic physical systems, without addressing the roots of H-Bar and big G, it is impossible to construct a workable model of final unification. With reference to our earlier proposed three large atomic gravitational constants, it is possible to reform and compactify the 10 dimensional String theory to 3+1 dimensions

For any odd positive integer $x$, define $(x_n)_{n\geqslant 0} $ and $(a_n )_{n\geqslant 1} $ by setting $x_{0}=x, \,\, x_n =\cfrac{3x_{n-1} +1}{2^{a_n }}$ such that all $x_n $ are odd. The 3x+1 problem asserts that there is an $x_n =1$ for all $x$. Usually, $(x_n )_{n\geqslant 0} $ is called the trajectory of $x$. In this paper, we concentrate on $(a_n )_{n\geqslant 1} $ and call it the E-sequence of $x$. The idea is that, we consider any infinite sequence $(a_n )_{n\geqslant 1} $ of positive integers and call it an E-sequence. We then define $(a_n )_{n\geqslant 1} $ to be $\Omega-$convergent to $x$ if it is the E-sequence of $x$ and to be $\Omega-$divergent if it is not the E-sequence of any odd positive integer. We prove a remarkable fact that the $\Omega-$divergence of all non-periodic E-sequences implies the periodicity of $(x_n )_{n\geqslant 0} $ for all $x_0$. The principal results of this paper are to prove the $\Omega-$divergence of several classes of non-periodic E-sequences. Especially, we prove that all non-periodic E-sequences $(a_n )_{n\geqslant 1} $ with $\mathop {\overline {\lim } }\limits_{n\to \infty } \cfrac{b_n }{n}>\log _23$ are $\Omega-$divergent by using the Wendel's inequality and the Matthews and Watts's formula $x_n =\cfrac{3^n x_0 }{2^{b_n }}\prod\limits_{k=0}^{n-1} {(1+\cfrac{1}{3x_k })} $, where $b_n =\sum\limits_{k=1}^n {a_k } $. These results present a possible way to prove the periodicity of trajectories of all positive integers in the 3x + 1 problem and we call it the E-sequence approach.

Aim: Sca-1+CD31− cells were shown to be endothelial stem/progenitor cells, found in many mammalian tissues, including heart, were able to differentiate into cardiomyocytes in vitro and in vivo. Our previous work indicated that heart derived Sca-1+CD31− cells increased Nr1d1 mRNA level and decreased cells plasticity with aging. However, little is known about how NR1D1 affects Sca-1+CD31− cells plasticity. Methods: Lentiviral vector was used to stably overexpress Nr1d1 in young Sca-1+CD31− cells and to knockdown Nr1d1 in aged Sca-1+CD31− cells. Cell differentiation, proliferation, apoptosis, and cell cycle were evaluated. Results and Conclusions: The overexpression of Nr1d1 in young Sca-1+CD31− cells inhibited cell proliferation and promoted apoptosis. Knockdown of Nr1d1 in aged Sca-1+CD31− cells promoted cell proliferation and inhib-ited apoptosis. Using mouse cardiac myocytes cell line, confirmed the effect of Nr1d1 and indi-cated that Nr1d1 induce Serpina3 expression via Nr1d1 interaction with Nr4a3. Nr1d1 may there-fore be identified as a potent anti-aging receptor and be a therapeutic target for aging relative diseases.

Salinity is considered as one of the most important abiotic challenges that affect crop productivity. Plant hormones, including salicylic acid (SA), are key factors in the defence signalling output triggered during plant responses against environmental stresses. We have previously reported in peach a new SA biosynthetic pathway from mandelonitrile (MD), the molecule at the hub of the cyanogenic glucoside turnover in Prunus sp. In this work, we have studied whether this new SA biosynthetic pathway is also present in plum and the possible role this pathway plays in plant plasticity under salinity, focusing on the transgenic plum line J8-1, which displays stress tolerance via an enhanced antioxidant capacity. The SA biosynthesis from MD in non-transgenic and J8-1 micropropagated plum shoots was studied by metabolomics. Then the response of J8-1 to salt stress in presence of MD or Phe (MD precursor) was assayed by measuring: chlorophyll content and fluorescence parameters, stress related hormones, levels of non-enzymatic antioxidants, the expression of two genes coding redox-related proteins, and the content of soluble nutrients. The results from in vitro assays suggest that the SA synthesis from the MD pathway demonstrated in peach is not clearly present in plum, at least under in vitro conditions. Nevertheless, in J8-1 NaCl-stressed seedlings, an increase in SA was recorded as a result of the MD treatment, suggesting that MD could be involved in the SA biosynthesis under NaCl stress conditions in plum plants. We have also shown that the plum line J8-1 was tolerant to NaCl under greenhouse conditions, and this response was somewhat different in MD-treated plants. In that regards, the MD treatment produced an increase in SA, jasmonic acid (JA) and reduced ascorbate (ASC) contents as well as in the coefficient of non-photochemical quenching (qN) and the gene expression of Non-Expressor of Pathogenesis-Related 1 (NPR1) and thioredoxin H (TrxH) under salinity conditions, suggesting a crosstalk between different signalling pathways (NPR1/Trx and SA/JA) leading to salinity tolerance in the transgenic plum line J8-1.

Infection by human immunodeficiency virus type I (HIV-1) requires virus particle binding to host cell-surface receptor CD4 via the viral envelope glycoprotein gp120. HIV-1 therapy and prevention efforts involve development of mimetic or recombinant gp120 vaccines or deployment of antiviral agents that target specific epitopes of gp120. The unliganded conformational state of gp120 is closed, whereas the CD4-bound state is open. However, in between, there exist dynamic conformational states, indicating intrinsically flexible region(s) of structural dynamics, imposing a structural challenge for developing drug or antibody targets. Known conformational states of gp120 were determined by X-ray crystallographic and cryo-electron microscopy, and neither method captures the population of gp120 species arising from conformational plasticity, motions, and transitions. gp120 plasticity brings up several important questions. How will differences in conformation affect receptor binding, antibody recognition, and neutralization? Which regions are crucial for gp120 structural plasticity? How could structural dynamics influence HIV-1 evasiveness against host immunity and drugs or vaccines, and facilitate the viral entry into its host? This review explores the structural constraints presented by conformational states of the glycoprotein to antibodies or drugs and how these conformational states provide structural avenues for the virus to escape neutralizing agents and evade host immunity.

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be largely explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.

The inhibition of heat shock protein 90 (Hsp90) a molecular chaperone for multiple oncogenic client proteins is considered as a promising approach to overcome radioresistance. Since most Hsp90 inhibitors activate HSF-1 that induces the transcription of cytoprotective and tumor-promoting stress proteins such as Hsp70 and Hsp27, a combined approach consisting of HSF-1 knockdown (k.d.) and Hsp90 inhibition was investigated. A specific HSF-1 k.d. was achieved in H1339 lung cancer cells using RNAi-Ready pSIRENRetroQ vectors with puromycin resistance. The Hsp90 inhibitor NVP-AUY922 was evaluated at low concentrations - ranging from 1-10nM - in control and HSF-1 k.d. cells. Protein expression (i.e., Hsp27/Hsp70, HSF-1, pHSF-1) and transcriptional activity was assessed by Western blot analysis and luciferase assays and radiosensitivity was measured by proliferation, apoptosis (Annexin V, active caspase 3), clonogenic cell survival, alkaline comet, γH2AX, 53BP1 and Rad51 foci assays. The k.d. of HSF-1 resulted in a significant reduction of basal and NVP-AUY922-induced Hsp70/Hsp27 expression levels. A combined approach consisting of HSF-1 k.d. and low concentrations of the Hsp90 inhibitor NVP-AUY922 potentiates radiosensitization which involves an impaired homologous recombination mediated by Rad51. Our findings are key for clinical applications of Hsp90 inhibitors with respect to adverse hepatotoxic effects.

Immune checkpoints are a set of molecules dysregulated in several human and canine cancers and aberrations of the PD-1/PD-L1 axis are often correlated with a worse prognosis. To gain insight into the role of immune checkpoints in canine diffuse large B-cell lymphoma (cDLBCL), we investigated PD-L1, PD-1 and CD8A expression by RNAscope. Results were correlated with several clinico-pathological features, including treatment, Ki67 index and outcome. A total of 33 dogs treated with CHOP (n=12) or CHOP plus APAVAC (n= 21) were included. PD-L1 signal was diffusely distributed among neoplastic cells, whereas PD-1 and CD8A were localized in tumor infiltrating lymphocytes. However, PD-1 mRNA was also retrieved in tumor cells. An association between PD-L1 and PD-1 scores was identified and a higher risk of relapse and lymphoma-related death was found in dogs treated with chemotherapy alone and dogs with higher PD-L1 and PD-1 scores. The correlation between PD-L1 and PD-1 is in line with the mechanism of immune checkpoints in cancers, where neoplastic cells overexpress PD-L1 that, in turn, binds PD-1 receptors in activated TIL. We also found that Ki67 index was significantly increased in dogs with the highest PD-L1 and PD-1 scores, indirectly suggesting a role in promoting tumor proliferation. Finally, even if the biological consequence of PD-1+ tumor cells is unknown, our findings suggest that PD-1 intrinsic expression in cDLBCL might contribute to tumor growth escaping adaptive immunity.

Type 2 diabetes mellitus (T2D) is a metabolic disorder characterized by inappropriate insulin function. Despite wide progress in genome studies, defects in gene expression for diabetes prognosis still incompletely identified. Prolonged hyperglycemia activates NF-κB, which is a main player in vascular dysfunctions of diabetes. Activated NF-κB, triggers expression of various genes that promote inflammation and cell adhesion process. Alteration of pro-inflammatory and profibrotic gene expression contribute to the irreversible functional and structural changes in the kidney resulting in diabetic nephropathy (DN). To identify the effect of some important NF-κB related genes on mediation of DN progression, we divided our candidate genes on the basis of their function exerted in bloodstream into three categories (Proinflammatory; NF-κB, IL-1B, IL-6, TNF-α and VEGF); (Profibrotic; FN, ICAM-1, VCAM-1) and (Proliferative; MAPK-1 and EGF). We analyzed their expression profile in leukocytes of patients and explored their correlation to diabetic kidney injury features. Our data revealed the overexpression of both proinflammatory and profibrotic genes in DN group when compared to T2D group and were associated positively with each other in DN group indicating their possible role in DN progression. In DN patients, increased expression of proinflammatory genes correlated positively with glycemic control and inflammatory markers indicating their role in DN progression. Our data revealed that the persistent activation NF-κB and its related genes observed in hyperglycemia might contribute to DN progression and might be a good diagnostic and therapeutic target for DN progression. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers.

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

Renal cell carcinoma (RCC) represents around 3% of all cancers, within which clear cell RCC (ccRCC) are the most common type (70–75%). The RCC disease regularly progresses asymptomatically and upon presentation is recurrently metastatic, so an early method of detection is necessary. The identification of one or more spe-cific biomarkers measurable in biofluids (i.e urine) by combined approaches could surely be appropriate for this kind of cancer, especially due to easy obtainability by non invasive method. OLR1 is a metabolic gene that encodes for the Lectin-like oxidized low-density lipoprotein re-ceptor-1 (LOX-1), implicated in inflammation, atherosclerosis, ROS and metabolic disor-der-associated carcinogenesis. Specifically, LOX-1 is clearly involved in tumor insurgence and progression of different human cancers. This work reports for the first time the presence of LOX-1 protein in ccRCC urine and its peculiar distribution in tumoral tissues. In parallel, urine samples headspace has been analyzed for the presence of the volatile compounds (VOCs) by SPME-GC/MS and gas sensor array. In particular, it was found by GC/MS analysis that 2-Cyclohexen-1-one,3-methyl-6-(1-methylethyl)- correlates with LOX-1 concentration in urine. Thus, the combined approach of VOCs analysis and protein quantification could led to promis-ing results in terms of diagnostic and prognostic potential for ccRCC tumor.

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

TRPOMI instrument aboard Sentinel-5P is a relatively new, high-resolution source of information about atmosphere composition. One of the primary atmospheric trace gases that we can observe through it is nitrogen dioxide. By now, we were using the chemical weather model (GEM-AQ) as a mean for estimating nitrogen dioxide concentration on a regional scale. Although well established in atmospheric science, the GEM-AQ simulations were always based on emission data, which in the case of the energy sector were reported by stack owners. In this paper, we attempted to compare the TROPOMI and GEM-AQ derived VCDs over Poland with a particular focus on large point emitters. We also checked how cloudy conditions influence TROPOMI results. Finally, we tried to link the NO2 column number densities with surface concentration using boundary layer height as an additional explanatory variable

Multi- and hyper-spectral, multi-angular top-of-canopy reflectance data call for an efficient retrieval system which can improve the retrieval of standard canopy parameters (as albedo, LAI, fAPAR), and exploit the information to retrieve additional parameters (e.g. leaf pigments). Furthermore consistency between the retrieved parameters and quantification of uncertainties are required for many applications. % (2) methods We present a retrieval system for canopy and sub-canopy parameters (OptiSAIL), which is based on a model comprising SAIL, PROSPECT-D (leaf properties), TARTES (snow properties), a soil model (BRDF, moisture), and a cloud contamination model. The inversion is gradient based and uses codes % created by Automatic Differentiation. The full per pixel covariance-matrix of the retrieved parameters is computed. For this demonstration, single observation data from the Sentinel-3 SY_2_SYN (synergy) product is used. The results are compared with the MODIS 4-day LAI/fPAR product and PhenoCam site photography. OptiSAIL produces generally consistent and credible results, at least matching the quality of the technically quite different MODIS product. For most of the sites, the PhenoCam images support the OptiSAIL retrievals. The system is computationally efficient with a rate of 150 pixel per second (7 millisecond per pixel) for a single thread on a current desktop CPU using observations on 26 bands. Not all of the model parameters are well determined in all situations. Significant correlations between the parameters are found, which can change sign and magnitude over time. OptiSAIL appears to meet the design goals, puts real-time processing with this kind of system into reach, seamlessly extends to hyper-spectral and multi-sensor retrievals, and promises to be a good platform for sensitivity studies. The incorporated cloud and snow detection adds to the robustness of the system.

It is proposed that both human creativity and human consciousness are (unintended) consequences of the human brain’s extraordinary energy efficiency. The topics of creativity and consciousness are treated separately, though have a common sub-structure. It is argued that creativity arises from a synergy between two cognitive modes of the human brain (which broadly coincide with Kahneman’s Systems 1 and 2). In the first, available energy is spread across a relatively large network of neurons. As such, the amount of energy per active neuron is so small that the operation of such neurons is susceptible to thermal (ultimately quantum decoherent) noise. In the second, available energy is focussed on a small enough subset of neurons to guarantee a deterministic operation. An illustration of how this synergy can lead to creativity with implications for computing in silicon are discussed. Starting with a discussion of the concept of free will, the notion of consciousness is defined in terms of an awareness of what are perceived to be nearby counterfactual worlds in state space. It is argued that such awareness arises from an interplay between our memories on the one hand, and quantum physical mechanisms (where, unlike in classical physics, nearby counterfactual worlds play an indispensable dynamical role) in the ion channels of neural networks. As with the brain’s susceptibility to noise, it is argued that in situations where quantum physics plays a role in the brain, it does so for reasons of energy efficiency. As an illustration of this definition of consciousness, a novel proposal is outlined as to why quantum entanglement appears so counter-intuitive.

Hepatic encephalopathy (HE) is a form of brain dysfunction that is specifically caused by liver insufficiency and/or portal-systemic shunt. The exact nature of HE is debated, so that conflicting uses of the term HE may cause inconsistencies in its detection and, in turn, issues with its management. This review highlights the meaning of the term HE on the basis of both its historical origins and current consensus. It also provides criteria for the diagnosis of the condition, on the basis of its phenotypes and the risk factors for its occurrence. The procedure for differential diagnosis from other conditions which result in similar phenotypes is considered, together with precipitants and confounders. Finally, the current multidimensional approach for the correct clinical recording of HE episodes is discussed.

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.

Either stereo reactants or stereo catalysis from achiral or chiral molecules are prerequisite to obtain pure enantiomeric lipid derivatives. We reviewed a few plausible organic syntheses of phospholipids under prebiotic conditions with a special attention to the starting materials as pro-chiral dihydroxyacetone and dihydroxyacetone phosphate (DHAP), which are the key molecules to break symmetry in phospholipids. The advantages of homochiral membranes compared to those of heterochiral membranes were analysed in term of specific recognition, optimal functions of enzymes, membrane fluidity and topological packing. All biological membranes contain enantiomeric lipids in modern bacteria, eukarya and archaea. The contemporary archaea, comprising of methanogens, halobacteria and thermoacidophiles are living under extreme conditions reminiscent of primitive environment and may indicate the origin of one ancient evolution path of lipid biosynthesis. The analysis of lipid metabolism reveals that all modern cells including archaea synthetize enantiomeric lipid precursors from prochiral DHAP. sn-glycerol-1-phosphate dehydrogenase (G1PDH), usually found in archaea, catalyses the formation of sn-glycerol-1-phosphate (G1P), while sn-glycerol-3-phosphate dehydrogenase (G3PDH) catalyses the formation of sn-glycerol-3-phosphate (G3P) in bacteria and eukarya. The selective enzymatic activity seems to be the main strategy that evolution retained to obtain enantiomeric pure lipids. The occurrence of two genes encoding for G1PDH and G3PDH, served to build up an evolution tree and the basis of our review focusing on the evolution of these two genes. Gene encoding for G3PDH in Eukarya may originate from G3PDH gene found in rare archaea indicating that archaea appeared earlier in the evolution tree than eukarya. Archaea and bacteria evolved probably separately, due to their distinct respective genes coding for G1PDH and G3PDH. The suggested hypothesis is that catalysis of homochiral G1P or G3P from DHAP are more efficient than those leading to racemic G1P and G3P, since there are no enzymes able to synthesize racemic G1P and G3P from DHAP. We propose that G1PDH or G3DPH, which are not “image mirror enzymes” but belonging to distinct family of proteins, emerged separately during evolution. They were probably selected for their efficient catalytic activities during evolution from large libraries of vesicles containing various biopolymers, including amino acids, carbohydrates, nucleic acids, lipids, and meteorite components to induce chemical imbalance.

Remote sensing (RS) has been widely adopted as a tool to investigate several biotic and abiotic factors, directly and indirectly, related to biodiversity conservation. European grasslands are one of the most biodiverse habitats in Europe. Most of these habitats are subject to priority conservation measure, and they are threatened by several human induced process. The broad expansions of few dominant species are widely reported as drivers of biodiversity loss. In this context, using Sentinel-2 (S2) images, we investigate the distribution of one of the most spreading species: <i>Brachypodium genuense</i>. We performed a binary Random Forest (RF) classification of <i>B. genuense</i> using a RS image and field sampled presence/absence points. Then, we integrate the occurrences obtained from RS classification into niche models to identify the topographic drivers of <i>B. genuense</i> distribution. Lastly, the impact of <i>B. genuense</i> distribution in the N2k habitats was assessed by overlay analysis. The RF classification process detected <i>B. genuense</i>'s cover with an overall accuracy of 91.18%. The integration of RS and topographic niche models shows that the most relevant topographic variables that influence the distribution of <i>B. genuense</i> are slope, elevation, solar radiation and Topographic Wet Index (TWI) in order of importance. The overlay analysis shows that 74.04% of the <i>B. genuense</i> identified in the study area falls on the semi-natural dry grasslands. The study highlights the importance of the RS classification and the topographic niche models as an integrated approach for mapping a broad-expansion species such as <i>B. genuense</i>. The coupled techniques presented in this work should be applicable to other plant communities with remotely recognizable characteristics for more effective management of N2k habitats.

Trueperella pyogenes is a common opportunistic pathogen which is one of the main causes of postpartum endometritis in dairy cows. As a substitute for antibiotics, the probiotic Lactobacillus rhamnosus GR-1 has been used in a wide range of clinical treatments. Our experiments were designed to establish a model of anti-damage which LGR-1 was used to protect bovine endometrial epithelial cells (BEECs) from inflammatory damage and cell destruction caused by T. pyogenes. Increased expression of NLRP3 inflammasomes and cytokines was observed following T. pyogenes challenge, but this increase was relieved by LGR-1 pretreatment. Immunofluorescence and Western blot analyses revealed that T. pyogenes infection also results in the damage of tight junction proteins in BEECs. The expression levels of Claudin-1, Occludin, and ZO-1 were decreased in cells only infected with T. pyogenes but not in cells pretreated with LGR-1. Moreover, the detection of the anti-apoptotic protein Bcl-2 and apoptotic proteins BAX, cytochrome c, as well as the activating effector caspase-3 revealed that T. pyogenes induced apoptosis of BEECs, which was also confirmed by DAPI staining to observe the morphological changes of the nuclei of cell apoptosis and by TUNEL staining to locate the cells undergoing apoptosis. Our data indicate that LGR-1 ameliorates the T. pyogenes–induced barrier dysfunction of BEECs and pre-application of LGR-1 could be an effective strategy for controlling T. pyogenes infection.

Evaluating the performance of water indices and mapping the spatial distribution of water-related ecosystems are important for monitoring surface water resources. This is particularly the case for Ethiopia since there is limited information available on water resources development over time despite its relevance for the people and ecosystems. To address this problem, this paper evaluates the performance of seven water indices for country-scale surface water detection based on high spatial and multi-temporal resolution Sentinel-2 data, processed using the Google Earth Engine cloud computing system. Results show that the water index (WI) and automatic water extraction index with shadow (AWEIsh) are the most accurate ones to extract surface water. Comparisons are based on qualitative visual inspections and quantitative accuracy indicators. For the latter, WI and AWEIsh obtained kappa coefficients of 0.96 and 0.95, respectively, and an overall accuracy of 0.98 each. Both indices accounted for similar spatial coverages of surface waters with 82,650 km2 (WI) and 86,530 km2 (AWEIsh) for the whole of Ethiopia.

The effectiveness of immunotherapy for cervical adenocarcinoma (CA) has not been demonstrated yet. It may be possible for us to use programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and CD8 as biomarkers of response to immune therapy in CA patients. In the present study, we aimed to investigate whether the expression levels of PD-1, PD-L1, and CD8 can predict the prognosis of CA patients and their response to ICI therapy. The levels of the PD-1, PD-L1, and CD8 proteins were analyzed by immunohistochemical analysis from formalin-fixed, paraffin-embedded tumor samples. The correlation between the expression levels and patient prognosis was analyzed by the Kaplan–Meier method and univariate and multivariate Cox proportional hazard regression model. We observed a significant inverse-correlation between the PD-1 and CD8 expression (p=0.001, chi square test). We also found a significant inverse-correlation between the PD-L1 and CD8 expression (p=0.027). The overall survival was significantly worse in patients with positive PD-1 expression (p=0.027). Similarly, the progression-free survival was also worse (p=0.087). Our results demonstrate that a high level of PD-1 expression is associated with a poor prognosis in CA patients. Further research is necessary to identify the molecular mechanisms that mediate this association.

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.

The KRAS mutant population has been undruggable for 40 years. G12C inhibitors and immunotherapy are the beginning of success. It is necessary to summarize the successful experience of the existing treatment model and explore the direction of the next treatment. In this review, we discuss the latest developments in targeted therapy and immunotherapy for KRAS-mutation NSCLC, aiming to provide direction or enlightenment for future treatment strategies.