Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g. anticancer treatment, genetic disorders, and enzymatic defects) may be identified. Although hormone replacement therapy, the principal therapeutic approach for POI, helps to alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, the effective approach to manage the patients with POI is highly warranted. Several mechanisms, associated with POI, have been identified, including lack of FSH receptor functioning, alterations in the apoptosis control, mutations in Sal-like 4 genes, thymulin or basonuclin-1 deficiency etc. The above-mentioned may be good targets for gene therapy in order to correct defects, leading to POI. The goal of this review is to summarize the current experience on the POI studies, that employed gene therapy, and to discuss the possible future directions in this field.

HIV-1 transcribes only one kind of transcript – the full length genomic RNA. To make the mRNA transcripts for the accessory proteins Tat and Rev, the genomic RNA must completely splice. The mRNA transcripts for Vif, Vpr, and Env must splice but not completely. Genomic RNA (which also functions as mRNA for the Gag and Gag/Pro/Pol precursor polyproteins) must not splice at all. HIV-1 can tolerate a surprising range in the relative abundance of individual transcript types, and a surprising amount of aberrant and even odd splicing; however, it must not over-splice, which results in the loss of full length genomic RNA and has a dramatic fitness cost. Cells typically do not tolerate unspliced/incompletely spliced transcripts, so HIV-1 has to circumvent this cell policing mechanism to allow some splicing while suppressing most. Splicing is controlled by RNA secondary structure, cis-acting regulatory sequences which bind splicing factors, and the viral protein Rev. There is still much work to be done to clarify the combinatorial effects of these splicing regulators. These control mechanisms represent attractive targets to induce over-splicing as an antiviral strategy. Finally, splicing has been implicated in latency, but to date there is little supporting evidence for such a mechanism. In this review we apply what is known of cellular splicing to understand splicing in HIV-1, and also present data from our newer and more sensitive deep sequencing assays quantifying the different HIV-1 transcript types.

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

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

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

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

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

Brazil, Russia, China, India, and the Republic of South Africa (BRICS) represent developing economies facing different energy and economic development challenges. The current study aims to forecast energy consumption in BRICS at aggregate and disaggregate levels using the annual time series data set from 1992 to 2019 and to compare results obtained from a set of models. The time-series data are from the British Petroleum (BP-2019) Statistical Review of World Energy. The forecasting methodology bases on a novel Fractional-order Grey Model (FGM) with different order parameters. This study contributes to the literature by comparing the forecasting accuracy and the forecasting ability of the FGM(1,1) with traditional ones, like standard GM(1,1) and ARIMA(1,1,1) models. Also, it illustrates the view of BRICS's nexus of energy consumption at aggregate and disaggregates levels using the latest available data set, which will provide a reliable and broader perspective. The Diebold-Mariano test results confirmed the equal predictive ability of FGM(1,1) for a specific range of order parameters and the ARIMA(1,1,1) model and the usefulness of both approaches for energy consumption efficient forecasting.

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.

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.

Background: Hepatic erythrophagocytosis is augmented in NASH and amplifies inflammation and fibrosis. Although various pro-phagocytic signals have been identified on erythrocytes of NASH patients, the role of bound thrombospondin-1 (TSP-1), which acts as an “eat-me” signal, arginase-1, which regulates the levels of nitric oxide in erythrocytes, and phosphatidylethano-lamine (PE) which can amplify erythrophagocytosis and hepatic inflammation have not been explored. Hence, we sought to investigate the levels of arginase-1 and TSP-1 in erythrocyte lysate and PE in erythrocyte membranes of NASH patients. Methods: Twenty-four patients and 14 healthy controls participated in our study. The levels of TSP-1 and arginase were quantified by ELISA in erythrocyte lysates, and the levels of PE in erythrocyte membranes by thin layer chro-matography. Results: Erythrocytes of NAFLD patients exhibit lower levels of arginase-1 and TSP-1 (p<0.01). Erythrocyte-bound TSP-1 levels correlated with the levels of erythrocyte surface CD47. Phosphatidylethanolamine was increased in erythrocytes of NASH patients and was accompanied by increased release, indicating exposure. Conclusion: Our results imply reduced TSP-1 binding by erythrocytes which could allow free TSP-1 molecules to act on macrophages, enhancing erythrophagocytosis. Increased PE which could amplify inflammation after efferocytosis, while downregulation of arginase-1 could lead to defective efferocytosis.

Background: Multidrug-resistant bacteria present resistance mechanisms against β-lactam antibiotics, such as Extended-Spectrum Beta-lactamases (ESBL) and Metallo-β-lactamases enzymes (MBLs) operon encoded in Gram-negative species. Likewise, Gram-positive bacteria have evolved other mechanisms through mec genes, which encode modified penicillin-binding proteins (PBP2). This study aimed to determine the presence and spread of β-lactam antibiotic resistance genes and the microbiome circulating in Quito’s Public Transport (QTP). Methods: A total of 29 station turnstiles were swabbed to extract the surface environmental DNA. PCRs were performed to detect the presence of 13 antibiotic resistance genes and to identify 16S rDNA barcoding, followed by clone analysis, Sanger sequencing and BLAST search. Results: ESBL genes blaTEM-1 and blaCTX-M-1 and MBL genes blaOXA-181 and mecA were detected along QPT stations. Two subvariants were found for blaTEM-1, blaCTX-M-1, and blaOXA-181. Almost half of the circulating bacteria found at QPT stations were common human microbiota species including those classified by the WHO as pathogens of critical and high-priority surveillance. Conclusions: β-lactam antibiotic resistance genes are widely spread throughout QPT. This is the first report of blaOXA-181 in environmental samples in Ecuador. Moreover, we detected a new putative variant of this gene. Some commensal coagulase-negative bacteria may have a role as mecA resistance reservoirs

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung, and high VCAM-1 expression correlated with poor survival of lung cancer patients. VCAM-1 knockdown reduced invasion in A549 human lung cancer cells, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1-mediated A549 cell invasion. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed invasion in A549 and NCI-H1299 lung cancer cell lines. Taken together, these results suggest that VCAM-1-D6 is a novel therapeutic target in VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.

Build a special identical equation, use its calculation characters to prove and search for solution of any odd converging to 1 equation through (*3+1)/2^k operation, change the operation to (*3+2^m-1)/2^k, and get a solution for this equation, give a specific example to verify. Thus prove the Collatz Conjecture is true. Furthermore, analysis the sequences produced by iteration calculation during the procedure of searching for solution, build a weight function model, prove it decrease progressively to 0, build a complement weight function model, prove it increase to its convergence state. Build a (*3+2^m-1)/2^k odd tree, prove if odd in (*3+2^m-1)/2^k long huge odd sequence can not converge, the sequence must outstep the boundary of the tree after infinite steps of (*3+2^m-1)/2^k operation.

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.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.

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.

A 2-year prospective study carried out on ventilator-associated pneumonia (VAP) patients in the intensive care unit at King Khalid hospital, Hail, Kingdom of Saudi Arabia (KSA), revealed a high prevalence of extremely drug-resistant (XDR) Acinetobacter baumannii. About a 9% increase in the incidence rate of A. baumannii has occurred in the VAP patients between 2019 and 2020 (21.4% to 30.7%). In 2019 the isolates were positive for IMP-1 and VIM-2 (31.1% and 25.7%, respectively) as detected by PCR. In comparison, a higher proportion of isolates produced NDM-1 in 2020. Here, we observed a high resistant proportion of ICU isolates towards the most common antibiotics in use. Colistin sensitivity dropped to 91.4% in the year 2020 as compared to 2019 (100%). Thus, the finding of this study has a highly significant clinical implementation in the clinical management strategies for VAP patients. Furthermore, strict implementation of antibiotic stewardship policies, regular surveillance programs for antimicrobial resistance monitoring, and screening for genes encoding drug resistance phenotypes have become imperative.

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.

Stress Granules formation is a pro-survival mechanism helping cells to cope with environmental challenges. Stress Granules have been studied for two decades in fundamental research, and are now being examined in the context of human pathogenesis. Here, we review studies highlighting stress granules’ involvement in cancer development through translational pattern modification.

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.

(R)-1-(4-Amino-3,5-dichlorophenyl)-2-bromoethan-1-ol has been synthesised in 93% enantiomeric excess (ee) by asymmetric reduction of the corresponding ketone catalysed by a ketoreductase and NADPH as the co-factor in DMSO. (S)-N-(2,6-Dichloro-4-(1-hydroxyethyl)phenyl)acetamide has been synthesised in >98% ee by the same system. Both synthons are potential precursors for clenbuterol enantiomers. Clenbuterol is a β₂-agonist used in veterinary treatment of asthma in several countries. The drug is listed on the World Anti-doping Agency’s Prohibited list due to its effect on increased protein synthesis in the body. However, racemic clenbuterol has recently been shown to reduce the risk of Parkinson’s disease. In order to reveal which one (or both) of the enantiomers that cause this effect, the pure enantiomers need to be studied separately. Our biocatalytic approach in order to obtain enantiopure clenbuterol should be applicable to industrial scale.

In green chemistry, filamentous fungi are regarded as a kind of robust microorganism for the biotransformation of natural products. Nonetheless, the screening of microorganisms is crucial for the effective biotransformation of natural products such as phenazine compounds. The precursor metabolite of most phenazine derivatives in Pseudomonas spp. is phenazine-1-carboxylic acid (PCA), the key constituent of shenqinmycin, widely used to control rice sheath blight in southern China. In this study, a new fungus strain Aspergillus sclerotiorum was isolated, which can efficiently convert PCA into 3-hydroxy-phenazine 1-carboxylic acid (3-OH-PCA). Moreover, an effective whole cells biotransformation system was constructed by screening optimal reaction conditions and carbon sources. Hence, Aspergillus sclerotiorum exhibited desirable adaptation by consumption of different carbon sources and maximum whole cell biomass (10.6 g/L DCW) was obtained as a biocatalyst from glucose. Optimal conditions for whole-cell biocatalysis of PCA were evaluated, including PCA concentration of 1120 mg/L, pH 7.0, temperature of 25°C, rotation rate 200 rpm and dry cell weight 15 g/L for 60 h, thus 1060 mg/L of 3-OH-PCA was obtained and the conversion efficiency of PCA was 94%. Hence, the results of repeated batch mood revealed that the biotransformation efficiency of fungus pellets reduced with each subsequent cycle but remained stable in all five cycles with the provision of glucose supplement. These findings open the prospective of using filamentous fungi for the whole cell biocatalysis of phenazine in enormous amount and efficient production of 3-OH-PCA. Moreover, these results laid the foundation for further research to disclose the genetic based mechanism of the strain responsible for PCA biotransformation.

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.

Among cross-sectional imaging modalities, computed tomography (CT) is more available and faster; however, magnetic resonance (MR) performs better in terms of sensitivity and specificity, due to its higher contrast resolution. The appearance of peritoneal deposits on CT and MR depends mainly on the primary tumour histology: in case of unknown primary tumour (3-5% of cases), their behaviour at imaging may provide insights on the tumour origin. The time-point of tumour evolution, previous or ongoing treatments and the peritoneal spaces where they occur, also play an important role in determining the appearance of peritoneal deposits. Thus, knowledge of peritoneal anatomy and fluid circulation is mandatory in detection and characterization of peritoneal deposits. Several benign and malignant conditions may show similar imaging features that overlap those of PC, making the differential diagnosis challenging. Clinical history, laboratory findings and previous imaging examinations must be considered to achieve the correct diagnosis.

Collatz conjecture states that an integer $n$ reduces to $1$ when certain simple operations are applied to it. Mathematically, the Collatz function is written as $f^k(n) = \frac{3^kn + C}{2^{z}}$, where $z, k, C \geq 1$. Suppose the integer $n$ violates Collatz conjecture by reappearing as $2^in$, where $i \geq 1$, then the equation modifies to $n \left(1 - \frac{3^k}{2^{z}2^i}\right) = \frac{C}{2^{z}2^i}$. The article takes an elementary approach to this problem by calculating the bounds on the values of $\frac{C}{2^{z}2^i}$ and $1 - \frac{3^k}{2^{z}2^i}$. Correspondingly, an upper limit on the integer $n$ is placed that can re-appear in the sequence. The integer $n$ lies in the $(-\infty, 5)$ range, and the limit on the number of odd steps is $k < 3$. Finally, it is shown that no integer chain exists that does not lead to 1.

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.

We describe an efficient and cost effective data access mechanism for Sentinel-1 TOPS 1 mode bursts. Our data access mechanism enables burst-based data access and processing, thereby 2 eliminating ESA’s Sentinel-1 SLC data packaging conventions as a bottleneck to large scale processing. 3 Pipeline throughput is now determined by available compute resources and efficiency of the analysis 4 algorithms. For targeted infrastructure monitoring studies, we are able to generate coregistered, 5 geocoded stacks of SLCs for any AOI in the world in a few minutes. In addition, we describe our 6 global scale radar backscatter and interferometric products and associated pipeline design decisions 7 that ensure geolocation consistency across the suite of derived products from Sentinel-1 data. Finally, 8 we discuss the benefits and limitations of working with geocoded SAR SLC data.

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.

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.

Purinergic receptors are inflammatory mediators activated by extracellular nucleotides released by dying or injured cells. Several studies have described an important role for these receptors in HIV-1 entry, particularly regarding their activity on HIV-1 viral membrane fusion. Several reports identify purinergic receptor antagonists that inhibit HIV-1 membrane fusion; these drugs are suspected to act through antagonizing Env-chemokine receptor interactions. They also appear to abrogate activity of downstream mediators that potentiate activation of the NLRP3 inflammasome pathway. Here we review the literature on purinergic receptors, the drugs that inhibit their function, and the evidence implicating these receptors in HIV-1 entry.

BACKGROUND: During the natural history, the incidence HTLV-1 related diseases were 0.5% until 10% after decades of infection. Despite relative low lethality, previous study observed that HTLV-1 infection is associated with significantly increased mortality. For example, the incidence of ATLL and HAM/TSP, co-infections with HIV and HCV, parasitic co-infection with Strongyloides stercoralis may increase morbidity and mortality. OBJECTIVE: Determine the mortality rate and its major variables as possible risk factors, analyzing the HTLV Clinic at Emilio Ribas Institute, a continuous open cohort of HTLV patients since 1997. METHODS: This cohort open cohort possesses new patients added at a rate of approximately 50 patients/year. There were 1100 HTLV-infected subjects identified by September 30th 2018. All clinical data including clinical and laboratory data, which have been updated on a regular basis over the last 22 years, were entered into a specific REDCap database. The Ethical Board of the IIER approved the protocol. RESULTS: Along 22 years of clinical care in the HTLV-out clinic, 727 HTLV-1-infected subjects and 248 HAM/TSP cases. Four-hundred sixty-eight patients of whom remaining under active follow up. The mean follow-up time of the cohort was 12 years. Twenty-seven patients died (median age of 51,5 years old). From this total, 13 was asymptomatic carriers and 14 HAM/TSP subjects, 12 of asymptomatic and seven HAM/TSP possess co-infected with HIV or/and HCV. Other seven presented HAM/TSP without co-infection, and all was female, and sepsis was the majority cases the majority of cases of sepsis were related to infection of the urinary tract (p=0.058) and to ulcers of decubitus (p=0.021), and it was associated with risk factors for mortality. CONCLUSIONS: Overall, the mortality rate for HAM-TSP patients was six percent. The mean life expectancy in Brazil is about 78 years in 2018, twenty-two years higher than HAM/TSP patients without any other coinfection. This study highlights the possibility of higher death risk among HTLV-1-infected patients and HAM/TSP subjects in Brazil, and identified some risk factors for this outcome. Also, these patients may possess higher risk for morbidity, usually urinary tract infections and decubitus scars, which could increase risk for death.

Plasma osteopontin (OPN) levels are elevated in mycobacterium tuberculosis patients and may involve granuloma formation. New inhibitors using brefelamide, an aromatic amide isolated from Dictyostelium cellular slim molds which may inhibit OPN transcription at concentration of 1M, were synthesized as compounds C, D and E. Their inhibitory activity against OPN synthesis in phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells was confirmed using enzyme-linked immunosorbent assay (ELISA), a multicolor immune-fluorescent microscope and western blot analysis. For the ELISA performed using the full-length OPN, each compound showed significant inhibition. Detailed analysis were done using C and D. They also showed inhibitory activity when used on another ELISA system to detect the immune-related form of OPN and their IC50 were 0.6 and 1.2 M for compounds C and D, respectively. Fluorescent particle count of stained cell numbers by O-17 showed the inhibition. Antibodies for O-17 and 34E3, which recognize OPN N-terminus and thrombin-cleaved site, respectively, detected distinct bands on the western blots following PMA stimulation. The decrease in full-length OPN detected by O-17 in the compound-treated cells was identified via western blot analysis. These newly-developed compounds may therefore be used in clinical trials for cancer and infectious diseases.

Data that have been processed to allow analysis with a minimum of additional user effort are often referred to as Analysis Ready Data (ARD). The ability to perform large scale Landsat analysis relies on the ability to access observations that are geometrically and radiometrically consistent, and have had non-target features (clouds) and poor quality observations flagged so that they can be excluded. The United States Geological Survey (USGS) has processed all of the Landsat 4 and 5 Thematic Mapper (TM), Landsat 7 Enhanced Thematic Mapper Plus (ETM+), Landsat 8 Operational Land Imager (OLI) and Thermal Infrared Sensor (TIRS) archive over the conterminous United States (CONUS), Alaska, and Hawaii, into Landsat ARD. The ARD are available to significantly reduce the burden of pre-processing on users of Landsat data. Provision of pre-prepared ARD is intended to make it easier for users to produce Landsat-based maps of land cover and land-cover change and other derived geophysical and biophysical products. The ARD are provided as tiled, georegistered, top of atmosphere and atmospherically corrected products defined in a common equal area projection, accompanied by spatially explicit quality assessment information, and

This paper deals with the merger of the two lightweight stream ciphers—A5/1 and Trivium. The idea is to make the key stream generation more secure and to remove the attacks of the individual algorithms. The bits generated by the Trivium cipher (output) will act as the input of the A5/1 cipher. The registers used in the A5/1 cipher will be filled by the output bits of the Trivium cipher. The three registers will then be connected to generate an output which will be our required key stream.

Herpes simplex virus type 1 (HSV-1) is among the most widely spread viruses on the planet. However, the rate of binding to the receptor is not among the greatest ones. Gibbs energy of binding, which represents the driving force for antigen-receptor binding, of HSV-1 is less negative than can be expected. Furthermore, the Gibbs energy of biosynthesis of HSV-1 is among the most negative in nature. This implies high rate of multiplication of HSV-1. Obviously, HSV-1 uses specific strategy in virus-host interaction. While most other viruses increase infectivity through a high rate of antigen-receptor binding and cell entry/ highly negative Gibbs energy of binding, HSV-1 uses another strategy. It is related to a relatively slow reaction of antigen-receptor binding, which is followed by a higher rate of multiplication, which is a consequence of a highly negative Gibbs energy of biosynthesis. We can conclude empirically that both strategies are successful.

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.

A finite-type immersion or smooth map is a nice tool to classify submanifolds of Euclidean space, which comes from eigenvalue problem of immersion. The notion of generalized 1-type is a natural generalization of those of 1-type in the usual sense and pointwise 1-type. We classify ruled surfaces with generalized 1-type Gauss map as part of a plane, a circular cylinder, a cylinder over a base curve of an infinite type, a helicoid, a right cone and a conical surface of $G$-type.

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.

The following system of equations {x_1 \cdot x_1=x_2, x_2 \cdot x_2=x_3, 2^{2^{x_1}}=x_3, x_4 \cdot x_5=x_2, x_6 \cdot x_7=x_2} has exactly one solution in ({\mathbb N}\{0,1})^7, namely (2,4,16,2,2,2,2). Hypothesis 1 states that if a system of equations S \subseteq {x_i \cdot x_j=x_k: i,j,k \in {1,...,7}} \cup {2^{2^{x_j}}=x_k: j,k \in {1,...,7}} has at most five equations and at most finitely many solutions in ({\mathbb N}\{0,1})^7, then each such solution (x_1,...,x_7) satisfies x_1,...,x_7 \leq 16. Hypothesis 1 implies that there are infinitely many composite numbers of the form 2^{2^{n}}+1. Hypotheses 2 and 3 are of similar kind. Hypothesis 2 implies that if the equation x!+1=y^2 has at most 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)}. Hypothesis 3 implies that if the equation x(x+1)=y! has at most finitely many solutions in positive integers x and y, then each such solution (x,y) belongs to the set {(1,2),(2,3)}. We describe semi-algorithms sem_j (j=1,2,3) that never terminate. For every j \in {1,2,3}, if Hypothesis j is true, then sem_j endlessly prints consecutive positive integers starting from 1. For every j \in {1,2,3}, if Hypothesis j is false, then sem_j prints a finite number (including zero) of consecutive positive integers starting from 1.

The restriction of normal blood flow is the cause of many diseases including stroke and coronary artery diseases. To study the consequences of vessel blockade, previous models mainly focused on major arteries and have been well studied. However, the sequela from interruption of capillary vessels by microemboli was less well characterized. In this study, we exploited polystyrene microspheres as a mimicry of microemboli and found that microspheres of this size can be trapped in capillary vessels of all organs without causing apparent acute morbidities of the host. Interestingly, we accidentally found significantly increased recruitment of monocyte to the brain vasculature expressing low levels of Ly6C expression, but not to other organs. Further study revealed the spleen is the major origin of the recruited monocyte. Most importantly, VCAM-1 which is constitutively expressed on mouse brain vasculature orchestrates the recruitment of monocyte. Blockade of VCAM-1 in mice can substantially reduce monocyte recruitment. Interestingly, monocytes get activated through TNF- signaling which likely happens in the spleen instead of the brain. Collectively, we found a unique monocyte recruitment strategy in the brain comparing to other orangs, in response to capillary blockade induced by polystyrene microspheres.

Methamphetamine (METH) has the potential to disrupt the activities of neurotransmitters in the Central Nervous System (CNS) and cause neurotoxicity through various pathways. These pathways include increased production of reactive nitrogen and oxygen species, hypothermia, and induction of mitochondrial apoptosis. In this study, we investigated the long-term effects of METH addiction on the structural changes in the amygdala of postmortem human brains, as well as the involvement of the CREB/BDNF and Akt-1/GSK3 signaling pathways. We examined ten male postmortem brains, comparing control subjects with chronic METH users, using immunohistochemistry, Real-time PCR (to measure levels of CREB, BDNF, Akt-1, GSK3, and TNF-α), Tunnel assay, stereology, and assays for ROS, GSSG, and GPX. The findings revealed that METH significantly reduced the expression of BDNF, CREB, Akt-1, and GPX, while increasing the levels of GSSG, ROS, RIPK3, GSK3, and TNF-α. Furthermore, METH was found to induce inflammation and neurodegeneration in the amygdala, with ROS production mediated by the CREB/BDNF and Akt-1/GSK3 signaling pathways.

Background: The prevalence of human T-lymphotropic virus type-1 (HTLV-1) infection is higher in women, and sexual intercourse has been described as an important route of male-to-female transmission. The present study aimed to quantify HTLV-1 proviral load (PVL) in vaginal fluid, and to investigate correlations with PVL in peripheral blood mononuclear cells (PBMC). Methods: HTLV-1-infected women were consecutively recruited at a multidisciplinary center for HTLV patients in Salvador-Brazil. All women underwent gynecological examinations to obtain cervicovaginal fluid and venipuncture for blood collection. PVL, as measured by real-time quantitative polymerase chain reaction (RT-qPCR), was expressed as the number of copies of HTLV-1/106 cells in blood and vaginal fluid samples. Light microscopy was used to assess cervicovaginal cytopathology and vaginal microbiota. Results: In the 56 included women (43 asymptomatic carriers and 13 diagnosed with HTLV-associated myelopathy/tropical spastic paraparesis-HAM/TSP), mean age was 35.9 (SD±7.2) years. PVL was higher in PBMCs [median: 23,264 copies/106 cells (IQR: 7,420 - 64,371)] than in vaginal fluid [451.9 copies/106 cells (IQR: 0 - 2,672)] (p<0.0001). PVL in PBMCs was observed to correlate directly with PVL in vaginal fluid (R=0.32, p=0.01). PVL was undetectable in vaginal fluid samples from 20 women (35.7%), most of whom were asymptomatic (19/20). Cytopathologic analyses revealed no differences between women with detectable or undetectable PVL. Conclusion: HTLV-1 proviral load is detectable in vaginal fluid and correlates directly with proviral load in peripheral blood. This finding suggests that sexual transmission of HTLV-1 from female to male may occur and vertical transmission, particularly in the context of vaginal delivery.

In this research, new setting is introduced for new SuperHyperNotions, namely, an 1-failed SuperHyperForcing and Neutrosophic 1-failed SuperHyperForcing. Assume a SuperHyperGraph. Then an ``1-failed SuperHyperForcing'' $\mathcal{Z}(NSHG)$ for a neutrosophic SuperHyperGraph $NSHG:(V,E)$ is the maximum cardinality of a SuperHyperSet $S$ of black SuperHyperVertices (whereas SuperHyperVertices in $V(G) \setminus S$ are colored white) such that $V(G)$ isn't turned black after finitely many applications of ``the color-change rule'': a white SuperHyperVertex is converted to a black SuperHyperVertex if it is the only white SuperHyperNeighbor of a black SuperHyperVertex. The additional condition is referred by ``1-'' about the usage of any black SuperHyperVertex only once to act on white SuperHyperVertex to be black SuperHyperVertex; a ``neutrosophic 1-failed SuperHyperForcing'' $\mathcal{Z}_n(NSHG)$ for a neutrosophic SuperHyperGraph $NSHG:(V,E)$ is the maximum neutrosophic cardinality of a SuperHyperSet $S$ of black SuperHyperVertices (whereas SuperHyperVertices in $V(G) \setminus S$ are colored white) such that $V(G)$ isn't turned black after finitely many applications of ``the color-change rule'': a white SuperHyperVertex is converted to a black SuperHyperVertex if it is the only white SuperHyperNeighbor of a black SuperHyperVertex. The additional condition is referred by ``1-'' about the usage of any black SuperHyperVertex only once to act on white SuperHyperVertex to be black SuperHyperVertex. Assume a SuperHyperGraph. Then an ``$\delta-$1-failed SuperHyperForcing'' is a \underline{maximal} 1-failed SuperHyperForcing of SuperHyperVertices with \underline{maximum} cardinality such that either of the following expressions hold for the (neutrosophic) cardinalities of SuperHyperNeighbors of $s\in S:$ $~|S\cap N(s)| > |S\cap (V\setminus N(s))|+\delta,~|S\cap N(s)| < |S\cap (V\setminus N(s))|+\delta.$ The first Expression, holds if $S$ is an ``$\delta-$SuperHyperOffensive''. And the second Expression, holds if $S$ is an ``$\delta-$SuperHyperDefensive''; a``neutrosophic $\delta-$1-failed SuperHyperForcing'' is a \underline{maximal} neutrosophic 1-failed SuperHyperForcing of SuperHyperVertices with \underline{maximum} neutrosophic cardinality such that either of the following expressions hold for the neutrosophic cardinalities of SuperHyperNeighbors of $s\in S:$ $~|S\cap N(s)|_{neutrosophic} > |S\cap (V\setminus N(s))|_{neutrosophic}+\delta,~ |S\cap N(s)|_{neutrosophic} < |S\cap (V\setminus N(s))|_{neutrosophic}+\delta.$ The first Expression, holds if $S$ is a ``neutrosophic $\delta-$SuperHyperOffensive''. And the second Expression, holds if $S$ is a ``neutrosophic $\delta-$SuperHyperDefensive''. A basic familiarity with SuperHyperGraph theory and neutrosophic SuperHyperGraph theory are proposed.

Abstract The expression patterns of microRNAs (small non-coding RNAs) are altered in many biological processes such as myogenesis. In this study, we aimed to investigate the impact of predicted miR-202, its target genes Akt2 and Rock-1 as a potential regulator of myoblast in the myocyte differentiation process using the C2C12 cell line. After confirmation of the differentiation process induced by 3% horse serum, the expression level of miRNA and its targets were evaluated. In the following, a luciferase assay was conducted to approve the effect of miRNA on its target. Our results indicated that miR-202 and Akt2 were significantly up-regulated during differentiation, while Rock-1 was downregulated. Co-transfection of miRNA with psiCHECK2-Rock-1 significantly presented that Rock-1 was directly targeted by miR-202. On the contrary, miR-202 has failed to enforce its inhibitory effect on Akt2 expression. In particular, miR-202 seems to be a regulator of muscle differentiation pathway thought targeting Rock-1.

Abstract: Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the antitumor response. Modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve therapy outcome for AML patients. However, the effect of mitochondrial inhibitors on the immune compartment in the context of AML is yet to be explored. Immune checkpoints such as the ecto-nucleotidase CD39 and programmed dead ligand 1 (PD-L1) have been reported to be expressed in AML and linked to chemoresistance and poor prognosis. In the present study, we first demonstrated that a novel selective electron transfer chain complex (ETC) I inhibitor, EVT-701, decreased OxPHOS metabolism of murine and human cytarabine (AraC)-resistant leukemic cell lines. Furthermore, we showed that, while AraC induced immune response regulation by increasing CD39 expression and by reinforcing interferon-γ/PD-L1 axis, EVT-701 reduced CD39 and PD-L1 expression in vitro in a panel of both murine and human AML cell lines, especially upon AraC treatment. Altogether, this work uncovers a non-canonical function of ETCI in controlling CD39 and PD-L1 immune checkpoints, thereby improving the anti-tumor response in AML.

Herpesviruses produce a plethora of pleomorphic and heterogeneous particle populations. The composition and biological role of these is not understood. Detailed analysis has been challenging due to the lack of multidimensional identification and purification methodologies. Fluorescence-activated cell sorting (FACS), originally developed to sort objects with at least ten thousand-fold larger volumes, has recently been applied to cellular exosomes as well as viral particles and has been dubbed nanoscale flow cytometry or “flow virometry”. In comparison to other nanoparticles, herpesvirus concentrations can be measured with high precision using simple culturing methods. Here, we used this unique capability to evaluate a standard FACS sorter. We demonstrate that detection and separation capabilities were insufficient to distinguish infectious fluorescent viral populations from populations lacking fluorescence and infectivity. Moreover, fluorescent populations did not contain single virus particles but mostly aggregates. On top, analysis of viral samples by flow cytometry was confounded by swarm detection, as multiple objects are measured simultaneously and interpreted as a single object. Despite these technical difficulties, comparison of crude supernatant to gradient purified HCMV revealed that infectious virus is a minor proportion of the particles released from infected cells. Our data stress the need for a set of standardized controls and protocols when applying FACS to biological nanoparticles and highlights technical challenges that need to be solved before flow virometry can achieve its full potential.

It has been long recognized that under hypoxia conditions cancer cells reprogram their metabolism through shift from oxidative phosphorylation (OXPHOS) to glycolysis to meet elevated requirements in energy and nutrients for proliferation, migration and survival. However, data accumulated over the last years increasingly evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism even in the same tumor. The phenomenon denoted as cancer cell metabolic plasticity or hybrid metabolism depends on a tumor micro-environment, which is highly heterogeneous and influenced by intensity of vasculature and blood flow, oxygen concentration, nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, reactive oxygen species (ROS), etc. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, GLUTs, and AMPK and other regulatory proteins including oncogenes such as c-Myc, p53 and KRAS, growth factor-initiated PKB/Akt, PI3K and mTOR signaling pathways and tumor suppressors such as LKB1 and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discovery novel anti-cancer drugs.

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.

Knowledge of the spatio-temporal occurrence of avalanche activity is critical for avalanche forecasting and hazard mapping. We present a near-real time automatic avalanche monitoring system that outputs detected avalanche polygons within roughly 10 min after Sentinel- 1 SAR data download. Our avalanche detection algorithm has an average probability of detection of 67.2 % with a false alarm rate averaging 45.9, with maximum POD's over 85 % and minimum FAR's of 24.9 % compared to manual detection of avalanches. The high variability in performance stems from the dynamic nature of snow in the Sentinel-1 data. After tuning parameters of the detection algorithm, we processed five years of Sentinel-1 images acquired over a 150 x 100 km large area in Northern Norway, with the best setup. Compared to a dataset of field-observed avalanches, 77.3 % were manually detectable. Using these manual detections as benchmark, the avalanche detection algorithm achieved an accuracy of 79 % with high POD's in cases of medium to large wet snow avalanches. For the first time, we can present a dataset of spatiotemporal avalanche activity over several winters from a large region. This unique dataset allows for research into the relationship between avalanche activity and triggering meteorological factors, mapping of avalanche prone areas and near-real time avalanche activity monitoring to assist public avalanche forecasting. Currently, the Norwegian Avalanche Warning Service is using our processing system for pre-operational use in three regions in Norway.

Metastasis is a major cause factor for breast cancer (BC)-associated mortality. During the metastatic process, disseminated tumor cells (DTCs) detach from the primary sites, and enter the bloodstream and establish the secondary colonies. Recent studies have provided substantial evidence for the importance of Notch signaling in BC metastasis. Therefore, this review focuses on the mechanisms by which Notch contributes to the origin of BC DTCs, increases their motility, regulates their intravasation and extravasation, protects them from host surveillance, and finally facilitates colonization. Identification of the mechanisms underlying Notch-related BC metastasis will lead to the development of novel Notch-targeted therapeutic strategies to reduce metastasis and significantly improve outcomes.

Aims/Hypothesis): Type 1 diabetes is an immune-mediated disease with destruction of the pancreatic β-cells, a process that is conditioned by multiple genes and other factors. HLA counts as the major susceptibility gene. Significant variations in HLA genetic susceptibility to type 1 diabetes between Caucasians, African and Asian and other ethnic groups may have led to the variation in incidence of type 1 diabetes globally. Type 1 diabetes is characterized upon HLA identification. In this chapter we discuss global variations in genetic susceptibility of HLA with regard to type 1 diabetes globally with a particular attention to Arab population. Methods): Haplotype configuration of HLA class I A, B, C and Class II –DR/DQ/DP were studied in Caucasians, African and Asian and in Arab population to see if that is responsible for the exponential rise in the rate of type 1 diabetes. Results): Although Arabs have one of the highest global incidence and prevalence rates of type 1 diabetes, unfortunately, there is a dearth amount of information regarding HLA genetic susceptibility to type 1 diabetes in the Arab world. HLA haplotype configurations contribute to its risk value. However, out of an insufficient present study there are examples of misjudgment of HLA risk according to HLA alleles rather than haplotypes. Conclusion): To date HLA outlooks for the characterization of type 1 diabetes. There is an ethnicity difference in HLA characteristics which is responsible for variation in type 1 diabetes. Although Arab population have contributed heavily in the rise of burden of type 1 diabetes, however, there is significantly a dearth amount of studies on HLA in Arab population. Obviously, any future prediction, prevention or cure of the disease will be based on the HLA genetics. There is a dire need for a systematic screening of HLA for Arab population with type 1 diabetes, identification of Arab HLA-risk values and identify those who are prone to get the disease.

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.

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p<0.001 and HR 0.77, p<0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p<0.012), with the exception of melanoma (in women, HR 0.80, p=0.006). PFS was longer in men than in women (HR 0.67, p<0.001 and HR 0.77, p=0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We here evaluated available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining antidiabetics, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To our best, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other novel antidiabetics and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Programmed cell death protein 1 (PD-1) is a biomarker on the surface of cells that has a role in promoting self-tolerance by suppressing the inflammatory activity of T cells. In this work, one peptide of PD-1 was used as the template in molecular imprinting. The magnetic peptide-imprinted poly(ethylene-co-vinyl alcohol) composite nanoparticles (MPIP NPs) were characterized by dynamic light scattering (DLS), high-performance liquid chromatography (HPLC), Brunauer-Emmett-Teller (BET) analysis and superconducting quantum interference device (SQUID) analysis. Natural killer-92 (NK-92) cells were added to these composite nanoparticles and then incubated with human hepatoma (HepG2) cells. The viability and apoptosis pathway of HepG2 were then studied using cell counting kit-8 (CCK8) and the quantitative real-time polymerase chain reaction (qRT-PCR), respectively. These nanoparticles were found significantly enhance the activity of natural killer cells toward HepG2 cells by increasing expression of NK-kB, caspase 8 and especially caspase 3.

Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were getting either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1.

The elderly present age-related morphological and histological changes of the oral cavity; Literature displays many studies regarding the specific pathologies of the oral cavity in elderly patients, but no etiologically based classification is available. The aim of this study was to analyze the series of patients over 65 who were treated by our Unit of Pathology between 2020 and 2022 for a suspicion of oral lesion or for preventive dental evaluation (in anticipation of cardiac surgery, anti-resorptive drugs intake, chemotherapy, radiotherapy of the head-neck district or transplantation). The analysis was conducted by dividing oral lesions into 5 groups depending on the etiology: reactive, immunological, traumatic, benign and malignant degenerative. The sixth group consisted of patients undergoing preventive dental evaluation. The study included 435 patients; 91 of them were diagnosed with a reactive origin pathology, 174 with immunological origin pathology, 48 with traumatic pathology and 86 with degenerative pathology (42 benign and 44 malignant). 36 patients went to our Unit for preventive specialist evaluation. Oral health has a major impact on the daily life of the elderly; The examination of oral mucosa in geriatric patients is a fundamental diagnostic moment to report lesions early, thus allowing easier prevention and treatment.

Our recent studies showed that the treatment of human ovarian tumor cells with NCX4040 resulted in significant depletions of cellular glutathione, formation of reactive oxygen/nitrogen species and cell death. NCX4040 is also cytotoxic to several human colorectal cancer cells (CRC) in vitro and in vivo. Here, we have examined ferroptosis-dependent mechanism(s) of cytotoxicity of NCX4040 in HT-29 and K-RAS mutant HCT116 colon cell lines. Ferroptosis is characterized by accumulation of reactive oxygen species (ROS) within the cell, leading to an iron-dependent oxidative stress-mediated cell death. However, its relevance in the mechanism of NCX4040 cytotoxicity in CRC is not known. We found that NCX4040 generated ROS in CRC cells without any depletion of cellular GSH. Combinations of NCX4040 with erastin (ER) or RSL3 (RAS-selective lethal 3), known inducers of ferroptosis, enhanced CRC death. In contrast, ferrostatin-1, an inhibitor of ferroptosis, significantly inhibited NCX404-induced cell death. Treatment of CRC cells with NCX4040 resulted in induction of lipid peroxidation in a dose- and time-dependent manner. NCX4040 treatment induced several genes related to ferroptosis (e.g., CHAC1, GPX4 and NOX4) in both cell lines. Metabolomic studies also indicated significant increases in both lipid and energy metabolism following the drug treatment in HT-29 and HCT116 cells. These observations strongly suggest that NCX4040 causes ferroptosis-mediated cell death of CRC cells. Furthermore, combinations of NCX4040 and ER or RSL3 may contribute significantly for the treatment of CRC, including those that are difficult to treat due to the presence of Ras mutation in the clinic. NCX4040 induced ferroptosis may also be a dynamic form of cell death for the treatment of other cancers.

Platinum-resistant high-grade serous ovarian cancer (HGSOC) is invariably a fatal disease, so a central goal in ovarian cancer research is to develop novel strategies to overcome platinum resistance. Treatment is thus moving towards personalized therapy. However, validated molecular biomarkers to predict patients’ risk of developing platinum resistance are still lacking. Extracellular vesicles (EVs) are promising candidates for biomarkers. EpCAM-specific EVs are largely unexplored biomarkers in predicting chemoresistance. Using transmission electron microscopy, nanoparticle tracking analysis and flow cytometry, we compared the characteristics of EVs released from a cell line derived from a clinically confirmed cisplatin-resistant patient (OAW28) and EVs released from two cell lines from tumors sensitive to platinum-based chemotherapy (PEO1, OAW42). We showed that characteristics of EVs released from the HGSOC cell line of chemoresistant patients had higher heterogeneity in size, a larger proportion of medium/large (&gt;200nm) EVs and a higher number of released EpCAM-positive EVs of different sizes, although expression of EpCAM predominated, especially on those larger than 400 nm. We also determined a strong positive correlation between the concentration of EpCAM-positive EVs and expression of cellular EpCAM. These results may contribute to prediction of platinum resistance in the future, although they should first be validated in clinical samples.

Small RNAs (sRNA) are epigenetic regulators of essential biological processes that have been linked to the onset and progression of leukemia, including acute adult T-cell leukemia-lymphoma (ATLL) caused by the retrovirus Human T-lymphotropic virus type 1. Here, we describe the sRNA profile of a 30-year-old female with ATLL at diagnosis and after maintenance therapy, with the goal of correlating their expression levels with response to therapy.

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that, occasionally, may spread to the central nervous system (CNS), being the most common cause of sporadic encephalitis. One of the main neurovirulence factors of HSV-1 is the protein ICP34.5 that, although initially seemed to be relevant only in neuronal infections, it can also promote viral replication in non-neuronal cells. New ICP34.5 functions have been discovered during the recent years, and some of them have been questioned. This review describes the mechanisms of ICP34.5 to control cellular antiviral responses and debates its most controversial functions. One of the most discussed roles of ICP34.5 is autophagy inhibition. Although autophagy is considered a defense mechanism against viral infections, current evidence suggests that this antiviral function is only one side of the coin. Different types of autophagic pathways interact with HSV-1 impairing or enhancing the infection, and both the virus and the host cell modulate these pathways to tip the scales in its favor. In this review, we will summarize the recent progress on the interplay between autophagy and HSV-1, focusing on the intricate role of ICP34.5 in the modulation of this pathway to gain the battle against cellular defenses.

Purpose: The study aimed to investigate if there were any links between liver function biomarkers and immunoglobulins levels in serum, and Toll-like receptors (TLRs) and neuropilin-1 (NRP1) in COVID-19 patients. The study also aimed to assess the accuracy—sensitivity, specificity, and area under the curve (AUC) by the receiver operator curve (ROC) analysis for immunoglobulins levels and TLRs expressions. Patients and Methods: This study included 150 patients (100 patients with confirmed COVID-19 and 50 healthy volunteers as a control group). Patients with COVID-19 were subdivided into two groups according to the severity of symptoms (moderate and severe, with 50 patients each). Serum C-reactive protein (CRP), alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), albumin, lactate dehydrogenase (LDH), immunoglobulin (Ig) G, and IgM levels were estimated. TLRs (TLR2 and TLR4) and NRP1 gene expression in blood samples were investigated using quantitative real-time polymerase chain reaction (qRT-PCR). ROC analysis was also applied to determine the accuracy of various detected parameters in predicting the possibility of COVID-19 infection. Results: In COVID-19 patients, serum parameters related to liver function, except serum albumin, CRP, IgG, IgM, and TLR2, TLR4, and NRP1 mRNA expression levels, significantly elevated compared to controls. Severe COVID-19 patients exhibited significantly higher liver enzymes (ALT, AST and LDH), CRP, and TLR2 mRNA expression levels and lower albumin levels than the moderate group. In the moderate and severe groups, ALT, CRP, TLR2, and TLR4 had a significant positive correlation with IgM levels. ALT, AST, LDH, CRP, TLR2, and TLR4 showed a significant positive correlation with IgG levels in both groups. In both the moderate and severe groups, NRP1 expression was found to be significantly correlated with CRP, IgG, IgM, TLR2, and TLR4. In contrast, serum albumin levels exhibited a significant negative correlation with IgG and IgM levels only in the severe group, but they showed a significant negative correlation with TLR2, TLR4, and NRP1 expression in both moderate and severe groups. Serum ALT and AST activities were positively correlated with NRP1 expression in the moderate group but not in the severe group and as well as TLR2 and TLR4 expression in both the moderate and severe groups. ROC analysis indicated that AUC was higher than 0.800 for serum IgM level and TLR4 gene expression in moderate COVID-19 group. Conclusions: The increased liver function biomarkers in serum and NRP1 expression are closely correlated with sustained activations in humoral and innate immune responses during COVID-19 infection. As a result, TLR2, TLR4, and NRP1 could be targets for limiting COVID-19 infection and impairment effects on liver function. Moreover, detection of IgM level in serum and TLR4 expression in blood have a good accuracy in predicting the possibility of infection with COVID-19 in moderate cases.

Penile squamous cell carcinoma (SCC) is a rare disease. Treatment options for advanced penile cancer are often limited and prognosis remains poor. We reported a 52-year-old male recurrent and metastatic penile SCC patient with high PD-L1 expression(90%) and TMB(14.4 muts/Mb). He had undergone penectomy, bilateral inguinal lymph node dissection and excision of the abdominal wall mass during two surgeries. Despite cisplatin-based concurrent chemoradiotherapy and sequential chemotherapy with docetaxel plus cisplatin were then carried out, the carcinoma still had progressed. The patient then obtained progression free survival exceeding 32 months with continuous sintilimab, although new onset of ICI-induced diabetes after 24 cycles of sintilimab and required sustained insulin treatment. He didn’t have positive type 1 diabetes associated autoantibodies, but had susceptible HLA genotype DR3-DQ2 haplotype. This is the first patient with radiation and multichemorefractory penile SCC obtained remarkable anti-tumor effect of partial regression exceeding 32 months during continuous sintilimab.

The development of inexpensive, fast and reliable screening tests for COVID-19 is, as yet, an unmet need. The present study was aimed at evaluating the usefulness of serum arylesterase activity of paraoxonase-1 (PON1) measurement as a screening test in patients with different severity levels of COVID-19 infection. We included 615 COVID-19 positive patients who were classified as asymptomatic, mildly symptomatic, severely symptomatic, or fatally symptomatic. Results were compared with 50 healthy volunteers, 330 patients with cancer and 343 with morbid obesity. Results showed PON1 activity greatly decreased in COVID-19 compared to healthy vol-unteers; receiver operating characteristics plot showed a high diagnostic accuracy. The degree of COVID-19 severity did not influence PON1 levels. Our results indicated that PON1 determination was efficient for disease diagnosis but not for prognosis. Further, patients with obesity or cancer presented alterations similar to those of COVID-19 patients. As such, elevated levels of PON1 in-dicate the absence of COVID-19, but low levels may be present in various other chronic diseases. The assay is fast and inexpensive. We suggest that PON1 measurement could be used as an initial, high cut-off point screening method, while lower values should be confirmed with the more ex-pensive nucleic acid amplification test.

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.

The use of recombinant human PTH (1-84) [rhPTH(1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. The objective of this study was to investigate the effects of 12 months of rhPTH (1-84) treatment in a cohort of patients selected according to the indications of recent hypoparathyroidism guidelines. It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers were involved. Fourteen adult subjects with chronic hypoparathyroidism treated with rhPTH (1-84) for 12 months were enrolled. Main outcome measures included serum and urinary parameters of mineral metabolism, renal function, oral calcium and vitamin D doses, and clinical manifestations. At 12 months, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p=0.009). Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p= 0.014). No severe adverse events were described. In conclusion, this study confirm the efficacy and safety of rhPTH (1-84) therapy.

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.

Environmental effects and climate change are lately representing an increasing strain of the coastal areas which topography strongly depends on these conditions. However, the processes by which weather and environmental phenomena influence the highly variable beach morphology are still unknown. A continuous monitoring of the beach environment is necessary to implement protection strategies. This paper presents the results of an innovative study performed on a coastal area using satellite remote sensing data with the aim of understanding how environmental phenomena affect beaches. Two-years of synthetic aperture radar (SAR) Sentinel-1 images are used over a test area in Noordwijk, the Netherlands. At the same time as the SAR acquisitions, information on tidal and weather conditions are collected and integrated from nearby meteorological stations. Dedicated codes are implemented in order to understand the relationship between the SAR amplitude and the considered phenomena: wind, precipitation, tidal conditions. Surface roughness is taken into account. The results indicate a strong correlation between the amplitude and the wind. No particular correlation or trend could be noticed in the relation with the precipitation. The analysis of the amplitude also shows a decreasing trend moving from the dry area of the beach towards the sea and the correlation coefficient between the amplitude and the tide level gets negative with the increase of the water content.

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.

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here we investigated how PBRM1 controls HIF-1alpha activity. We find that PBRM1 is required for HIF-1alpha transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1alpha mRNA translation, as absence of PBRM1 results in reduced activly transalting HIF-1alpha mRNA. Interestingly, we find that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1alpha mRNA is m6A modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1alpha mRNA and reduction of YTHDF2 results in reduced HIF-1alpha protein expression in cells. Our results identify a SWI/SNF independent function for PBRM1, interacting with HIF-1alpha mRNA and the epitranscriptome machinery. Furthermore, our results suggests that the epitranscriptome associated proteins play a role in the control of hypoxia signalling pathways

Exposure of phosphatidylserine (PS) in the outer leaflet of the plasma membrane is induced by infection with several members of the Alphaherpesvirinae subfamily. There is evidence that PS is used by the equine herpesvirus type 1 (EHV-1) during entry, but the exact role of PS and other phospholipids in the entry process remains unknown. Here, we investigated the interaction of differently charged phospholipids with virus particles and determined their influence on infection. Our data show that liposomes containing negatively charged PS or positively charged DOTAP [N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium)] inhibited EHV-1 infection, while neutral phosphatidylcholine (PC) had no effect. Inhibition of infection with PS was transient, decreased with time, and was dose dependent. Our findings indicate that both cationic and anionic phospholipids can interact with the virus and reduce infectivity, while acting through different mechanisms. Charged phospholipids were found to have antiviral effects and can may be used to inhibit EHV-1 infection.

Resistance of tumor cells to anticancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin inT24R2, a derived T24 cell line. Treatment with cordycepin or cisplatin (2 g/ml) alone could not induce cell death of T24R2, but combination treatment of these drugs significantly induced apoptosis of the cells through mitochondrial pathway including depolarization of mitochondrial membrane, decrease of anti-apoptotic proteins, Bcl-2, Bcl-xL, and Mcl-1, and increase of pro-apoptotic proteins, Bak and Bax. . High expression of MDR1 was the cause of cisplatin resistance in T24R2, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on a transcription factor, Ets-1, in T24R2 cells. Although there is a correlation between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr-38 phosphorylated form (pThr-38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 level through inhibition of AKT, which reduced MDR1 transcription and induced the resensitization of T24R2 to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of anti-cancer drug resistant patients.

Solid porous materials, like zeolites, have been widely used in a variety of fields such as size and shape-selective absorption/separation and catalysis because of their porosity. But there are few liquid materials exhibit permanent porosity. Porous liquids are a novel material that combine the properties of fluidity and permanent porosity. It has potential applications in many fields such as gas separation, storage and transport. Herein, we report a novel Type 1 porous liquid prepared based on Silicalite-1. The pore size of this porous liquid was determined by positron annihilation lifetime spectroscopy (PALS), and the CO2 capacities was determined by the intelligent gravimetric analyser (IGA). The unique properties of this porous liquid can promote its application in many fields such as gas storage and transport.

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.

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.

HIV-1 assembly is a complex mechanism taking place at the plasma membrane of the host cell. It requires nice spatial and temporal coordination to end up with a full immature virus. Researchers have extensively studied HIV-1 assembly molecular mechanism during the past decades, in order to dissect the respective roles of viral proteins, viral genome and host cell factors. Nevertheless, the time course of the process has been observed in living cells only a decade ago. The very recent revolution of optical microscopy, combining high speed and high spatial resolution now permit to study assemblies and their consequences at the single molecule level within (living) cells. In this review, after a short description of these new approaches, we will show how HIV-1 assembly in cells has been revisited using these advanced super resolution microscopy techniques and how much it could make a bridge in studying assembly from the single molecule to the host cell.

A novel and simple method to improve the corrosion resistance of copper by constructing a 3D 1-dodecanethiol self-assembled monolayers (SAMs) in 3.5% NaCl solution is reported in this study. Several drops of 1% H3PO4 solution are thinly and uniformly distributed on copper surface to form a 3D nanostructure constituted by Cu3(PO4)2 nanoflowers. The anticorrosion properties of 1-dodecanethiol SAMs on copper surface and on copper surface treated with H3PO4 solution were evaluated. Results demonstrated that 1-dodecanethiol SAMs on bare copper surface exhibit good protection capacity, whereas a copper surface pretreated with H3PO4 solution can substantially enhance the corrosion resistance of 1-dodecanethiol SAMs.

Lung adenocarcinoma with EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) resistance was reported to harbor higher ability of invasion and migration than those sensitive to EGFR-TKI, but the function of MMPs (matrix metalloproteinases) has not been explored in EGFR-TKI resistant lung adenocarcinoma. In this study, the correlation between immunohistochemical status of MMP-1 and clinicopathological factors were analyzed in 89 lung adenocarcinoma. We performed microarray, migration assay and invasion assay using EGFR-TKI sensitive cell lines and EGFR-TKI resistant cell lines. To clarify the mechanism of MMP-1 induction, we treated lung adenocarcinoma cells with EGF and rapamycin, performed phosphorylation antibody array and analyzed the correlation between MMP-1 expression and EGFR or mTOR (mammalian target of rapamycin) pathway. As a result, we firstly demonstrated that MMP-1 played an important role in migration and invasion abilities of EGFR-TKI resistant lung adenocarcinoma, and that mTOR pathway could be associated with an induction of MMP-1. We demonstrated the significant positive correlation between MMP-1 status in lung adenocarcinoma cells and the history of smoking, and the subtype of invasive mucinous adenocarcinoma. In conclusion, This study provides insights into the development of a possible alternative therapy manipulating MMP-1 and mTOR signaling pathway in EGFR-TKI resistant lung adenocarcinoma.

Radar altimetry provides valuable measurements to characterize the state and the evolution of the Antartica and Greenland ice sheet cover. Global Navigation Satellite System Reflectometry (GNSS-R) has the potential capacity of complementing the dedicated radar altimeters incrementing the temporal and spatial resolution of the surface height measurements. In this work we perform an study of the Greenland ice sheet using data obtained by the GNSS-R instrument aboard the British TechDemoSat-1 (TDS-1) satellite mission, designed primarily to provide sea state information, like sea surface roughness or wind, but not altimetric products. The data has been analyzed with altimetric methodologies, already proved in aircraft based experiments, to extract signal delay observables to be used to infer the topography of the Greenland cover. The penetration depth of the GNSS signals into ice has also considered. The topographic signal obtained is consistent with those obtained with other passive or active microwave sensors. The main conclusion derived from this work is that GNSS-R also provides valuable measurements of the ice sheet cover and, as taken at a variety of geometries and at least two frequency bands, they prospect different depths into the ice. They have thus potential to complement our understanding of the ice firn and its evolution.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein. Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

Background. Wnt-pathway proteins play a vital role in kidney development and defects in the Wnt-pathway are associated with kidney disorders. However, the knowledge on the role of Wnt/β-catenin pathway proteins in end-stage renal disease (ESRD) is limited.Aim of the study. To delineate the association of ESRD and Wnt-proteins including the agonistR-spondin 1, the transducer β-catenin and the antagonists Dickkopf-related protein 1 (DKK1) and sclerostin.Methods. Serum Wnt-pathway proteins levels were measured by ELISA, while other biochemicals were measured spectrophotometrically in 60 ESRD patients and 30 normal controls.Results. DKK1 and sclerostin were significantly higher in ESRD than in controls, and β-catenin and the catenin + R-Sponin-1 / DKK1 + sclerostin ratio, reflecting the ratio of agonist and transducer on antagonists (AT/ANTA), were significantly lower in ESRD. Logistic regression analysis showed that ESRD was significantly predicted by increased levels of DDK1 and sclerostin and lowered β-catenin (p<0.001). eGFR was significantly associated with DKK1 and sclerostin (inversely), β-catenin (positively) and the AT/ANTA ratio (r=0.468, p<0.001). DKK1 levels were significantly and positively correlated with urea, creatinine, and copper. DKK1 and sclerostin were inversely associated with hemoglobin and packet cell volume. Catenin was significantly negatively associated with copper, urea and creatinine.Conclusion. Wnt/β-catenin pathway proteins show significant alterations in ESRD, indicating significantly increased levels of antagonists and, therefore, attenuated Wnt/β-catenin pathway activity. The latter is associated with lowered eGFR and increased serum copper levels. Wnt/β-catenin pathway proteins are possible drug targets to treat ESRD or its consequences.

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.

Cattle occasionally develop brassica-associated liver disease (BALD) and photosensitisation when grazing turnip or swede (Brassica spp.) forage crops. The liver toxin in these brassica varieties has yet to be discovered. Progoitrin is the dominant glucosinolate in incriminated crops. Apart from goitrin, progoitrin hydrolysis yields the nitrile, 1-cyano-2-hydroxy-3-butene (CHB), and the epithionitrile, 1-cyano-2-hydroxy-3,4-epithiobutane (CHEB). The two compounds were custom-synthesised. In a small pilot trial, New Zealand White rabbits were given either CHB or CHEB by gavage. Single doses of 0.75 mmol/kg of CHB or 0.25 mmol/kg of CHEB were subtoxic and elicited subclinical effects. Higher doses were severely hepatotoxic causing periportal to massive hepatic necrosis associated with markedly elevated serum liver biomarkers often resulting in severe illness or death within 24 h. The possibility that one or both of these hepatotoxic nitriles causes BALD in cattle requires further investigation.

By generalizing the notion of pointwise 1-type Gauss map, the generalized 1-type Gauss map has been recently introduced. Without any assumption, we classified all possible ruled surfaces with generalized 1-type Gauss map in a 3-dimensional Minkowski space. In particular, null scrolls do not have the proper generalized 1-type Gauss map. In fact, it is harmonic.

This study focuses on one of the most famous open problems in mathematics, namely the Collatz conjecture. The Collatz conjecture or 3x + 1 Problem is perhaps today's most enigmatic unsolved mathematical problem. It is named after Lothar Collatz, who rst proposed it in 1937. It may be stated as as follow: Take any positive integer n. If n is even then divide it by 2, else do \triple plus one" and get 3n + 1. The conjecture is that this process will eventually reach the number 1, regardless of which positive integer is chosen initially. In this paper, we present a simple proof for the Collatz conjecture.

A fundamental tool in mathematical physics is the logarithmic Sobolev inequality. A quantitative version proven by Carlen with a remainder involving the Fourier-Wiener transform is equivalent to an entropic uncertainty principle more general than the Heisenberg uncertainty principle. In the stability, the remainder is in terms of an entropy, not a metric. Recently, a stability result for H¹ was obtained by Dolbeault, Esteban, Figalli, Frank, and Loss in terms of an L^p norm. Afterwards, Brigati, Dolbeault, and Simonov discussed the stability problem involving a stronger norm. A full characterization with a necessary and sufficient condition to have H¹ convergence is identified in this paper. Moreover, an explicit H¹ bound via a moment assumption is shown. Also, the L^p stability of Dolbeault, Esteban, Figalli, Frank, and Loss is proven to be sharp.

In this research, new setting is introduced for new SuperHyperNotion, namely, 11 Neutrosophic 1-failed SuperHyperForcing. Two different types of SuperHyperDefinitions 12 are debut for them but the research goes further and the SuperHyperNotion, 13 SuperHyperUniform, and SuperHyperClass based on that are well-defined and 14 well-reviewed. The literature review is implemented in the whole of this research. For 15 shining the elegancy and the significancy of this research, the comparison between this 16 SuperHyperNotion with other SuperHyperNotions and fundamental 17 SuperHyperNumbers are featured. The definitions are followed by the examples and the 18 instances thus the clarifications are driven with different tools. The applications are 19 figured out to make sense about the theoretical aspect of this ongoing research. The 20 “Cancer’s Neutrosophic Recognition” are the under research to figure out the challenges 21 make sense about ongoing and upcoming research. The special case is up. The cells are 22 viewed in the deemed ways. There are different types of them. Some of them are 23 individuals and some of them are well-modeled by the group of cells. These types are all 24 officially called “SuperHyperVertex” but the relations amid them all officially called 25 “SuperHyperEdge”. The frameworks “SuperHyperGraph” and “neutrosophic 26 SuperHyperGraph” are chosen and elected to research about “Cancer’s Neutrosophic 27 Recognition”. Thus these complex and dense SuperHyperModels open up some avenues 28 to research on theoretical segments and “Cancer’s Neutrosophic Recognition”. Some 29 avenues are posed to pursue this research. It’s also officially collected in the form of 30 some questions and some problems. Assume a SuperHyperGraph. Then a “1-failed 31 SuperHyperForcing” Z(NSHG) for a neutrosophic SuperHyperGraph NSHG : (V,E) 32 is the maximum cardinality of a SuperHyperSet S of black SuperHyperVertices 33 (whereas SuperHyperVertices in V (G) \ S are colored white) such that V (G) isn’t 34 turned black after finitely many applications of “the color-change rule”: a white 35 SuperHyperVertex is converted to a black SuperHyperVertex if it is the only white 36 SuperHyperNeighbor of a black SuperHyperVertex. The additional condition is referred 37 by “1-” about the usage of any black SuperHyperVertex only once to act on white 38 SuperHyperVertex to be black SuperHyperVertex; a “neutrosophic 1-failed 39 SuperHyperForcing” Zn(NSHG) for a neutrosophic SuperHyperGraph NSHG : (V,E) 40 is the maximum neutrosophic cardinality of a SuperHyperSet S of black 41 SuperHyperVertices (whereas SuperHyperVertices in V (G) \ S are colored white) such 42 that V (G) isn’t turned black after finitely many applications of “the color-change rule”: 43 a white SuperHyperVertex is converted to a black SuperHyperVertex if it is the only 44 1/128 white SuperHyperNeighbor of a black SuperHyperVertex. The additional condition is 45 referred by “1-” about the usage of any black SuperHyperVertex only once to act on 46 white SuperHyperVertex to be black SuperHyperVertex. Assume a SuperHyperGraph. 47 Then an “δ−1-failed SuperHyperForcing” is a maximal 1-failed SuperHyperForcing of 48 SuperHyperVertices with maximum cardinality such that either of the following 49 expressions hold for the (neutrosophic) cardinalities of SuperHyperNeighbors of s ∈ S : 50 |S ∩N(s)| > |S ∩(V \N(s))|+δ, |S ∩N(s)| < |S ∩(V \N(s))|+δ. The first Expression, 51 holds if S is an “δ−SuperHyperOffensive”. And the second Expression, holds if S is an 52 “δ−SuperHyperDefensive”; a“neutrosophic δ−1-failed SuperHyperForcing” is a maximal 53 neutrosophic 1-failed SuperHyperForcing of SuperHyperVertices with maximum 54 neutrosophic cardinality such that either of the following expressions hold for the 55 neutrosophic cardinalities of SuperHyperNeighbors of s ∈ S : |S ∩ N(s)|neutrosophic > 56 |S ∩ (V \ N (s))|neutrosophic + δ, |S ∩ N (s)|neutrosophic < |S ∩ (V \ N (s))|neutrosophic + δ. 57 The first Expression, holds if S is a “neutrosophic δ−SuperHyperOffensive”. And the 58 second Expression, holds if S is a “neutrosophic δ−SuperHyperDefensive”. It’s useful to 59 define “neutrosophic” version of 1-failed SuperHyperForcing. Since there’s more ways to 60 get type-results to make 1-failed SuperHyperForcing more understandable. For the sake 61 of having neutrosophic 1-failed SuperHyperForcing, there’s a need to “redefine” the 62 notion of “1-failed SuperHyperForcing”. The SuperHyperVertices and the 63 SuperHyperEdges are assigned by the labels from the letters of the alphabets. In this 64 procedure, there’s the usage of the position of labels to assign to the values. Assume a 65 1-failed SuperHyperForcing. It’s redefined neutrosophic 1-failed SuperHyperForcing if 66 the mentioned Table holds, concerning, “The Values of Vertices, SuperVertices, Edges, 67 HyperEdges, and SuperHyperEdges Belong to The Neutrosophic SuperHyperGraph” 68 with the key points, “The Values of The Vertices & The Number of Position in 69 Alphabet”, “The Values of The SuperVertices&The maximum Values of Its Vertices”, 70 “The Values of The Edges&The maximum Values of Its Vertices”, “The Values of The 71 HyperEdges&The maximum Values of Its Vertices”, “The Values of The 72 SuperHyperEdges&The maximum Values of Its Endpoints”. To get structural examples 73 and instances, I’m going to introduce the next SuperHyperClass of SuperHyperGraph 74 based on 1-failed SuperHyperForcing. It’s the main. It’ll be disciplinary to have the 75 foundation of previous definition in the kind of SuperHyperClass. If there’s a need to 76 have all SuperHyperConnectivities until the 1-failed SuperHyperForcing, then it’s 77 officially called “1-failed SuperHyperForcing” but otherwise, it isn’t 1-failed 78 SuperHyperForcing. There are some instances about the clarifications for the main 79 definition titled “1-failed SuperHyperForcing”. These two examples get more scrutiny 80 and discernment since there are characterized in the disciplinary ways of the 81 SuperHyperClass based on 1-failed SuperHyperForcing. For the sake of having 82 neutrosophic 1-failed SuperHyperForcing, there’s a need to “redefine” the notion of 83 “neutrosophic 1-failed SuperHyperForcing” and “neutrosophic 1-failed 84 SuperHyperForcing”. The SuperHyperVertices and the SuperHyperEdges are assigned 85 by the labels from the letters of the alphabets. In this procedure, there’s the usage of 86 the position of labels to assign to the values. Assume a neutrosophic SuperHyperGraph. 87 It’s redefined “neutrosophic SuperHyperGraph” if the intended Table holds. And 88 1-failed SuperHyperForcing are redefined “neutrosophic 1-failed SuperHyperForcing” if 89 the intended Table holds. It’s useful to define “neutrosophic” version of 90 SuperHyperClasses. Since there’s more ways to get neutrosophic type-results to make 91 neutrosophic 1-failed SuperHyperForcing more understandable. Assume a neutrosophic 92 SuperHyperGraph. There are some neutrosophic SuperHyperClasses if the intended 93 Table holds. Thus SuperHyperPath, SuperHyperCycle, SuperHyperStar, 94 SuperHyperBipartite, SuperHyperMultiPartite, and SuperHyperWheel, are 95 “neutrosophic SuperHyperPath”, “neutrosophic SuperHyperCycle”, “neutrosophic 96 SuperHyperStar”, “neutrosophic SuperHyperBipartite”, “neutrosophic 97 2/128 SuperHyperMultiPartite”, and “neutrosophic SuperHyperWheel” if the intended Table 98 holds. A SuperHyperGraph has “neutrosophic 1-failed SuperHyperForcing” where it’s 99 the strongest [the maximum neutrosophic value from all 1-failed SuperHyperForcing 100 amid the maximum value amid all SuperHyperVertices from a 1-failed 101 SuperHyperForcing.] 1-failed SuperHyperForcing. A graph is SuperHyperUniform if it’s 102 SuperHyperGraph and the number of elements of SuperHyperEdges are the same. 103 Assume a neutrosophic SuperHyperGraph. There are some SuperHyperClasses as 104 follows. It’s SuperHyperPath if it’s only one SuperVertex as intersection amid two given 105 SuperHyperEdges with two exceptions; it’s SuperHyperCycle if it’s only one 106 SuperVertex as intersection amid two given SuperHyperEdges; it’s SuperHyperStar it’s 107 only one SuperVertex as intersection amid all SuperHyperEdges; it’s 108 SuperHyperBipartite it’s only one SuperVertex as intersection amid two given 109 SuperHyperEdges and these SuperVertices, forming two separate sets, has no 110 SuperHyperEdge in common; it’s SuperHyperMultiPartite it’s only one SuperVertex as 111 intersection amid two given SuperHyperEdges and these SuperVertices, forming multi 112 separate sets, has no SuperHyperEdge in common; it’s SuperHyperWheel if it’s only one 113 SuperVertex as intersection amid two given SuperHyperEdges and one SuperVertex has 114 one SuperHyperEdge with any common SuperVertex. The SuperHyperModel proposes 115 the specific designs and the specific architectures. The SuperHyperModel is officially 116 called “SuperHyperGraph” and “Neutrosophic SuperHyperGraph”. In this 117 SuperHyperModel, The “specific” cells and “specific group” of cells are 118 SuperHyperModeled as “SuperHyperVertices” and the common and intended properties 119 between “specific” cells and “specific group” of cells are SuperHyperModeled as 120 “SuperHyperEdges”. Sometimes, it’s useful to have some degrees of determinacy, 121 indeterminacy, and neutrality to have more precise SuperHyperModel which in this case 122 the SuperHyperModel is called “neutrosophic”. In the future research, the foundation 123 will be based on the “Cancer’s Neutrosophic Recognition” and the results and the 124 definitions will be introduced in redeemed ways. The neutrosophic recognition of the 125 cancer in the long-term function. The specific region has been assigned by the model 126 [it’s called SuperHyperGraph] and the long cycle of the move from the cancer is 127 identified by this research. Sometimes the move of the cancer hasn’t be easily identified 128 since there are some determinacy, indeterminacy and neutrality about the moves and 129 the effects of the cancer on that region; this event leads us to choose another model [it’s 130 said to be neutrosophic SuperHyperGraph] to have convenient perception on what’s 131 happened and what’s done. There are some specific models, which are well-known and 132 they’ve got the names, and some SuperHyperGeneral SuperHyperModels. The moves 133 and the traces of the cancer on the complex tracks and between complicated groups of 134 cells could be fantasized by a neutrosophic SuperHyperPath(-/SuperHyperCycle, 135 SuperHyperStar, SuperHyperBipartite, SuperHyperMultipartite, SuperHyperWheel). 136 The aim is to find either the longest 1-failed SuperHyperForcing or the strongest 137 1-failed SuperHyperForcing in those neutrosophic SuperHyperModels. For the longest 138 1-failed SuperHyperForcing, called 1-failed SuperHyperForcing, and the strongest 139 SuperHyperCycle, called neutrosophic 1-failed SuperHyperForcing, some general results 140 are introduced. Beyond that in SuperHyperStar, all possible SuperHyperPaths have 141 only two SuperHyperEdges but it’s not enough since it’s essential to have at least three 142 SuperHyperEdges to form any style of a SuperHyperCycle. There isn’t any formation of 143 any SuperHyperCycle but literarily, it’s the deformation of any SuperHyperCycle. It, 144 literarily, deforms and it doesn’t form. A basic familiarity with SuperHyperGraph 145 theory and neutrosophic SuperHyperGraph theory are proposed.

Human T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive spinal cord disorder with no effective treatment. There is much of interest in developing potential biomarkers for predicting the pathogenesis of HAM/TSP disorder. This study used Illumina massive parallel sequencing (MPS) technology to assess the cellular global noncoding RNAome expression profile in HAM/TSP patients (n = 10), asymptomatic HTLV-1 infected carriers (ASP, n = 8), and a second group of healthy controls (n = 5). Using various bioinformatics tools, the sRNA MPS reads were aligned, annotated, and profiled. There were 251 known and 50 potential novel sRNAs among the 402 detected sRNAs in the HAM and ASP groups versus the HC group. Sixty-eight known sRNAs were found to be significantly different between the ASP and HAM groups. In HAM vs ASP subjects, 88 mature miRNAs were downregulated. Three of these miRs (hsa-miR-185-5p, 32-5p, and 192-5p) have the potential to be used as biomarkers for predicting the pathogenesis of HAM/TSP. The top seven deregulated miRS target genes were linked to a variety of biological processes and molecular functions. Relevant reactome pathways to our findings provide a rich source of data and an opportunity to further understand sRNA regulation and function in HTLV-1 pathophysiology.

We propose Reduced Collatz Conjecture that is equivalent to Collatz Conjecture, which states that every positive integer can return to an integer less than it, instead of 1. Reduced Collatz Conjecture should be easier because some properties are presented in reduced dynamics, rather than in original dynamics (e.g., ratio and period). Reduced dynamics is a computation sequence from starting integer to the first integer less than it, and original dynamics is a computation sequence from starting integer to 1. Reduced dynamics is a component of original dynamics. We denote dynamics of x as a sequence of either computations in terms of ``I'' that represents (3*x+1)/2 and ``O'' that represents x/2. Here 3*x+1 and x/2 are combined together, because 3*x+1 is always even and followed by x/2. We formally prove that all positive integers are partitioned into two halves and either presents ``I'' or ``O'' in next ongoing computation. More specifically, (1) if any positive integer x that is i module $2^t$ (i is an odd integer) is given, then the first t computations (each one is either ``I'' or ``O'' corresponding to whether current integer is odd or even) will be identical with that of i. (2) If current integer after t computations (in terms of ``I'' or ``O'') is less than x, then reduced dynamics of x is available. Otherwise, the residue class of x (namely, i module $2^t$) can be partitioned into two halves (namely, i module $2^{t+1}$ and $i+2^t$ module $2^{t+1}$), and either half presents ``I'' or ``O'' in intermediately forthcoming (t+1)-th computation.

The presence of a non-structural protein 1 (NS1) in tick-borne encephalitis (TBE) vaccines and the possible induction of an NS1-specific immune response in vaccinated individuals remains a somewhat controversial topic. Previously, we detected the presence of NS1 in Encepur TBE vaccine by mass spectrometry and found the induction of NS1-specific IgG antibodies in mice vaccinated with FSME-Immun TBE vaccine. Here, in this follow-up study, we examined the dynamics and extent of the NS1-specific IgG response in mice vaccinated with these two vaccines in more detail and compared it with the IgG response to the whole virus (WV). Mice were vaccinated at two-week intervals with a total of six doses of each vaccine, and levels of IgG antibodies to TBE virus WV and NS1 were measured by ELISA after each dose. Both vaccines elicited a robust anti-WV IgG response after two doses. The Encepur vaccine did not elicit NS1-specific IgG even after all six doses. In contrast, FSME-Immun vaccine triggered production of NS1-specific IgG after four doses. The results indicate that FSME-Immun is the only vaccine that elicits an NS1-specific antibody response in mice. However, compared to WV-specific IgG, the NS1-specific response is weaker, and a higher number of doses is required to induce detectable levels of NS1-specific IgG antibodies.

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.

Copernicus is Europe's space-based Earth monitoring asset, which consists of a complex set of systems that collect data from different sources: remote sensing satellites (RS) and in-situ sensors such as ground stations, airborne and marine sensors. This study was originally prepared for the needs of the Czech agricultural community, where we provided an in-depth analysis of articles related to Earth observation in precision agriculture. At a later stage, we extended this study by comparing the recommendations of the European EO4Agri project and scientific articles published in MDPI. We had two important objectives, one was to validate the results of the EO4Agri project and the other was to look for gaps in current research and community needs. To recognize the importance of using Sentinel 1 data, we also added a specific analysis of methods for data fusion of Sentinel 1 and Sentinel 2 data.

Clonal evolution and cellular plasticity are the genetic and non-genetic driving forces of tumor heterogeneity that in turn determines the tumor cell response towards therapeutic drugs. Sever-al lines of evidence suggest that therapeutic interventions foster the selection of drug resistant neural crest stem-like cells (NCSCs) that establish minimal residual disease (MRD) in melano-ma. Here we established a dual reporter system enabling the tracking of NGFR expression and mRNA stability, providing insights into the maintenance of NCSC-states. We observed that the transcriptional reporter that contained a 1kb fragment of the human NGFR promoter was acti-vated only in a minor subset (0.72±0.49%, range 0.3-1.5) and ~2-4% of A375 melanoma cells re-vealed stable NGFR mRNA. The combination of both reporters provided insights into pheno-type switching and revealed that both cellular subsets gave rise to cellular heterogeneity. Moreover, whole transcriptome profiling and gene set enrichment analysis (GSEA) of the minor cellular subset revealed hypoxia-associated genes serving as potential drivers of a NGFR-associated phenotype switching in vitro and in relapsed, post-BRAF inhibitor treated tu-mors. Concordantly, we observed that the minor cellular subset increased in response to dabrafenib over time. In summary, our reporter-based approach provided insights into plastici-ty and identified a cellular subset that might be responsible for the establishment of MRD in melanoma.

Lichens are a life form in which algae and fungi have a symbiotic relationship. A lichen has various biological activities, including anti-inflammatory and anti-proliferative activities. Inflammation is a response caused by various factors, such as infection by pathogens or tissue damage; excessive reactions can contribute to the etiology of chronic diseases, such as asthma, brain damage, and serious tissue damage. This study demonstrates the anti-inflammatory effect of ethyl acetate extract from Phlebia sp. on NF-κB and AP-1 pathways in the lipopolysaccharide-treated RAW 264.7 cell. Especially, Phlebia sp. extract inhibits the phosphorylation of AP-1 signaling (c-Fos and c-Jun) and its upstream MKK/MAPKs (MKK4, MKK7 and JNK), which induced a decrease in the production of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in downstream of AP-1 signaling. Furthermore, Phlebia sp. extract inhibited the production of final inflammatory effector molecules involved in AP-1 signaling, including nitric oxide (NO) and prostaglandin E2 (PGE2). Here, we report that Phlebia sp. extract has the potential to be developed as an anti-inflammatory agent.

The transition of people from paediatric to adult diabetes services is associated with worsening glycaemia and increased diabetes-related hospitalisation. This study compared the clinical characteristics of those with and without mental health conditions among attenders at a diabetes young adult clinic diabetes before and after changes in service delivery. Retrospective review of 200 people with diabetes attending a Sydney public hospital over eight years corresponding to the period before (2012-2016) and after (2017-2018) restructuring of a clinic for young adults aged 16-25 years. Characteristics of those with and without mental health conditions (depression, anxiety, diabetes related distress, eating disorders), were compared. Among clinic attenders (type 1 diabetes n=184, 83.2%), 40.5% (n=89) had a mental health condition particularly, depression (n=57, 64%), which was higher among Indigenous than non-Indigenous people (5.6% vs 0.8% p=0.031) but similar between diabetes type. Over eight years, those with, compared with those without a mental health condition had higher HbA1c at the last visit (9.4%[79 mmol/mol] vs 8.7% [71 mmol/mol], p=0.027), the proportion with diabetic ketoacidosis (DKA 60.7% vs 42.7%,p=0.009), smoking (38.4 vs 13.6%,p=0.009), retinopathy (9.0 vs 2.3%,p=0.025), multiple DKAs (28.4 vs 16.0%,p=0.031) were significantly higher. Having a mental health condition was associated with 2.02 (95% Confidence intervals 1.1-3.7) fold increased risk of HbA1c ≥ 9.0%[75mmol/mol]. Changes to the clinic were not associated with improvements in mental health condition (39.0% vs 32.4%, p=0.096). In conclusion, we found that mental health conditions, particularly depression, are common in this population and are associated with diabetes complications. Diabetes type and clinic changes did not affect the reported mental health conditions. Additional strategies are required to reduce complication risks among those with mental health conditions. .

Dengue is an overlooked tropical disease for which billions of people are at risk. The disease, caused by a Flavivirus with four distinct serotypes, is transmitted primarily by urbanized Aedes mosquito species. The infection leads to a spectrum of clinical manifestations, with the majority being asymptomatic. Primary dengue and, to a greater extent, subsequent infection, mainly secondary dengue infection, are associated with increased severity. Increased global travel and recreational tourism expose naïve individuals to dengue, the most common arboviral infections in travelers. We describe a cluster of possible primary acute dengue infections in a group of 12 individuals who presented to Bangkok Hospital for Tropical Diseases in 2017. Infection was confirmed by dengue NS1 antigen and multiplex real-time RT-PCR. Nine individuals required hospitalization, and four developed dengue warning signs. The mean arterial pressure was significantly lower in the group with dengue warning signs. The period from the day of arrival in Thailand and the first day of symptoms was significantly shorter in adolescents with warning signs. Leukocytes, neutrophils, and platelets declined significantly at defervescence and were negatively correlated with day of illness. Six clinical isolates were identified as dengue serotype-1, with identical sequences suggesting that these patients were infected with the same virus.

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. MicroRNA-375 (miR-375) ranks among top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 hour before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to identification of 8 microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients, by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.

The purpose of our study was to discuss Rab 7 effects in chronic kidney disease (CKD). Methods: Using WT and Rab 7-/- mice as target animal, and HK-2 and HMEC-1 cell co-cultured to make cell model. Measuring kidney tissues were evaluated by Sirius red staining, immunohistochemistry staining to CD 34 protein, Transmission electron microscope (TEM) and gelatin zymography to MMP-2 activities. The cell proliferation were measured by CCK-8 and Ki67 protein expression. Measuring cell invasion and total length were evaluated by transwell and in vitro angiogenesis assay. MMP-2 activities were evaluated by gelatin zymography in cell groups. The relative proteins expression were evaluated by Western blot in kidney tissues and cell groups. Results: Hypoxia promoted the expression of Rab7 in HMEC-1, and the activity of MMP-2 related with regulatory molecules such as reversion-inducing-cysteine-rich protein with kazal motifs (RECK), negative correlation with membrane-type 1 MMP (MT1-MMP or MMP-14) on the membrane of TECs. In addition, the up-regulation of the expression of Rab7 inhibited the activity of MMP-2 and proliferation and cyclization of endothelial cells, and the inhibitor of MMP-2 partially blocked the effects of Rab7 on angiogenesis. Furthermore, the similar data were also obtained in the fibrosis kidney tissues of mice. Conclusion: Rab 7 might be an important role in hypoxic TECs regulated angiogenesis, Rab 7 knockdown could improve hypoxic TECs regulated angiogenesis, the relative mechanisms might be correlation with RECK pathway and MMP-2 activities in vivo and vitro study.

The need for antiserum for immunohistochemical (IHC) detection of enterovirus (EV) in formaldehyde fixed and paraffin-embedded (FFPE) specimens is increasing. The standard monoclonal antibody against EV-envelope protein (VP1), clone 5D8/1, was proven to cross-react with other proteins. Another candidate marker of EV proteins is 2A protease (2Apro), which is coded by the EV gene and translated by host cells during EV replication. We raised polyclonal antiserum by immunizing rabbits with an 18-mer peptide of Coxsackievirus B1 (CVB1)-2A protease (2Apro) and examined the specificity and sensitivity for EV on FFPE tissue samples. ELISA study showed a high titer of antibody for CVB1-2Apro. IHC demonstrated that antiserum against 2Apro reacted with CVB1-infected Vero-cells. Confocal microscopy demonstrated that 2Apro labelled by the antibody located in the same cell with VP1 stained with 5D8/1. IHC demonstrated dense positive reactions pancreatic islets of EV-associated fulminant type 1 diabetes (FT1DM), and located in the same cell stained positive with 5D8/1. Specificity of IHC staining FT1DM pancreas was confirmed by absorption with an excessive concentration of immunized peptide. In conclusion, our study provides a new polyclonal antiserum against CVB1 2Apro which may be useful for detection of EV-infected human tissues stored as archive of FFPE tissue samples.