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Sex and FOXP3 gene rs2232365 polymorphism may be associated with the clinical and pathological aspects of chronic viral diseases
Leonn Mendes Soares Pereira1,
Max Willy da Silva Madureira1,
Renata Bezerra Hermes de Castro2,
Isabella Nogueira Abreu1,
Simone Regina Souza da Silva Conde3,
Sâmia Demachki3,
Maisa Silva de Sousa4,
Maria Alice Freitas Queiroz1,
Andrea Nazaré M. Rangel da Silva1,
Sandra Souza Lima1,
Marluísa de Oliveira Guimarães Ishak1,
Ricardo Ishak1 &
Antonio Carlos Rosário Vallinoto ORCID: orcid.org/0000-0003-1135-65071
The forkhead box protein 3 (FOXP3) transcription factor is one of the main markers of immunological suppression in different pathological profiles, and the presence of polymorphic variants may alter the gene expression of this factor. Despite descriptions of an association between the presence of the rs2232365 polymorphism and chronic diseases, the role of the sex variant in this context has not yet been elucidated, as the FOXP3 gene is located on the human sex chromosome X.
To contribute to this topic, 323 women and 373 men were enrolled in the study, of which 101 were diagnosed with chronic viral liver diseases (39 women and 62 men), 67 with HTLV-1 infection (44 women and 23 men), 230 with coronary artery disease (91 women and 139 men) and 298 healthy and uninfected blood donors (149 women and men). They were genotyped for the rs2232365 polymorphism. The rs2232365 polymorphism was associated with clinical and pathological aspects and biomarkers of viral infections only in men, with functional differences between different infections.
A relationship is suggested between sex and FOXP3 rs2232365 polymorphism, resulting in different biological repercussions.
The forkhead box protein 3 (FOXP3) transcription factor is the main marker of regulatory T-cell (Treg) activation, a subpopulation specialized in the suppression of immune responses and the maintenance of homeostatic tolerance in different microenvironments [1]. The impact of Treg frequency on the progression of chronic diseases is important because these cells mediate the inflammatory balance in an immunologically polarized environment [2].
FOXP3 gene is located on the short arm of the human sex chromosome (X on XY model) (Xp11.23; 21 kb) and consists of 11 exons [3]. The relevance of single nucleotide polymorphisms (SNPs) located in the promoter region of the FOXP3 gene has been investigated due to they are involved in the transcription activation, as well as in the interaction with regulatory elements of the gene expression, possibly reflecting on the level of expression of FOXP3 and, thus, in the activation of Treg cells [4, 5].
In this context, the rs2232365 polymorphism in the FOXP3 gene is related to functional changes that predispose individuals to diseases due to the mutant allele (C) changing the binding site of transcription factors that interact with the region [6]. Although the knowledge about the association of this polymorphism with different diseases is based on the literature [7, 8], the relationship between genetic variants of FOXP3 and sex, remain unclear. Thus, the present study evaluated the association of the rs2232365 polymorphism with clinical and pathological aspects and markers of progression of viral and non-viral chronic diseases between the sexes.
At first, we researched the biological meaning of the rs2232365 polymorphism in public databases of gene expression (GText portal - https://www.gtexportal.org/home/snp/rs2232365). The TT genotype has the highest level of expression of the FOXP3 gene in different tissues investigated (Fig. 1). We collected expression data in whole blood and arterial tissue, the bank does not yet have liver tissue data.
Biological implications of the rs2232365 polymorphism: Gene expression graph containing normalized FOXP3 expression data by genotype of the rs2232365 polymorphism in whole blood and arterial tissue (GText portal). The numbers subscribed to the genotypes correspond to the total of samples collected
In our results, the allele frequency of the rs2232365 polymorphism was similar between sexes, however statistical differences were observed between genders when assessing viral infections (Table 1). The polymorphism was in Hardy-Weinberg equilibrium (p > 0.05).
Table 1 Association of sex and allele frequency of the rs2232365 polymorphism in patients with chronic diseases, stratified according to the clinical-pathological profile
In the present study, no significant association between sex and chronic viral liver diseases was observed, although the prevalence of males was higher among those infected. The frequency of polymorphic variants was the same between the sexes when the viral hepatopathy itself was evaluated. (Table 1). In males the allele T was associated with advanced fibrosis, with a relative risk of 4 fold in the bivariate analysis (p:0.05; OR:4.18; CI 95%: 1.13–15.4). In multiple logistic regression the risk of the genetic factor is reduced, however, it still maintains the significance (0.05 ≥ p ≥ 0.01; OR:1.11; CI 9%:0.43–2.90) (Table 1). The viral load (VL) was high among males carrying allele T (p: 0.0007) as compared to carriers of the allele C (Fig. 2a), but the transaminase ratio (AST/ALT) was not significant between alleles and sex, although in males this rate is increased (Fig. 2b). The levels of gamma-glutamyl transferase (GGT) in males with allele C were higher than in those with allele T, but without significant differences (Fig. 2c). These associations were not observed in women. Hepatic inflammation was not associated with the gender or genetic profile of those infected (Table 1).
Association of the rs2232365 polymorphism with biomarkers of the pathologies: In men with chronic viral liver diseases and advanced fibrosis, the viral load was higher in patients with the allele T (a); the ratio of transaminases (AST/ALT) was higher in men, however, with no differences between alleles (b); the level of GGT fluctuated between genotypes/sexes (c). In men infected with HTLV-1, the proviral load (d), T CD4+ lymphocytes (e) and the level of IL-8 (f) were low in allele T carriers; the level of IL-10 was biased lower in patients with the allele T (g), but without statistical significance. (h) In CAD patients, CRP levels were statistically similar between genotypes/sexes
Our data indicate that women are more associated with HTLV-1 than the rs2232365 polymorphism itself (p:0.001; OR: 1.20; CI 95%:0.63–2.29), although the allele T has been associated as a protective factor against infection, especially in males (p:0.04; OR:0.46; CI 95%:0.18–1.18) (Table 1). Again in men, variant T was also associated with low levels of proviral load (p: 0.0396), T CD4+ lymphocytes (p: 0.0483) and IL-8 cytokine (p: 0.0549); the elevation of the levels of the cytokine IL-10 was a trend observed, however, with low statistical power (p: 0.1102) (Fig. 2d-g). The T CD8+ lymphocytes count was similar between genotypes/sexes (data not shown). Both gender and polymorphism were not associated with an asymptomatic carrier or with more advanced infection profiles (HAM / TSP) (Table 1).
The risk of coronary heart disease was associated only with males, although the significance was lost when analyzing the history of risk infection by Chlamydia (Table 1). The frequency of polymorphism was not associated with either the pathological profile or the history of risky infection in both sexes (Table 1). Chlamydia pneumoniae was the most frequent species in the study, however, the infection was not associated with the sex and genetic profile of the patients (Table 1). Levels of C-reactive protein (CRP) were low and similar between sexes and alleles (Fig. 2h).
To avoid false positive claims, we infer the value of false positive report probability (FPRP) for all significant associations. All findings remained noteworthy in the prior probability between 0.25 to 0.1; except for CAD (Female vs Male), whose notability is evident from the 0.01 probability (Table 2).
Table 2 Calculation of the false-positive report probability (FPRP) for the risk associations of sex and rs2232365 polymorphism to chronic diseases and their clinical and pathological profiles
There are controversies regarding the genetic changes caused by the rs2232365 polymorphism [6, 9]; however, based on the analysis of gene expression, it is suggested that the polymorphisms alter the expression of FOXP3, predisposing the individual to different clinical and pathological outcomes related to the disease in question. From an immunological point of view, there is a tendency for the T allele to favor an anti-inflammatory profile, while the C allele favors a pro-inflammatory profile.
It seems counterintuitive to associate an anti-inflammatory factor with the risk of tissue aggression; however, these findings corroborate previous studies that suggest that variant T favors the persistence of viral infection in patients with fibrosis [10]. With the increase in VL, there is a long-term pro-fibrogenic tendency induced by chronic inflammation and continuous response to healing [11], resulting in the fluctuation of pre-cirrhotic biomarkers [12], such as GGT. The transaminase ratio was stable between genotypes and sexes, indicative of chronic infection, but not relevant for estimating the stage of fibrosis [13]. Recent studies by our group show that in liver fibrosis, viral load, in fact, is more associated with the histological profile than liver integrity enzymes [14].
In the multiple logistic regression, the allele T was also associated with advanced fibrosis; however, the decrease in the statistical probability is indicative of other factors influencing liver histopathology. In recent publications, we discard alcoholism as a behavioral factor associated with liver fibrosis [14].
In HTLV-1 infection, the high prevalence of infected women is an epidemiological fact observed in different populations studied [15, 16], and is related to the effectiveness of sexual transmission from male to female. With the present study, we suggest that not only transmissivity, but also sex-linked immunogenetic factors can influence susceptibility to HTLV-1 infection. The observed associations suggest that intrinsic mechanisms regulate the action of FOXP3 variants between sexes. Studies show that, in women, epigenetic processes modulate the expression of FOXP3 and alter the susceptibility to diseases [17]; the normal development of cells carrying mutant genes is a consequence of mixed chimerism [18], which is suggested in the present study due to the marked frequency of heterozygous women (data not shown). In men, changes in FOXP3 tend to be more relevant due to heredity [19], regulation induced by the Y chromosome [20] and sex hormones [21].
Although there are no studies on the association of the polymorphism with HTLV-1 infection, it is suggested that, in men, the anti-inflammatory tendency induced by the allele T reduces chronic immune hyperactivity, typically seen in the pathogenesis of the infection, reflecting the decrease in the proviral load and the cytokines of cellular immunity [22]. The relationship of the polymorphism with the T CD4+ lymphocytes and IL-8 is indicative of the constitution of an atypical pro-inflammatory immune network [23], however, already observed in HTLV-1 infection, mainly in patients with Adult T-cell leukemia (ATL) [24].
In the present study, we did not associate the polymorphism with the clinical and pathological aspects of HTLV-1 infection. However, given the prevalence of asymptomatic patients observed, a cohort study in patients with allele T in this clinical group can clarify whether, in the long term, there will be polarization for a pro-inflammatory profile and changes in the pathogenesis of infection.
Only males were associated with the risk of CAD, however, unrelated to the history of Chlamydia infection. The history of Chlamydia penumonie prevailed and CRP levels fluctuated, but both were not associated with sex and polymorphism. Recent reports confirm that men are generally more likely to develop CAD than women, with the highest death rate in middle age. Women, on the other hand, are at greater risk of stroke, which usually occurs at older ages [25].
We defend the legitimacy of our data based on the FPRP values obtained that support the proposed findings. All values remained noteworthy between 0.25 to 0.001 of prior probability, which, according to Wacholder and collaborators, for polymorphisms whose functional data are suggestive of a possible association (as shown in the literature for rs2232365) is the ideal probability range [26].
In conclusion, the results of the present study indicate a relationship between sex and the polymorphism rs2232365 in gene FOXP3, in which gene variants seem to be more associated with men and with different immunological roles that vary between chronic viral infections.
A total of 323 females and 373 males diagnosed with chronic viral liver disease (CVLD), human T-cell leukemia virus type 1 (HTLV-1) infection or coronary artery disease (CAD) and healthy groups of blood donors, all from regional reference centers in the state of Pará, Brazil (Tropical Medicine Nucleus of the Federal University of Pará, Foundation of Hemotherapy and Hematology Center of Pará (HEMOPA) and Institute of Health Sciences of the Federal University of Pará), were evaluated. Participants were informed about the objectives of the study and, after agreeing to participate, signed a consent form. The study was approved by the ethics committees of the participating entities (CAAE: 73782017.8.0000.0018; CAAE: 0011.0.324.000–09 and CAAE: 31223214.2.0000.0018). All patients were not undergoing treatment.
The inclusion/exclusion criteria and the biological data for patients CVLD were established in our previous study [10, 14].
Patients HTLV-1+ were classified as asymptomatic or with paraparesis (HTLV-1-associated myelopathy/tropical spastic paraparesis - HAM/TSP) according to pre-established criteria [27]. The quantification of the proviral load was based on previously described protocols [27, 28]. Quantification of lymphocytes TCD4+ and CD8+ was performed by immunophenotyping in flow cytometry (FACSCountTM Reagents - TriTEST™/TruCount, BD Biosciences, San Jose, CA, EUA). Pro-inflammatory (TNF-α, TNF-β, IFN-γ, IL6 and IL8) and anti-inflammatory (IL-10) cytokine levels were determined by immunoenzymatic assays (Human ELISAReady-SET-Go, EBioscience, Inc., San Diego, CA, USA).
Patients with coronary disease had arterial obstruction presenting with severe arterial obstruction with or without ischemia (infarction) and another group of patients with cardiac valvulopathy, presenting with volume overload and cardiac pressure. The history of Chlamydia infection in these patients was obtained by immunoenzymatic assays (NovaTec Immundiagnostica GmbH, Germany); and C-reactive protein (CRP) levels were measured by immunoturbidimetry (DiaSys, Waterbury, CT, USA).
Genotyping of the polymorphism (rs2232365) was performed by real-time PCR (C_15942641_10 - Applied Biosystems, Foster City, CA, USA) with established temperature and cycling protocols [10]. To explore the biological potential of the polymorphism, we evaluated the gene expression of genotypes based on the public database of the GTex portal (https://www.gtexportal.org/home/snp/rs2232365).
The estimation of the Hardy-Weinberg equilibrium was performed using the chi-square test, in which only the genotype data of the women (diploids) were used, because the FOXP3 gene is located on the human sex chromosome (X on XY model).
The chi-square test and G test were applied to assess the association of sex and the frequency of polymorphism with the clinical and pathological aspects of chronic diseases, following the recommendations of each test; Fisher's Exact test was applied with the same intention, however, for comparisons arranged in 2 × 2 contingency tables. Followed by the calculation of Odds ratio (OR) to determine the advantage (or disadvantage) of the factors with significant associations. The calculation of multiple logistic regression was proposed to assess the degree of dependence of clinical and pathological variables on sex and the frequency of polymorphism. For CVLD and CAD, we assume the male gender and the frequency of the T allele as "1" (success) and the female gender and the frequency of the C allele as "0" (failure). For HTLV-1 infection, we assume the female sex and the frequency of the T allele as "1"; the male gender and the frequency of the C allele as "0".
The Kruskal-Wallis test was used to calculate the association of the polymorphism with the quantitative biomarkers of the studied pathologies. The Mann-Whitney test was used as a confirmatory method, this time, comparing two independent samples.
To calculate the probability of false positives for significant associations, we predefine an FPRP limit value of 0.5. The Odds ratio was 1.5 for the calculation of statistical power. Associations that remained noteworthy between the ranges of 0.25 to 0.01 of prior probability were considered true positive, according to Wacholder's recommendations [26].
Statistical analysis was performed using BioEstat 5.0 [29] and GraphPad Prism 6.1, with a significance level of 95% (p ≤ 0.05). FPRP was calculated using R 3.4.2 software [30].
The original data sets generated and analyzed during this study are made available by the corresponding author upon reasonable request. Gene expression data was collected from the public database of the Gtext portal (https://www.gtexportal.org/home/snp/rs2232365).
rs2232365:
Polymorphism of the substitution of thymine base for a cytosine base in the promoter region (− 924) of the FOXP3 gene
ALT:
Alanine transaminase
AST:
Aspartate transaminase
CVLD:
Chronic Viral Liver Diseases
FOXP3:
Forkhead box protein 3
FPRP:
False positive report probability
GGT:
Gamma-glutamyl transferase
HAM/TSP:
HTLV-1-associated myelopathy/tropical spastic paraparesis
HTLV-1:
Human T-cell leukemia virus type 1
Treg:
Regulatory T-cell
VL:
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We thank all the patients requested and willing to participate in the study, and all the professionals who are members of the multidisciplinary boards involved.
The study was funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico do Brasil (CNPq #480128/2013–8; # 301869/2017–0) in the acquisition of tests for genotyping of polymorphism by real time PCR; Fundação Amazônia Paraense de Amparo à Pesquisa (FAPESPA/ICAAF-092/2010) in the acquisition of screening immunoassays for Chlamydia and quantification of levels of CRP; and Universidade Federal do Pará (PROPESP/PAPQ/2019), in the acquisition of immunoassays to screen for HTLV-1 infection, quantification of anti and pro-inflammatory cytokines, and quantification of lymphocytes by flow cytometry.
Virology Laboratory, Biological Sciences Institute, Federal University of Pará (Universidade Federal do Pará – UFPA), Belém, Brazil
Leonn Mendes Soares Pereira, Max Willy da Silva Madureira, Isabella Nogueira Abreu, Maria Alice Freitas Queiroz, Andrea Nazaré M. Rangel da Silva, Sandra Souza Lima, Marluísa de Oliveira Guimarães Ishak, Ricardo Ishak & Antonio Carlos Rosário Vallinoto
Hematology and Hemotherapy Center Foundation of the State of Pará (Fundação Centro de Hematologia e Hemoterapia do Estado do Pará), Belém, Brazil
Renata Bezerra Hermes de Castro
Medical School, Biological Sciences Institute, UFPA, Belém, Brazil
Simone Regina Souza da Silva Conde & Sâmia Demachki
Tropical Medicine Center, UFPA, Belém, Brazil
Maisa Silva de Sousa
Leonn Mendes Soares Pereira
Max Willy da Silva Madureira
Isabella Nogueira Abreu
Simone Regina Souza da Silva Conde
Sâmia Demachki
Maria Alice Freitas Queiroz
Andrea Nazaré M. Rangel da Silva
Sandra Souza Lima
Marluísa de Oliveira Guimarães Ishak
Ricardo Ishak
Antonio Carlos Rosário Vallinoto
LMSP, MWSM and RBHC performed the molecular analysis, interpretation of results. LMSP writing of the article. SD, MAFQ and INA participated in the sample collection, biochemical, histopathological profile and virological analysis. SRSSC and MSS performed medical consultations, patient interviews and clinical information collection. LMSP and SSL perform statistical analysis. ANMRS, MOGI, RI and ACRV idealized the project. RI and ACRV guided and reviewed the article. All authors read and approved the final manuscript.
Correspondence to Antonio Carlos Rosário Vallinoto.
The present study was submitted to and approved by the Research Ethics Committee of the Tropical Medicine Nucleus of the Federal University of Pará (CAAE: 73782017.8.0000.0018), Foundation of Hemotherapy and Hematology Center of Pará (HEMOPA) (CAAE: 0011.0.324.000–09) and Institute of Health Sciences of the Federal University of Pará (CAAE: 31223214.2.0000.0018). All individuals who agreed to participate in the study signed an informed consent form.
The authors declare no competing financial interests exist.
Pereira, L.M.S., da Silva Madureira, M.W., de Castro, R.B.H. et al. Sex and FOXP3 gene rs2232365 polymorphism may be associated with the clinical and pathological aspects of chronic viral diseases. BMC Immunol 21, 60 (2020). https://doi.org/10.1186/s12865-020-00387-4
FOXP3
Chronic viral diseases


Note: "Please be advised that under current Anne Arundel County Law, biking (motorize or not) off of a paved surface in a County Park is prohibited."
Nice network of singletrack and a bit of gravel access road (which can be avoided all together). A few built up log obstacles, some small climbs and a few short steep decents, a couple creek crossings. Generally well maintained except for a few sections. Can easily ride for an hour or so without going over the same section of trail.
Review: As with most trails around here, you need to knownwhere to go to find the good runs and get the loops figured out. Been back here 40 times in the past few years. There's a long climb which leads out to power lines, turn right at a small fenced in station and enter the woods for a good descent trail with roots and rocks. I've gotten speeds in upwards of 34mph down this trail. Very very fast and fun. A few other good loops back here as well.
Review: Basically a walking trail with no obstacles. Many overgrown spots.
Review: Great place to ride after work. I have been to this area about 10 times and still find some hidden areas, but can definitely tell this trail has seen some much better days. Log rolls are rotted and some areas are slightly over grown. There are a few creek crossings and a bridge, some jumps and decent downhills round out the features. Great place to have some fun after work.
Review: I used to do a mountain bike race here by Team Snow Valley in the 90's called "Pshchocross". Really fun, multiple lap, muddy courses (changed every week). Been here the other day, and the area has seen better days. Looks like a lot of motorized vehicles and little trail maintenance. Great local or afterwork ride. You have to do multiple laps to get a decent ride in.
Review: Very fun trail. One of my local rides. Not an epic singletrack trip, but a lot of fun. Jump lines, a drop or two, decent climbs and some good flow. Good for XC, AM, and even FR on some features. Definitely worth a short trip to explore. Agree with other post that it is a fun trail to ride and stop to play at various locations.
Review: Nice ride in a not-so-isolated suburban area. Built-up opstacles and stream crossings are the park's best attraction, though there are a few nice, albeit short, climbs and descents.
Similar Trail: Portions of Potapsco.
Review: This trail is not great singletrack and could be ridden by a beginner. Although, there is plenty to do for an advanced rider. All kinds of obstacles, challenging ramps up and down logs and over water, log steps up cement sewer pipes, dirt ramps and more. I like to go and chill on one obstacle. Oh, and I have went over my handlebars twice here.
Odenton Park MTB Trail 3.30 out of 5 based on 10 ratings. 10 user reviews.


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Nikki Reed Responds To Controversy Over Ian Somerhalder Throwing...
Nikki Reed Responds To Controversy Over Ian Somerhalder Throwing Out Her Birth Control Pills
By Stephanie Chase in Lifestyle / Showbiz on 23 September 2017
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Nikki Reed Ian Somerhalder
People were not happy with 'The Vampire Diaries' actor.
Nikki Reed has responded to the backlash over the revelation that husband Ian Somerhalder threw out her birth control pills.
The actress was appearing on Dr. Berlin's Informed Pregnancy podcast with her husband when she told the story about how Ian had disposed of her birth control pills when they decided to start a family.
The story was subsequently picked up by media outlets including Cosmopolitan, who wrote an article entitled, 'Ian Somerhalder threw away Nikki Reed's birth control pills and we don't like him anymore'.
Nikki Reed and Ian Somerhalder welcomed their first child in July
On the Informed Pregnancy podcast the couple were asked when they decided the time was right to have a baby. "May," Ian answered (via E! News), to which Nikki replied, "Oh yeah...oh when you threw out all my birth control pills."
Ian then attempted to explain himself, saying: "It was just time. But unbeknownst to poor Nikki, she didn't realise that I was gonna go in her purse and take out her birth control and pop them.
"By the way it was at the beginning of the pack so I had to pop all those suckers out, there was like 25 of them."
Ian then revealed that there's also a six-minute video of his wife "freaking out" as he flushed the pills down the toilet. "Actually, now thinking about it, I guess I kind of decided [to start a family]," he added.
More: Ian Somerhalder Writes Open Love Letter To His 'Inspiring' Wife
Understandably, Ian faced some backlash and on Friday Nikki took to Twitter to defend him. "WOMEN'S RIGHTS MATTER, so please don't use false narratives to highlight issues that are truly important!" the actress tweeted.
"We should be talking about these things,but using a funny interview between married ppl &twisting it to perpetuate gossip is irresponsible."
She later followed up with a note addressed to the writer of the Cosmopolitan article, accusing them of 'irresponsible journalism'.
"Quote from an article this morning claiming my husband tried to 'force (me) into pregnancy?!' Oh and my favourite line 'That is some unconsented bulls--t right there,'" Reed wrote.
"My response: Yep. When you actually listen to the podcast (which I'm sure you didn't) you'll hear how 'unforced' I felt. Ha! Also, 'unconsented' bulls**t is you speaking on my behalf in a story admittedly taken out of context for the purpose of stirring up drama WITHOUT my approval.
"Don't talk about consent to me. And lastly, how dare you try to cast a dark shadow over one of the happiest most memorable days of my life – you're not only disrespecting me but my baby."
Nikki signed off the note by adding: "Oh, and next time you try to stand up for women by writing an article 'about women's rights', try properly conveying the way I felt. It's a shame that this was your way in. You have a platform, write about things that matter by using truthful stories, not gossip. Thanks and goodbye."
Nikki and Ian announced they were expecting their first child in May 2017 and they welcomed a daughter, Bodhi Soleil Reed Somerhalder, in July.
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redpajama_set_name: RedPajamaCommonCrawl


Subject: Re: Who is Nexus?
>you can play very interesting chess?
>Please give us more informations.
>Are you a part of the wonderful uci- and winboardworld?
>Will we see you soon on our pc�s?
seems they are among the very best.


text:
Q: How can I store data derived from Firebase, converted to an UIImage, to an UIImage array? I am trying to retrieve pictures saved from the database (in this case I hard coded the exact picture I want from the database). I have two UIImage variables initiated: imageView and rawImage. imageView is using SDWebImage from FirebaseUI to load the image, but I don't know how to save it into a UIImage array.
rawImage is grabbing the data from the path of the exact image from Firebase. I am converting it to a UIImage but when I want to append it to my UIImage array, the application crashes.
class GalleryViewController:UIViewController{
    @IBOutlet weak var imageView: UIImageView!

    @IBOutlet weak var rawImage: UIImageView!

    override func viewDidLoad() {
        super.viewDidLoad()
        view.addVerticalGradientLayer(topColor: primaryColor, bottomColor: secondaryColor)
        self.tabBarController?.tabBar.isHidden = true
        retrievePicture()
    }

    func retrievePicture()
    {
        guard let user_email = Auth.auth().currentUser?.email else { return }
        let storageRef = Storage.storage().reference()

        // Reference to an image file in Firebase Storage
        let reference = storageRef.child("\(user_email)").child("/top").child("1.jpg")

        // UIImageView in your ViewController
        let imageView: UIImageView = self.imageView

        // Placeholder image
        let placeholderImage = UIImage(named: "placeholder.jpg")
        //UploadViewController.Clothing.top_images.append(<#UIImage#>)

        // Load the image using SDWebImage
        imageView.sd_setImage(with: reference, placeholderImage: placeholderImage)

        // this is the code for the rawImage portion I described above
        reference.getData(maxSize: 1 * 1024 * 1024) { data, error in
            if let error = error {
                print("Error \(error)")
            } else {
                let picture = UIImage(data: data!)
                UploadViewController.Clothing.top_images.append(picture!)
            }
        }

        // loading the image to the rawImage imageview
            rawImage.image = UploadViewController.Clothing.top_images[0]

    }
}

A: If you already load the images using SDWebImage then you can also append the image in your UIImage array with that.
Just use SDWebImage with a completed block like this
var arr_image = [UIImage]()

imageView.sd_setImage(with: reference_url, placeholderImage: UIImage(named: "placeholder.jpg"), options: options: [.highPriority]) { (img, error, cachtype, url) in
    if img != nil{
        arr_image.append(img) // append UIimage in array
    }
}

A: You have overlooked force unwrapping optionals, and I propose to you to remove ! usage to avoid crashes, use following instead
reference.getData(maxSize: 1 * 1024 * 1024) { data, error in
    guard let data = data else {
        print(error?.localizedDescription ?? "Check remote url or service")
        return
    }

    if let picture = UIImage(data: data) {
        UploadViewController.Clothing.top_images.append(picture)
    } else {
        print("Invalid image data\n\(String(data: data, encoding: .utf8))")
    }
}

or following if statement is safe
if error == nil && data != nil, let picture = UIImage(data: data!) {
    UploadViewController.Clothing.top_images.append(picture)
}

You can also try path without leading slash, like so:
let reference = storageRef.child("\(user_email)/top/1.jpg")

redpajama_set_name: RedPajamaStackExchange


I'm not sure if every girl likes cosmetic bags but I'm sure every girl likes their cosmetics organized! I mean, who doesn't like to have their makeup items neatly organized and easily accessible in one nice bag especially when on the move? And better still if it's stylish in design at the same time! Well, this Hold Me Bag is just that as it not only holds and organizes your cosmetics, brushes, and tools, but also keeps everything accessible at a glance. It's also very handsome looking and definitely does not resemble the usual floral cosmetic bags.
When I first received this bag, which the company sent me on a complimentary basis for a review, I was so impressed by the look and feel. It comes in a nice black outer bag and the exterior of the Hold Me Bag, which is made of black Knew Suede, feels very velvety soft and luxurious to the touch. The bag is fashioned with a wrap-a-round self-tie without the use of Velcro, metal, or magnets. As such, it would be able to accommodate varying degrees of depth, depending upon the number and shapes of your enclosed items.
The interior is a mix of Knew Suede and an all-cotton print that has been over-laid with a washable surface. The one I received comes designed with graphics of Japanese girls. The design is called 'Miss Suki' and it's really kawaii. There are choices of other designs as well as one that is completely made of Knew Suede.
The center section, or the "heart" of the bag can hold various cosmetic items such as primer, foundation, makeup palettes, lipsticks, mascaras, and more. The section also has a separate liner in the bottom, easily removable for cleaning, and for use outside the bag if needed.
The brush/tool section has fifteen compartments; some will hold single items and some, multiple items. It can hold my basic brushes but not all my kabuki brushes because the brushes are rather fat and space consuming. But those I couldn't hold, I just placed them in the other section.
The bag is pretty user friendly. I like that I can access my makeup items and tools all at once and I didn't need to fumble around for the brushes. However, because of the design and size of this bag, I need to have a wide flat surface area to lay it down to access all my stuff. The black Knew Suede material also means dust and stains are much more visible so it can get rather unsightly after just one or two usage. But, the good thing is, the material makes it easy to wipe and so the bag can be back to its pristine condition without too much effort too.
this bag is way cool! and i like you using the brush guard. they are so useful.
Yeah, they're especially good for drying the brushes!
Oh my goodness, how cute is that?!
This is really nice n cute.
It can only purchase online? Or can get it locally?
Online, as per the link I've provided.
wow! i think i also need this one! hehehe…. i'm not a very organized person….
Yeah, the graphics are too cute!


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  icon = "twitter"
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%}

redpajama_set_name: RedPajamaGithub


text:
Home Chevron icon It indicates an expandable section or menu, or sometimes previous / next navigation options. Crime
A 73-year-old New York grandmother outsmarted scammers who pretended to be her grandson and said he needed $8,000 to be bailed out of jail
Katie Balevic
Jean watches from her porch while police officers arrest the suspect.
Courtesy of the Nassau County Police Department
A Long Island grandmother outsmarted a group of scammers who wanted $8,000 from her.
The woman said a man called her and pretended to be her grandson, claiming he needed $8,000 in bail money.
The woman said she had money at her house and told him to come get it. Then, she called the police.
A Long Island grandmother outsmarted scammers who tried to steal thousands from her.
The woman from Seaford, who asked to be identified as Jean, told CBS2 that she received a call from someone claiming to be her grandson. The man said he was arrested for drunk driving and needed to be bailed out of jail.
"I knew he was a real scammer. I just knew he wasn't going to scam me," Jean, 73, told CBS2. "He starts calling me 'grandma,' and then I'm like, I don't have a grandson that drives, so I knew it was a scam."
The scam took several phone calls to play out and involved multiple unidentified males, police said in a press release. One person claiming to be a lawyer for Jean's grandson told her that he needed $8,000 to get out of jail. A third person called claiming to be a bail bondsman coming to collect the money.
"I told him I had the money in the house, and I figured, he's not going to fall for that," Jean said, adding that she called the police. "Well, he fell for that hook, line, and sinker."
A man impersonating a bail bondsman arrived at Jean's home to collect the money, and she handed him an envelope filled with paper towels. As he turned to leave, police officers tackled him, according to CBS2.
Officers of the Nassau County Police Department arrested Joshua Estrella Gomez, 28, and charged him with attempted grand larceny in the third degree. He was released on an appearance ticket and is due to appear in court on February 3.
"I feel like gotcha, and I feel like, like you say, so many people fall for this and you only hear about it on the other end after they've lost $8,000," Jean said.
Nassau County PD spokesperson Richard Lebrun told Insider that people should block unwanted calls and texts to avoid being scammed. If someone calls claiming to have been arrested, call that person or a family member to confirm.
"Resist the pressure to act immediately," Lebrun said in a statement. "Legitimate business will give you time to make payments."
"Never pay with gift cards or wire money to an unknown person or business," he added.
NOW WATCH: I infiltrated the UK's most dangerous drug gangs — here's what I learned about drug crime
New York Scam calls Scammer


text:
Isuzu PH opens door in Pagadian City with 3rd IOS dealership facility
Aug 07, 2020 | NEWS
Isuzu Philippines Corporation (IPC) continues its aggressive expansion and modernization efforts with the recent opening of its 43rd dealership and its third Isuzu Outlet Standardization (IOS) dealership facility, this time in Pagadian City in Zamboanga del Sur.
In ceremonies streamed online to the motoring media on August 7, 2020, executives of IPC and North-Min Automotive Dealership Inc (NMADI) presented a walk-through of Isuzu Pagadian, which is strategically located at Barangay Tiguma, one of the rapidly developing commercial and agricultural locations in Pagadian City.
To serve as a satellite of Isuzu Butuan, Isuzu Pagadian showcases a total floor space of 3,871 sqm that will include a 4-vehicle showroom display, service bays that can accommodate five light commercial vehicles and two commercial vehicles, a wash bay and wheel alignment facility, and five slots for body repair and paint works.
Isuzu Pagadian' IOS will enhance the overall customer journey, highlighting an aesthetic, functional design that not only provides a more spacious and organized area for its users, but expresses Isuzu's new brand identity and its long-standing reputation for durable and reliable products. The new facilities will also contribute greatly to a more seamless automotive retail experience for both customers and dealership personnel.
During the virtual presentation, IPC President Hajime Koso remarked, "The addition of a new Isuzu dealership in our rapidly expanding network is a strong testament to the growing preference for the Isuzu brand as we continue to widen our reach to our customers in Region 9. This is another major milestone that we share with our new dealer partner North-Min Automotive Dealership Inc, and we look forward to serving our customers in this area with the Isuzu Pagadian."
Mr. George Ongchua, Isuzu Pagadian General Manager, described Isuzu as a "renowned automotive brand in Mindanao." He added, "Isuzu trucks and light commercial vehicles have proven time and again that they are perfectly suited to the varying and challenging terrains and road conditions of Mindanao. With the establishment of Isuzu Pagadian that is of world-class standards, we are very confident that the good reputation of the Isuzu brand in the region will be extended to its dealership services. Pagadian is one of the most industrialized and business-savvy cities in Mindanao, and we're very optimistic that people and businesses in this side of the Zamboanga Peninsula will come to us to provide them with Isuzu products and services."
Now on its 23rd year, IPC aims to further strengthen its market leadership in trucks and LCVs in the country, particularly in the Philippines' fastest-growing regions. With the Isuzu Pagadian, new world-class IOS dealership facility, Pagadianons will have one more reason to make Isuzu "Your Responsible Partner".


text:
Valencia (valencianska: València, Comunitat Valenciana; inofficiellt País Valencià – spanska: Comunidad Valenciana; País Valenciano) är sedan 1977 en autonom region i Spanien. Huvudstad är Valencia. De officiella språken är valencianska (en varietet av katalanska) samt spanska.

Regionen består av tre provinser: Castellón (Castelló), Valencia (València) och Alicante (Alacant).

Historia
Ursprunget till dagens region dateras tillbaka till kungadömet Valencia, grundat år 1233. Jakob I (Jaume I) ledde den gemensamma katalanska och aragoniska återerövringen av den islamiska taifan Al-Andalus i Balansiya och Denia. Den beryktade riddaren El Cid förde styrkorna som till slut erövrade området. Kungadömet Valencia (Regne de Valencia) var ett fritt land inom den aragoniska kronan fram till år 1707. Då avskaffade den förste bourbonske kungen av Kastilien och Aragonien konstitutionen, språket, institutionerna samt lagarna inom dessa kungadömen för att underordnade dessa den kastilianska strukturen. Han skapade därmed det centraliserade kungadömet Spanien.

Det första försöket till självstyre för regionen Valencia i modern tid var under den andra spanska republiken år 1936, men det spanska inbördeskriget bröt ut och försöket avbröts. Valencia förklarades nyligen officiellt för nation, efter en tvådelad reform av Valencias autonomistatut.

Valencias autonomistatut förklarar kastilianska (spanska) och valencianska som officiella språk. Även om den spanska konstitutionen från år 1978 tvingar spanska medborgare i Spanien att kunna spanska så ger statutet valenciskan ett särskilt skydd som den autonoma regionens eget språk (llengua pròpia).

Den officiella flaggan i regionen har fem röda streck på gul botten samt guldkrönad blå kant. Det rödgula kan härledas till La senyera, den heraldiska symbolen för kungen av den aragoniska kronan, som idag även används i Aragoniens, Kataloniens, Balearernas och flera andra regioner och städers flaggor och vapen.

Territoriet blev en autonom region 1982 och gränserna blev i stort sett de som fanns under den aragoniska kronan.

Geografi
Valencia gränsar i norr till Katalonien, i väster till Aragonien och Kastilien-La Mancha och i söder till Murcia. Hela östkusten vetter mot Medelhavet, mellan floden La Sénia i norr till floden La Segura i söder sträcker sig kustremsan 518 kilometer lång. I regionen ingår även öarna Columbretes och Nova Tabarca. Nordväst om regionen är exklaven Rincón de Ademuz beläget. Dessa gränser speglar i stort kungadömet Valencias gränser.

I norr ligger det Iberiska bergssystemet, i söder Béticobergen och de centrala delarna består av bergsområden, högplatåer och slätter. i den nordligaste provinsen Maestrazgo ligger de högsta bergen i regionen. Peñagolosa når 1 813 meter över havet och många anser att det är det högsta berget. Calderón i Rincón de Ademuz når dock 1 839 meter. I detta område finns även Gavilán (1 747 meter), La Cruz de los Tres Reinos (1 555 meter) och Tortajada (1 541 meter). Ytterligare ett berg som når över 1 500 meter ligger i La Marina, norr om Alicante, Aitana (1558 meter).

Kustområdena Costa Blanca och Costa del Azahar ingår i Valenciaregionen.

Större floder

Turia
Júcar
Segura

På 1950-talet leddes floden Turias utlopp om efter stora översvämningar. Staden Valencia ligger vid flodens mynning och drabbades mycket hårt. Numera går Turiaflodens utlopp strax söder om staden, och den uttorkade delen är ombyggd till ett uppskattat rekreationsområde mitt i centrala Valencia.

Klimat

Hela kusten ligger vid Medelhavet vilket påverkar regionens klimat. Ändå är klimatet inte likadant i hela regionen.

Typiskt medelhavsklimat: Finns efter norra kusten och mitt i regionen. Somrarna är långa, torra och varma med temperaturer över 30 grader Celsius. Vår och höst har mer nederbörd.
Bergsklimat: Det typiska medelhavsklimatet påverkar de större delarna av inlandet, men i bergsområdena påverkar altituden både temperaturen och nederbörden. Vintrarna är kalla, somrarna är svalare än vid medelhavsklimat med mer nederbörd. Under vintrarna kommer nederbörden ofta i snö.
Mycket torrt medelhavsklimat och torrt klimat: Detta klimat finns från norra Alicanteprovinsen till gränsen mot södra grannregionen Múrcia. Temperaturen är mycket hög under somrarna och på vintrarna kan det nå upp över 15 grader Celsius. Nederbörden är låg. I södra Alicanteprovinsen kan temperaturen nå 20 grader i februari. Somrarna är långa, torra och varma, och temperaturen kan ofta gå över 35 grader. Nederbörden faller mest på våren och hösten.

Som många andra regioner i Spanien har Valencia drabbats av omfattande skogsbränder under de torra och varma årstiderna.

Politik
Valencia styrs av det generalförsamlingen Corts Valencianes för La Generalitat Valenciana, presidenten och den valencianska regeringen. Presidenten är även regeringschef. Den lagstiftande församlingen lyder under generalförsamlingen som representeras av 89 parlamentariker med säte i huvudstaden.

Varje provins har eget självstyre och beslut av provinsiell karaktär fattas oberoende av regionens parlament. Även varje kommun inom provinserna har ett visst mått av självstyre.

Ekonomi

Valencia har en oregelbunden topografi vilket historiskt har gjort det svårt med kommunikationer samt att bruka marken i inlandet. Endast kustområdena hade förbindelser med övriga världen, antingen sjövägen över medelhavet eller landvägen genom Katalonien mot norr. Staden Valencias hamn har alltid varit viktig men inför arrangemanget av segeltävlingen Americas Cup år 2007 har den tidigare industrityngda hamnen fräschats upp och en större marina har tillkommit.

Medelhavsklimatet med lite regn gör naturresurserna knappa. Det finns ett behov av färskvatten och situationen är allvarligast i de sydliga delarna. Situationen löses genom restriktioner och vattenreservoarer, och det finns projekt på att leda vatten från floder, till exempel Ebrofloden strax norr om Valencia.

Turismen är en av de viktigaste inkomstkällorna men övrig näring inkluderar stora citrusfruktodlingar, vinodlingar, keramik och möbelindustri. Biltillverkaren Ford har en av sina fabriker i regionen.

År 2002 var regionens bidrag till nationens BNP 10,5% och 12% av exporten. Arbetslösheten var 10,5%, med en större andel kvinnor. Trots en ekonomisk kris mellan 1973 och 1985 är Valencia Spaniens näst största exportregion.

Demografi

Provinser
Historiskt har regionen varit indelad i comarques, och 1883 blev den, liksom övriga Spanien, indelad i provinser. Det finns 32 comarques och tre provinser – Castelló, València och Alacant.

Större städer
 Valencia, 805 304 invånare
 Alicante (Alacant), 322 431 invånare
 Elche (Elx), 219 032 invånare
 Castelló de la Plana (Castellón de la Plana), 172 110 invånare
 Torrevieja, 92 034 invånare
 Orihuela, 77 979 invånare
 Gandia 74 827 invånare
 Torrente (Torrent), 74 616 invånare
 Benidorm, 67 627 invånare
 Sagunto (Sagunt), 62 702 invånare

Kultur

Festivaler
I många städer hålls varje år festivalen "Moros y Cristianos" till minne av slagen mellan muslimer och kristna under medeltiden. I mars varje år firas Les Falles i flera städer, framförallt i huvudstaden Valencia. Alicante är berömt för sin festival Hogueras de San Juan som hålls i juni. I augusti firas i Castelló Fiestas de la Magdalena och i Elx Misterio de Elche. I Bunyol (eller Buñol), som ligger omkring 40 kilometer väster om staden Valencia i riktning mot Madrid, äger sista onsdagen i augusti varje år världens största tomatkrig rum, La Tomatina.

Övrigt
Från Valencia härstammar nationalrätten paella, baserad på ris.

I Valencias spelas Pilota Valenciana, en bollsport som liknar den baskiska varianten pelota.

Referenser

Noter

Externa länkar

redpajama_set_name: RedPajamaWikipedia


text:
Over 100 Car Dealers to Accept Crypto Payments in the UK Boosting Crypto Adoption
Brian Njuguna Apr 09, 2020 03:00 2 Min Read
At least 100 car dealers in the UK have inked a partnership with London-based AutoCoinCars, the nation's market leader in trading cars with cryptocurrencies. Through the strategic collaboration, clients will be able to purchase cars using cryptos in some of the biggest car dealers in the UK, such as Benz Bavarian, Saxton4x4, and Redline Specialist Cars.
Crypto adoption growing in the UK
The decision to allow people to buy cars in the UK using cryptocurrencies has been propelled by their integration into the community. At least 7% of the population has direct access to virtual currencies.
Since its inception in 2019, AutoCoinCars has proven to be a game-changer as it has been offering crypto solutions to car dealers in the UK. During its first year of operations, its services were sought after by nearly 50% of the country's car dealers.
Luke Wilmott, the commercial director at AutoCoinCars, noted that the partnership with more than 100 car dealers would be instrumental in crafting the way forward in the UK car sales industry.
He said, "With five million people in the UK already using cryptocurrency, we can see that it's definitely the way of the future. It all started with Bitcoin, and now there are several other currencies available. […] For dealers, offering cryptocurrency as a purchasing option to your customers opens up another great avenue of business."
The current UK economic climate necessitates different industries to be creative to remain afloat. The country's car sales industry is touting crypto payments to be game-changers as they will maximize customers' satisfaction rates.
Cryptos in the car sales industry
The financial director at Redline Specialist Cars, John Graeme, acknowledged that optimizing cryptocurrency usage was the way forward for the car sales industry irrespective of a car's cost.
He added, "From our own experience, I think people believe that to buy a car with cryptocurrency, it must be a high-value supercar, but we've sold a whole multitude of cars from Lamborghinis to Audis. Don't be fooled by the big numbers in cryptocurrency; people can buy cars of any value; our stock ranges in value from £20k to £2m."
Graeme also revealed that they have been getting numerous enquiries from potential customers about purchasing cars using cryptocurrencies. Nevertheless, this challenge will be solved based on the company's partnership with AutoCoinCars.
Blockchain technology is also making a name for itself in the automotive industry. Recently, the BMW Group expanded its blockchain project by seeking the services of Amazon Web Services (AWS) and Microsoft Azure to propel the traceability and traceability of crucial raw materials in its international supply chains.
Image via Shutterstock
CAR SALES INDUSTRY