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Anti-viral and pro-inflammatory functions of Toll-like receptors during gamma-herpesvirus infections
Marta Maria Gaglia ORCID: orcid.org/0000-0002-1791-06631
Toll-like receptors (TLRs) control anti-viral responses both directly in infected cells and in responding cells of the immune systems. Therefore, they are crucial for responses against the oncogenic γ-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus and the related murine virus MHV68, which directly infect immune system cells. However, since these viruses also cause lifelong persistent infections, TLRs may also be involved in modulation of inflammation during latent infection and contribute to virus-driven tumorigenesis. This review summarizes work on both of these aspects of TLR/γ-herpesvirus interactions, as well as results showing that TLR activity can drive these viruses' re-entry into the replicative lytic cycle.
The oncogenic human γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) need to overcome the immune system's protective responses to establish lifelong latent infections in patients and to intermittently re-enter the lytic cycle. While the ability to cause a latent infection allows these viruses to persist, the lytic replicative cycle is key for spread within and between hosts. Moreover, both types of infection are important for the development of γ-herpesvirus-linked diseases [1]. EBV infection is largely ubiquitous, but if acquired past childhood EBV often gives rise to infectious mononucleosis [2]. In a subset of infected individuals, EBV infection leads to the development of various types of B cell lymphomas, as well as specific subtypes of nasopharyngeal carcinoma (NPC) and gastric carcinoma [3]. In addition, EBV infection has also been linked to the development of autoimmune diseases [4]. KSHV infection is less prevalent, with a striking geographical bias, whereby seropositivity is much higher in Africa and some other regions of the world [5]. In some infected individuals, KSHV can give rise to Kaposi's sarcoma and two B cell lymphoproliferative diseases, primary effusion lymphoma (PEL) and Multicentric Castleman disease (MCD), as well as KSHV-associated inflammatory cytokine syndrome (KICS) [3]. These diseases are predominantly found in immunosuppressed patients, although an endemic form of Kaposi's sarcoma not clearly related to immunosuppression is also common in parts of Africa [5].
Infected cells are endowed with multiple mechanisms to sense the infection and initiate a local and systemic response. In turn, viruses have evolved a plethora of approaches to counteract and limit these responses. In this review, we will focus on the interactions between γ-herpesviruses and Toll-like receptors (TLRs), a class of membrane-associated pathogen-associated molecular pattern (PAMP) receptors that detects PAMPs in the extracellular space and in endosomes. Interestingly, while many studies have studied the anti-viral functions of TLRs in γ-herpesvirus infections and viral TLR evasion strategies, interactions with TLR signaling are also relevant for other aspects of γ-herpesvirus biology (Fig. 1). Several studies suggest that TLR activation may be one of the triggers for lytic reactivation. Moreover, TLR modulation of inflammatory responses has been linked to tumorigenesis and autoimmunity, particularly during EBV infection. This review will summarize the current knowledge on these aspects of TLR biology during infection with the human viruses EBV and KSHV. I will also cover studies on the related murine herpesvirus 68 (MHV68). As EBV and KSHV do not infect mice, MHV68 is widely used as a small animal model virus for these infections, and is used to dissect γ-herpesvirus biology in vivo [6].
Summary of potential functions of TLR signaling in γ-herpesvirus infection. TLRs contribute to anti-viral responses against γ-herpesviruses, and their expression is induced in some situations, presumably as a result of anti-viral signaling (grey arrows). However, γ-herpesviruses also reduce expression and signaling of TLRs as an immune evasion strategy (light blue arrow). In addition, TLRs modulate γ-herpesvirus-caused diseases through their effect on inflammation (yellow arrows). Moreover, TLR activation can also reactivate the lytic cycle of γ-herpesviruses in latently infected cells (purple arrows)
Basics of TLR signaling
Mammalian TLRs are a family of transmembrane pathogen-recognition receptors (10 in humans and 12 in mice) discovered in the mid-1990s (Fig. 2). They have leucine-rich repeat containing ectodomains and cytosolic Toll-IL-1 receptor (TIR) domains. They are named for their homology to the Toll protein in Drosophila melanogaster, which has roles in development. Different TLRs respond to different PAMPs (Fig. 2). However, they all trigger signaling pathways that culminate in the activation of the transcription factors NF-κB and/or interferon regulatory factor 3 and 7 (IRF3 and IRF7, Fig. 2). NF-κB induces transcription of pro-inflammatory cytokines like interleukin-6 (IL-6), while IRF3 and 7 induce transcription of type I interferons (IFNs), which are potent anti-viral cytokines. In addition to responding to different cues, different TLRs have different localization, either at the plasma membrane or internal membranes, predominantly endoplasmic reticulum, endosomes and endolysosomes. Many of the internal TLRs respond to nucleic acids, which are not exclusively pathogen molecules. Their localization is thought to naturally limit the autoactivation of these TLRs by endogenous DNAs and RNAs [7]. Despite many differences in signaling, all TLRs use one of two adaptor proteins to transduce their signaling – MyD88 or TRIF (Fig. 2). Both proteins contain TIR domains. Two additional adaptors, TRAM and TIRAP, are also involved in some of the signaling, although they are thought to act mostly as sorting adaptors, helping to recruit MyD88 and TRIF to the correct locale [7].
Summary of human TLRs and their ligands. Diagram of the 10 human TLRs, indicating their adaptor molecules and the downstream result of their signaling. For each TLR, canonical ligands are listed in bold, artificial stimuli used to test their functions in parentheses, and described ligands from γ-herpesviruses ("γ-HV") in italics. pDC = plasmacytoid dendritic cells; poly(I:C) = polyinosinic:polycytidylic acid; LPS = lipopolysaccharide. Sspoly(U) = single-stranded polyuridylic acid
While intracellular PAMP-recognition receptors like RIG-I and cGAS are expressed in most if not all cell types, the expression of many TLRs is more restricted and they are found predominantly on cells of the immune system [8]. Because of this distribution, they have an important role in orchestrating organism-wide responses and modulating adaptive immunity [8]. In naïve B cells, which are the critical long term reservoir of EBV, KSHV and MHV68 infections, TLR activation promotes B cell activation [9], and may be sufficient for naïve B cell proliferation without B cell receptor ligation [10]. TLR stimulation, particularly CpG DNA activation of TLR9, also leads to proliferation in memory B cells [11] and increased antibody production in plasma cells [12].
Although activation of inflammatory cytokines and IFNs appears to be the main consequence of TLR activation, at least two TLRs, TLR3 and TLR4 have been reported to directly cause cell death [13, 14]. They do so by activation of caspase-8 through formation of a TRIF-containing signaling complex [13, 14]. However, this process has largely been described in response to purified TLR ligands and it remains unclear if and when it is invoked during pathogen infection.
TLR signaling as anti-viral mechanism and evasion during γ-herpesvirus infection
Because of the central role of TLRs in anti-viral responses, many studies have investigated which and how TLRs contribute to innate immune responses to γ-herpesviruses (Table 1). They have uncovered roles both in the infected cells themselves and in other cells of the immune system that are key to the response to infection, like monocytes and dendritic cells. TLR2, 7 and 9 (but not TLR3) are required for responses to MHV68 ex vivo in dendritic cells and in vivo [15,16,17,18,19]. However, TLR9 only has a role in protecting animals from MHV68 infection when MHV68 is administered from the intraperitoneal or intravenous route, not the intranasal route [16, 18, 19], possibly because TLR9 is not expressed in lung dendritic cells. Depending on the dose of the inoculum, loss of TLR9 in vivo can increase the number of latently infected cells in the spleen and/or the frequency of reactivation of lytic infection in these cells [16, 18, 19], both parameters that are important for tumor development in human herpesviruses. Consistent with the reports that TLRs sense and contribute to blocking MHV68 infection, MyD88 knockout mice were reported by Michaud et al. to have higher MHV68 infection rates [15]. However, a second study of MyD88 -/- mice reported instead that MyD88 loss impaired MHV68 infection, perhaps due to a role for MyD88 in B cell activation [17]. Possibly, these differences are linked to the dose of the inoculum, as proposed by Michaud et al. [15]. It is notable that inoculation doses used in the TLR studies summarized above vary by 2–3 orders of magnitude. The dynamics of the host response and/or the effect on different cell types may be different depending on the strength of the stimulus. In general, these studies highlight the complexity of the system, as TLR signaling occurs in both myeloid cells and B cells and can have different biological roles depending on the cell type.
The data available for anti-viral effects in KSHV and EBV infection are more limited. TLR9 also induces type I IFN responses in dendritic cells after KSHV and EBV infection [20,21,22]. It also mediates IL-17 secretion after peritoneal injection of EBV DNA in mice or ex vivo mouse monocyte treatment with EBV DNA [23]. TLR4 is activated during KSHV infection of lymphatic endothelial cells, the cells that give rise to KS, likely by the envelope glycoprotein [24]. This activation stimulates type I IFN production [24]. Moreover, loss of TLR4 increases the susceptibility of these and other cell types to KSHV infection [24]. TLR2 signaling is activated by the EBV dUTPase BLLF3, likely secreted in extracellular vesicles (exosomes), and/or a virion component [21, 25,26,27], and TLR3 and 7 signaling are activated by Epstein–Barr virus-encoded small RNAs (EBERs), likely also secreted by infected cells in exosomes [21, 22, 28]. Stimulation of these TLRs by EBV cues induces type I IFN and cytokine responses in monocytes and dendritic cells and promotes plasmacytoid dendritic cell maturation [21, 25,26,27,28]. The TLR mediated signaling in dendritic cells may be crucial to promote survival to infection through activation of NK and T cells, as shown by a study in a humanized mouse model of EBV [29]. Also, consistent with an important role for TLR signaling in EBV responses, a patient with a MyD88 mutation was reported to have persistent EBV viremia, albeit asymptomatic [30]. Like other data on the role of TLRs, these data point to a role for TLR signaling in protective responses against KSHV and EBV, and also highlight the range of signals from these viruses that can elicit a TLR response.
In addition to TLR activation by γ-herpesviruses, the anti-viral role of TLRs against these viruses is demonstrated by the fact that stimulation of TLRs reduces replication and reactivation of KSHV, EBV and MHV68 (Table 1). In particular, several studies have shown that TLR9 activation reduces EBV and MHV68 reactivation from a latent infection in B cells and EBV infection and/or replication in B cells and monocytes after a de novo infection [19, 21, 31,32,33]. The EBV studies did not test other TLR ligands, whereas Haas et al. also found an effect of TLR7 (but not TLR3) ligands on MHV68 reactivation in B cells [19, 31,32,33]. Seemingly in contrast with these results, Doyle et al. reported that TLR3 and TLR4 activation reduces MHV68 replication after de novo infection in bone marrow macrophages, whereas TLR9 activation in these cells has no effect [34]. However, the reported differences are most likely due to the expression levels of different TLRs and/or the downstream signaling that they elicit in the different cell types, as in macrophages TLR3/4 but not TLR9 stimulate type I IFN signaling [34]. In the case of KSHV, there may also be differences in the activity and role of TLRs depending on cell type. TLR4 activation reduces replication in endothelial cells infected de novo [24], while activation of TLR3 or TLR5 reduces spontaneous reactivation in PEL cells [35]. In addition to cytokine-based anti-viral responses, stimulation of TLR3 and 9 may also elicit another time of protective response, cell death, in latently EBV-infected cells, including some Burkitt's lymphoma cell lines and NPC cells [36, 37]. In turn, EBV may counteract this pathway by inducing high levels of cellular inhibitor of apoptosis 2 (cIAP2) in some NPC cells, which protects them from TLR3-induced apoptosis [38]. While all these studies show a protective effect of TLR signaling, some studies suggest that TLR activation can actually increase γ-herpesvirus reactivation, which will be more extensively discussed in a later section.
If signaling from TLRs blocks γ-herpesvirus infection, it stands to reason that infection itself may modulate expression of these receptors. There are reports of both increase [15, 21, 39,40,41] and reduction of TLR expression and/or signaling [24, 39, 42,43,44,45,46] after infection with KSHV, EBV and MHV68 (Table 1). The direction of the detected changes depends on the virus, the cell type and the TLR studied. There are some discrepancies that are again likely to be linked to the normal function of the TLR and its ability to exert anti-viral activity in the specific cell type. Only a couple of the studies looked at more than one TLR in the same cells [39, 42, 45], so it is difficult to compare across studies. Moreover, multiple transformed B cells lines are used for KSHV and EBV studies, further complicating the picture. One consistent observation is the downregulation of TLR9 by EBV in B cells [39, 44, 45] and the reduction of signaling from multiple TLRs during MHV68 infection of macrophages and conventional dendritic cells [42, 43]. The effect of EBV on TLR9 is also consistent with the fact that activation of this TLR reduces EBV replication [21, 31,32,33]. Reports of reduction in TLR expression and/or signaling by γ-herpesviruses are also generally consistent with the poor responses of many cells to these viruses [42, 43], and suggest that these viruses have evolved evasion mechanisms to deal with TLR activation. Indeed, several viral proteins have been implicated in inhibition of TLR signaling: for KSHV, the master lytic regulator ORF50/RTA [42, 47,48,49], the virus interferon regulatory factor-like (vIRF) proteins K9/vIRF1 [50], K11/vIRF2 [50], K10.5/vIRF3 [42], the viral macrophage inflammatory protein III K4.2 [42], the viral thymidine kinase ORF21 [42], the regulators of viral gene expression ORF31 [42] and ORF57/MTA [51] and the KSHV microRNAs, particularly miR-K5 and miR-K9 [52]; for EBV, the non-coding EBER RNAs [53], the latent protein LMP1 [44], the deubiquitinase BPLF1 [54], and the host shutoff protein BGLF5 [45, 55]. These proteins and RNAs act through a variety of mechanisms. Some may alter the levels and localization of TLRs [21, 42, 45, 55] or of downstream signaling molecules like MyD88 and interleukin 1 receptor-associated kinase 1 (IRAK1) [47,48,49, 52]. Others may inhibit signal transduction downstream of TLR, for example through deubiquitination of signaling proteins [54]. Of note, some of the genes in the list above have homologs across the γ-herpesviruses (the regulators of gene expression ORF50/RTA/BRLF1, ORF57/MTA/BMLF1/SM, and ORF31/BDLF4, the viral thymidine kinase ORF21/vTK/BXLF1, the host shutoff protein ORF37/SOX/BGLF5, and the deubiquitinase ORF64/BPLF1). While these genes share other functions across the viruses, they were only identified in one of the viruses as TLR inhibitors. This could represent a different virus-specific function, or may simply be a limitation of the current studies. For example, to my knowledge no systematic screen of EBV or MHV68 proteins for TLR inhibition has yet been published, precluding a direct comparison with the KSHV results [42]. Lastly, in addition to these active mechanisms of TLR inhibition, Pezda et al. suggested that the paucity of CpG sequences in the MHV68 genome may also be responsible for reducing the TLR9 responsivity, as it reduces the viral DNA sequences that TLR9 can recognize [43]. Nonetheless, this and other studies have also reported TLR9-dependent responses to MHV68, particularly in plasmacytoid dendritic cells [16, 18, 43], potentially because there is less viral replication in these cells and thus less expression of TLR inhibiting factors [43].
Interestingly, a recent study reports an even more complicated interaction between MHV68 and TLR signaling, whereby MHV68 takes advantage of TLR3 signaling to evade other immune responses. Shen et al. found that in MHV68-infected bone marrow-derived macrophages, TLR3 responses result in increased SOCS1 expression, which protects MHV68 from the anti-viral effects of IFN-γ treatment [56]. Along similar lines, TLR activation in EBV infected monocytes induces programmed death-ligand 1 (PD-L1) expression [57]. As PD-L1 reduces susceptibility to killing by cytotoxic T cells, it may protect the EBV-infected monocytes [57].
While collectively the reviewed studies point to a role for TLRs in the host protective response to γ-herpesviruses, the exact effects reported differ among the viruses and in some cases in studies using the same viruses. Since the pattern of TLR expression changes depending on the cell type and in some cases the signals elicited by TLR activation are also different, many of the apparent discrepancies are likely due to differences in the experimental setup. Discrepancies in MHV68 mouse studies are more puzzling but may be at least in part due to the choice of route of infection and inoculum size. Despite the remaining questions, it is clear that multiple TLRs protect humans and mice against γ-herpesviruses, acting both in the infected cells and of the innate immune cells that respond to the infection. Further studies, particularly systematic comparisons of the same TLR in different cell types and different TLRs in the same cell type, are needed to fully dissect the contributions of TLRs in protective responses to γ-herpesviruses.
TLR signaling as a trigger for lytic reactivation of γ-herpesviruses
In infected individuals or model organisms, EBV, KSHV and MHV68 undergo recurrent reactivation to the lytic cycle. This process has been linked to tumor development [1, 58, 59]. The cues that stimulate reactivation are only partially known, but they are generally thought to encompass many signals that trigger the death of the infected cells. The viruses are thought to have evolved to detect conditions that will lead to the death of the latently infected cells, and to respond by re-entering the lytic cycle, so that newly formed virions can infect new cells and the virus can continue to propagate. Interestingly, several studies have suggested that TLR activation can constitute a signal that triggers lytic replication in KSHV, EBV and MHV68 (Table 1). Indeed bacterial products were shown several years ago to induce lytic reactivation of KSHV in cell culture and MHV68 in an ex vivo setting, likely by stimulating TLRs [60, 61]. A recent study suggests that production of reactive oxygen species downstream of TLR2 may mediate this effect in the oral cavity following Staphyloccocus aureus infections [62]. Gargano et al. also showed that well-characterized ligands for TLR3, 4, 5 and 9 can induce MHV68 reactivation from latently infected B cells in culture, in explanted splenocytes, and even in vivo [63]. This effect did not extend to other TLRs despite similar downstream signaling. Lytic infection is stimulated after TLR stimulation because the treatment induces activation and proliferation of the B cells [63]. This effect is similar to that of B cell receptor ligation, which also induces MHV68 and EBV reactivation [61, 64]. Interestingly, in mice TLR-induced reactivation leads to an increase in the population of latently MHV68-infected cells [63]. The authors attributed this increase to increased viral production and seeding of new infections, and speculated that this may be a way in which the latent reservoir is maintained in the presence of heterologous infections [63]. However, a later study suggested that the MHV68 latent reservoir could be expanded after TLR9 stimulation also in the absence of active replication [65]. In KSHV-infected PEL cells, stimulation of the TLR7/8 with single-stranded polyU and other artificial ligands or vesicular stomatitis virus infection induces lytic reactivation [35]. Although multiple other TLRs are expressed in PEL cells, this study did not detect significant increases in lytic reactivation after activation of other TLRs [35]. Nonetheless, another group found that TLR3 activation directly increases RTA expression in a transfection setting [66], suggesting other TLRs may induce KSHV lytic reactivation in other conditions. In the case of EBV, virus reactivation and EBV-linked hepatitis were reported in a patient with infection with the syphilis pathogen Treponema pallidum, a known inducer of TLR2 [67]. In addition, stimulation of multiple TLRs can induce expression of the lytic regulator ZEBRA in EBV latently infected cell lines [68]. Collectively, these studies underscore the multiplicity of functions that TLR signaling can have during γ-herpesvirus infection, including a role in promoting lytic replication. As TLR signaling can act as an activating stimulus for B cell, this positive effect on reactivation may be particularly pronounced in B cells, where reactivation is also coupled to other activating stimuli.
TLR signaling and inflammation in connection to cancer and other diseases caused by EBV and KSHV
Although much of the research on TLR and γ-herpesviruses has focused on their antiviral roles, another aspect of TLR signaling is the regulation of inflammation. Inflammation has been connected to disease progression and cancer development in both EBV and KSHV infections. Moreover, TLRs regulate B cell responses, proliferation and antibody secretion [9,10,11,12], which means that TLR stimulation could promote viral persistence and expansion of infected cells. Indeed, TLR9 inducing cues have been used to improve immortalization of EBV infected B lymphocytes in cell culture [69]. Moreover, in experimental de novo EBV infections treatment with TLR ligands increased EBV-driven B cell activation and proliferation [70, 71]. Some reports also suggest that EBV-transformed B cells express more TLR9 and TLR10 [72], although other reports found the opposite [39]. The EBV oncogenes LMP1 and LMP2A can also increase expression and responses of subset of TLRs, which provides a survival advantage to B cells and NPC cells, although these studies were done using overexpression and not EBV infection [73, 74]. In the context of NPC, the EBERs may induce TLR3 expression and cytokine-driven responses to promote tumorigenesis, as TLR3 knockdown reduces formation of NPC tumors in nude mice [75]. However, the relationship between TLR signaling and tumorigenesis may be more complex than these studies suggest. For example, a study of Finnish patients with NPC found that the low levels of TLR7 and 9 were correlated with worse disease outcomes, while lower levels of TLR5 were correlated with better outcomes [76].
Data on TLR and tumorigenesis in KSHV is limited. In a model of KSHV transformation using rodent mesenchymal stem cells, TLR4 activity was linked to increased proliferation, cytokine secretion and tumorigenesis in mouse xenografts [77]. Moreover, these KSHV-immortalized cells had increased TLR4 and MyD88 levels, suggesting the virus actively promotes their induction in the process of tumorigenesis [77]. Another potential connection between TLR signaling and KSHV tumors was identified in PEL cells, where Yang et al. reported that interleukin 1 receptor-associated kinase 1 (IRAK1), which acts downstream of TLRs, promotes PEL cell survival and is commonly mutated in PEL samples [78]. Moreover, MyD88/IRAK signaling is constitutively active in PEL cells [79].
EBV infection may also contribute to the development of autoimmune diseases [4]. The effect of EBV infection in autoimmunity has been linked to increased IFN responses downstream of TLR activation in some studies of scleroderma [46, 80], myasthenia gravis [81] and lupus [82]. In particular, TLR7 activation in EBV-transformed B cells may potentiate both LMP1 expression and responses to agonists of other TLRs, amplifying inflammation and potentially contributing to pathology in lupus patients [82].
Many of the studies on cancer and autoimmune disease modulation by TLR in the context of γ-herpesviruses show that these effects are mediated by increased TLR levels or signaling. This may seem paradoxical, since increased TLR activation would be expected to help clear infections. A potential explanation for these observations is that while activation of TLR early in γ-herpesvirus infection of a new host or during lytic reactivation has an antiviral function (see earlier section), activation of this pathway once latency has been established may promote disease progression. This could occur as a result of inflammatory cytokine expression, or because reactivation is blocked, favoring persistence of the latently infected cells.
Genetic associations between TLR polymorphisms, γ-herpesvirus infection and γ-herpesvirus-linked diseases
Several studies have identified polymorphisms in TLRs that modify susceptibility to immune and infectious diseases [83, 84]. In the context of γ-herpesviruses, there have been positive and negative findings on the connection between TLR polymorphisms and susceptibility to EBV infection and disease. In general, single-nucleotide polymorphisms that reduce TLR activity or expression were found to increase infection and/or disease risk in these studies. Polymorphisms in the TLR9 coding region or promoter have been linked to metrics of EBV infection and disease in various patient groups. These include risk of EBV infection, levels of EBV in the blood, development of infectious mononucleosis, development of oral cancers, NPC tumor size and survival of NPC patients [85,86,87,88]. Polymorphisms in the TLR4 coding region and 3' UTR have also been reported to modify risk of infectious mononucleosis, NPC and oral cancers [85, 88, 89]. In addition, in one study polymorphisms in TLR2 affected the levels of EBV DNA in the blood of infectious mononucleosis patients and the development of specific symptoms [85]. In contrast, a study of Northern Chinese gastric carcinoma patients found no connection between known polymorphisms in TLR2, 3 and 9 and susceptibility to EBV-associated gastric carcinoma [90].
Less in known about the connection of TLR polymorphisms and KSHV infection and diseases. Two studies investigated the TLR4 Asp299Gly polymorphism and found it is more common in HIV-positive patients with MCD than ones with KS or cancers unrelated to KSHV [24], and it is also more frequent in patients of African descent [91]. MCD development may be linked to poorer control of KSHV replication, as these patients also had higher viremia [24, 91]. This is consistent with the fact that the Asp299Gly sequence change results in lower level of TLR4 at the plasma membrane and lower LPS-triggered IFN induction [24, 91]. However, a recent genome-wide association study for both EBV and KSHV infection in an African cohort did not identify any TLR genes among their hits [92].
EBV, KSHV and MHV68 all interact with TLRs during the course of infection, particularly as they infect cells of the immune system that express multiple TLRs. Multiple components of these viruses appear to be recognized by different TLRs, including both proteins and nucleic acids (Fig. 2). As illustrated in this review, there is extensive evidence that TLRs can act in anti-viral fashion against γ-herpesviruses. However, TLR activation can also control the latent-lytic switch in B cells, acting to promote viral replication. Moreover, TLR activity may be connected to tumorigenesis and development of autoimmune diseases in response to γ-herpesvirus infection, because of the key role of TLRs in modulating inflammatory responses. These findings suggest that modulation of TLR signaling could be used as a potential therapeutic intervention for EBV or KSHV, perhaps combined with other treatments. However, leveraging the role of TLR will require a much more precise and comprehensive understanding of the role of specific key TLRs in the dynamics of infection and disease. Currently, there are inconsistencies in the literature that need to be resolved within the study of each of the three viruses reviewed here. Many of these inconsistencies may stem from complex biology of TLRs and the multiple functions these receptors have in different cell types. However, this remains to be thoroughly tested by comparing the effects of different TLRs in different cell types in a systematic fashion. In addition, there are contradicting results in the in vivo infection results with MHV68. The in vivo MHV68 infection system is currently the best small animal model for γ-herpesviruses, and the only one available to examine the effect of TLRs at different stages of infection in a whole organism. A more systematic comparison of TLR activation and function at different inoculum doses would begin to address potential confounds in this system. Additional studies like these may point to the potential usefulness of TLR agonists and antagonists for anti-viral and/or anti-tumor therapies.
Table 1 Summary of studies on TLR activity during γ-herpesvirus infection
cGAS:
Cyclic GMP-AMP synthetase
cIAP2:
Cellular inhibitor of apoptosis 2
EBERs:
Epstein–Barr virus-encoded small RNAs
IL-6:
Interleukin 6
IRAK1:
Interleukin 1 receptor-associated kinase 1
IRF:
Interferon regulatory factor
KICS:
Kaposi's sarcoma-associated herpesvirus-associated inflammatory cytokine syndrome
Kaposi's sarcoma
KSHV:
Kaposi's sarcoma-associated herpesvirus
LMP:
Latent membrane protein
MCD:
Multicentric Castleman Disease
MHV68:
Murine herpesvirus 68
MTA:
mRNA transcript accumulation
MyD88:
Myeloid differentiation primary response 88
NPC:
Nasopharyngeal carcinoma
NF-κB:
Nuclear factor κ-light-chain-enhancer of activated B cells
pDC:
Plasmacytoid dendritic cells
PD-L1:
Programmed death-ligand 1
PAMP:
Pathogen-associated molecular pattern
PEL:
Primary effusion lymphoma
poly(I:C):
polyinosinic:polycytidylic acid
RIG-I:
Retinoic acid-inducible gene I
Replication and transcription activator
Sspoly(U):
Single-stranded polyuridylic acid
TIR domain:
Toll/interleukin 1 receptor domain
TIRAP:
Toll/Interleukin-1 receptor domain-containing adapter protein
TLR:
Toll-like receptor
TRAM:
TRIF-related adaptor molecule
TRIF:
TIR-domain-containing adapter protein inducing interferon-β
vIRF:
Viral interferon regulatory factor
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I apologize for not referencing all relevant studies because of length limitations.
Work on KSHV in the Gaglia laboratory is supported by American Cancer Society Research Scholar Grant 131320-RSG-17–189-01-MPC.
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, 02111, USA
Marta Maria Gaglia
MMG – writing. The author read and approved the final manuscript.
Correspondence to Marta Maria Gaglia.
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Gaglia, M.M. Anti-viral and pro-inflammatory functions of Toll-like receptors during gamma-herpesvirus infections. Virol J 18, 218 (2021). https://doi.org/10.1186/s12985-021-01678-x
DOI: https://doi.org/10.1186/s12985-021-01678-x
KSHV
HHV-8
MHV68
Gammaherpesvirus
Immune evasion


text:
Our Samsung Galaxy S10+ Review
Thread: Our Samsung Galaxy S10+ Review
Smartphones have been maturing for over a decade now. A while back we reached a point where even phone enthusiasts stopped replacing their phone yearly. The difference between a flagship and the previous year's is growing smaller and smaller.
Samsung had their work cutout with their 2019 flagship; the S10+. Don't forget that these days anyone can make an Android phone. Android itself has matured and thus has become less interesting. Couple that with the fact that Samsung phones usually command a price premium and prices in general across the industry have been rising and you can see how their job gets even harder.
Note I've been a bit backed up recently which has slowed down the pace at which I review phones.`
Here are the S10+'s key features:
Screen cut-out with dual front-facing cameras
In-screen fingerprint reader
3 rear cameras; regular, zoom and now ultra wide angle
128GB base storage with available 512GB and 1TB built-in storage options
huge 4100mAh battery with the ability to wirelessly charge other devices
Available ceramic back (instead of glass)
The Galaxy S line, which used to consist of a regular S and a larger S+ model now includes a 3rd S10e model. They're all quite similar and only differ in screen size, battery size, RAM/storage configuration number of included cameras and type of fingerprint reader.
While most other flagships including the regular S10+ have glass sandwiching a metal frame, this S10+ is the ceramic edition which has a, wait a moment - a ceramic back which is available in either white or black whereas the "regular" non-ceramic S10's come in shimmery finishes.
While I'm not really strongly opinionated about what colour my phone is, I have to admit the white is quite understated in a good way - there's something really "unSamsung" about the finish.
What's the point? Think of it this way; what's less likely to scratch? An eraser or a glass cup? The cup of course because it's harder than the eraser. Ceramic is denser and harder than glass so a ceramic back is less likely to get scratched.
That said, if you were to drop the eraser and the glass cup which one is more likely to shatter? The cup will shatter because it's harder and more brittle. Since a ceramic back is more brittle it will shatter more easily than a glass back.
Still, there are videos of people dropping regular and ceramic S10+'s and it's hard to say which one is truly more durable.
The real benefit of the ceramic version is that it's heftier so it feels fancier and is less common and thus more interesting and special than glass. Lets not forget that the ceramic models are only available with more RAM and storage than the regular non-ceramic ones so there's that too. Just remember that the front is still glass.
The S10+ is very tricky to use with one hand. Whenever I try to type, the palm of my hand touches the side of the screen and I end up hitting the letter P or the backspace key. That plus the small bezels means I'm unintentionally touching the screen most times when I pick it up. This would be okay if the S10+ was really good at knowing when you're touching the screen accidentally but sadly they still haven't figured this out.
Whenever this happens, I wonder what the benefits, besides looking cool a curved screen brings. Of course, I've been saying this for years now about Samsung curved display so maybe it's just me.
With all that said, I get the narrow bezels. Some designs are not all about function over form. A phone with thick bezels looks cheap and clunky next to one with skinnier bezels. The same thing can be said about the curved display. They're like a pair of high heels; they're not as functional as a pair of regular shoes but some people like them for how they look.
Still, I have to admit, once you put one of these phones in a thick case you end up giving it bezels which makes it more pleasant to use.
There's a power button on the right side along with a volume and a Bixby button on the left. If the Bixby voice assistant isn't your thing, you can reconfigure it to launch your favorite app.
Despite the slim bezels I'm very happy that there's a front facing speaker at the top. Like the S9 there's a second speaker at the bottom. You'll also find 3.5mm headphone jack and USB Type-C connectors at the bottom.
On the back are a trio of cameras along with some other sensors. Unlike the S9, the fingerprint reader has been relocated under the screen in front.
Samsung bucks the trend of housing the front facing camera(s) in a notch. Instead, there are a pair of front-facing cameras located in a cut-out at the top right of the screen. The screen actually wraps around the hole. Samsung uses the pixels around the hole for animations when you're using the biometrics. The cut-out is flush with the screen. Thankfully Samsung hasn't named this feature S-hole.
Here's my take, I don't mind notches since I mostly look at the top of the screen to check out the network signal the battery level and the time. Having notifications there can be useful but often I find they just make the top look more cluttered. So, I don't mind that a notch can take up a bit of screen real estate. I have the same feelings for a cut-out.
They're also symmetrical when you're holding the phone in portrait mode (which is most of the time) so I they don't bother me from an aesthetic perspective.
That's the big difference between a notch and the S10+'s cut-out - the S10+'s is asymmetrical, it just doesn't blend in. Eventually the novelty of it wears out and then it just sticks out because your notification area ends about ⅘ of the way across the top while the clock isn't in the top right corner anymore.
I think the fact that it's off-center and isn't at the edge of the screen really draws attention to it in a bad way. I also notice it because I tend to look at the top right of the screen when I'm pulling down the notification screen.
The screen itself looks fantastic; the slim bezels coupled with the curved edges makes a really great first impression.
When display 100% white in Chrome, I measured a maximum brightness of around 350 cd/m2 with the screen in vivid mode which isn't bad. You might run into problems when it's really sunny outside.
Putting the screen in natural color mode reduces the maximum brightness about 5%.
As far as color goes, compared to the iPhone's more calibrated looking whites which are a tad warmer - the S10's are much whiter without being cold. As far as I'm concerned both are good approaches.
It has very nice accurate color that's never obnoxious looking.
Viewing angles are excellent but not good enough that you don't notice that there's something off about the curved parts of the display. That said, you get used to it.
As I mentioned earlier, the screen has a fingerprint reader built-in it. While it's extremely cool feature, it's slow and half the time it doesn't work.
Fortunately the front-facing camera allows a second way to unlock the S10+. It works much more quickly and is more reliable than the fingerprint reader. What usually happens is I put my thumb on the fingerprint reader but it's actually the facial recognition that unlocks the phone.
To test the facial recognition I tried it with a baseball cap, large sunglasses than then both and compared it with the S9+ and XS Max. All 3 phones were able to recognize my face when I wore a baseball cap and when I took off my glasses. The S9+ and S10+ failed to recognize me when I wore large sunglasses.
For best results you should setup both fingerprint and facial unlock so that both get a chance to recognize you.
In out-right terms, the biometrics on the S10+ aren't as reliable as on the S9+ but they still work well enough that I wouldn't complain about them that loudly.
You know what's funny? I actually wrote this entire section and was going to publish it when I realized I didn't mention the screen resolution. It used to be the screen resolution was one of the first things I'd mention pixel density has reached the point where it just isn't terribly interesting.
Anyways, the S10+ has a resolution of 3040×1440. Flagships have had 1440 pixel displays for a while now but they've slowly been getting taller. Like the S9+, it has an option to process the graphics at 1080 internally to help save battery life and like on the S9+, I can't tell any difference in image quality when this setting is on - even when I look real close.
There's an even lower 720p setting but there is a difference so I recommend staying at 1080.
There are 3 cameras on the back with the following lenses; super wide angle, regular and portrait. I tested all phones with the HDR setting on.
I compared it to the S9+, iPhone XS Max, Pixel 3 and the P30 Pro.
Compared to the iPhone XS Max and Pixel 3 the S10+ photos tend to be a little bit more saturated (at the expense of color accuracy) a tad more processed looking due to stronger noise reduction and sharpening but it's pretty subtle. It's the sort of thing you have to zoom in to really notice. I found it also tended to expose scenes a tiny bit brighter.
In the low light scene with night mode activated it got the white balance wrong - it's a bit too warm as you can see by the reddish carpet
The real story here is the inclusion of an ultra-wide angle camera. While UWA's have been found LG flaghips for a few years now, having a UWA and a zoomed in camera along with the regular one is still not always a standard feature.
Compared to the Huawei P30 Pro the S10+'s UWA camera is noticeably wider. It captures a bit more on the sides. The S10+ also takes much cleaner looking UWA photos plus it's much better indoors. The difference is pretty drastic when you're shooting video.
If you're shooting video be mindful that the UWA camera can't record video in 4K - instead it records video at up to 1080P. This wouldn't be a big deal to me except that there's no option to use the UWA if you've set the video to record at 4K. Initially I thought the UWA couldn't record video at all until I played around with the settings. It's mostly a convenience thing; If you want the flexibility to shoot video with the UWA quickly, you need to leave the video at 1080P.
There are 2 front-facing cameras. You get a normal wide-ish angle selfie camera along with a slightly more zoomed in one that's FOV is similar to one found on an iPhone. The difference is subtle but that's what makes it so great; I actually prefer a more zoomed in one if it's just me while the wider angle one is better if I want more than one person in the frame.
The camera app has a lot of different modes and options this can be a good thing but somehow on the S10+ it just feels needlessly complex and cluttered.
A couple of months ago Samsung actually ditched their TouchWiz Android user interface in favor of their new One UI. Is it a case of same wine, different bottle? Actually no, it's a pretty big difference and not just a rebranding.
The first thing I noticed is that there is less duplication of preloaded apps. Basically with the exception of Gmail, Chrome and Google Play, the S10+ only comes with alternate versions of the usual apps preloaded Android apps.
Here's something interesting; the S10+ doesn't come with a dedicated music app. It doesn't come with Play Music or a Samsung music program or Spotify.
Instead of Google Drive you get Microsoft OneDrive/Office Mobile, Samsung's Gallery app instead of photos, etc. Anyways you can always download whatever app you want to use and uninstall a lot of the included ones.
Another thing I noticed is that the One UI doesn't push you as hard to sign up for a Samsung ID. If you don't want to signup or login you won't be bothered much.
Under it all is Android 9.0 Pie. The One UI doesn't use the Pie task switcher where you swipe up to switch apps like on a Pixel. Instead it uses the older task switcher/home button/back buttons along the bottom.
I liked the One UI though I must say once I got my apps launched I spent very little time interacting with it.
Despite the smaller bezels the S10+ has very impressive speakers. Initially I thought they were less meaty sounding than the speakers on the S9+ and iPhone XS Max but after listening more I find them much clearer and less processed sounding. I think they're the best pair of speakers on any phone I've tried and actually one of the best things about the S10+.
The curved screen and minimal bezels makes it tiring to hold for long periods of time. A thick case helps to fix this.
Samsung included a 3.5mm headphone jack at the bottom.
The S10+ is available with 128, 512GB or 1TB of built-in storage which can be augmented with MicroSD cards. We've come a long way, I remember the original Samsung Galaxy came with 8GB of built-in storage.
Inside is Qualcomm's Snapdragon 855 SoC which feels a tad faster than the 845. Depending on the configuration the S10+ either comes with 8 or 12GB of RAM. 8GB is a good amount and should be for the next while so I doubt you'll find any difference between it and 12GB.
To test battery life, I put Prime Video on the S10+, downloaded a season of the Grand Tour in good quality and set it to play for a few hours. I didn't run the test from full to empty because most phones will activate a low power mode when the battery is low plus. I also ran the test when the battery was no higher than 99% full.
I wrote down the starting and ending percentage and time and then worked out how many minutes on average it took for the meter to drop one percentage. I used a colorimeter to set each phone's screen brightness as close to 100 nits when displaying a 100% bright background in Chrome as I could (usually within 10%).
The S10+ would last around 7.5 mins in WQHD+ mode before the battery would drop a percentage. Switching to FHD+ mode would take it to around 8 mins. The Huawei P30 Pro get around 11 mins in FHD+ mode (it has a lower resolution display that isn't WQHD+).
In the end one of the S10+ 's signature features, the in-screen fingerprint reader is a bit of a dud in that it's noticeably slower than the facial recognition. It's fast becoming a vestigial feature that they might as well omit entirely. That said, the facial recognition, while not quite as reliable as the S9+ works well enough that overall I don't have serious complaints about the S10+ 's biometrics.
The extra camera on the back allows for a greater deal of flexibility with your taking pictures. You probably won't use the ultra wide-angle camera that frequently but when you do need it, there's no replacement for it.
The 4100mAh battery is a boon for heavy users. While there's always gonna be some users who need more, 4100mAh gets you that much further between charges.
In a market full of notched displays, the screen cut-out is very cool. That said, after the novelty wears off, I don't think it's a better solution than the notch - at best it's just different take.
While we've reached peak smartphone, the S10+ moves the needle enough to keep things interesting.
Flexibility of 3 cameras
Camera image quality
Large battery
Difficult to hold
Fingerprint reader doesn't work
Cut-out is ugly
My addition to the review:
https://www.howardforums.com/showthr...-grows-Venting
Colecaz
Galaxy S10+, Moto X4, Moto G5 Plus, Blu R1HD, IPhone 6s, Defective Umidigi Power
VerizonPP, Red Pocket A,T,V
Having the screen cutout off to one side lets the rest of the top be used for notification space instead of splitting the line like notch phones. It keeps the notification area together and keeps notification icons from being obscured by the notch. And the three lens for the camera are extraordinarily convenient for framing shots.
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redpajama_set_name: RedPajamaCommonCrawl


When tire inflation pressures are maintained within the specified limits (par. 6-8) the tire will make a full contact across the entire width of tread, thereby distributing the wear evenly over the total surface of the entire tread area.
When the front wheels have an excessive amount of either toe-in or toe-out, the tires are actually dragged sideways when they travel straight down the road, and cross wear or scraping action takes place, rapidly wearing away the tread of tires. This cross wear condition will usually produce a tapered or feathered edge on the ribs of the tire tread. See figure 6-11.
In most cases this can be detected by rubbing the hand across the tire tread.
Heel and toe wear is not so prevalent on the rear tires because of the propelling action which creates a counteracting force which wears the opposite end of the tread block. These two stresses on the rear tires wear the tread blocks in opposite directions and result in more even wear, while on the front tires the braking stress is the only one which is effective. This may be counteracted by interchanging tires (par. 6-8).
Wabble or runout of a tire, either front or rear, due to bent wheel or to tire being improperly mounted will cause uneven wear. The runout of wheel and tire when rotated should not exceed 1;8″ at side of tire.
Measurement of the trim dimension with springs installed is the only practical method of checking chassis springs that are reported . to be weak. See paragraph 6-17 for checking trim dimension of front springs and paragraph 6-20 for rear springs. The strength of chassis springs cannot be determined by measurement of the free length when removed from car, because springs of equal strength under rated load may vary considerably in length when not loaded.
Before attempting to test shock absorbers make sure that all attaching bolts are tight and that the units are filled with specified fluid (par. 6-23). Tires should be uniformly inflated to specified pressure (par. 6-8). The chassis should be well lubricated to make sure that suspension parts are free moving.
Lack of resistance to movement of the arm indicates air in shock absorber, internal leakage due to wear, or that the valve is held open by dirt. Excessive resistance indicates that bleeder hole in valve is plugged with dirt. Air may be worked out of a shock absorber by removing filler cap and moving the arm up and down through full range and adding fluid as described in paragraph 6-23. If a valve is plugged or held open by dirt, or internal leakage due to wear exists, the shock absorber must be removed for replacement of valve or shock absorber assembly (par. 6-24).
Steering action is dependent upon the chassis suspension members as well as the steering gear assembly and tie rods. Improper steering actions which are most likely to be caused by chassis suspension are covered in this paragraph, while conditions most likely to be caused by the steering gear assembly or tie rods are covered in paragraph 7-3.
Brakes dragging on one side (par. 8-7) .
( 5) Incorrect or uneven caster or camber (par. 6-30).
Shock absorbers inoperative or leaking (par. 6-10). Wrong valving (par. 6-1).


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Málaga, Spain – arts & fun in the sun
Posted bythewriterontheroad March 17, 2020 March 18, 2020 Posted inBlog
Some travel guides bypass Malaga, an important seaport and the largest city in the southern part of the Andalusian region of Spain, on the Costa del Sol (coast of the sun). A prominent travel writer in the USA even advises people to skip the 'overbuilt and overcrowded' Costa del Sol altogether.
The problem with that is, if you skip the Costa del Sol, overcrowded in some spots as it may be (Torremolinos beach comes to mind), you will miss the beautiful Málaga, one of the most welcoming and happening cities in Andalusia and in Spain. After a few days there, I found Málaga more real and more authentic than many of the better-known tourist destinations in Spain. Málaga is a lively regional center, a place where people actually live and work, rather than just visit on vacation. And it has a lot to offer.
Why go to Málaga:
The friendly people
The arts scene
The museums
The flamenco
The Mediterranean beaches
The nightlife
The prices
A charming downtown
My friend Margo and I got to Málaga at the end of a bright day in February of 2020. The sun was so strong, despite being winter in Spain, that even my very dark sunglasses could not keep the light out of my eyes.
On the taxi to our hotel we passed by long stretches of nondescript 1970's high rises, the kind that we see in the outskirts of every modern city in the world – not pretty. I was starting to think that Málaga perhaps didn't deserve a visit, after all.
Our hotel was nice, but on a charmless and modern city block. We left our suitcases in the room, got a city map at the front desk, and set out to explore the city. I was not expecting much, at that point, but as soon as we crossed River Guadalmedina, and walked towards the center of town, things changed drastically: we had entered a much older area, with narrow cobblestoned streets and beautiful buildings. That was the Casco Antiguo (old quarter), and that's where we found the beautiful, friendly and fun Málaga.
Larios Street
Málaga is mostly flat, and walking or riding a bike are great ways to explore it. We walked a few blocks until we got to Plaza de la Constitución (Constitution Square), the heart of the city's old quarter. Surrounded by coffee shops, banks, boutiques and confeitarias (tea houses), the plaza was buzzing with people at the end of a Sunday, and the atmosphere was happy and relaxed: people smiling, children having ice cream with their parents, older and well-dressed couples strolling leisurely. It was the paseo time, the daily ritual when Spanish people take a break and walk the streets – usually the same streets, downtown – with family and friends. I find it a refreshing ritual.
Constitution Square is also the place to have Málaga-style coffee. In Málaga, each coffee has a different name, depending on the amount of coffee served. For example, a 'cafe mitad' is half coffee and half milk, a 'sombra' is three quarters milk and one quarter coffee. There are at least nine ways to order coffee in Málaga. Whichever you pick, try a 'churro' with it. They are rich in calories, sure, but simply delicious and made to perfection in Málaga.
Downtown houses
We followed the crowd and moved on to Calle Larios (Larios Street), Málaga's main pedestrian shopping street, where the most exclusive shops, cafeterias and ice cream parlors are located. We found Casa Mira easily; it's home to Málaga's most famous homemade ice cream, known internationally for its local flavors. The place was crowded with people waiting in line, but I'm glad we joined them: the ice cream was so delicious it certainly deserved the wait. Next to Casa Mira is Lepanto, a classy shop favored by local Malaguenos (as the natives are called), where staff in uniform will inform you about a variety of pastries, cakes and sweets in all shapes and tastes.
The mighty Mediterranean
View from the old port
At the end of Larios Street we could see the Mediterranean- shining bright under the sun – and the port of Málaga, with ships big and small on the horizon. After a brief stop at the tourism office to get maps and information on the city's main attractions (some of which I used in this post), we crossed a beautiful park with many tall trees – Paseo Park – before joining a sidewalk by the water, where locals were enjoying the day's last rays of sun and tourists were taking pictures.
Palmeral de las Sorpresas
Called the Paseo de la Farola, or Muelle 1, it ends in the historic La Farola, a lighthouse that marks the entrance of the port and is the symbol of Málaga. Muele 1 has shopping centers, boutiques and bars with tables by the water. Its continuation, Muelle 2, is a boulevard named Palmeral de las Sorpresas (palm grove of surprises), built in 2011 under a metal 'palm tree' frame.
Both Muelles form a very pleasant leisure center. They are part of a popular modern project, started in 1998, to remodel the port's derelict docks, when their use declined. After its completion, a total of 2 million square feet of new urban area were added to the city, integrating the old port and the sea as vital parts of Málaga. It's where luxury cruise ships depart for tours of the bay, and some mega yachts are docked. No less than nine million people visited the complex in 2016.
Malaga's old port and the Alcazaba
Between the two Muelles there's a museum, Center Pompidou Málaga, the first international branch of the famous Pompidou Center of Paris. It's called El Cubo (the cube), because of its form. It opened in 2015 and has a permanent exhibition of major art works from the headquarters in Paris, including Francis Bacon, Georg Baselitz, Constantin Brancusi, Alexander Calder, Marc Chagall, Giorgio de Chirico and Pablo Picasso, who, by the way, was born in Málaga.
In 2016 Málaga had a population of 569,000 people, which makes it the second largest city of Andalusia – after Seville – and the sixth most populated in Spain. But Malaga holds a great advantage over the other five: it's in the sunny south of Spain, not far from Gibraltar and northern Africa. That means its climate is very mild, and its Mediterranean beaches can be enjoyed during most of the year. Not bad at all…
Water everywhere
Winters are not cold in Malaga – the thermometer never dips below 64 degrees Fahrenheit. Summers last from April to November; that's when temperatures can be around 93 degrees Fahrenheit. Fortunately, there's always the wind blowing from the sea, which makes the heat more manageable. Malaga has an average of about 300 days of sunshine, very little rain during the year, and is one of the few cities in Europe which is green all year round.
With a blessed climate – and a major international airport – Málaga has become the city of choice for northern Europeans getting away from harsh winters in their countries. Brits come in droves, either on vacation or to live year round, after retirement. Right after them are the French and the Germans. The number of resident foreign nationals has risen significantly recently.
Narrow and shady streets
The architecture reflects the styles of many centuries
A smart decision
Less than two decades ago, Malaga's authorities made a crucial decision: to invest massive amounts of money to transform the city into a cultural destination. The idea was to draw the kind of visitors that want more than just sunny beaches and great food, like those who flock to other destinations on the Costa del Sol. As a result, Málaga now has 28 museums, many art galleries, international art shows and festivals, and is firmly established as an international hub for the arts.
The 10 most-visited museums in Málaga:
The Museum of Málaga
The Picasso Museum
Th Picasso Birthplace Museum
The Carmen Thyssen Museum
The Contemporary Art Museum
The Pompidou Center Malaga (The Cube)
The Russian Museum
The Municipal Art Museum (MUPAM)
The Flamenco Art Museum
The Gibralfaro Interpretation Center
Picasso Museum
Picasso's hometown
Perhaps the most influential artist of the 20th century, Pablo Ruiz Picasso's full name was Pablo Diego José Francisco de Paula Juan Nepomuceno María de los Remedios Cipriano de la Santísima Trinidad Ruiz y Picasso! A long name for a great genious. He was born in 1881 in Málaga, where his father, Don Jose Ruyz y Blasco, was a painter who specialized in depictions of birds and other nature themes. For most of his life Ruiz was a professor of art at the School of Crafts in Málaga, and the curator of a local museum. Pablo Picasso's training under his father began before he was 10 years old.
Atelier of Picasso's father
On the year he turned 10, Pablo's family moved to La Coruna, in the north of Spain. He returned to Málaga with a friend a few times after that, but at nineteen he left the city and never returned. From that point on, Picasso embarked on a career that was marked by success in Barcelona, and subsequently in France, where he achieved international fame.
Museum Picasso-Málaga
Picasso's desire to offer his native city part of his works materialized through his daughter-in-law Christine and her son, Bernard Ruiz Picasso. Called the Collection, the donated works are now housed in a museum in the Palacio de los Condes de Buenavista, a beautiful Renaissance building that was once home to the Buenavista counts.
The works displayed in the many galleries of the museum relate to different phases of Picasso's artistic life, especially to his sense of origins and family. Interestingly, they are the ones Picasso kept for himself, or gave as a gift to his family, including the portrait of his sister Lola and the amazing 'Three Graces.'
Museum Carmen Thyssen
María del Carmen Rosario Soledad Cervera y Fernández de la Guerra, born in Barcelona in 1943 and popularly known as Tita, was Miss Spain in 1961. Her third husband (she was his fifth wife) was the legendary German baron Hans Heinrich Thyssen-Bornemisza, whose private art collection was one of the largest and most important in the world.
Upon the baron's death, in 2002, Tita (called by then Baroness Bornemisza) donated a big part of her husband's collection to Spain, a controversial decision at the time, as Germany thought the treasure should stay in the late baron's native country. Nevertheless, a big part of his collection is now in the Thyssen-Bornemisza Museum, in Madrid, and in the Carmen Thyssen Museum, in Málaga.
The Carmen Thyssen Museum in Málaga, inaugurated in March 2011, has a permanent collection of more than 200 works by 19th-century Spanish artists, especially Andalusian painters. The collection also features two Spanish masters of the 20th century, Joaquín Sorolla y Bastida and Romero de Torres. In addition to that, the museum has a very dynamic program of temporary exhibitions.
People love to go out
A 'handicapped' cathedral
Málaga's cathedral is monumental, like most cathedrals are in Spain – a predominantly Catholic country. But this one has a peculiar characteristic: it only has one tower. Although its construction started during the Gothic period (16th century), on the site of an old mosque from the Moorish period, the current building is of Renaissance style and is still unfinished. Funds ran out in 1782 and work was stopped, leaving the southern tower unbuilt. This led to the Cathedral's nickname of La Manquita, or 'one-armed lady'. It is indeed a peculiar site, when one faces its facade. But the interior is majestic and opulent.
La Manquita
Interior of the Cathedral
The Alcazaba and the Gibralfaro
The main sea port in Andalusia – and Spain – Málaga was for centuries under the rule of the Moors, Arab and Berber tribes from northern Africa who ruled what they called Al-Andalus for over 700 years, from the year 711 AD to 1492. The Moors were Muslims, and their exquisite legacy is seen everywhere in the city – from the architecture to the food, from literature to the vibrant colors of fabrics and decorations.
Roman columns and Moorish arches in the Alcazaba
The Alcazaba has many gardens and fountains
Malaga's bull ring seen from the Alcazaba
Nowhere is this influence more palpable than in the Alcazaba (fortress), Málaga's greatest monument. Built as a fortress in the 8th century, when Malaga's port was the main entrance to the Moorish kingdom, the Alcazaba was the residence of the local ruling emirs from 1057 to 1063. Centuries later, king Fernando and queen Isabel lived there as well, after conquering the city, in 1487. The Alcazaba has many beautiful buildings and gardens, and offers impressive views of the city. At its foot is the Roman Theater, built by the occupying Romans in the 1st century B.C. and now used as a theater for special public performances.
The Roman Theater
Roman ruins and the walls of the Alcazaba
Right above the Alcazaba, connected to it by a path easily conquered by foot, is the Castle of Gibralfaro. Built as a fortification by Abdemarran III from the existing ruins on top of the mountain – among them a Phoenician lighthouse called 'Yabal Faruh' by the Arabs – the fortress was extended in 1340 by Nazari King Yusuf I, to become a castle. Its main use, since Phoenician times, was as a coastal vantage point. The fortification now contains a small museum with all the 'new' defensive devices of the time, like the big flanking tower, the rampart perimeter adapted to the terrain by zigzag walls, and the angled gateway. On a clear day – like the day I visited – the Gibralfaro offers unlimited views of the city and the of the Mediterranean, and it's one of the best spots for picture taking in Malaga.
The Gibralfaro
Old city walls
Tapas & friendly people
Malaga has very lively nightlife. Even on weekdays, starting with the paseo at the end of the day, the streets of the town's center are bustling with people, restaurants and bars are full, and the fun goes on until late at night. Double that on weekends.
For our last night in the cit, Margo and I chose to have tapas for dinner. An Andalusian institution that is becoming more and more popular around the world, tapas in Malaga are served everywhere, with drinks.
With the friendly staff
People we had met in the city recommended a tapas bar called Casa Lola (Lola's House), which the concierge in our hotel confirmed as the best place for tapas in town. We later had to agree with our sources: the food was fresh, the variety of tapas huge, the price was great and the friendly service certainly was the best we encountered during our stay in Málaga. And that is no small accomplishment, in a city where people are exceptionally friendly and fun.
I liked Málaga. Unpretentious, open, friendly, beautiful and inexpensive. I intend to go back.
Granada, Spain – a place of dreams
Nerja, Spain – the Balcony of Europe
2 thoughts on "Málaga, Spain – arts & fun in the sun"
Lovely blog from Malaga – though I would say a couple of the bigger cities do look down at the med – like Barcelona.
thewriterontheroad says:
Yes, I know. But I love the Med, all things considered. Thanks for your comment.


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Nesting Waterbirds on Islas San Martin and Todos Santos, Baja California
Eduardo Palacios, Eric Mellink
ABSTRACT: A survey of Isla San Martin on 2 June 1999 revealed about 30 Brown Pelican, 600 Double-crested Cormorant, and over 300 occupied Western Gull nests, plus a mixed pair of oystercatchers. Thus the Double-crested Cormorant has reoccupied what was once its largest colony in North America. Surveys of Islas Todos Santos on 3 June 1999 and 27 March 2000 revealed 115 Double-crested Cormorant and at least 184 occupied Brandt's Cormorant nests, plus about 1400 nesting pairs of Western Gulls. On Todos Santos, at least two nests of the Pelagic Cormorant represent a southward extension of that species' breeding range, whereas two nesting pairs of the Reddish Egret represent a northward extension.
Download—Nesting Waterbirds on Islas San Martin and Todos Santos, Baja California


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Olean General Hospital Hosts Annual Reception for Residents in UB Rural Track Family Medicine Program
Olean General Hospital (OGH) hosted its annual reception on Thursday, May 26 for residents in the State University of New York (SUNY) at Buffalo's rural track family medicine residency program. The program, which is affiliated with Olean General, provides residents with a comprehensive exposure to the practice of medicine in a rural environment.
"Our hospital is committed to the education and training of future physicians through active involvement in medical education at multiple levels," said Timothy J. Finan, president and CEO of Upper Allegheny Health System and member hospitals Bradford Regional Medical Center and Olean General Hospital. "We're pleased to be affiliated with the State University of New York at Buffalo and sponsor the only rural track family medicine residency program in New York State."
Program residents spend an initial year in Buffalo and their second and third years in Olean working at Universal Primary Care's (UPC) Family Medicine Center in the hospital's health services building. The program is directed by full time, on-site University at Buffalo faculty members.
This year, the hospital recognized the graduation of Priyanka Patnaik, MBBS and Nupur Batra, MBBS from the program. Two residents—Anil Kopparapu, MBBS and Harpreet Singh, MBBS—will be entering their third and final year, while Kelvin Gold, M.D. and Amandeep Singh, MBBS will be transitioning from Buffalo to Olean in their second year of residency.
Dr. Kopparapu will take over as chief resident, and will be responsible for scheduling didactic teaching sessions with area doctors for residents, along with managing the on-call schedule for members of the program.
"With New York State's only rural track family medicine program, our likelihood of recruiting and retaining quality physicians to the local area is significantly enhanced," said William Mills, M.D., MMM, CPE, FACPE, CMSL, FAAFP, Senior Vice President of Quality and Professional Affairs for Upper Allegheny Health System. "This program not only benefits the residents involved, but it has a positive impact on our community, our hospital and our patients."
Olean General Hospital is a member of Upper Allegheny Health System. For more information, visit www.ogh.org.


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Danny Ezralow opens hearts, minds through dance around the world
Dancechained to the rhythm dance dance dance daniel ezralow ezralow dance company julie taymor katy perry lisa smith wengler center for the arts momix moses pendleton open pepperdine university smothers theatre sochi olympics spider man: turn off the dark the juilliard school
by gillian anne renault
Choreographer Daniel Ezralow is a global citizen. The Los Angeles native speaks fluent Italian, and a smattering of Russian and Japanese, having directed and choreographed projects in all three countries — the massive 2015 Sochi Olympics Opening Ceremony and Japanese Men's Rhythmic Gymnastics among them. He's currently a judge on a new Italian TV talent show, "Dance, Dance, Dance" and his evening-length, OPEN, premiered in Italy in 2013. It's getting a new showcase at Pepperdine University's hilltop Smothers Theatre, in Malibu, on January 10.
Gillian Renault: Hi Danny. Tell us about OPEN.
Daniel Ezralow: The idea was to present movement to music you've heard before but will experience in a wonderfully new, inventive way. Anyone who listens to a classical music radio station will know these pieces, but no one would think to put together visually what they'll see in OPEN.
The idea was to create something very uplifting. Open your mind. Open your heart. Open your joy. How do we live another day with joy? We are off this planet so fast, we need to inspire people, even if it's one moment of a curtain opening and [revealing] a beautiful vision, or one second of a jump of one dancer. Art is here to renovate life.
We pre-sold the show in Italy for about three months, which is very unusual. I don't think I could do that in America. We played it at The Wallis in 2016. It was sold out. Everyone loved it.
GR: You have created movement for Katy Perry's video "Chained to the Rhythm," you've choreographed twice for the Oscars, once for the Grammys, and you continue to present concert dance. Do the same dancers work with you in every medium?
DE: Yes. I have about 20 to 25 dancers whom I call when I am doing a project. They are not Juilliard trained where they do concert work, and don't know the first thing about a movie set. They're not commercial dancers who "hit it and quit it" and don't know how to sustain a five day a week, four hours a day rehearsal schedule. They are disciplined, expansive dancers who can do both. I trust them and they flourish.
GR: You danced in New York with the Paul Taylor Dance Company and you've choreographed on Broadway (Julie Taymor's Spider Man: Turn Off The Dark. How do you feel about Los Angeles as an artistic center?
DE: That's a big question. It could get me into trouble! I came back to LA in the nineties reluctantly but then I got my first commercial job with a six figure salary and thought whoa, what is this place!
Los Angeles was always the commercial hub. It still is. But it has come up enormously artistically. Body Traffic is a great LA company. So is the Ate9 Dance Company. You no longer have to be from New York if you want to do concert work. I think LA is still a bit behind New York because here commerce will always drive you (as a dancer.) If you want to buy a car, you have to do a commercial. But I love that it's cross pollinated. You can go back and forth between commercial and artistic.
GR: You have chosen to be a for-profit enterprise, not a non-profit concert dance company that depends upon grants and donations. Why?
DE: Live dance theater is a tough business. After leaving Paul, Moses [Pendleton] and I created MOMIX. We didn't want to go the normal route, with a board of directors, a company, funding. To this day MOMIX is a for-profit business. I tip my hat to Moses. He has created works and kept the company running with no grants, no donations. It's beyond amazing. It's very difficult but since I hop, skip and jump between all the different disciplines of dance, commercial and artistic, I can do film and television to survive. I am still for profit. It's a feeling of being autonomous.
GR: What do you want people to get out of the show?
DE: I want a football fan to come to this show and say it was worth the money. I chose for it to be accessible. I would love to see people in America as excited about dance as they are about football. That can mean make them cry, or laugh. I am not determining what emotion is elicited. But I do want them to have a good evening.
Gillian Anne Renault has written about dance for the Los Angeles Daily News, Herald Examiner and artsATL in Atlanta .
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Episode 16 of the ReadJunk Podcast is a tribute to The Vans Warped Tour, which just ended for good. I curated an awesome playlist of bands that have played the tour, as well as tell some stories about the tour. I give some perspective as someone who's took photos of the tour since 90s as well.


Supporting produce peak perfomers based on mastering recovery, nutrition and training.
I'm an commissioning engineer working for the nuclear industry since 12 years. In the same time I'm a strength and performance coach with the best certifications worldwide and solid results in the strength and performance world. My passion is to help people getting better every day until they are able to peak their performance.
Solving sleep patterns, helping with stress management, educating to have a fueling nutrition and avoid allergens which induce inflammations and challenging training to achieve the specific client goal.


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Beginning in the 1970s, with the popularity of J.R.R. Tolkien's The Lord of the Rings series, a variety of independent bookstores specializing in science fiction, fantasy, horror, and related genres (often mystery, comics, games, and/or collectibles), began opening. Among the first were Andromeda Books in Birmingham, England, established in 1971, and Bakka-Phoenix Bookstore in Toronto and A Change of Hobbit in Southern California, both established in 1972.  As independent bookstores suffered during the business shifts of the late 20th and early 21st century, many of these closed. During their heyday, however, they were a key part of science fiction fandom, facilitating not just publishing, distribution, and promotion of books, but public events, social events, and community-building.

List of notable bookstores
This list is meant to include past and present "brick-and-mortar" bookstores.  Bookstores that were once "brick-and-mortar", but have moved online, should be included.  Bookstores that have only ever been solely online vendors should be listed separately.

 A Change of Hobbit, 1972–1991, in Southern California
 The Other Change of Hobbit, established 1974 in Berkeley, later in El Cerrito (now mail-order only)
 DreamHaven Books, Minneapolis, Minnesota (established 1977)
 Forbidden Planet, New York City and London

Notes

External links
 "Bookstores Specializing in Science Fiction", Biblio.com (last visited March 31, 2014)
 Independent Genre Bookstores, Worlds Without End (last visited March 31, 2014)

Bookstores
Lists of bookstores

redpajama_set_name: RedPajamaWikipedia


text:
Lawrence Sheldon Gelman dit Larry Gelman, né le  à Brooklyn, New York et mort le , est un acteur américain.

Biographie
Il a joué dans des films et des séries, mais il est plutôt connu pour avoir joué Dr Bernie Tupperman dans la série The Bob Newhart Show.

Il a aussi interprété Albert Einstein dans le jeu de stratégie à temps réel Red Alert 2.

Il est aussi apparu dans le film Alice in Wonderland: A Musical Porno, au côté de Kristine DeBell sous le pseudo de Larry Spelman, où il jouait le rôle de  Rabbit.

Filmographie

 1967 : The Busy Body de William Castle
 1977 : Chatterbox ! de Tom DeSimone
 1984 : Dreamscape de Joseph Ruben
 1992 : Mr. Saturday Night de Billy Crystal

Notes et références

Liens externes

Acteur américain
Naissance en novembre 1930
Naissance à Brooklyn
Décès en juin 2021
Décès à 90 ans