Mutations in the gene encoding for the E3 ubiquitin ligase Parkin are associated to a rare form of familiar autosomal recessive Parkinsonism. Despite decades of research on the Parkin protein, whose structure has been recently solved, little is known about the specific signalling pathways that lead to Parkin activation. Parkin activity spans from mitochondria quality control to tumor suppression and stress protection; it is thus tempting to hypothesize that the broad impact of Parkin on cellular physiology might be the result of different post translational modifications that can be controlled by balanced opposing events. Sequence alignment of Parkin from different species indicates high homology between domains across Parkin orthologs and identifies highly conserved amino acid residues that, if modified, impinge on Parkin functions. In this review, we summarize findings on post translational modifications that have been shown to affect Parkin activity and stability.
This article was reviewed by Prof. Dr. Konstanze F. Winklhofer and by Prof. Thomas Simmen. Both reviewers have been nominated by Professor Luca Pellegrini.
Parkinson's Disease (PD) is the second most common neurodegenerative disorder affecting primarily the survival of a specific subset of dopaminergic neurons residing in the Substantia Nigra Pars Compacta of the midbrain . Most PD cases are sporadic in origin. However, a small proportion of PD cases derive from mutations in PD associated genes, which have been mainly identified by characterizing familiar Mendelian inherited PD forms [2, 3]. The discovery of these genes (S, PINK1, Parkin, DJ1, LRRK2, VPS35, FBXO7, PLA2G6 and ATP13A2) (see  for a review), has greatly enhanced our understanding of the neurodegenerative pathways leading to dopaminergic neurons loss. Although there seem to be various causes of PD, genetic and sporadic forms are almost undistinguishable in terms of specific hallmarks, which at the cellular level includes formation of intracellular inclusions named Lewy Bodies, mitochondria abnormalities and selective loss of DA neurons, leading to the well characterized locomotor impairments at the systemic level . The reason for studying genetic mutations of PD is the belief that the similarities between the sporadic and the inherited forms share a common mechanism of neurodegeneration, which can be more easily dissected at the molecular level in the genetic forms.
Although there are no unequivocally accepted scientific data that explain the selective neurodegeneration of dopaminergic neurons, the pathogenesis of PD appear to converge on three common features: mitochondria dysfunction, oxidative stress and proteins misfolding and aggregation . Indeed studies on Parkin (PARK2), an E3 ubiquitin ligase, which mutations have been associated to the early onset of autosomal recessive Parkinsonism , have provided evidences for a direct role of mitochondrial dysfunction in the onset of the disease by regulating the mitochondria quality control via mitophagy. In the mitophagy process, Parkin is selectively recruited to depolarised mitochondria by PINK1 , a mitochondrial serine/threonine kinase, also a PD related protein . In healthy mitochondria PINK1 is imported into mitochondria by the TOM/TIM translocase complex, cleaved and rapidly degraded by the proteasome [9–11]. However, on depolarised mitochondria PINK1 remains stable on the surface of mitochondria where it mediates the phosphorylation of Parkin, Parkin substrates and ubiquitin [7, 12–15]. Primed phospho-ubiquitin is specifically used by Parkin to ubiquitinate its targets on the outer mitochondrial membrane (OMM) , leading to the recruitment of downstream cytosolic receptors that are required for the activation of autophagy, including p62/SQSTM1, HDAC6, NDP52 and Optineurin [17–20].
Parkin leads to the ubiquitination of a broad number of targets that are expressed on the OMM, among others TOM20, Mitofusins, VDAC and Fis1 [16, 20–22]. Moreover, by targeting proteins with ubiquitin molecules, Parkin plays a crucial role in the degradative pathways mediated by the ubiquitin–proteasome system (UPS), which is required for both clearance of misfolded proteins and stress-induced mitophagy . The available literature suggests that Parkin mediated mitochondrial outer membrane protein ubiquitination recruits proteasome complex to mitochondria, in turn causing rupture of the outer membrane, thus exposing inner membrane proteins which can interact with LC3 and guides mitochondria to mitophagy [23, 24]. It is possible that widespread ubiquitination of mitochondrial surface proteins by Parkin, acts as a general signal for mitochondrial quality control. In that respect, Parkin substrate specificity is debatable because no single Parkin substrate is essential for mitophagy and mitochondrial localization of a number of deubiquitinating enzymes (DUBs), including USP30 and USP2 , is sufficient to inhibit mitophagy, where DUBs like USP30 or USP15 knock down [26, 27] rescues defective mitophagy even in the absence of Parkin.
In addition to its established role in mitophagy and UPS, Parkin impacts other neuroprotective cellular pathways , including TNFα signaling [29, 30], and Wnt/β catenin signaling . Parkin is also a putative tumor suppressor [32–34]. Interestingly, many of these pleiotropic functions of Parkin, which are dependent on its E3 ubiquitin ligase activity, do not result in ubiquitin dependent degradation of Parkin targets [35–38].
How does Parkin fulfill its many biological functions? Recent studies proposed ubiquitination as a modulator of protein activity, via regulating its subcellular localization and its ability to interact with other proteins [39, 40]. In the ubiquitination process, multiple lysine residues on the target protein can be ubiquitinated to produce multi-monoubiquitination . Alternatively, an ubiquitin chain can form upon linear ubiquitination, in which the carboxy-terminal glycine of one ubiquitin molecule form a peptide bond with the amino-terminal methionine of another (linear or M1-linked ubiquitination) [42, 43]. Also, following addition of a single ubiquitin molecule to the target protein, further ubiquitin molecules can be added to the first ubiquitin molecule via linkage on lysine residue, producing an ubiquitinated chain (polyubiquitination). Ubiquitin itself contains seven lysine residues (Lys 6, Lys 11, Lys 27, Lys 29, Lys 33, Lys 48 and Lys 63), which allows the generation of ubiquitin chains with different orientations. Although some chain-types (specifically, K48 and K63-chains ) are more common than others, all possible linkages have been detected in cells . Interestingly, the type of ubiquitin chain attached impinges on chain conformation and impacts the physiological outcome. For example, Lys 48 and Lys 11-linked chains adopt compact conformation and target proteins to the 26S proteasome [46–50]. Lys 63-linked chains or monoubiquitination, on the other hand, are the post-translational modifications that regulate lysosome dependent degradation [51, 52]. Monoubiquitination, Lys 63-linked chains and linear ubiquitination have also been described as non-degradative ubiquitination, which can control protein-protein interaction, protein subcellular localization and protein activity [53–59]. Very little is known regarding the physiological relevance of Lys 6, Lys 27, Lys 29 and Lys 33-linked chains and which biological outcomes these modifications would lead to. In that respect, ubiquitin ligases are extremely versatile enzymes that can potentially control almost every cellular process.
It is known that Parkin can promote both degradative Lys 48-mediated ubiquitination and non classical, proteosome-independent ubiquitination, including Lys 6, Lys 11, Lys 63, mono ubiquitination and linear ubiquitination [30, 60, 61]. Although Parkin dependent "regulative" ubiquitination has only recently started to be specifically addressed, emerging evidences suggest that Parkin activity necessarily includes "functional" ubiquitination and has the potential of controlling a broad subset of cellular processes depending on the activating stimuli. Not surprisingly, Parkin exists in an inactive state and it is normally repressed under basal conditions by several mechanisms of autoinhibition.
High resolution Parkin crystal structure gave insight into the mechanisms of Parkin autoinhibition. Parkin belongs to the RBR (RING-between-RING) type of E3 ubiquitin ligases, also known as RING/HECT hybrids, consisting of an ubiquitin like domain (Ubl), followed by two RING fingers domains (RING0 and RING1), an in between RING finger domain (IBR), a linker domain called Repressor Element of Parkin (REP) and a third RING finger domain called RING2 [62–65] (Fig. 1a). In the ubiquitin process, ubiquitin-activating enzymes (E1s) activate the C-terminus of the ubiquitin molecule and pass it to E2 conjugating enzymes that accept the activated ubiquitin and coordinate with E3 ubiquitin ligases to finally transfer ubiquitin to the amino group of a substrate protein [66–68]. Ubiquitin coordination and transfer is allowed by forming a thioester bond between catalytic cysteine residues on the E ubiquitin enzymes and the C-terminal carboxyl group of ubiquitin. Parkin can selectively interact and coordinate with different E2 ubiquitin ligase to ubiquitinate its substrates. Interestingly, these E2s are selectively expressed in specific subcellular compartments. For example, Ubc6 and Ubc7 are endoplasmic reticulum-associated E2s that specifically interact with Parkin. Parkin can also interact with E2 enzymes UbcH7, UbcH8 and UbcH13/Uev1. Depending on which E2 enzyme Parkin couples with, different types of ubiquitin modification can arise, resulting in different biological outcomes. For example, Parkin can employ UbcH7 E2 ligase for K48-linked proteasome dependent polyubiquitination, and UbcH13/Uev1a for K63-linked autophagy dependent polyubiquitination [69–73]. How Parkin can choose to couple with a specific E2 ubiquitin ligase is largely unknown.
Two mechanisms of auto inhibition control Parkin activity. Fist, the RING1 domain that contains the binding site for the E2 ubiquitin-conjugating enzyme is occluded by the Ubl and the REP domains. Second, the catalytic site in the RING2 domain is blocked by the RING0 domain. Notably, Parkin catalytic Cys 431 in the RING2 domain is physically distant from the E2 conjugating site, which further suggest that Parkin needs to undergo a conformational change in order to function [62–65]. Therefore, under basal conditions, Parkin maintains a close structure that resembles that of a coiled snake  and its ubiquitin ligase activity is repressed (Fig. 1b). Not surprisingly, disease-associated mutations disrupt these interactions.
Post translational modifications have emerged as a powerful tool to modulate proteins activity, via regulation of their subcellular localization and ability to interact with other proteins to form signaling complexes. Most Post translational modifications, such as phosphorylation, acetylation, ubiquitination, are reversible modifications, mediated by large families of opposing enzymes. Balanced opposing events mediated by antagonistic enzymes might provide a potential molecular switch to modulate Parkin activity upon specific stimulation. Accordingly, Post translational modifications are required to trigger Parkin activity or to keep it repressed.
In the following sections, we summarize the so far reported Post translational modifications affecting Parkin activity and stability. Sequence alignment of Parkin indicates high homology between domains across Parkin orthologs and identifies highly conserved amino acid residues, most of which are post translationally modified from mammals to insects to impinge on Parkin functions. This analysis highlights evolutionarily conserved posttranslational processes, in relation to Parkin activation, which is not characterized yet.
There are multiple proteins, which are involved in Parkin phosphorylation, PINK1 being the most studied [74–79]. It was first reported by Kim et al.  that Parkin activity and mitochondrial localization is PINK1 kinase activity dependant. Authors further described that RING1 and REP domains are indispensable for PINK1 mediated mitochondrial translocation of Parkin, as well as PINK1 dependent phosphorylation of Thr 175/Thr 217 is crucial for its translocation. In a separate study  the same was confirmed, and it was further shown that phosphorylation of Parkin is required for Parkin to interact with E2 ubiquitin ligase UbcH13/Uev1a to mediate K63-linked polyubiquitination of IKKγ in NFκB stress response pathway.
Later, it was reported by two simultaneous studies [80, 81] that the PINK1-dependent phosphorylation of Ser 65 of the Ubl domain is required for Parkin translocation as well as stress-induced mitophagy. These findings were confirmed in a subsequent study that used as read out the degradation of Miro1, a bona fide Parkin substrate, upon expression of full-length wild type or PD disease-associated Parkin mutants . In vivo data from Drosophila also confirmed these findings and additionally showed that phosphorylation of Parkin regulates spontaneous dopamine release from the neuron terminals, flight activity as well as survival of the flies .
One recent study deciphered the sequence of Parkin activation, and demonstrates that upon mitochondrial depolarization PINK1 phosphorylates ubiquitin at Ser 65, which goes to bind Parkin and Parkin substrates. Primed phospho-ubiquitin makes Parkin more accessible for PINK1 mediated Ser 65 phosphorylation . So, in a nutshell, it has become evident that phosphorylation by PINK1 is the central point of Parkin activation and target recognition [81, 84, 85].
Phosphorylation is not only required for Parkin activation. Quite intriguingly, phosphorylation of Parkin by cyclin dependent kinase 5 (Cdk-5), casein kinase 1 (CK-1) and c-Abl modulates Parkin folding and/or activity [74–76, 86]. Phosphorylation by both Cdk-5 on Ser 131 and CK-1 on Ser 101, Ser 127 and Ser 378 influence the solubility of the protein, leading to increased Parkin aggregation . Quite surprisingly, in both cases Parkin phosphorylation does not seem to particularly affect Parkin E3 ubiquitin activity. The role of c-Abl in regulating Parkin activity was reported by two different studies where the authors found that phosphorylation of Parkin by c-Abl at Tyr 143 can inactivate its E3 ligaes activity [74, 86] in human cell lines and MPTP treated mice. Consistent with this, increased protein levels of c-Abl and tyrosine phosphorylation of Parkin was reported in human post mortem brains from PD patients.
As previously mentioned, poly ubiquitination of proteins in general is the signal for proteasomal degradation. Parkin, though an E3 ubiquitin ligase itself, faces the same fate when multiple ubiquitin chains are attached to it. It has been reported that Parkin mediates its own ubiquitination via K48 proteosome dependent ubiquitin chain formation , thus impinging on its own protein turnover. Co-localization of ubiquitinated Parkin and Lewy body in PD patients brain might ignite the idea that ubiquitinated Parkin is a inactive form of the enzyme. However, in reality Parkin mono-ubiquitination at different sites can activate the enzyme. Mutations causing ubiquitination of the Ubl domain of Parkin makes the enzyme constitutively active and thus supports the idea of 'regulative" Parkin autoubiquitination . One intriguing possibility is that Parkin dependent non-degradative self-ubiquitination might be required to regulate Parkin subcellular localization and its interaction with specific E2 ubiquitin ligases and/or Parkin substrates. In that context, further studies are required to identify the precise site of Parkin ubiquitination and dissect the functional role of specific site ubiquitination.
Consistent with the hypothesis that Parkin self-ubiquitination is a functional ubiquitination, Parkin autoubiquitination is subjected to tight regulation by other factors. Deubiquitinating enzymes (DUBs), for example, antagonize Parkin autoubiquitination . Durcan and colleagues identified DUB Ataxin-3 as a binding partner of Parkin, which interacts with both the Ubl and IBR-RING2 domain of Parkin and promotes Parkin de-biquitination. Mutant Ataxin-3, which polyglutamine expansion is associated with the onset of Machado-Joseph neurodegenerative disease, promotes the degradation of Parkin via autophagy and leads to decreased Parkin levels in vivo [90, 91]. In a subsequent study, the same group showed that Ataxin-3 in fact binds to and coordinate with E2 ubiquitin ligase Ubc7 rather than Parkin, and promotes Parkin de-ubiquitination only upon Parkin autoubiquitination .
Recently, the same group has reported that DUB USP8 preferentially remove K6 linked Ub conjugates from Parkin and USP8 silencing hindered Parkin recruitment to depolarised mitochondria, suggesting that USP8 is required for active mitophagy .
Overall, these works highlighted an intricate regulation of Parkin ubiquitination that involves the coordinated activities of Parkin, DUBs and E2 ubiquitin ligases. It is tempting to hypothesis that such complex interplay is required to prime Parkin for further Post translational modifications that affect Parkin activity via regulation of its subcellular localization and/or interaction with specific E2 and/or substrates.
Post-translational modification of proteins by small ubiquitin like modifiers (SUMO) or in general SUMOylation is still not fully unravelled, though holds the indications that like ubiquitination or phosphorylation, it might have far reaching implications as well. In a very simplistic way, SUMO gets matured, activated and attached to target proteins by a series of specific enzyme complexes, much like the ubiquitination process . Interestingly, from the point of view of PD, three of the prominent proteins that are mutated in familiar Parkinsonism, SNCA, DJ-1 and Parkin, fall under the targets of SUMOylation [95–98]. At first sight, it appears that reports connecting SUMOylation of SNCA and aggregate formation followed by cell death are contradictory [97, 99], but the precise site of SUMOylation might be the deciding factor for aggregate formation and cell death by α-synucleinopathy . As far as Parkin is concerned, reports are significantly less which properly deciphers the physiological role of SUMO attachment to Parkin. One solitary report by Um and Chung  demonstrates that covalent attachment of SUMO-1 (but not SUMO-2, which possible due to differential preference of subtrates by SUMO-1, 2 and 3) to Parkin, both in vitro and in vivo, increases its nuclear localization and auto-ubiquitination. In the nucleus, Parkin transcriptionally represses p53 by interacting with p53 promoter. Interestingly, this activity of Parkin is independent of its ligase function.
NEDD8 is another protein that shows similarity with ubiquitin, in terms of structural homology and the way of getting attached to other proteins as post-translational modification . Like ubiquitin, NEDD8 is also expressed in most tissue types and strikingly concentrated in different types of protein aggregates, which includes Mallory bodies in liver, Rosenthal fibres in astrocytoma, neurofibrillary plaques of Alzheimer's disease and Lewy bodies in PD . Um et al.  showed that attachment of NEDD8 to Parkin increase the E3 ligase activity by increasing affinity towards E2 ubiquitin ligase UbcH8 and the putative substrate the p38 subunit of aminoacyl trasferase. Choo et al.  also reported increased Parkin E3 ligase activity upon neddylation. The also found that PINK1 undergoes neddylation, which results in increased stability of PINK1 55KDa proteolytic fragment. Interestingly, genetic enhancement of neddylation was shown to rescue the phenotypes associated with a Drosophila in vivo model of PINK1 deficiency. Moreover, PD neurotoxin MPP+ treatment showed decreased neddylation of both PINK1 and Parkin, clearly indicating a causal link between NEDD8 modification of PINK1/Parkin and PD pathogenesis.
Among many other contributing factors, nitric oxide (NO), hydrogen sulphide (H2S) and oxidative stress have been found to influence the progression of PD .
Increased attachment of NO to thiol groups (S-nitrosylation) of Parkin in PD was first reported by Ted Dawson's group  where the authors showed increased nitosylation of Parkin in MPTP treated mice and human patient's brains. They also demonstrated that nitrosylation decreased the protective effect of Parkin by inhibiting its E3 ligase activity. A concurrent study by Stuart Lipton's group also reported the same while showing a steep increase of the Parkin E3 ubiquitin ligase activity, which autoubiquitinates the enzyme, followed by decreased activity .
In contrast to these works, one solitary study demonstrates that S-nitrosylation of Parkin, more specifically at Cys 323, increases the Parkin E3 ligase activity, and it is required for efficient removal of depolarised mitochondria . The authors suggest that Cys 323 is not involved in zinc ion coordination and therefore its modification can regulate Parkin activity without disrupting the ability of the protein to coordinate ion zinc that is required for Parkin activity. Furthermore, the authors give evidences that PINK1 dependent phosphorylation and nitrosylation of Parkin act independently and that Parkin nitrosylation is mostly cytosolic.
These conflicting studies identified sites of potential S-nitrosylation within the RING1, RING2 and the IBR domain [106, 107]. Most of those that were identified as potential sites of nitrosylation are highly conserved among different species (except for Cys 323 that is only conserved in vertebrates), although further studies are required to understand whether these nitrosylated sites are responsible for altered Parkin E3 activity. Cysteine sites in these domains are important for zinc coordination and their nitrosylation is likely to distrupt the conformation of these domains that are both important for E2 coordination and Parkin catalytic activity. It is therefore not surprisingly that nitrosylation at those sites affect Parkin E3 ligase activity.
Interestingly, a recent work demonstrated that nitrosylation of Parkin increased p53 level . Authors suggested that cell death due to nitrosative stress occurs via increase of pro apoptotic factor p53 and correlated the increased nitrosylation of Parkin to p53 levels in human post mortem PD brains. It was reported that nitrosylated Parkin preferentially accumulates in the cytoplasm and does not translocate to the nucleus, where Parkin operates as repressor of p53 promoter. This finding might explain the correlation between increased p53 levels and nitrosylated Parkin in PD brains, and potentially p53 dependent-cell death due to nitrosative stress, the later being the causative factor for the increase of p53 levels.
Modification of Parkin by H2S, termed sulfhydration, was found to be protective in nature. Three independent studies documented the protective effect of systemic administration of NaHS as H2S donor in preventing the progression of Parkinsonism in toxin induced animal models of PD [109–111]. In a subsequent study, Vaniver et al. , specifically discovered the sulfhydrated cysteine residues which enhanced Parkin protective activity. The authors systematically mutated the various Parkin cysteines and measured Parkin activity. Mutation C95S completely abolished Parkin enhanced ubiquitination activity upon administration of GYY4137, a H2S donor. Mutants C59S and C182S also result in substantial diminution of the enhancement of ubiquitination upon sulfhydration. Though the protective effect of sulfhydration against neurotoxin-induced Parkinsonism has been widely documented, the molecular mechanism is largely known.
Interestingly, the level of Parkin sulfhydration was found to be reduced in PD patient's brain, while nitrosylation showed a steep increase. These findings suggest that nitosylation and sulfhydration are two reciprocal, opposing events that both impinge on cysteine residues and provide them with chemical groups that opposingly impact Parkin E3 ligase activity .
In a slightly different context, it was shown that heat shock, oxidative stress induced by H2O2 or deletion of 13 amino acids from the C terminal end of Parkin can lead to its aggregation, which is inhibited by the overexpression of heat shock protein chaperones . More recently, a study by Meng et al.  showed that oxidative stress induced by either MPP+ or H2O2 treatment result in oxidation of a specific subset of cysteine residues of Parkin. The process of cysteine oxidation, also known as sulfonation, alters Parkin solubility and leads to Parkin inactivation. Upon mass spectrometry analysis of Parkin oxidation, authors also showed that several of the Parkin cysteine that are sulfonated upon oxidative stress (Cys 212, Cys 253, Cys 268, Cys 289, Cys 431 and Cys 441) were previously reported to be mutated in familial PD cases, supporting the hypothesis that rare hereditary mutations and environmentally linked PD cases might share a common mechanism of inactivation of Parkin.
In order to keep their function, proteins need to preserve their three-dimensional structure, meaning that they have to keep the same or similar amino acid sequence. If there are conserved amino acids in some regions of orthologous proteins, it can be concluded that these amino acids are important for the function of the protein. This is especially relevant when the conservation occurs at the protein rather than at the DNA level. Interestingly, amino acids sequence alignment between Parkin orthologs revealed that the Parkin residues that are post translationally modified are highly conserved from mammals to insects (Fig. 1a). These include sites of phosphorylation (Ubl and RING0 resident residues Ser 65, Tyr 175 and Tyr 217), sulfhydration (Ubl and RING0 resident residues Cys 59 and Cys 182) and sulfonation (RING1 and RING2 resident residues Cys 212, Cys 253, Cys 268, Cys 289, Cys 431 and Cys 441) (Fig. 1a).
It is interesting to note that phosphorylation sites leading to Parkin activation are highly conserved, whereas those which impairs Parkin activity are only conserved in mammals. It is intriguing to hypothesis that evolution might have been more stringent when it comes to mechanisms of Parkin activation.
This analysis also led us to the interesting observation that the residues that are post translationally modified to activate Parkin are either in the Ubl or the RING0 domain, whereas the inactivating modifications mainly affect residues of the RING1 or RING2 domain, that contain the E2 binding site and the catalytic site, respectively (Fig. 1c).
Parkin is an E3 ubiquitin ligase with various pleiotropic functions. Elucidating the molecular mechanisms that control its function can have important implications not only in the regulation of mitochondria quality control and proteosomal dependent degradation of abnormal proteins, but also in the context of various Parkin cytoprotective functions, that include inhibition of the activity of pro apoptotic proteins p53 and Bax, and enhancement of expression of pro survival protein OPA1 via NF-kB signalling [29, 30].
Under basal conditions, Parkin adopts a coiled inhibited conformation and its activity is repressed [62–65, 115, 116]. Post translational modifications can control Parkin activity, subcellular localization, conformation, solubility, E2 choice and interaction with cofactors that are required for Parkin activation, substrate affinity as well as specificity. Post translational modifications can occur rapidly to respond to changes in metabolism or when cell experience environmental stress. More importantly, Post translational modifications are reversible and are controlled by the counteracting activities of opposing enzymes, which can be timely and rapidly regulated. Protein phosphatases oppose protein kinases, de-ubiquitinating enzymes oppose ubiquitin ligases, protein deacetylases counteract acetyltransferases, denitrosylation opposes S-nitrosylation and so on. Balanced regulation of opposing events can result in complex biological outcomes, particularly when the targets of this regulation are proteins with pleiotropic functions, like Parkin.
Potentially each PTM can be targeted for therapeutic intervention as long as its physiological outcomes is known and specific synthetic molecules are available to either inhibit or enhance such modification depending on its outcome. In this context, much effort has been recently put towards the identification of specific deubiquitinating enzymes that directly or indirectly oppose Parkin activity. Along the same line, it will be important to evaluate whether specific protein phosphatases are in place to oppose PINK1 in the phosphorylation of Parkin.
Future works will also clarify whether other modifications, such as acetylation (second most common PTM after phosphorylation) or glycosylation (third most common PTM) might play a role in the control of Parkin activation.
The next challenge will be to identify appropriate in vitro system that allows rapid and specific read out of Parkin activation. In that respect, in a very recent report Pao et al.  developed a newly engineered probe to monitor the thansthiolation activity of E3 ligases to decipher mechanisms of Parkin activation. Interestingly, this report demonstrates that initial phosphorylation of ubiquitin is upstream Parkin phosphorylation and subsequent activation, allowing the precise dissection of a rather complex multi step process.
The compatibility of newly generated probes to study Parkin activity from cell extracts and the potential reproducibility of the assay in samples extracted from human patients, will pave the way for the development of rapid methods to address how different post-translational modifications affect Parkin activity in vitro as well as in vivo.
This article was reviewed by Prof. Dr. Konstanze F. Winklhofer, Faculty of Medicine, Biochemistry and Pathobiochemistry department, University of Ruhr-Bochumand (reviewer 1) and by Prof. Thomas Simmen, Department of Cell Biology, University of Alberta, Canada (reviewer 2).
Reviewer 1 summary: In their manuscript, the authors provide a comprehensive and timely review on the regulation of the E3 ubiquitin ligase Parkin by posttranslational modifications. This overview is well-balanced and includes a wide spectrum of Parkin functions. Therefore it will be interesting and helpful for a broad readership.
Reviewer 2 summary: The review article by Chakraborty et al. provides a useful, up-to-date resource for Parkin researchers by describing the complete set of known Parkin post-translational modifications. There is a three-part figure that accompanies the manuscript, which provides a helpful illustration of what is described within the manuscript. The sequence of chapters is logical, starting with phosphorylation. Ultimately, my suggestions are minor changes that would hopefully make the manuscript even more useful that it already is.
Response to reviewers: First of all we would like to thank both reviewers for their valuable and relevant comments. As specified in the following chapters, reviewers concerns have been carefully addressed in the revised version of the manuscript.
Comment: Some suggestions to increase linguistic clarity: Page 10, line 15 to 18: "Quite intriguingly, phosphorylation of Parkin by cyclin dependent kinase 5 (Cdk-5), casein kinase 1 (CK-1) and c-Abl leads to either increased Parkin aggregates properties or Parkin inhibition." … modulates Parkin folding and/or activity.
Response: we have modified the sentence according to the suggestion.
Comment: Page 11, line 15: The statement that "mutation in the Ubl domain leads to multi ubiquitinated Parkin that is constitutively active" should be substantiated by a reference.
Response: We have modified the sentence and supported the statement by reference.
Response: we have modified the specified sentences.
Comment: what is the mechanism that causes proteasome degradation of mitochondrial proteins? Are these proteasomes mitochondria-localized? This is not well explained.
Response: we have explained this in the updated manuscript.
Comment: the description of highly conserved residues within Parkin on page 9 is confusing. Are all of these post-translationally modified? Are only these post-translationally modified?
Response: we have mentioned in the manuscript that most of these are post translationally modified. This list might not be exclusive and we have focused on the so far reported ones.
Comment: I would reconsider using the PTM abbreviation. I had some trouble getting used to it.
Response: to our knowledge, PTM is quite frequently used abbreviation for posttranslational modification. We however reconsidered using the abbreviation in the manuscript, as suggested by the reviewer.
Comment: on page 5, it is stated that PINK1 is a serine/threonine kinase, but on page 9, PINK1 is said to phosphorylate tyrosines on Parkin. It is later mentioned that Parkin serines are also phosphorylated. What is the relationship between tyrosine and serine phosphorylation? This needs to be better explained. What phosphorylation occurs in D. melanogaster? What is the relationship between phosphorylation by PINK1 and other kinases? What is known about Parkin serine phosphorylation in PD patient brains?
Response: We would like to thank the reviewer for actually spotting this. We realised that the abbreviation for Threonine was misspelled (Tyr instead of Thr): PINK1 indeed is a serine/threonine kinase that phosphorylates substrates on threonine (Thr) residues. We apologise for the confusion the misspelled abbreviation might have caused.
To our knowledge, nothing is known about Parkin serine phosphorylation in PD patients brains.
Comment: What is the functional difference between SUMO-1 and SUMO-2?
Response: The basic difference between SUMO-1 and 2 is their substrate preference. We have mentioned this in the manuscript.
Comment: Where could NO originate that modifies Parkin and why does it increase in PD brain? It is unclear whether there is a correlative or causative link between Parkin nitrosylation and p53.
Response: NO is synthesized by nitric oxide synthase (NOS), which comes in three forms: endothelial, neuronal and inducible NOS. So, in the brain the origin of NO could be due to the functionality of neuronal NOS. The increase in NO in PD brain and its relevance is quite controversial as it can be marked as both causative and/or after effect of neuro-inflammation. It is beyond the scope of this review to discuss that in details.
In the stated report the authors discovered that nitrosylation of Parkin decreases its activity as a repressor of P53. Later increase in both nitrosylated Parkin and P53 was found in human patients brain and the conclusion was drawn stating nitrosylated Parkin is the causal factor for P53 increase. We have mentioned this in the updated MS.
Comment: The authors may consider swapping panels a and b in Fig. 1 .
Response: We don't understand the reason for this request. Panel a is described before panel b in the text.
Comment: English grammar and spelling needs to be improved in some spots. This is especially the case in the abstract, which I suggest to rewrite from scratch, but also in some other instances (e.g., lines 19–23 p. 5; line 18 p. 6; lines 11–13 p.9; lines 8–14 p. 11; lines 7, 13 p.12). Some issues with singular/plural confusion and wrong usage of articles.
Response: We have modified the manuscript according to the suggestions.
The authors would also like to acknowledge Dr Lena Pernas for critically reading the manuscript.
This work was supported by grants from Italian Ministry of Health "Ricerca Finalizzata" [GR-2011-02351151], Rita Levi Montalcini "Brain Gain" program and Michael J. Fox RRIA 2014 [Grant ID 9795] to E.Z. Dr Joy Chakraborty is a recipient of the Marie Curie- Padova University co- funded award "PISCOPIA".
JC, VB and EZ wrote the manuscript. VB drew the figure. All authors read and approved the final manuscript.
Joy Chakraborty has received a PhD Degree in Life Science and Biotechnology in the year of 2014. His research activities are mainly focused on mitochondrial clearance and maintenance. He is a Post Doctoral student of Biological Science at University Padova. He is author of 7 publications in International peer-reviewed Journals.
Valentina Basso has received a Master Degree in Health Biotechnology at University of Padua in 2013. Her research activity is focused on the study of post translational modifications, in particular ubiquitination; and their importance in the regulation of ER-Mitochondria tethering. She is a PhD student of Biosciences and she works in the mitochondrial biochemistry, biology and pathophysiology group at University of Padua.
Dr Elena Ziviani accomplished her PhD in Neuroscience at the MRC toxicology Unit in Leicester, UK, under the supervision of Professor P. Nicotera where she investigated the effect of nicotine in primary neurons on neuroprotection and synaptic plasticity. In 2007, she joined Dr. Alex Whitworth's group in Sheffield, UK, where she studied the role of Parkinson's Disease (PD)-related proteins PINK1 and Parkin in mitochondrial dynamic and mitophagy. In 2010 Dr Ziviani was awarded with both EMBO long term and Marie Curie Action fellowships to investigate the role of Parkin-dependent ubiquitination of Mitofusin-2 in regulating mitochondria-endoplasmic reticulum tethering in the onset of PD at the Department of cellular physiology and metabolism, Geneva medical school, Switzerland. Since 2014, she became assistant professor at the Department of biology, University of Padova.
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	* There are two types of transaction within this system: SMS and DMS.
	* SMS - is direct payment, where money is charged in 1 event.
	* DMS - is delayed. Requires two events: first event blocks money on the card, second event takes this money. Second event can be carried out when product is shipped to the customer for example.
	*
	* Every 24 hours, the merchant must send a request to server to close the business day.
	*
	* Detailed instructions can be found in README.md or online
	* https://github.com/wearede/tbcpay-php
	*
	* Written and maintained by sandro@weare.de.com
	*
	*/
	class TbcPayProcessor
	{
		/**
		 * gateway endpoint
		 * @var string
		 */
		private $submit_url = 'https://securepay.ufc.ge:18443/ecomm2/MerchantHandler';
		/**
		 * absolute path to certificate
		 * @var string
		 */
		private $cert_path;
		/**
		 * certificate passphrase
		 * @var string
		 */
		private $cert_pass;
		/**
		 * client IP address, mandatory (15 characters)
		 * @var string
		 */
		private $client_ip_addr;
		/**
		 * transaction amount in fractional units, mandatory (up to 12 digits)
		 * 100 = 1 unit of currency. e.g. 1 gel = 100.
		 * @var numeric
		 */
		public $amount;
		/**
		 * transaction currency code (ISO 4217), mandatory, (3 digits)
		 * http://en.wikipedia.org/wiki/ISO_4217
		 * GEL = 981 e.g.
		 * @var numeric
		 */
		public $currency;
		/**
		 * transaction details, optional (up to 125 characters)
		 * @var string
		 */
		public $description;
		/**
		 * authorization language identifier, optional (up to 32 characters)
                 * EN, GE e.g,
		 * @var string
		 */
		public $language;
		/**
		 * ? this seems to be ignored by tbcbank
		 * @var string
		 * private $property_name;
		 */
		/**
		 * ? this seems to be ignored by tbcbank
		 * @var string
		 * private $property_value;
		 */

		/**
		 * @param string  $cert_path
		 * @param string  $cert_pass
		 * @param string  $client_ip_addr
		 */
		function __construct( $cert_path, $cert_pass, $client_ip_addr )
		{
			$this->cert_path      = $cert_path;
			$this->cert_pass      = $cert_pass;
			$this->client_ip_addr = $client_ip_addr;
		}
		/**
		 * curl is responsible for sending data to remote server, using certificate for ssl connection
		 * @param  string $query_string created from an array using method build_query_string
		 * @return string               returns tbc server response in the form of key: value \n key: value. OR error: value.
		 */
		private function curl( $query_string )
		{
			$curl = curl_init();
			curl_setopt($curl, CURLOPT_POSTFIELDS,     $query_string);
			curl_setopt($curl, CURLOPT_VERBOSE,        1);
			curl_setopt($curl, CURLOPT_SSL_VERIFYHOST, 0);
			curl_setopt($curl, CURLOPT_SSL_VERIFYPEER, 0);
			curl_setopt($curl, CURLOPT_RETURNTRANSFER, 1);
			curl_setopt($curl, CURLOPT_SSLCERT,        $this->cert_path);
			curl_setopt($curl, CURLOPT_SSLKEY,         $this->cert_path);
			curl_setopt($curl, CURLOPT_SSLKEYPASSWD,   $this->cert_pass);
			curl_setopt($curl, CURLOPT_URL,            $this->submit_url);
			$result = curl_exec($curl);
			$info = curl_getinfo($curl);
			return $result;

		}
		/**
		 * building string from array
		 * @param  array  $post_fields
		 * @return string
		 */
		private function build_query_string( $post_fields )
		{
			return http_build_query( $post_fields );
		}
		/**
		 * parse tbcbank server response string into an array
		 * @param  string $string
		 * @return array
		 */
		private function parse_result( $string )
		{
			$array1 = explode( PHP_EOL, trim( $string ) );
			$result = array();
			foreach( $array1 as $key => $value )
			{
				$array2 = explode( ':', $value  );
				$result[ $array2[0] ] = trim( $array2[1] );
			}

			return $result;
		}
		/**
		 * Takes array and transforms into a POST string
		 * curls it to tbc server
		 * parses results
		 * returns parsed results
		 * @param  array $post_fields
		 * @return array
		 */
		private function process( $post_fields )
		{
			$string = $this->build_query_string( $post_fields );
			$result = $this->curl( $string );
			$parsed = $this->parse_result( $result );
			return $parsed;
		}
		/**
		 * Registering transactions
		 * start SMS transaction. This is simplest form that charges amount to customer instantly.
		 * @return array  TRANSACTION_ID
		 * TRANSACTION_ID - transaction identifier (28 characters in base64 encoding)
		 * error          - in case of an error
		 */
		public function sms_start_transaction()
		{
			$post_fields = array(
				'command'        => 'v', // identifies a request for transaction registration
				'amount'         => $this->amount,
				'currency'       => $this->currency,
				'client_ip_addr' => $this->client_ip_addr,
				'description'    => $this->description,
				'language'       => $this->language,
				'msg_type'       => 'SMS'
			);
			return $this->process( $post_fields );
		}
		/**
		 * Registering DMS authorization
		 * DMS is different from SMS, dms_start_authorization blocks amount, and than we use dms_make_transaction to charge customer.
		 * @return array  TRANSACTION_ID
		 * TRANSACTION_ID - transaction identifier (28 characters in base64 encoding)
		 * error          - in case of an error
		 */
		public function dms_start_authorization()
		{
			$post_fields = array(
				'command'        => 'a', // identifies a request for transaction registration
				'amount'         => $this->amount,
				'currency'       => $this->currency,
				'client_ip_addr' => $this->client_ip_addr,
				'description'    => $this->description,
				'language'       => $this->language,
				'msg_type'       => 'DMS'
			);
			return $this->process( $post_fields );
		}
		/**
		 * Executing a DMS transaction
		 * @param  string $trans_id
		 * @return array  RESULT, RESULT_CODE, BRN, APPROVAL_CODE, CARD_NUMBER, error
		 * RESULT         - transaction results: OK - successful transaction, FAILED - failed transaction
		 * RESULT_CODE    - transaction result code returned from Card Suite Processing RTPS (3 digits)
		 * BRN            - retrieval reference number returned from Card Suite Processing RTPS (12 characters)
		 * APPROVAL_CODE  - approval code returned from Card Suite Processing RTPS (max 6 characters)
		 * CARD_NUMBER    - masked card number
		 * error          - in case of an error
		 */
		public function dms_make_transaction( $trans_id )
		{
			$post_fields = array(
				'command'        => 't', // identifies a request for transaction registration
				'trans_id'       => $trans_id,
				'amount'         => $this->amount,
				'currency'       => $this->currency,
				'client_ip_addr' => $this->client_ip_addr,
				'description'    => $this->description,
				'language'       => $this->language,
				'msg_type'       => 'DMS'
			);
			return $this->process( $post_fields );
		}
		/**
		 * Transaction result
		 * @param  string $trans_id
		 * @return array  RESULT, RESULT_PS, RESULT_CODE, 3DSECURE, RRN, APPROVAL_CODE, CARD_NUMBER, AAV, RECC_PMNT_ID, RECC_PMNT_EXPIRY, MRCH_TRANSACTION_ID
		 * RESULT        	   - OK              - successfully completed transaction,
		 * 				 	     FAILED          - transaction has failed,
		 * 				 	     CREATED         - transaction just registered in the system,
		 * 				 	     PENDING         - transaction is not accomplished yet,
		 * 				 	     DECLINED        - transaction declined by ECOMM,
		 * 				 	     REVERSED        - transaction is reversed,
		 * 				 	     AUTOREVERSED    - transaction is reversed by autoreversal,
		 * 				 	     TIMEOUT         - transaction was timed out
		 * RESULT_PS     	   - transaction result, Payment Server interpretation (shown only if configured to return ECOMM2 specific details
		 * 				 	     FINISHED        - successfully completed payment,
		 * 				 	     CANCELLED       - cancelled payment,
		 * 				 	     RETURNED        - returned payment,
		 * 				 	     ACTIVE          - registered and not yet completed payment.
		 * RESULT_CODE   	   - transaction result code returned from Card Suite Processing RTPS (3 digits)
		 * 3DSECURE      	   - AUTHENTICATED   - successful 3D Secure authorization
		 * 				 	     DECLINED        - failed 3D Secure authorization
		 * 				 	     NOTPARTICIPATED - cardholder is not a member of 3D Secure scheme
		 * 				 	     NO_RANGE        - card is not in 3D secure card range defined by issuer
		 * 				 	     ATTEMPTED       - cardholder 3D secure authorization using attempts ACS server
		 * 				 	     UNAVAILABLE     - cardholder 3D secure authorization is unavailable
		 * 				 	     ERROR           - error message received from ACS server
		 * 				 	     SYSERROR        - 3D secure authorization ended with system error
		 * 				 	     UNKNOWNSCHEME   - 3D secure authorization was attempted by wrong card scheme (Dinners club, American Express)
		 * RRN           	   - retrieval reference number returned from Card Suite Processing RTPS
		 * APPROVAL_CODE 	   - approval code returned from Card Suite Processing RTPS (max 6 characters)
		 * CARD_NUMBER   	   - Masked card number
		 * AAV           	   - FAILED the results of the verification of hash value in AAV merchant name (only if failed)
		 * RECC_PMNT_ID            - Reoccurring payment (if available) identification in Payment Server.
		 * RECC_PMNT_EXPIRY        - Reoccurring payment (if available) expiry date in Payment Server in form of YYMM
		 * MRCH_TRANSACTION_ID     - Merchant Transaction Identifier (if available) for Payment - shown if it was sent as additional parameter  on Payment registration.
		 * The RESULT_CODE and 3DSECURE fields are informative only and can be not shown. The fields RRN and APPROVAL_CODE appear for successful transactions only, for informative purposes, and they facilitate tracking the transactions in Card Suite Processing RTPS system.
		 * error                   - In case of an error
		 * warning                 - In case of warning (reserved for future use).
		 */
		public function get_transaction_result( $trans_id )
		{
			$post_fields = array(
				'command'        => 'c', // identifies a request for transaction registration
				'trans_id'       => $trans_id,
				'client_ip_addr' => $this->client_ip_addr
			);
			return $this->process( $post_fields );
		}
		/**
		 * Transaction reversal
		 * @param  string $trans_id
		 * @param  string $amount          reversal amount in fractional units (up to 12 characters). For DMS authorizations only full amount can be reversed, i.e., the reversal and authorization amounts have to match. In other cases partial reversal is also available.
		 * @param  string $suspected_fraud flag, indicating that transaction is being reversed because of suspected fraud. In such cases this parameter value should be set to yes. If this parameter is used, then only full reversals are allowed.
		 * @return array  RESULT, RESULT_CODE
		 * RESULT         - OK              - successful reversal transaction
		 *                  REVERSED        - transaction has already been reversed
		 * 		    FAILED          - failed to reverse transaction (transaction status remains as it was)
		 * RESULT_CODE    - reversal result code returned from Card Suite Processing RTPS (3 digits)
		 * error          - In case of an error
		 * warning        - In case of warning (reserved for future use).
		 */
		public function reverse_transaction( $trans_id, $amount = '', $suspected_fraud = '' )
		{
			$post_fields = array(
				'command'         => 'r', // identifies a request for transaction registration
				'trans_id'        => $trans_id,
				'amount'          => $amount,
				'suspected_fraud' => $suspected_fraud
			);
			return $this->process( $post_fields );
		}
		/**
		 * Transaction refund
		 * full original amount is always refunded
		 * @param  string $trans_id
		 * @return array  RESULT, RESULT_CODE, REFUND_TRANS_ID
		 * RESULT          - OK     - successful refund transaction
		 * 	             FAILED - failed refund transaction
		 * RESULT_CODE     - result code returned from Card Suite Processing RTPS (3 digits)
		 * REFUND_TRANS_ID - refund transaction identifier - applicable for obtaining refund payment details or to request refund payment reversal.
		 * error           - In case of an error
		 * warning         - In case of warning (reserved for future use).
		 */
		public function refund_transaction( $trans_id )
		{
			$post_fields = array(
				'command'         => 'k', // identifies a request for transaction registration
				'trans_id'        => $trans_id
			);
			return $this->process( $post_fields );
		}
		/**
		 * Credit transaction
		 * @param  string  $trans_id original transaction identifier, mandatory (28 characters)
		 * @param  string  $amount   credit transaction amount in fractional units (up to 12 characters)
		 * @return array   RESULT, RESULT_CODE, REFUND_TRANS_ID
		 * RESULT          - OK     - successful credit transaction
		 * 		     FAILED - failed credit transaction
		 * RESULT_CODE     - result code returned from Card Suite Processing RTPS (3 digits)
		 * REFUND_TRANS_ID - credit transaction identifier - applicable for obtaining credit payment details or to request credit payment reversal.
		 * error           - In case of an error
		 * warning         - In case of warning (reserved for future use).
		 */
		public function credit_transaction( $trans_id, $amount = '' )
		{
			$post_fields = array(
				'command'         => 'g', // identifies a request for transaction registration
				'trans_id'        => $trans_id,
				'amount'          => $amount
			);
			return $this->process( $post_fields );
		}
		/**
		 * needs to be run once every 24 hours.
		 * this tells bank to process all transactions of that day SMS or DMS that were success
		 * in case of DMS only confirmed and sucessful transactions will be processed
		 * @return array RESULT, RESULT_CODE, FLD_075, FLD_076, FLD_087, FLD_088
		 * RESULT        - OK     - successful end of business day
		 * 		   FAILED - failed end of business day
		 * RESULT_CODE   - end-of-business-day code returned from Card Suite Processing RTPS (3 digits)
		 * FLD_075       - the number of credit reversals (up to 10 digits), shown only if result_code begins with 5
		 * FLD_076       - the number of debit transactions (up to 10 digits), shown only if result_code begins with 5
		 * FLD_087       - total amount of credit reversals (up to 16 digits), shown only if result_code begins with 5
		 * FLD_088       - total amount of debit transactions (up to 16 digits), shown only if result_code begins with 5
		 */
		public function close_day()
		{
			$post_fields = array(
				'command'         => 'b' // identifies a request for transaction registration
			);
			return $this->process( $post_fields );
		}
		// Regular payments need to be implemented!
	}
?>

redpajama_set_name: RedPajamaGithub


I want to eliminate chargebacks from credit card users.
However, I still want cc users to use their cards.
There will be a disclaimer in our terms/conditions stating that using our "credit card-to-Bitcoin conversion feature" cc users waive the "chargeback" option.
Does any of this make sense, and is it possible and if not why not?
Monty, If you're asking to be head of this project? the answer is definitely "yes".
Ms. Gallippi, BitGive's Founder and Executive Director, has presented internationally on the social impact of Bitcoin and Blockchain.
Founded in 2013, BitGive is the first Bitcoin 501(c)(3) nonprofit, giving it tax exemption status at the federal level in the United States.
BitGive has built a positive philanthropic representative organization for the Bitcoin and Blockchain industry, bridging the gap between an innovative technology and its practical applications for nonprofits and humanitarian work in the developing world.
BitGive has established strong partnerships and raised funds with well-known nonprofits including Save the Children, The Water Project, TECHO, Medic Mobile, and more.
In 2015, BitGive announced its Bitcoin Charity 2.0 Initiative, which includes a variety of projects aimed at leveraging Bitcoin and blockchain technology to benefit charitable organizations worldwide.
Our flagship project is GiveTrack™, a revolutionary donation platform for nonprofits to provide transparency and accountability to donors by sharing financial information and direct project results in real time.
BitGive has been featured in Forbes, Entrepreneur, Wall Street Journal, US News and World Report, Non Profit Times, Inside Philanthropy, Chronicle of Philanthropy, and more.


text:
Oeneis elwesi är en fjärilsart som beskrevs av Otto Staudinger 1901. Oeneis elwesi ingår i släktet Oeneis och familjen praktfjärilar. Inga underarter finns listade i Catalogue of Life.

Källor

Externa länkar

Praktfjärilar
elwesi

redpajama_set_name: RedPajamaWikipedia


text:
El Salvador reopens the 'Ellacura case'
Justice Slaughter of Ellacura and the Spanish Jesuits; the horror of the only surviving case of universal justice
Historic resolution in El Salvador, after the Constitutional Chamber of the Supreme Court of Justice decided this Wednesday to reopen the case of the massacre that occurred on November 16, 1989 in that country of six Jesuits, five of them SpanishAmong them, Ignacio Ellacura, ideologist of the Liberation Theology. In this way, the Central American country will be able to do justice, after declaring the appeal for amparo filed on November 16 by the Attorney General of El Salvador, Rodolfo Delgado, on the 32nd anniversary of the massacre. As requested by the Prosecutor, the Supreme Court of Justice has "invalidated" the resolution of September 8, 2020, by means of which the Criminal Chamber of this Court shelved the 'Ellacura case' by confirming the definitive dismissals in favor of those involved in the crime after considering that the crimes had prescribed.
Therefore, according to the new resolution of the judges of the Supreme Court of Justice appointed on May 1, 2021, "things return to the state in which they were before the issuance of said order", so that the dismissals are annulled by estimating that the previous Criminal Chamber "violates the rights of the relatives of the victims and of the society to the jurisdictional protection and to know the truth ".
In this sense, the brief indicates that the previous Criminal Chamber "violated fundamental rights of the victims and of society by closing the trial," which meant "obstacles to the victims' relatives and society in general from accessing the to the jurisdictional body so that it could rule on their claim and, therefore, justice and subsequent comprehensive reparation have not been possible. "
From now on, there may be justice in El Salvador, after the resolution of September 8, 2020 of the Criminal Chamber confirming the definitive dismissal of the ex-military Juan Orlando Zepeda, Francisco Elena Fuentes, has been annulled. and Rafael Humberto Larios, accused of being the masterminds of the crime. As a consequence of this, the criminal proceedings brought against them, as well as against Ren Castillo Ponce, Juan Rafael Bustillo, Inocente Orlando Montano and former Salvadoran president Alfredo Flix Cristiani had been declared completely null.
Thus, the Constitutional Chamber considers that the Criminal Chamber that issued the dismissal "failed to take into consideration that the facts denounced and that are intended to be investigated in the criminal process could be considered, at least provisionally, as crimes against humanity or crimes against humanity. war constituting serious violations of International Humanitarian Law ".
In other words, he adds, these are events of "extreme gravity, since the patterns, behaviors, or practices of violence in which they occurred are absolutely reprehensible, given the impact they have produced on the victims, the offended, society and the community. international community". For this reason, it points out that the cassation appeals filed in its day by the defendants who supposed their dismissal were admitted "improperly and were unconstitutionally resolved, so that things return to the state in which they were before the issuance of said order" .
THE LAST SENTENCE WAS IN SPAA
The last person to be convicted of these events was the former colonel and former Deputy Prime Minister of Public Security of El Salvador. Innocent Orlando Montano. The National Court of Spain condemned him on September 11, 2020 to 133 years as one of the masterminds of the massacre ordered by the Salvadoran Army in 1989. That day, Ignacio Ellacura and the also nationalized Spanish Jesuits from El Salvador, Ignacio Martín, were shot dead. Segundo Montes, Armando Lpez and Juan Ramn Moreno, as well as Joaqun Lpez, born in the Central American country, the employee Elba Julia Ramos and her 16-year-old daughter Celina Ramos.
Montano could be tried in Spain after a US judge, Kimberly Swank, approved his extradition, while, on the contrary, the Contentious Chamber of the Supreme Court of Justice of El Salvador rejected the arrest warrant issued by Spain. against 17 soldiers accused of the crime of the six priests and the two women. All of them had been arrested after on February 5, 2016, the National Civil Police of El Salvador and Interpol agents began an operation to arrest them a month after the judge of the National Court Eloy Velasco reiterated on January 5, that year the validity of a red alert in Interpol for the capture of these soldiers accused of terrorist murder and against humanity.
The murder of the six Jesuits and the two women occurred when a group of soldiers from the Salvadoran Army entered the Jos Simn Caas Central American University (UCA). In January 1992, a jury in El Salvador sentenced Colonel and former director of the Military School Guillermo Alfredo Benavides and Lieutenant Yussi Mendoza to 30 years in prison. However, in April 1993 they were released, after the General Amnesty Law was approved that year, to protect those involved in crimes during the civil war that ravaged the Central American country between 1980 and 1992. However, in July 2016 the The Supreme Court of Justice declared the Amnesty Law unconstitutional, which led Benavides back to jail, who is still in prison.
The President of El Salvador himself, Nayib Bukele, referred last night to the new resolution of the Criminal Chamber of the Supreme Court of Justice and stressed that "from now on, no crime will be tolerated" no matter how high it is. be the position of the person who commits it. He also remarked that the resolution of the Constitutional Chamber sends a message that "not only will the criminal be sought down there, that he will also be persecuted and we are not saying that it is worth stealing chickens, but for a greater crime now. The greater the charge, the greater the penalty and the repercussion that he must pay for having committed it. "
For Bukele, a "great message is being sent, both nationally and internationally that El Salvador is going to fight to achieve justice in this and other cases, but it is important to highlight this because it is a case that spent 30 years in impunity with the protection of the former Constitutional Chamber and of the former magistrates of the same and other chambers ". For this reason, he hopes that the judges "are up to the task to ensure that justice is done, because it is important since the message is sent that not only the criminal from below will be persecuted, but also the one from above. If really we want to fight against impunity, we must demonstrate it from the top down, just as the stairs are swept ", he concluded.
Among the people pointed out by the Attorney General is the former president of El Salvador Alfredo Cristiani (1989-1994) against whom the Asociación Pro Derechos Humanos de Espaa (APDHE) and the Center For Justice and Accountability (CJA) filed a complaint at the National High Court on November 13, 2008 for crimes against humanity, terrorism of State, murder and torture. In this complaint, former Defense Minister Humberto Larios and several military personnel were also included. For this reason, the Prosecutor said in his day that if the door is opened to start the case again, all those involved in this case will be prosecuted, including former President Cristiani. " Instead, Rodolfo Delgado stressed that the case would be reopened, so "we are going to pursue those responsible to achieve justice for these vile murders."
According to the criteria of
www.elmundo.es
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redpajama_set_name: RedPajamaCommonCrawl


ARTICLE OVERVIEW: Got the blues? Depression can sabotage your addiction recovery program. This article reviews when and how you can seek professional help for depression.
Numerous factors can trigger us to get off track with sobriety. Depression is one of them. In fact, this study found that people with alcohol use disorder (AUD) were 3.7 times more likely to experience a major depressive disorder than those without it. That means people in recovery have to realize they may have certain traits that make them prone to lapse into depression.
But, are you even depressed in the first place?
Sometimes it's difficult to determine if you're going through a low point…and if it's normal, or not. You can possibly bounce back from short-term depression without professional help. But sometimes intervention is necessary.
It's common for people in addiction recovery to feel sad for short periods, but clinical depression occurs when sadness — or other emotions like loss, frustration or worthlessness — persist for weeks at a time or even longer.Sometimes, a down mood can be so all-consuming that it's hard for us to remember when it started or when we last felt happy.
While experiencing clinical depression, people may discover that the things they once loved no longer bring them joy. They can have major changes in their appetites or sleep habits, have frequent thoughts of suicide, and have trouble concentrating or staying motivated.How can you know if you're clinically depressed, or not? A mood diary can help.
Keeping a mood diary is an excellent way to see how what you're feeling affects your life. One of the reasons why a mood diary could be so useful in learning whether it's time to get extra help is that it allows you to see the time frames surrounding moods, as well as the things that may have triggered them.
Learn something new, such as cooking food or playing an instrument.
Those things can also help keep the blues away, so they're useful as proactive measures as well as preventive techniques.
Conversely, a mood diary indicating a long stretch of depression could highlight how important it is to take the step of getting extra help from a professional. As a start, it could show just how long it has been since you have felt good about yourself.
Recovering addicts know how crucial it is for them to avoid medications that could cause them to fall into harmful usage patterns. However, they may not realize that a 2018 study of U.S. adults found that some well-known prescriptions cause depression.
Getting extra help may be as straightforward as being honest with a doctor and mentioning that a depressed feeling began soon after taking a new medication. Before moving forward with that approach, though, people should perform self-assessments so they can feel relatively confident that something else isn't causing the feeling.
If a person can assert that there are no other new factors in their life that could be causing depression, it should be easier for the doctor to establish that link, too. Seeing a doctor promptly after suspecting a connection between depressed feelings and new medication is crucial. Then, the person and their physician can determine if a different medication could resolve the downward mood plunge.
People sometimes know, deep down, that they're feeling different than usual but keep dismissing the change as something that's not serious. When that happens, the issue could progress into clinical depression even if it began as something less severe. Frequently, though, well-meaning individuals in a person's life will speak up and say that a person's mood has shifted.
That could be a sign that extra help is needed. For example, counselors are instrumental in the recovery process because they encourage recovery and help patients create relapse prevention plans. They may be among the first to point out that something has changed. On the other hand, a counseling session may only occur once a week or infrequently enough where the change may not be noticeable.
That's why the input from trustworthy friends is also worth taking into account. It may be difficult for someone to hear it at first, especially if they perceive that they are being judged or failing in their recovery efforts. However, most friends will gently persist and point out that they're saying something because they care and want the person to get help if it's necessary.
Everyone gets trapped in negative thought loops at least occasionally. When a person is in recovery, those negative thoughts could increase the probability of relapse. Some of the most common negative thoughts or beliefs conjured by people in recovery are that they are not capable of recovering, that others will judge them or that it is not possible to have fun without using.
When people let those negative thoughts take hold, they become anxious and could get depressed soon afterward. In some cases, people find that the negative thoughts make them feel paralyzed and unable to make progress in their recovery or other parts of life. They may become so fearful of what the negative thoughts tell them that they get fixated by expectations of catastrophes.
When negative thoughts become so dominant they regularly prevent you from sleeping, concentrating, or engaging in typical activities, that's a sign that you need to seek help from a professional. If you can usually shut those negative thoughts down with rationalization but have difficulty being successful occasionally, a friend with a listening ear may be able to alter that perspective that could otherwise lead to depression.
A person in recovery learns how important it is to cut ties with people who may encourage them to use, such as the individuals they spent time with at bars or those who were their drug dealers. Taking that step could be especially hard in intimate relationships that are abusive.
Perpetrators love to exert control, and they often do that by demeaning their victims. Hearing hurtful words from a partner who's supposed to be loving is extraordinarily damaging and can wreak havoc on a person's mental state. If someone starts to believe what an abuser says, depression could occur. That's especially likely to happen when those individuals don't have opposing input from people who help them see their worth.
Scientists have found that addictive substances affect genders differently and that women who experience domestic abuse are at an increased risk of using substances. It's easy to see, then, why a history of substance abuse and the act of being in an abusive relationship could disrupt a person's recovery and cause strong, negative emotions that could spiral into depression.
Even if a relationship is not abusive, it's still important for people — especially those in recovery — to monitor how they feel after being around certain friends or family members. If it seems some individuals make them question their self-worth, their progress in recovery and other factors, it may be necessary to limit the amount of time spent around them. Otherwise, a momentary down mood could turn into depression.
Similarly, it's crucial for those in recovery to surround themselves with others who understand the challenges of overcoming dependency and are honest with them, but don't give feedback that's ultimately degrading or show behavior that's otherwise abusive or unhealthy. Having a supportive network of friends is especially worthwhile when aspects of recovery become tough.
Keeping a routine can help stave off depression… and getting out of the house for scheduled activities is often part of sticking to a daily plan. But depressed people often discover that the things they once enjoyed no longer give them pleasure. If you continually spends more time coming up with excuses not to attend recovery activities, it's a signal that extra help is likely needed to overcome a probable instance of depression.
Another sign of depression is that people sleep more than usual. They may also have trouble getting out of bed and find they lack the motivation to do so. Together, these factors could mean recovering addicts gradually stop going to 12-step meetings, counseling sessions and other recovery-related appointments.
In any case, it's helpful to have at least one friend who will hold you accountable and realize that you can't just stay home even if that's what a down mood tells them to do. Proactively asking that a person call you or show up on your doorstep to demand you get out of the house could you from ceasing engagement with the recovery process.Moreover, that caring and motivating friend may be the first person who detects that you are experiencing depression and not only a low mood that will soon pass, necessitating a professional intervention.
We've covered some of the symptoms of depression, but it's ideal for people in recovery to research those in more depth and become familiar with them. Then, they should be more able to spot problems in themselves and seek help. However, the symptoms don't always present in clear-cut ways.
If a person thinks to themselves, "I just don't feel like myself," and that awareness persists for weeks, that's another indicator it's time to get more help. People should remember that realizing extra help is required doesn't show weakness — it displays strength.


LAS VEGAS (AP) — A jury has ended a second full day of deliberations with no verdict in the federal trial of six men who brought assault-style weapons to a standoff that stopped government agents from rounding up cattle near Cliven Bundy's ranch in April 2014.
A court official said Tuesday the U.S. District Court jury will return to work Wednesday.
The jury deliberated about three hours Thursday before returning for a full day Monday.
Trial took two months, and each defendant faces 10 charges including threatening and assaulting a federal officer, extortion, obstruction, weapon violations and conspiracy.
The standoff near Bunkerville ended when the federal Bureau of Land Management gave up the roundup.
That was seen as a victory by states' rights advocates in an ongoing battle over federal control of vast rangelands in the West.


text:
THE GIRL ON THE TRAIN is an average fare, but it impresses due to the fast-paced narrative and performances.
February 26, 2021 by Techno Sunil
The Girl On The Train review {2.5/5} and review rating
Parineeti Chopra started off brilliantly with bubbly and light-hearted roles and this became her trademark. After a hiatus, she is back and her 2.0 cinematic avatar promises to be unlike anything she has done in the past. The Girl on the Train is the first film of her new era. The film was scheduled to release in theaters on Mother's Day 2020. But due to the pandemic, it has made its way to Netflix. So does The Girl on the Train manage to impress the audience and have a thrilling time? Or does it fail in its attempt? Let's analyze.
Girl in the Train is the story of a troubled alcoholic who gets involved in the murder of a girl he hardly knows. Meera Kapoor (Parineeti Chopra), who lives in London, is happily married to Shekhar (Avinash Tiwari). Mira takes up the case of an African man who is killed in a shootout. He then receives threats from the family of accused Jimmy Baga. Nevertheless, she proves in court that Jimmy is the killer. Jimmy Baga has been sent to jail. On the same day Meera learns that she is pregnant. 6 months later, Mira is in a happy place as motherhood is something she deeply aspires to. Unfortunately, Meera and Shekhar get into a car accident. Meera has a miscarriage. Her doctor tells her that she is not fit to conceive again. Meera breaks down and turns to alcohol to make up for the loss. She drinks so much that she becomes violent and suffers from blackouts. And then the next day he doesn't remember anything. While he is intoxicated, Meera assaults Shekhar and also insults his boss, due to which Shekhar is fired. Shekhar finally divorces Meera. Meera also loses her job. With nothing else to do in life, she begins traveling by train from London to its suburbs and back. On the way, she crosses the place where her house with Shekhar is located. However, right next to Shekhar's house, Meera sees Nusrat John (Aditi Rao Hydari). Whenever her train passes near her house, Meera starts watching her. Meera sees Nusrat leading a lovely married life with Anand Joshi (Simon Ahmed). She also sees Nusrat dancing carelessly in the world. Meera wishes that she had a life like Nusrat. However, one day Meera sees Nusrat hugging someone who is not her husband. The way Nusrat hugs, it is known that their affair is going on. Meera broke down. The perfect image of Nusrat that she had created in her mind has been shattered and this has angered her. She feels that she should not cheat on her husband as she knows the pain. This is because Shekhar also started an affair with Anjali (Natasha Benton), with whom he is now happily married. Meera therefore decides to teach Nusrat a lesson. She goes to the latter's house but the house remains locked. Then she sees him in the nearby forest. Meera accuses him and then blacks out. Meera wakes up at her home with a wound on her forehead and no memory of the previous night. Nusrat goes missing the next day. Officer Kaur (Kirti Kulhari) comes on board to investigate. During his investigation, he learns that Meera had come to meet Nusrat in anger and hence, Meera becomes the prime suspect. A few days later Nusrat's body was found in the same forest. What happens next becomes the rest of the story.
The Girl on the Train is based on the 2016 Hollywood film of the same name, which was adapted from the bestselling novel by Paula Hawkins. The Hindi remake is not a scene-by-scene remake of the Emily Blunt-starrer and the makers have added new characters and plot points, which will surprise those who have watched the original film. Ribhu Dasgupta's screenplay (additional screenplay by Videsh Malandkar) is average. Although it is entertaining and fast-paced, there is no character development of the supporting characters. The dialogues of Gaurav Shukla and Abhijeet Khuman are excellent.
Ribhu Dasgupta's direction is not good. Talking about the merits, he manages to woo the audience. There is a lot going on in the film and he does not let the audience's attention wander even for a moment. There was a lot of non-linear narrative in the original flick. Ribhu simplifies this to a great extent. Some of the scenes are extraordinary and at the same time, he manages to extract the best performance from his actors. On the other hand, he mainly focuses on Parineeti Chopra's character. The original film also focused on the supporting characters and their backstories, and the dynamics between the various characters. Here, it doesn't suffice. Even those who haven't seen the original will feel the drawback and won't be able to connect with some of the characters. Also, the ending has been changed from the original film and novel. Ribhu has added a double twist. The effort doesn't really work out because the original, second twist is flawed and full of cinematic liberties.
Parineeti on The Girl On The Train: "I just fell on the floor and I burst into tears, I started…"
The girl on the train starts an interesting note. In the first 20 minutes, the makers presented the trajectory in Meera's rollercoaster life. The parallel track of Nusrat's disappearance is also interesting. As the film progresses, more and more characters are added to the story. But one realizes that they do not have much to do. This hinders the effect to a great extent. Still, various developments in the last 45 minutes are on the edge of seats. The ending should have been the best part of the venture, but instead, it's devoid of logic.
Parineeti Chopra has given a stellar performance and will surely benefit from this film. She surprises the audience as she has never entered the field before and has managed to put on a solid performance. As a chronic alcoholic, she is good enough. Kirti Kulhari dazzles with her on-screen presence and dialogue delivery. Aditi Rao Hydari is lovely and one wishes she had a bigger role, especially since her character is crucial to the plot. Avinash Tiwari is dependable as always. Natasha Benton and Simon Ahmed don't get any scope at all. The same goes for Tota Roy Chowdhury (Dr. Hamid). Visakh Vadgama (Kunal; junior police officer), Diljohn Singh (Rajeev), Monisha Hassan (Zehra; Shekhar's boss) and Suresh Sippy (Meera's doctor) are fine.
Music is surprisingly good but it doesn't have a shelf life. 'Cheated ring' Quite attractive. 'Meanwhile friends' Well woven with the narrative. 'You are my queen' worth forgetting. The background score of Gilead Benaram adds to the excitement.
Tribhuvan Babu Sadaneni's cinematography is simple yet effective. Sunil Nigvekar's production design is rich. The costumes of Subodh Srivastava and Sanam Ratansi are very attractive and yet realistic and harmonize with the respective personality of the character. Mithali Vakil's makeup is commendable, especially the wound on Parineeti's forehead. Music Editing by Prakash Varghese is slick.
Overall, the girl in the train is an average fare. It impresses with its fast-paced narrative and performances, especially by Parineeti Chopra. But the lack of character development and flawed climax proves detrimental.


text:
Q: NullPointerException on expired session I'm using Spring, and I need to expire the session of a user when I update said user. I'm using the following configuration:
@Bean
@Override
public AuthenticationManager authenticationManagerBean () throws Exception {

    return super.authenticationManagerBean();

}

@Bean
public SessionRegistry sessionRegistry () {

    return new SessionRegistryImpl();

}
@Bean
public ServletListenerRegistrationBean httpSessionEventPublisher() {    //(5)
    return new ServletListenerRegistrationBean(new HttpSessionEventPublisher());
}

@Override
public void configure(AuthenticationManagerBuilder authenticationMgr) throws Exception {

    authenticationMgr.userDetailsService(inMemoryUserDetailsManager());

}

@Override
protected void configure (HttpSecurity http) throws Exception {

    http.authorizeRequests()
        .antMatchers("*.jsp").authenticated()
        .and()
            .formLogin().loginPage("/login.html")
            .defaultSuccessUrl("/")
            .failureUrl("/login.html?failed=1")
            .usernameParameter("email").passwordParameter("password")
        .and()
            .logout().logoutUrl("/logout.html")
        .and()
            .logout().logoutSuccessUrl("/")
        .and()
            .sessionManagement()
            .maximumSessions(100)
            .maxSessionsPreventsLogin(true)
            .expiredUrl("/ejercicios-programacion/")
            .sessionRegistry(sessionRegistry());

}

And this is how I expire sessions:
public void expireUserSessions(String username) {
    for (Object principal : sessionRegistry.getAllPrincipals()) {
        if (principal instanceof User) {
            UserDetails userDetails = (UserDetails) principal;
            if (userDetails.getUsername().equals(username)) {
                for (SessionInformation information : sessionRegistry.getAllSessions(userDetails, false)) {
                    information.expireNow();
                }
            }
        }
    }
}

When this is done, and I reload the page on the browser where I had my updated user, it will show the Exception:
java.lang.NullPointerException
org.springframework.security.web.session.ConcurrentSessionFilter$1.onExpiredSessionDetected(ConcurrentSessionFilter.java:107)

Which redirects to:
@Override
public void onExpiredSessionDetected(SessionInformationExpiredEvent event) throws IOException, ServletException {
    HttpServletRequest request = event.getRequest();
    HttpServletResponse response = event.getResponse();
    SessionInformation info = event.getSessionInformation();

    redirectStrategy.sendRedirect(request, response, determineExpiredUrl(request, info));
}

In particular, it's the last line of code the one throwing the exception. If I reload the page again, after getting the exception, then everything is fine; I get no exception and I'm logged out. I have no idea why this is happening. Does anybody know?

A: Ok, I finally managed to solve this problem. The answer is to use your own ConcurrentSessionFilter, since many of the methods used by the default one are deprecated. Add this bean:
 @Bean public ConcurrentSessionFilter concurrentSessionFilter() {

    ConcurrentSessionFilter c = new ConcurrentSessionFilter(sessionRegistry(), new SessionInformationExpiredStrategy() {

        @Override
        public void onExpiredSessionDetected(SessionInformationExpiredEvent event) throws IOException, ServletException {

            HttpServletRequest request = event.getRequest();
            HttpServletResponse response = event.getResponse();
            SessionInformation info = event.getSessionInformation();

            redirectStrategy().sendRedirect(request, response, "/ejercicios-programacion/");

        }
    });

    return c;

}

And do whatever you want in the overwritten method, in my case I used my new RedirectStrategy to move users to the index page.
And then add this to your config method:
protected void configure (HttpSecurity http) throws Exception {

    ...
    // Whatever you want to configure

    http.addFilterBefore(concurrentSessionFilter(), ConcurrentSessionFilter.class);

}

I can't believe how unintuitive this was, I don't know how such a simple thing as expiring sessions can be so hard and obtuse in Spring

redpajama_set_name: RedPajamaStackExchange


In order to make a routine and stick to the routine is to believe in yourself, and when you fall off just dust your self off and get back on track. Routines are good for people who do the same things every day and like to stay on schedule and in order. Routines are also good for little ones, if you have any. It helps them prepare for what is to come next. So to begin your routine you must first decide what you want to get done and if this will be your morning routine, before or after work, before bed, or even a weekend routine.
So I have a pretty consistent schedule. Monday through Friday I work 7 AM-4 PM, I take my baby to daycare and pick her up and the weekends I'm a little free. During the week, in the mornings I know I have to make our lunch and breakfast for the day. Usually they are already cooked I just have to put it in the bag. Then I also want to work out in the mornings, because I don't seem to have time to do it through out the rest of the day and baby can be sleep while I work out. Then the rest is getting us ready for the day and getting out the door before 6:15 AM. Ha!
The Schedule I decided for my self is 4 AM- *DING*DING*DING* alarm goes off 4:10 – Finally get out of bed 4:15 pick a work out video from YouTube and make my apple cider vinegar lemon water drink 4:20/4:30 begin work out 5:00 AM- finish work out, Finish morning drink 5:10, then I get ready, 5:45 ish Wake baby up and get her ready 6:05 AM- pack lunches/breakfast, baby is playing/ running around the house 6:15 ish leave the house I know I gave myself a lot of time to accomplish these small tasks but I don't think I'm a morning person and sometimes i still be running late. I really be lazy and tired, but by the time I get to work and have my coffee I'm ready for another day! A routine doesn't have to be time specific, for my morning routine as long as I work out first and get out the door on time it doesn't matter what I do first or last, sometimes I get baby dressed before me and I'll have lunch packed then all I have to do is shower and get ready then leave. If your thinking of doing a night time routine, just write down what you want to get done and when would you like to relax or go to bed or whatever. Then develop the routine backwards.
EXAMPLE: You want to be in the bed by 9 PM, so 9 PM- be in bed! 8:30- shower/wash face 8:00 PM- get ready for tomorrow, 7 put away dinner, pack lunch, spend time on social media/ or with family. 6:30 eat dinner 5:30 start cooking dinner 5 get home from work.
Well I hope you got the idea. I hope this helped you create a routine for your life. Routines are very convenient and help you get back on track in life. Write out your routine and post it on your wall, somewhere were you will look at it every day and become consistent and good luck to you!
Leave me a comment on whats apart of your routine and how do you stay consistent!
How to have a POPPIN 2019 !


There's no better way to get an impression of a travel destination than to see how people who've been there experienced their visit.
We've checked out the most recent Instagram posts hashtagged, #grandsunsetgiliair, and our jaws dropped. Sure, we've seen these views before, but it's refreshing to see them through the eyes of someone who's visiting. Check out these posts at your own risk – you might just be on a plane sooner than you think!
We aren't called Grand Sunset Gili Air for nothing!
Beach cocktails? Don't mind if we do!
Don't forget to follow Grand Sunset Gili Air on Instagram and Facebook for the latest updates and beautiful views on the island, and please use the hashtag, #grandsunsetgiliair on your next visit to paradise.
What makes Gili Air unique?


The Game Boy is an 8-bit handheld video game device developed and manufactured by Nintendo. It was released in Japan on April 21, 1989, in North America in August 1989, and in Europe on September 28, 1990, meaning that it's anniversary of its first release was on Monday!!
It is the first handheld console in the Game Boy line, and was created by Gunpei Yokoi and Nintendo Research & Development.
When the Game Boy was first released it was released into Japan. It is here that all 300,000 units of stock were sold within the first two weeks. When it went over to the United States to be released it sold 40,000 units on its very first day!!
Research from 1995 stated that 46% of Game Boy' users were female, which was much higher then any of Nintendo's other products, proving the great popularity of the Game Boy.


Savings with Softball Sales coupon codes and promo codes in April 2019. Today's top Softball Sales coupon: Free Standard Ground Shipping on $99+.
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Softball.com is an American-based retailer of premium quality softball gear, apparel and footwear. Currently, it is offering savings of $64.98 on the purchase of the All Star "Player Series 12-16 Catcher's Set" and knee savers are included in the set for free. Customers recommend Softball Sale for its low prices and excellent customer service.


Townhobo ("us", "we", or "our") operates www.townhobo.com (the "Site"). This page informs you of our policies regarding the collection, use and disclosure of Personal Information we receive from users of the Site.
When ordering or registering on our site, as appropriate, you may be asked to enter your name, email address, mailing address, phone number, Website Address or other details to help you with your experience.


Now you don't have to switch back to Moodle to get access to employee training – you can do it right from Salesforce!
Data originating from Moodle can be used to run custom reports from Salesforce thanks to our integration.
With SSO log into either Moodle or Salesforce just once and enjoy free movement between the two platforms via the dashboard.
From one tab on the Salesforce dashboard you can access all of Moodle's features and records. Users can view course material, assign courses and even use social tools – all from the comfort of the Salesforce platform.
Certifications, completions and statuses are automatically captured from Moodle by Salesforce.
User and organizational data from Salesforce (name, address, birth date, social security number etc.) is automatically pushed and synced to Moodle, and you can even view Moodle learning records from within Salesforce.


text:
Nuneaton är en stad i grevskapet Warwickshire i England. Staden är huvudort i distriktet Nuneaton and Bedworth och ligger vid Coventry Canal, 13 kilometer norr om Coventry samt 30 kilometer öster om Birmingham. Tätortsdelen (built-up area sub division) Nuneaton hade 86 552 invånare vid folkräkningen år 2011.

Staden var tidigare känd för sin industri: järnverk, textilindustrier och omgivande kolgruvor. Staden nämndes i Domedagsboken (Domesday Book) år 1086, och kallades då Etone.

Referenser

Externa länkar

Orter i Warwickshire
Unparished areas i Warwickshire
Tidigare civil parishes i Warwickshire
Domesday Book


The Russian cyber security company Kaspersky Lab announced yesterday that they have filed a complaint against Apple for the Russian FAS (Federal Antimonopoly Service of Russia) for what they believe to be the tendency to be monopolistic at Apple's application-buying store.
Kaspersky Lab is number two in the series, barely one week after Spotify received a whole industry's attention to them as they complained to Apple for the European Commission in the hope that the US company would comply with new and fairer rules.
The cybersecurity company goes after Apple to overcome their pattern of action which, according to Kaspersky Lab, is that the company is positioning itself as both a platform owner and a kind of guide on the App Store to prevent other developers from operating with the same conditions as they do.
The Russian company specifically mentions the Screen Time feature found in iOS 12. They believe Apple last year knocked down their application Kaspersky Safe Kids where parents could use it to monitor children's use on iOS devices.
This was removed, according to Kaspersky Labs, with what Apple justified in using some configuration profiles that are not in compliance with the App Store policy, specifically one for controlling applications and another for blocking in Safari.
The two configurations were soon used by Apple in the Screen Time feature introduced with iOS 12 and sharing many of the same elements.
Kaspersky tells in their post that they hope FAS forces Apple to make changes to its App Store practice so that the various players together with Apple can compete on the same basis.