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Structure, Expression, and Regulation of the HIV Genome
Thomas J. Hope, PhD, The Salk Institute
Didier Trono, MD, The Salk Institute
Viral Proteins and Their Functions
Structural Proteins
Gag-Pol Precursor
Integrase (In)
Regulatory Proteins
Accessory Proteins
Regulation of HIV Gene Expression
Transcription of the Proviral Genome
Regulation of Transcription
mRNA Splicing and Cellular Localization
Figure 1. Expression of the HIV-I Genome
Presentations, Interviews, and Roundtable Discussions
The integrated form of HIV-1, also known as the provirus, is approximately 9.8 kilobases in length.(1) Both ends of the provirus are flanked by a repeated sequence known as the long terminal repeats (LTRs). The genes of HIV are located in the central region of the proviral DNA and encode at least nine proteins (Figure 1).(2) These proteins are divided into three classes:
The major structural proteins, Gag, Pol, and Env
The regulatory proteins, Tat and Rev
The accessory proteins, Vpu, Vpr, Vif, and Nef
The first part of this chapter reviews the individual viral proteins and their functions. The second part discusses factors regulating the transcription and processing of viral mRNA.
The gag gene gives rise to the 55-kilodalton (kD) Gag precursor protein, also called p55, which is expressed from the unspliced viral mRNA. During translation, the N terminus of p55 is myristoylated,(3) triggering its association with the cytoplasmic aspect of cell membranes. The membrane-associated Gag polyprotein recruits two copies of the viral genomic RNA along with other viral and cellular proteins that triggers the budding of the viral particle from the surface of an infected cell. After budding, p55 is cleaved by the virally encoded protease(4) (a product of the pol gene) during the process of viral maturation into four smaller proteins designated MA (matrix [p17]), CA (capsid [p24]), NC (nucleocapsid [p9]), and p6.(4)
The MA polypeptide is derived from the N-terminal, myristoylated end of p55. Most MA molecules remain attached to the inner surface of the virion lipid bilayer, stabilizing the particle. A subset of MA is recruited inside the deeper layers of the virion where it becomes part of the complex which escorts the viral DNA to the nucleus.(5) These MA molecules facilitate the nuclear transport of the viral genome because a karyophilic signal on MA is recognized by the cellular nuclear import machinery. This phenomenon allows HIV to infect nondividing cells, an unusual property for a retrovirus.(6)
The p24 (CA) protein forms the conical core of viral particles. Cyclophilin A has been demonstrated to interact with the p24 region of p55 leading to its incorporation into HIV particles.(7,8) The interaction between Gag and cyclophilin A is essential because the disruption of this interaction by cyclosporine A inhibits viral replication.(9)
The NC region of Gag is responsible for specifically recognizing the so-called packaging signal of HIV.(10) The packaging signal consists of four stem loop structures located near the 5' end of the viral RNA, and is sufficient to mediate the incorporation of a heterologous RNA into HIV-1 virions.(11) NC binds to the packaging signal through interactions mediated by two zinc-finger motifs. NC also facilitates reverse transcription.(12)
The p6 polypeptide region mediates interactions between p55 Gag and the accessory protein Vpr, leading to the incorporation of Vpr into assembling virions.(13) The p6 region also contains a so-called late domain which is required for the efficient release of budding virions from an infected cell.
The viral protease (Pro), integrase (IN), RNase H, and reverse transcriptase (RT) are always expressed within the context of a Gag-Pol fusion protein.(14) The Gag-Pol precursor (p160) is generated by a ribosomal frame shifting event, which is triggered by a specific cis-acting RNA motif(15) (a heptanucleotide sequence followed by a short stem loop in the distal region of the Gag RNA). When ribosomes encounter this motif, they shift approximately 5% of the time to the pol reading frame without interrupting translation. The frequency of ribosomal frameshifting explains why the Gag and the Gag-Pol precursor are produced at a ratio of approximately 20:1.
During viral maturation, the virally encoded protease cleaves the Pol polypeptide away from Gag and further digests it to separate the protease (p10), RT (p50), RNase H (p15), and integrase (p31) activities. These cleavages do not all occur efficiently, for example, roughly 50% of the RT protein remains linked to RNase H as a single polypeptide (p65).
The HIV-1 protease is an aspartyl protease(16) that acts as a dimer. Protease activity is required for cleavage of the Gag and Gag-Pol polyprotein precursors during virion maturation as described previously. The three-dimensional structure of the protease dimer has been determined.(17,18) Knowledge of this structure has led to a class of drugs directed toward inhibiting the HIV protease function. These antiviral compounds have greatly improved treatment for HIV-infected individuals.
The pol gene encodes reverse transcriptase. Pol has RNA-dependent and DNA-dependent polymerase activities. During the process of reverse transcription, the polymerase makes a double-stranded DNA copy of the dimer of single-stranded genomic RNA present in the virion. RNase H removes the original RNA template from the first DNA strand, allowing synthesis of the complementary strand of DNA. Viral DNA can be completely synthesized within 6 hours after viral entry, although the DNA may remain unintegrated for prolonged periods.(19) Many cis-acting elements in the viral RNA are required for the generation of viral DNA. For example, the TAR element, a small RNA stem-loop structure located at the 5' end of viral RNAs and containing the binding site for Tat, is required for the initiation of reverse transcription.(20) The predominant functional species of the polymerase is a heterodimer of p65 and p50. All of the pol gene products can be found within the capsid of free HIV-1 virions. Because the polymerase does not contain a proof-reading activity, replication is error-prone and introduces several point mutations into each new copy of the viral genome. The crystal structure of HIV-1 RT has been determined.(21)
The IN protein mediates the insertion of the HIV proviral DNA into the genomic DNA of an infected cell. This process is mediated by three distinct functions of IN.(22) First, an exonuclease activity trims two nucleotides from each 3' end of the linear viral DNA duplex. Then, a double-stranded endonuclease activity cleaves the host DNA at the integration site. Finally, a ligase activity generates a single covalent linkage at each end of the proviral DNA. It is believed that cellular enzymes then repair the integration site. No exogenous energy source, such as ATP, is required for this reaction. The accessibility of the chromosomal DNA within chromatin, rather than specific DNA sequences, seems to influence the choice of integration sites.(23) Sites of DNA kinking within chromatin are thus "hot-spots" for integration, at least in vitro.(24) It is possible to promote integration within specific DNA regions by fusing integrase to sequence-specific DNA binding proteins.(25) Preferential integration into regions of open, transcriptionally active, chromatin may facilitate the expression of the provirus. Viral genes are not efficiently expressed from nonintegrated proviral DNA.(26)
The 160 kD Env (gp160) is expressed from singly spliced mRNA. First synthesized in the endoplasmic reticulum, Env migrates through the Golgi complex where it undergoes glycosylation with the addition of 25 to 30 complex N-linked carbohydrate side chains that are added at asparagine residues. Env glycosylation is required for infectivity.(27) A cellular protease cleaves gp160 to generate gp41 and gp120. The gp41 moeity contains the transmembrane domain of Env, while gp120 is located on the surface of the infected cell and of the virion through noncovalent interactions with gp41. Env exists as a trimer on the surface of infected cells and virions.(28)
Interactions between HIV and the virion receptor, CD4, are mediated through specific domains of gp120.(29) The structure of gp120 has recently been determined.(30) The gp120 moeity has nine highly conserved intrachain disulfide bonds. Also present in gp120 are five hypervariable regions, designated V1 through V5, whose amino acid sequences can vary greatly among HIV-1 isolates. One such region, called the V3 loop, is not involved in CD4 binding, but is rather an important determinant of the preferential tropism of HIV-1 for either T lymphoid cell lines or primary macrophages.(31) Sequences within the V3 loop interact with the HIV co-receptors CXCR4 and CCR5, which belong to the family of chemokine receptors and partially determine the susceptibility of cell types to given viral strains.(32,33) The V3 loop is also the principal target for neutralizing antibodies that block HIV-1 infectivity.(34) The gp120 moeity also interacts with the protein DC-SIGN which is expressed on the cell surface of dendritic cells. Interaction with DC-SIGN increases the efficiency of infection of CD4 positive T cells.(35) Further, it is believed that DC-SIGN can facilitate mucosal transmission by transporting HIV to lymphoid tissues. The gp41 moiety contains an N-terminal fusogenic domain that mediates the fusion of the viral and cellular membranes, thereby allowing the delivery of the virions inner components into the cytoplasm of the newly infected cell.(36) A new class of antiviral therapeutics, which prevent membrane fusion, are showing promise in clinical trials.
Tat is a transcriptional transactivator that is essential for HIV-1 replication.(37) The 72 and 101 amino acid long forms of Tat are expressed by early fully spliced mRNAs or late incompletely spliced HIV mRNAs, respectively. Both forms function as transcriptional activators and are found within the nuclei and nucleoli of infected cells. Tat is an RNA binding protein, unlike conventional transcription factors that interact with DNA.(38,39) Tat binds to a short-stem loop structure, known as the transactivation response element (TAR), that is located at the 5' terminus of HIV RNAs. Tat binding occurs in conjunction with cellular proteins that contribute to the effects of Tat. The binding of Tat to TAR activates transcription from the HIV LTR at least 1000-fold.
The mechanism of Tat function has recently been elucidated. Tat acts principally to promote the elongation phase of HIV-1 transcription, so that full-length transcripts can be produced.(40,41) In the absence of Tat expression, HIV generates primarily short (>100 nucleotides) transcripts. Stimulation of polymerase elongation is accomplished by the recruitment of a serine kinase which phosphorylates the carboxylterminal domain (CTD) of RNA polymerase II. This kinase, which is known as CDK9, is part of a complex which binds directly to Tat.(42) Tat function requires a cellular co-factor, known as Cyclin T, which facilitates the recognition of the TAR loop region by the Cyclin T-Tat complex.(43) The cellular uptake of Tat released by infected cells has been observed,(41) although the impact of this phenomenon on pathogenesis is unknown. Tat has been shown to activate the expression of a number of cellular genes including tumor necrosis factor beta(44) and transforming growth factor beta,(45) and to downregulate the expression of other cellular genes including bcl-2(46) and the chemokine, MIP-1 alpha.(47)
Rev is a 13-kD sequence-specific RNA binding protein.(48) Produced from fully spliced mRNAs, Rev acts to induce the transition from the early to the late phase of HIV gene expression.(49) Rev, which is encoded by two exons, accumulates within the nuclei and nucleoli of infected cells. Rev binds to a 240-base region of complex RNA secondary structure, called the Rev response element (RRE), that lies within the second intron of HIV.(50) Rev binds to a "bubble" within a double-stranded RNA helix containing a non-Watson-Crick G-G basepair.(51) This structure, known as the Rev high affinity binding site, is located in a region of the RRE known as stem loop 2.
The binding of Rev to the RRE facilitates the export of unspliced and incompletely spliced viral RNAs from the nucleus to the cytoplasm. Normally, RNAs that contain introns (ie, unspliced or incompletely spliced RNA) are retained in the nucleus. High levels of Rev expression can lead to the export of so much intron containing viral RNA that the amount of RNA available for complete splicing is decreased, which, in turn, reduces the levels of Rev expression. Therefore, this ability of Rev to decrease the rate of splicing of viral RNA generates a negative feedback loop whereby Rev expression levels are tightly regulated.(52)
Rev has been shown to contain at least three functional domains.(53) An arginine-rich RNA binding mediates interactions with the RRE. A multimerization domain is required for Rev to function.(54) Rev is believed to exist as a homo-tetramer in solution.(55) Rev also contains an effector domain, which is a specific nuclear export signal (NES).(56,57) The export of the viral RNA by Rev is through a pathway typically used by the small nuclear RNAs (snRNAs) and the ribosomal 5s RNA rather than the normal pathway for cellular mRNAs.(57) Rev Export is mediated through interactions with the NES receptor known as CRM1. NES mutants of Rev are dominant negative.(53) Inhibition is caused by the formation of non-functional multimers between NES-mutant and wild type Rev monomers.(58) Rev is absolutely required for HIV-1 replication: proviruses that lack Rev function are transcriptionally active but do not express viral late genes and thus do not produce virions.
In addition to the gag, pol, and env genes contained in all retroviruses, and the tat and rev regulatory genes, HIV-1 contains four additional genes: nef, vif, vpr and vpu, encoding the so-called accessory proteins. HIV-2 does not contain vpu, but instead harbors another gene, vpx. The accessory proteins are not absolutely required for viral replication in all in vitro systems, but represent critical virulence factors in vivo. Nef is expressed from a multiply spliced mRNA and is therefore Rev independent. In contrast, Vpr, Vpu, and Vif are the product of incompletely spliced mRNA, and thus are expressed only during the late, Rev-dependent phase of infection from singly spliced mRNAs. Most of the small accessory proteins of HIV have multiple functions as described below.
Nef (an acronym for negative factor) is a 27-kD myristoylated protein that is encoded by a single exon that extends into the 3' LTR. Nef, an early gene of HIV, is the first viral protein to accumulate to detectable levels in a cell following HIV-1 infection.(49) Its name is a consequence of early reports claiming that Nef down-regulated transcriptional activity of the HIV-1 LTR. It is no longer believed, however, that Nef has a direct effect on HIV gene expression. Nef has been shown to have multiple activities, including the downregulation of the cell surface expression of CD4, the perturbation of T cell activation, and the stimulation of HIV infectivity.
Nef acts post-translationally to decrease the cell-surface expression of CD4, the primary receptor for HIV.(59) Nef increases the rate of CD4 endocytosis and lysosomal degradation.(60) The cytoplasmic tail of CD4, and in particular a dileucine repeat sequence contained in its membrane proximal region, is key for the effect of Nef on CD4.(60) CD4 downregulation appears to be advantageous to viral production because an excess of CD4 on the cell surface has been found to inhibit Env incorporation and virion budding.(61,62) Nef also down-regulates the cell surface expression of Class I MHC, albeit to a lesser degree.(63) The downregulation of Class I MHC decreases the efficiency of the killing of HIV infected cells by cytotoxic T cells.
Nef perturbs T cell activation. Studies in the Jurkat T cell line indicated that Nef expression has a negative effect on induction of the transcription factor NF-kappa B and on IL-2 expression.(64) In contrast, results obtained in Nef transgenic mice revealed that Nef led to elevated T cell signalling.(65) The expression of a CD8-Nef chimeric molecule in Jurkat cells had either positive or negative effects depending on the cellular localization of the hybrid Nef molecule.(66) When the CD8-Nef protein accumulated in the cytoplasm, there was a block in normal signaling through the T cell receptor. When the CD8-Nef chimera was expressed at high levels on the cell surface, however, spontaneous activation followed by apoptosis was detected. Together, these observations suggest that Nef can exert pleiomorphic effects on T cell activation depending on the context of expression. Consistent with this model, Nef has been found to associate with several different cellular kinases that are present in helper T lymphocytes.
Nef also stimulates the infectivity of HIV virions.(67) HIV-1 particles produced in the presence of Nef can be up to ten times more infectious than virions produced in the absence of Nef. Nef is packaged into virions, where it is cleaved by the viral protease during virion maturation.(68) The importance of this event, however, is not clear. Virions produced in the absence of Nef are less efficient for proviral DNA synthesis, although Nef does not appear to influence directly the process of reverse transcription.(69) The downregulation of CD4 and the effect on virion infectivity by Nef are genetically distinct as demonstrated by certain mutations that affect only one of these two activities.(70)
There is compelling genetic evidence that the Nef protein of simian immunodeficiency virus is absolutely required for high-titer growth and the typical development of disease in adult animals.(71) It is possible, however, for Nef-defective mutants of SIV to cause disease in newborn animals.(72) Further, Nef-defective virions do cause an AIDS-like disease in infected animals although onset is delayed.(73)
The Vpr protein is incorporated into viral particles. Approximately 100 copies of Vpr are associated with each virion.(74) Incorporation of Vpr into virions is mediated through specific interactions with the carboxyl-terminal region of p55 Gag,(19) which corresponds to p6 in the proteolytically processed protein.
Vpr plays a role in the ability of HIV to infect nondividing cells by facilitating the nuclear localization of the preintegration complex (PIC).(75) Vpr is present in the PIC. However, rather than tethering additional nuclear localization signals to the PIC, Vpr may act as a nucleocytoplasmic transport factor by directly tethering the viral genome to the nuclear pore. Consistent with this model, Vpr expressed in cells is found associated with the nuclear pore and can be biochemically demonstrated to bind to components of the nuclear pore complex.(76) Vpr can also block cell division.(77) Cells expressing Vpr accumulate in the G2 phase of the cell cycle.(78) The expression of Vpr has been shown to prevent the activation of the p34cdc2/cyclin B complex, which is a regulator of the cell cycle important for entry into mitosis.(79,80) Accordingly, expression of a constitutively active mutant of p34cdc2 prevents the Vpr-induced accumulation of cells in the G2 phase of the cell cycle.
Vpr has also been shown to interact with the cellular protein uracil-DNA glycosylase (UNG).(81) The biological consequences of this phenomenon have yet to be determined. Another enzyme involved with the modification of deoxyuracil (dUTP), deoxyuracil phosphatase (dUTPase), is expressed by two lentiviruses that do not contain a vpr gene: equine infectious anemia virus and feline immunodeficiency virus. It is believed that the dUTPase depletes the dUTP within the cell thus preventing the deleterious consequences of dUTP incorporation into viral DNA.(82)
The 16-kD Vpu polypeptide is an integral membrane phosphoprotein that is primarily localized in the internal membranes of the cell.(83) Vpu is expressed from the mRNA that also encodes env. Vpu is translated from this mRNA at levels tenfold lower than that of Env because the Vpu translation initiation codon is not efficient.(84) The two functions of Vpu, the down-modulation of CD4 and the enhancement of virion release, can be genetically separated.(85)
In HIV-infected cells, complexes form between the viral receptor, CD4, and the viral envelope protein in the endoplasmic reticulum causing the trapping of both proteins to within this compartment. The formation of intracellular Env-CD4 complexes thus interferes with virion assembly. Vpu liberates the viral envelope by triggering the ubiquitin-mediated degradation of CD4 molecules complexed with Env.(86)
Vpu also increases the release of HIV from the surface of an infected cell. In the absence of Vpu, large numbers of virions can be seen attached to the surface of infected cells.(87)
Vif is a 23-kD polypeptide that is essential for the replication of HIV in peripheral blood lymphocytes, macrophages, and certain cell lines.(88) In most cell lines, Vif is not required, suggesting that these cells may express a protein that can complement Vif function. These cell lines are called permissive for Vif mutants of HIV. Virions generated in permissive cells can infect nonpermissive cells but the virus subsequently produced is noninfectious.
Complementation studies indicate that it is possible to restore the infectivity of HIV Vif mutants by expression of Vif in producer cells but not in target cells.(89) These results indicate that Vif must be present during virion assembly. Vif is incorporated into virions of HIV.(90) This phenomenon, however, might be nonspecific because Vif is also incorporated into heterologous retroviruses such as murine leukemia viruses.(91) Studies producing HIV from heterokaryons generated by the fusion of permissive and non-permissive cells revealed that non-permissive cells contain a naturally occurring antiviral factor that is overcome by Vif.(92) Further support for a model that Vif is counteracting an antiviral cellular factor comes from the observation that Vif proteins from different lentiviruses are species specific.(93) For instance, HIV Vif can modulate the infectivity of HIV-2 and SIV in human cells while SIV Vif protein does not function in human cells. This observation suggests that cellular factors, rather than viral components, are the target of Vif action. Vif-defective HIV strains can enter cells but cannot efficiently synthesize the proviral DNA.(89) It is not clear whether the Vif defect affects reverse transcription per se, viral uncoating, or the overall stability of the viral nucleoprotein complex. Vif mutant virions have improperly packed nucleoprotein cores as revealed by electron microscopic analyses.(94)
The regulation of HIV gene expression is accomplished by a combination of both cellular and viral factors. HIV gene expression is regulated at both the transcriptional and post-transcriptional levels. The HIV genes can be divided into the early genes and the late genes.(68,69) The early genes, tat, rev, and nef, are expressed in a Rev-independent manner. The mRNAs encoding the late genes, gag, pol, env, vpr, vpu, and vif require Rev in order to be cytoplasmically localized and expressed.
HIV transcription is mediated by a single promoter in the 5' LTR. Expression from the 5' LTR generates a 9-kb primary transcript that has the potential to encode all nine HIV genes. The primary transcript is roughly 600 bases shorter than the provirus. The primary transcript can be spliced into one of more than 30 mRNA species(95) or packaged without further modification into virion particles (to serve as the viral RNA genome).
The LTRs are composed of three subregions designated U3, R, and U5.(96) These regions are named because of their location within the primary transcript of HIV. The U3 region (for unique 3' sequence) is approximately 450-basepairs (bp) in length and is located at the 5' end of each LTR. The U3 region contains most of the cis-acting DNA elements, which are the binding sites for cellular transcription factors. The central region of each LTR contains the 100-bp R (for repeated sequence) region. Transcription begins at the first base of the R region and polyadenylation occurs immediately after the last base of R. The U5 region (for unique 5' sequence) is 180-bp in length and contains the Tat binding site and packaging sequences of HIV. The 3' end of U5 is defined by the location of a lysyl tRNA binding site. The lysyl tRNA acts as a primer for reverse transcription.
The LTR of HIV contains DNA binding sites for several cellular transcription factors. Key among the DNA binding sites required for the activation of the transcription of the HIV provirus are those for the NF-kappa B family of transcription factors.(97) Two adjacent NF-kappa B sites are present in the U3 region of the HIV-1 LTR. The NF-kappa B protein allows the virus to be responsive to the activation state of the infected T cell. Stimulation of the T cell receptor (TCR) causes the inactive form of NF-kappa B, localized in the cytoplasm, to be translocated into the nucleus where it induces the expression of a series of T cell activation-specific genes. NF-kappa B and subsequent activation of HIV transcription can also be induced by the cytokines tumor necrosis factor alpha (TNF alpha)(98) and interleukin-1 (IL-1).(99) The HIV LTR also contains binding sites for the constitutive transcription factors SP-1, Lef, and Ets, along with binding sites for the inducible transcription factors NF-AT and AP-1.(100,101) Lef and NF-At are all T cell specific factors. The SP-1 binding sites are essential for the function of the HIV promoter.
The initial activation of the HIV LTR is a consequence of inducible and constitutive cellular transcription factors. Activation of the LTR by cellular transcription factors leads primarily to the generation of short transcripts.(40) These short transcripts are caused in part by an element located just downstream from the site of the initiation of transcription, known as the inducer of short transcripts (IST).(102) Some complete transcripts, however, are generated and allow the production of the Tat protein. The Tat protein then interacts with the TAR element to greatly increase the levels of transcription of viral RNAs. The Tat protein thus plays a key role in the activation and maintenance of high levels of transcription from the proviral DNA.
The primary HIV-1 transcript contains multiple splice donors (5' splice sites) and splice acceptors (3' splice sites), which can be processed to yield more than 30 alternative mRNAs.(95) Many of the mRNAs are polycistronic; ie, they contain the open reading frame of more than one protein. The polycistronic mRNAs typically express a single gene product. Open reading frame choice is governed by the efficiency of the initiation codon and the proximity of the initiation codon to the 5' end of the mRNA.(103) HIV-1 mRNAs fall into three size classes (see Figure 1):
Unspliced RNA. The unspliced 9-kb primary transcript can be expressed to generate the Gag and Gag-Pol precursor proteins or be packaged into virions to serve as the genomic RNA.
Incompletely spliced RNA. These mRNAs use the splice donor site located nearest the 5' end of the HIV RNA genome in combination with any of the splice acceptors located in the central region of the virus. These RNAs can potentially express Env, Vif, Vpu, Vpr, and the single-exon form of Tat. These heterogeneous mRNAs are 4- to 5-kb long and retain the second intron of HIV.
Fully spliced RNA. These mRNAs have spliced out both introns of HIV and have the potential to express Rev, Nef, and the two-exon form of Tat. These heterogeneous mRNAs do not require the expression of the Rev protein.
Normally, intron-containing RNAs must be completely spliced before they can exit the nucleus. This regulation is essential because it prevents the translation of intronic sequences contained in partially spliced mRNAs. The Rev protein binds to viral RNAs that retain intron sequences, and directs their export from the nucleus. This export allows the unconventional viral RNAs to bypass the normal "check point" of RNA splicing. The fully spliced viral mRNAs exit the nucleus by using the export pathway followed by the majority of cellular mRNAs. Threshold levels of Rev are necessary for exporting intron-containing HIV mRNAs, explaining why those encode the viral late gene products. In contrast, the proteins encoded by the fully spliced mRNAs, Nef, Tat, and Rev, can be produced immediately, and are thus early viral gene products.
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40. Kao SY, Calman AF, Luciw PA, et al. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987;330:489-493.
41. Feinberg MB, Baltimore D, Frankel AD. The role of Tat in the human immunodeficiency virus life cycle indicates a primary effect on transcriptional elongation. Proc Natl Acad Sci USA 1991;88:4045-4049.
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43. Wei P, Garber ME, Fang SM, Fischer WH, Jones KA. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell. 1998;92:451-62.
44. Brother MB, Chang HK, Lisziewicz J, et al. Block of Tat-mediated transactivation of tumor necrosis factor beta gene expression by polymeric-TAR decoys. Virology 1996;222(1):252-256.
45. Rasty S, Thatikunta P, Gordon J, et al. Human immunodeficiency virus tat gene transfer to the murine central nervous system using a replication-defective herpes simplex virus vector stimulates transforming growth factor beta 1 gene expression. Proc Natl Acad Sci USA 1996;93:6073-6078.
46. Sastry KJ, Marin MC, Nehete PN, et al. Expression of human immunodeficiency virus type I tat results in down-regulation of bcl-2 and induction of apoptosis in hematopoietic cells. Oncogene 1996;13:487-493.
47. Sharma V, Xu M, Ritter LM, et al. HIV-1 tat induces the expression of a new hematopoietic cell-specific transcription factor and downregulates MIP-1 alpha gene expression in activated T cells. Biochem Biophys Res Commun 1996;223:526-533.
48. Zapp ML, Green MR. Sequence-specific RNA binding by the HIV-1 Rev protein. Nature 1989;342:714-716.
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51. Bartel DP, Zapp ML, Green MR, et al. HIV-1 Rev regulation involves recognition of non-Watson-Crick base pairs in viral RNA. Cell 1991;67:529-536.
52. Felber BK, Drysdale CM, Pavlakis GN. Feedback regulation of human immunodeficiency virus type 1 expression by the Rev protein. J Virol 1990;64:3734-3741.
53. Malim MH, Bohnlein S, Hauber J, et al. Functional dissection of the HIV-1 Rev trans-activator'' derivation of a trans-dominant repressor of Rev function. Cell 1989;58:205-214.
54. Hope TJ, McDonald D, Huang XJ, et al. Mutational analysis of the human immunodeficiency virus type 1 Rev transactivator: Essential residues near the amino terminus. J Virol 1990;64:5360-5366.
55. Zapp ML, Hope TJ, Parslow TG, et al. Oligomerization and RNA binding domains of the type 1 human immunodeficiency virus Rev protein: A dual function for an arginine-rich binding motif. Proc Natl Acad Sci USA 1991;88:7734-7738.
56. Wen W, Meinkoth JL, Tsien RY, et al. Identification of a signal for rapid export of proteins from the nucleus. Cell 1995;82:463-473.
57. Fischer U, Huber J, Boelens WC, et al. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 1995;82:475-483.
58. Hope TJ, Klein NP, Elder ME, Parslow TG. Trans-dominant inhibition of human immunodeficiency virus type 1 Rev occurs through formation of inactive protein complexes. J Virol. 1992;66:1849-55.
59. Garcia JV, Miller AD. Downregulation of cell surface CD4 by nef. Res Virol 1992;143:52-55.
60. Aiken C, Konner J, Landau NR, et al. Nef induces CD4 endocytosis: Requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 1994;76:853-864.
61. Lama J, Mangasarian A, Trono D. Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner. Curr Biol. 1999;9:622-31.
62. Ross TM, Oran AE, Cullen BR. Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein. Curr Biol. 1999;9:613-21.
63. Schwartz O, Marechal V, Le Gall S, et al. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Medicine 1996;2:338-342.
64. Luria S, Chambers I, Berg P. Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA. Proc Natl Acad Sci USA 1991;88:5326-5330.
65. Skowronski J, Parks D, Mariani R. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene. EMBO J 1993;12:703-713.
66. Baur AS, Sawai ET, Dazin P, et al. HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. Immunity 1994;1:373-384.
67. Miller MD, Warmerdam MT, Gaston I, et al. The human immunodeficiency virus-1 nef gene product: A positive factor for viral infection and replication in primary lymphocytes and macrophages. J Exp Med 1994;179:101-113.
68. Pandori MW, Fitch NJ, Craig HM, et al. Producer-cell modification of human immunodeficiency virus type 1: Nef is a virion protein. J Virol 1996;70:4283-4290.
69. Schwartz O, Marechal V, Danos O, et al. Human immunodeficiency virus type 1 Nef increases the efficiency of reverse transcription in the infected cell. J Virol 1995;69:4053-4059.
70. Goldsmith MA, Warmerdam MT, Atchison RE, et al. Dissociation of the CD4 downregulation and viral infectivity enhancement functions of human immunodeficiency virus type 1 Nef. J Virol 1995;69:4112-4121.
71. Kestler 3d HW, Ringler DJ, Mori K, et al. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 1991;65:651-662.
72. Baba TW, Jeong YS, Pennick D, et al. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 1995;267:1820-1825.
73. Collins KL, Nabel GJ. Naturally attenuated HIV--lessons for AIDS vaccines and treatment. N Engl J Med. 1999;340:1756-7.
74. Cohen EA, Dehni G, Sodroski JG, et al. Human immunodeficiency virus vpr product is a virion-associated regulatory protein. J Virol 1990;64:3097-3099.
75. Heinzinger NK, Bukinsky MI, Haggerty SA, et al. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci USA 1994;91:7311-7315.
76. Vodicka MA, Koepp DM, Silver PA, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection. Genes Dev. 1998 Jan 15;12(2):175-85.
77. Rogel ME, Wu LI, Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J Virol 1995;69:882-888.
78. Jowett JB, Planelles V, Poon B, et al. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J Virol 1995;69:6304-6313.
79. Braaten D, Franke EK, Luban J. Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B. J Virol 1995;69:6859-6864.
80. He J, Choe S, Walker R, et al. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J Virol 1995;69:6705-6711.
81. Bouhamdan M, Benichou S, Rey F, et al. Human immunodeficiency virus type 1 Vpr protein binds to the uracil DNA glycosylase DNA repair enzyme. J Virol 1996;70:697-704.
82. Steagall WK, Robek MD, Perry ST, et al. Incorporation of uracil into viral DNA correlates with reduced replication of EIAV in macrophages. Virology 1995;210:302-313.
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85. Schubert U, Bour S, Ferrer-Montiel AV, et al. The two biological activities of human immunodeficiency virus type 1 Vpu protein involve two separable structural domains. J Virol 1996;70:809-819.
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Before the tragedy in Tucson only a year ago, I only knew one thing about Congresswoman Gabrielle Giffords: That she was a Blue Dog Democrat. And I'll be honest, as a proud and outspoken progressive Democrat, I'm not a fan of Blue Dog Democrats. Gabby Giffords may still be a Blue Dog, but either way, to me, she will always be a hero.
As a kid, I spent entire years of my life in and out of surgeries, recuperations, and physical therapy. I didn't know anything else, really, but there's absolutely no use feeling sorry for someone like me. It's not as if I was afflicted with a sudden tragedy, that I'd known life one way and, in an instant, everything had changed. And in a way, I sensed, even as a kid, that I was lucky– not just because I was born into this amazingly supportive and encouraging family– but because I never knew any other reality or state of being.
When I was around ten years old, I had a series of major orthopedic surgeries. My bones were growing in the wrong directions, so they needed to point everything the right way. That's how it was explained to me at the time. No one ever said, "If we don't do this, once you're an adult, you'll never be able to walk." But I understood.
And even though I was sometimes reluctant and sometimes slow, I always followed instructions, because I had absolutely no intention of living with those casts. As a kid, it was as simple as that: The sooner I can recover, the better. And I was doubly fortunate because my mother was a trained, registered nurse; she pushed me harder than anyone else.
Across the room from me, there was another little boy, right around my age but with a crop of bright blonde hair; he was also recovering from a major surgery. He'd been in some sort of accident.
His mother kept shuffling in and out of the room. The nurses and the doctors were telling this kid the same things they were telling me: "Up, up, up." But the kid didn't want to exercise, and for his mother, this seemed perfectly okay.
"Don't push him too much," she said. "He's been through enough. If my baby wants to rest, let him rest." She was obviously distraught. She probably hadn't slept or taken a shower since her child was hurt, yet she remained forceful and adamant.
That afternoon, my mother hoisted me onto a wheelchair and rolled me out of the hospital room and into the common area. All of the rooms in this particular wing encircled an enormous space with every kind of toy a kid can imagine and an endless supply of video games– a reward for doing your exercises and obeying instructions and, looking back, an ingenious way to incentivize a kid recovering from surgery.
After spending a healthy amount of time playing video games, my mother wheeled me into the parent's break room, which was really just a nook with a small table, three or four chairs, an old vending machine, and a couple of windows that were frozen over with snow and ice.
"That poor kid," my mom said. "His mother shouldn't be doing that to him. You have to work to get better." It wasn't necessarily advice for me. She was genuinely upset.
"Why is his mom telling him that he doesn't have to do what the doctors tell him to do?" I asked.
For kids like me, kids that were born with something and never knew life any other way, hospitals become ordinary. Sure, there was always a sense of fear and dread, but after you've gone through the experience a few times, it's easier, almost perfunctory, to believe that things will get better. Time slows down; life sometimes seems to come to a standstill, a holding pattern, and somewhere, you can find solitude in that.
To me, it always seemed more difficult for the kids with ordinary lives who, in a flash, were suddenly sharing the room with kids like me, veterans of the pediatric surgery recovery unit who were surrounded and encouraged by stubborn, battle-tested families.
Gabby Giffords is not my hero because I can relate to her experience. I can't, at all. She's my hero because she sets an example for kids and families who confront sudden and unexpected tragedy with overwhelming helplessness and resignation, instead of unwavering hope. She demonstrates the resiliency of the body and the spirit and the absolute necessity of fierce and unrelenting determination.
Find a way to be. Up, up, up.
Great post Lamar. I admire Congresswoman Gifford as well.


With SoundTouch, we put a lot of thought into taking the thinking out. You can listen whichever way you want, without worrying about which technology is best. This speaker lets you play music directly from a phone or tablet using Bluetooth®, or connect the speaker to your Wi-Fi network for instant in-home listening, without the need for your phone.
Experience your favorite music from your SoundTouch speaker with the SoundTouch app. SoundTouch lets you take total control of your listening experience, right from your smartphone or tablet. Browse popular music services like Spotify® and Deezer, Internet radio through TuneIn, or your stored music library. Easily personalize presets for one-touch access to the music you love, and control one or many SoundTouch speakers around your home.
Can a single speaker reproduce music with the power and emotion you want from your favorite songs? Ours can. The SoundTouch 30 speaker uses a proprietary waveguide and high-performance drivers to fill your biggest rooms with deep, rich, true-to-life sound.


text:
<?php

declare(strict_types=1);

/*
 * This file is part of SolidInvoice project.
 *
 * (c) Pierre du Plessis <open-source@solidworx.co>
 *
 * This source file is subject to the MIT license that is bundled
 * with this source code in the file LICENSE.
 */

namespace SolidInvoice\NotificationBundle\Tests;

use Mockery\Adapter\Phpunit\MockeryPHPUnitIntegration;
use Mockery as M;
use Namshi\Notificator\NotificationInterface;
use PHPUnit\Framework\TestCase;
use SolidInvoice\NotificationBundle\Notification\ChainedNotification;

class ChainedNotificationTest extends TestCase
{
    use MockeryPHPUnitIntegration;

    public function testAddNotifications(): void
    {
        $notification = new ChainedNotification();
        $message1 = M::mock(NotificationInterface::class);
        $message2 = M::mock(NotificationInterface::class);
        $message3 = M::mock(NotificationInterface::class);
        $notification->addNotification($message1);
        $notification->addNotification($message2);
        $notification->addNotification($message3);

        self::assertSame([$message1, $message2, $message3], $notification->getNotifications());
    }

    public function testAddNotificationThroughConstructor(): void
    {
        $message1 = M::mock(NotificationInterface::class);
        $message2 = M::mock(NotificationInterface::class);
        $message3 = M::mock(NotificationInterface::class);
        $notification = new ChainedNotification([$message1, $message2, $message3]);

        self::assertSame([$message1, $message2, $message3], $notification->getNotifications());
    }
}

redpajama_set_name: RedPajamaGithub


text:
require 'test_helper'

class ResourceTest < ActiveSupport::TestCase
  setup do
    @books = create :resource, name: 'Free books'
    @videos = create :resource, name: 'Free videos'

    @books.tag_list.add('books')
    @books.save
  end

  test '.with_tags returns all resources when no arguments are passed' do
    assert_equal Resource.with_tags, [@books, @videos]
  end

  test '.with_tags returns only relevant tagged resources when tagged arguments are passed' do
    assert_equal Resource.with_tags('books'), [@books]
  end
end


Point of View: The "Club Med" In Point Richmond?
The "Club Med" In Point Richmond?
No, that infamous playground of the tropics does not have plans to come here--yet something similar lurks furtively on the horizon. Overlooking the panorama of San Francisco Bay in Point Richmond are five lots, each of which is considered sub-standard in size by the zoning ordinances, thus requiring the utilization of more than one as a building site. Along comes Anthony Murphy and his construction company and acquires all five lots.
As required, Mr. Murphy trots down to the Point Richmond Neighborhood Design Review Board (PRNCDRB) and presents his proposed structures. Not surprisingly, the neighbors and the PRNCDRB are all up in arms and hotly protest the construction of five mega-homes on sub-standard lots. Back to the drawing board and the kindly Mr. Murphy returns to a subsequent meeting, bending to the will of the masses and concedes by agreeing to build only three homes on the five lots. He plans to build a house on one lot at 3408 sq. feet, another one at 3585 sq. feet and on the sub-standard lot, a house at 3016 sq. feet. The neighbors were somewhat mollified and the PRNCDRB was delighted with the design Murphy presented. Which incidentally is reminiscent of a "Club Med" and wholly inappropriate for the area. Perhaps the nice Mr. Murphy had three houses in mind from the start and sweet-talked the PRNCDRB by his concession from five to three houses. Clever rascal, eh?
Fresh from a perceived victory, Murphy applied for a sub-division map to break the five lots down to three lots, one of which would have to be a sub-standard lot. He also applied to the Planning Commission for a variance on the remaining sub-standard lot. This is akin to the old cliché where the man on trial for murder of his parents pleads to the Judge for leniency because he is now an orphan. Does he think we are all so naïve?
The neighbors, now awakened from the mesmerizing trance imparted by Murphy at the PRNCDRB, are once again organized in opposition to this new development. The Richmond Planning Department has submitted a recommendation to the Planning Commission in opposition to Murphy's plans. The matter has been scheduled to be heard on November 6th, 2003 at 7:00 P.M. at the old City Hall before the Planning Commission.
It is interesting to note that Murphy has submitted petitions signed by numerous alleged residents in the neighborhood. It appears that very few of the signatories are actually neighbors or even close to the property in question. In fact it many of them may not even own homes here. In direct contrast, the opposing petition consists primarily of actual neighbors that will be affected by Murphy's proposed "colossus".
It is time for the Planning Commission to take heed and follow the well-reasoned recommendation by their own Planning Department and send this "carpetbagger" scurrying back into the woodwork where he came from. Point Richmond does not need to become another high-density enclave, with mega-houses on little lots. I would suggest that all those of you who care about the future of the Point to be there and speak your piece. This is your right and your duty as citizens of this very special place.
Your condescending tone and fearful attitude is highly contradictive of the welcoming portrait of people and children happily skipping through the winding streets of the "Point" that was painted by residents in the Planning meeting of Nov. 6th.
I would imagine that articulate people such as yourselves would offer your congratulations to any hardworking person who builds a successful business and keeps it running strong in your community, particularly in this economic climate. I am sure you are proud citizens who are happy to hear that a family will move into a home that Mr. Murphy will offer, who will love and utilize the streets with care, as they appreciate their incredible view (like you do everyday) of such a diverse and beautiful region. I am sure that you don't want some exclusive Blackhawk (Danville) fence surrounding you in some sort of monarch-style kingdom. I am sure you appreciate the different styles of architecture that keep your neighborhood from looking like some cookie cutter, beige sea.
If not, if you would like to limit a business man to make only the living you approve of, of providing reasonable housing on privately owned land and who trying to utilize it while making efforts not to exploit it, I am not sure of what country you should like to live in.
Furthermore, I am sure your city officials would be insulted to hear you imply that they can be "sweet talked" into approving projects without giving them the professional scrutiny they are hired to give.
Enjoy your own "perceived victory".
You are spot on. I don't know if he's a "carpetbagger" ... he DOES live in the Point ... but he has been less than honest and is certainly intent on wrecking the Point. Wish us luck tonight!
P.S.: Interesting that I had the same cliche about orphan baked into MY talk to the Planning Commission tonight. Soft minds run together I guess.


Where are all the Great Shooters?
It's much easier to win when you have good players. Great game-coaching cannot make up for poor talent and unskilled players. Players must be taught the correct fundamentals starting early in their development.
Youth coaches should spend most or their practice time (80-90%) teaching fundamentals and not worry too much about wins and losses. High school coaches will continue teaching fundamentals (about 50% of practice time) and also teach team skills, plays, etc.
Players must learn footwork, how to handle the ball, dribble, basic dribble moves, pass and catch, shoot correctly, play defense, rebound, cut, screen, etc.
And don't forget the mental aspects, conditioning, training and nutrition that are just as important.
Playing the Point Guard Position... tips for point guards.
Seven Key Concepts that Every Good Point Guard Needs to Know... tips from All-American Dena Evans at PGC Basketball.
Ganon Baker Interview... Premier basketball trainer Ganon Baker has a great DVD series for point guards.
Guard Moves, Perimeter Play... how to play on the perimeter, triple-treat, jab step moves, attacking the defender, cutting, etc.
Pro (Advanced) Guard Moves for Finishing Around the Basket... Rondo Fake Finish, Euro Step Finish, Pro Hop Finish, Jamal Crawford Finish, Kobe Bryant Pound Pivot Finish, and Steve Nash Back Leg Finish.
Rebounding... box-out, defensive and offensive rebounding, free-throw rebounding.
Ball-Handling... ball-handling tips and drills.
Dribbling and Dribble-Moves... all players must learn to dribble well.
Teaching/Learning How to Shoot... teach your players how to shoot correctly.
Shot Selection... the importance of getting good shots.
Where are all the Great Shooters?... why is there so much poor shooting nowadays?
Basketball Shooting - 3 Simple C's... 3 simple things to foucs on.
Individual Shooting Work-Out... individual shooting practice work-out for players.
Shooting Tips from NBA Coach Hal Wissel ... a series of shooting articles from an expert.
Jump-Shot... teaching how to shoot the jump-shot.
Hook-Shot... teaching how to shoot the classic hook-shot, the sky-hook and the jump-hook.
Free-Throw Shooting Techniques... good free-throw shooting will win those close games for you.
Foul Shooting... tips from coach Ari Fisher.
Correct Lay-up Technique... correct footwork and technique will result in players "finishing" more often.
Footwork Fundamentals... triple threat position, pivoting, defensive stance and slides, jab step, cutting, jump-stop, etc.
Passing Fundamentals... good passing is key.
Offensive Tips for Players... basic, simple offensive tips.
Cutting and Faking... teach your players how to cut and fake and move without the ball.
Setting (and Using) Screens... teach how to set good screens.
Spacing and Movement - Moving Without the Ball... what to do when you don't have the ball.
Escaping from a Trap... how to avoid and escape a trap.
Transition Offense Fundamentals... teaching transition offense, the fast-break, 2-on-1, 3-on-2, etc.
Defensive Tips for Players... some basic defensive tips for players are presented.
Defensive Close-Outs and Drills... how to close-out on defense.
Man-to-Man Defensive Techniques... teach on-ball defense, deny, helpside, etc.
Mental Prep Playbook... how to become mentally prepared.
The Exceptional Player... what makes a good player great.
Keys to Becoming a Great Player... Roles, Training, Intelligence, and Determination.
Things Good Basketball Players Do... a list of tips for players.
Basketball Tips: Being a Team Leader... how to be a leader, by Lamar Hull.
How to Make the Team, Try-Outs... what coaches are looking for in try-outs.
Things to Think About... a few things players should consider.
Attitude, the "Right Stuff"... having the correct attitude.
The Role Player... good role players who can come off the bench are a tremendous asset to any team.
Mental Focus - Stay in the Present... how to focus and stay in the present.
Play Big: Believe in Greatness!... how all players regardless of skill level can contribute.
Reading The Court - Mastering The Moment... how players should make decisions, how to read the court, the situation and the moment.
Imagine... challenge your players to imagine greatness.
Playing Smart... how to play smart and make good decisions.
Make Your Mark - Selecting a College... how to select a college.
Academics and the Student Athlete... academics from an athlete's perspective, dealing with time constraints, fatigue, stress.
When Individual Basketball Instruction Goes Too Far... having your own individual instructor or trainer.
Smaller Basketball Players: Perhaps the Best Athletes of All... by Tom Emma.
Dealing with Lack of Playing Time... by Tom Emma.
Having a Practice Program... how to practice correctly on your own.
Seven Benefits of Playing Multiple Sports... from Adam Eyal.
6 Benefits of Playing Sports in School... from Sarah Daren.
How Sports and Exercise Impact Your Health... from Sarah Daren.
Sports and Exercise Tips for Students... from Sarah Daren.
Playing AAU or Club Basketball... yes or no?
Why Doesn't Johnny Practice Any More?... from Paul Hoover.
Individual Shooting Work-Out... how to practice shooting on your own.
Conditioning... get in shape to play the game.
Alan Stein's Drills... strength, conditioning, warm-up and more drills from training expert Alan Stein.
Basketball Speed Starts with Stopping... by "The Speed Guy" Lee Taft.
Nutrition, What To Eat... have good nutrition. What players should eat.
Food Supplements... about food supplements, growth hormone (HGH), creatine, andro, etc.
Simple, Fun Driveway Games... here are several fun games that you can play in your driveway.
Basketball Terminology... learn the language of the game.
Basketball History... Learn about the interesting history of the game.
Many more basketball DVDs at the Coach's Clipboard Basketball DVD Store! These DVDs feature many excellent player instructional DVDs, covering every facet of the game.
Many more basketball DVDs at the Coach's Clipboard Basketball DVD Store! 5-Star has been a premier source of basketball information and player camps for 50 years! Many professional and collegiate players are 5-Star graduates.
Many more basketball DVDs at the Coach's Clipboard Basketball DVD Store! These DVDs feature many drills and instruction for player development.
Many more basketball DVDs at the Coach's Clipboard Basketball DVD Store! From some the best instructors in the world, these workout DVDs will provide players with the expert instruction and many useful drills they need for improvement.
Many more basketball DVDs at the Coach's Clipboard Basketball DVD Store! Videos in this category strive to demonstrate 1-on-1 moves that will help you to blow your defender away!


Companies hoping to market their products using the colorful Maasai image might soon have to consult with the ethnic group's elders first.
"We all know that we have been exploited by people who just come around, take our pictures and benefit from it," Maasai leader Isaac ole Tialolo told BBC News.
As chair of the newly-created organization Maasai Intelletcual Property Initiative, Tialolo and other Maasai elders are working with the African IP Trust and non-profit organization Light Years IP to determine the best course of action for branding Maasai culture.
Land Rover, Louis Vuitton and Masai Barefoot Technology are some of the 80 companies currently using the Maasai image or name to sell their products. Light Years IP founder and head Ron Layton estimated that if the Maasai "brand" were owned by a corporation, it would be worth more than $10 million a year — possibly as much as "tens of millions."
"I think people need to understand the culture of others and respect it," said Tialolo. "You should not use it to your own benefit, leaving the community — or the owner of the culture — without anything."
Tialolo and Light Years IP have reportedly discussed the issue with about 1.2 million Maasai members thus far throughout Kenya and Tanzania. If a consensus is reached among the elders, then a General Assembly trained in intellectual property would act as a legal body specifically on this issue, negotiating with companies via a licensing agent, on a case-by-case basis, according to BBC News.
Asked whether the Maasai's branding efforts would be successful, experts in IP law and branding advised pursuing trademarks — which several companies have already claimed — or securing a voluntary code to shame Western multinational companies into playing fair. The Aborigines of Australia, Ethiopian coffee farmers and the Native American Navajo have all challenged the use of their name or cultural and intellectual property in recent years.
"The Maasai are an ancient and sophisticated people," said African IP Trust board member Lord Boateng. "They know they are being ripped off and they want this to stop."


Our skip hire company in Crookes and Crosspool Sheffield is one of the top businesses and are definitely the best in the waste disposal industry. Skips are valuable and practical containers and they are often hired by companies or property owners for easier facilitation of waste material and general household junk. Whenever you rent a Skip in Crookes and Crosspool Sheffield, it would make cleaning-out jobs a lot easier and far more convenient. Also, it is more affordable to hire a skip for waste disposal, as skip hire Crookes and Crosspool Sheffield charges are usually very fair.
There are numerous skip hire companies in Crookes and Crosspool Sheffield who provide these kinds of services, and a lot of them will have different sizes to fit their customers' demands. In case you have never ever hired a skip in Crookes and Crosspool Sheffield before, you could be wondering exactly where you could find a good skip company, well you have discovered us. Quite often than not, when you call most companies, they assume you to already know the specifics, therefore if you're not aware of the terminologies and the jargon, it would be a challenging task.
What Size Skip Do You Actually Need In The Crookes and Crosspool S10 1LS Area?
This is certainly hard to understand when you've never ever hired a skip previously. In the event you hire a skip that is way too small, you could possibly end up having to get an additional skip to accommodate the waste type you need to get rid of. If you hire a large skip, you could end up overpaying slightly for your waste needs. The easiest way to understand skip sizes is to look at the kind of waste product that you have, if it is a dressing table for instance, could it be broken down into flat packs to allow more space in the skip?
What type of waste products are you currently throwing out? If it's your backyard waste, could it be cut up into small pieces so you can get more in the skip and ultimately get more for your money? Or are they sizeable bulky things that cannot be broken down, therefore you may need a larger skip. It's better to be safe and obtain a larger skip than it is to get a smaller sized skip and have to obtain an additional one to accommodate your current waste material collection needs.
Have you been doing a building job? Are you just simply cleaning your residence of unwanted junk? Are you currently carrying out backyard garden work? These types of things do depend on the price however, we can accommodate for any kind of waste. Just let us know what kind of waste material you want to throw out and we can offer you a quote on that.
When you can keep it on your own premises you could avoid the council charges for permits. If you can put it on your front garden, that's wonderful. On the other hand, we need to know exactly how we could get the skip onto that front garden.
If there is a tiny wall structure we need to go over, or if there is an expansive footway, the truck that we use to deliver the skips cannot drive onto the footway. Driveways are the best option for this. However, consider if you are adding heavy items into a large skip on the driveway and your drive is block paving or tarmac there could quite possibly be some kind of damage to your private drive due to the excess weight.
If you need it on the streets, honestly, that is not a problem, we will deal with the local authority or council and arrange council permits for you. The council do ask for an additional cost for this and we could let you know the price should you give us a call . Please be aware that, even if it is not on the streets and it's over the pavement it's still council property. It should be your personal property so we can easily deliver the skip without getting a permit. If you need it on the footpath or a grass verge and it is not actually owned by you, we still have to get a Sheffield council permit in your case.


At Sharp Clinic, we are more than just a hormone replacement center. We include nutrition and exercise, and evaluate your overall health. Sharp Clinic's doctors believe it's about creating a health-conscious lifestyle that will diminish the effects of aging and allow you to live the life you love for many more years to come. Global leader Cenegenics® Medical Institute and Tulsa physician Patrick Sharp, DO partnered to launch Tulsa Oklahoma's first age management medical center, where they work to prevent problems on the front end, rather than waiting for them to arise and then treat them.
There are many reasons people look into hormone replacement therapy and treatment of an age management doctor. Your body might not be keeping up with your mental abilities and goals in life or maybe you're suffering from low T (low testosterone), which can occur in men as they age and cause a decline in overall health. For these reasons and more, you may be considering hormone replacement therapy to slow down and possibly reverse the aging process.
"Dr. Sharp's Cenegenic's program changed my life. I feel young again, with a vengeance. I have the energy and the attitude to do what I want to do. The results are amazing."


text:
Trump holds firm on border wall, offers steel option as compromise
Reuters Top News Posted on January 6, 2019
By Jeff Mason and Ginger Gibson
WASHINGTON (Reuters) – U.S. President Donald Trump pledged on Sunday not to bend in his demand for a wall along the southern border with Mexico but said the barrier could be made of steel instead of concrete as a potential compromise with Democrats who refuse to fund it.
Trump's comments came at the start of the third week of a partial government shutdown resulting from the dispute that has left hundreds of thousands of federal workers idled or without paychecks.
Trump threatened again, without providing specifics on where the funding would originate, to declare a national emergency as an alternative way to build the wall, depending on the outcome of talks in the coming days.
Democrats have declined to approve the $5.6 billion Trump wants to fulfill a 2016 campaign promise to curb illegal immigration. Led by new Speaker Nancy Pelosi, Democrats passed a bill in the House of Representatives last week to reopen the government without wall funding. Pelosi has called a border wall immoral.
"This is a very important battle to win from the standpoint of safety, number one, (and) defining our country and who we are," Trump told reporters at the White House before leaving for a short trip to the Camp David presidential retreat.
"The barrier, or the wall, can be of steel instead of concrete, if that helps people. It may be better," he said.
The White House painted that offer, which Trump floated previously, as an olive branch.
In a letter to congressional leaders on Sunday detailing its funding demands, the Trump administration included a request for an additional $800 million to address urgent humanitarian needs at the southern border.
Mick Mulvaney, Trump's acting chief of staff, told NBC's "Meet the Press" that agreeing to a steel barrier would allow Democrats to stick to their refusal to fund a wall.
"That should help us move in the right direction," he said.
House Majority Leader Steny Hoyer did not show his hand when asked whether the White House offer to move away from a concrete structure was evidence of compromise.
"It'll be discussed," he said on NBC.
Vice President Mike Pence led a second round of talks with congressional aides on Sunday about the issue, but Trump said he did not expect those talks to produce results, noting that the principals – himself, Pelosi and Senate Democratic leader Chuck Schumer – were the ones who could solve it quickly.
"If we don't find a solution, it's going to go on for a long time. There's not going to be any bend right here," Trump said.
He later tweeted that the Pence talks were productive. But a Democratic aide familiar with the meeting said Democrats urged the White House to pass measures to reopen the government without wall funding and Pence said Trump would not do that. The aide said no progress was made and no further meetings of the group were scheduled.
OTHER CONCESSIONS?
Democrats could demand other concessions from the White House, such as protections for immigrants brought illegally to the United States as children, known as Dreamers, or changes to other spending provisions. Trump said he wanted to help on the Dreamer issue but preferred to wait for a Supreme Court ruling on it first.
Democratic U.S. Senator Dick Durbin reacted coolly to Trump's suggestion of declaring a national emergency. "I don't know what he's basing this on, but he's faced so many lawsuits when he ignores the law and ignores tradition and precedent," Durbin said on CBS' "Face the Nation."
Large chunks of the federal government were shut down on Dec. 22 after lawmakers and the president hit an impasse over Trump's demand that a bill to keep the federal government operational include money to help build a $23 billion wall along the U.S. border with Mexico. About 800,000 government workers are either furloughed or working without pay.
"I can relate," Trump, a former New York businessman, said when asked if he could relate to the pain of federal workers struggling to pay their bills. "I'm sure that the people that are on the receiving end will make adjustments." Asked if workers would get paid on Friday, Trump said: "We'll see whether or not it's settled."
Not all Republicans agree with Trump's insistence on keeping government agencies shuttered until the border debate is resolved.
"It is not a sign of weakness to try to figure out a middle ground, and I think that both sides need to indicate a willingness to listen and to compromise," U.S. Senator Susan Collins of Maine said on NBC. She called the debate over using steel versus concrete "bizarre."
House Democrats plan to pass a series of bills this week to reopen government, breaking up legislation they have already approved in a bid to get Republicans to agree to reopen certain agencies, Hoyer said on "Meet the Press."
"We need to open up government and then negotiate. Not the other way around," he said.
(Reporting by Jeff Mason and Ginger Gibson; Additional reportering by Amanda Becker and Pete Schroeder; Editing by Lisa Shumaker and Peter Cooney)

redpajama_set_name: RedPajamaCommonCrawl


text:
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Cybersecurity Sector in Focus Amid National Cyber Attack
© Markus Spiske/ Unsplash
Rachel Hemple 22.12.2020
Governments and major corporations worldwide have sounded alarms in the past few days that they have been the victim of a global cyber-espionage campaign that hacked into multiple United States government agencies. The cyber attack involved a commonly used software product developed by the U.S. company SolarWinds (SWI ).
While the extend and motive behind the hacking are still unknown, software developers at the cybersecurity company FireEye (FEYE )--who discovered the attack--believe the hack began as early as March. The attack involved hackers sneaking malware code into SolarWinds Orion software and using the malicious code to gain remote access to dozens of corporate and governmental networks.
The Cybersecurity and Infrastructure Security Agency (CISA) warned on Thursday that the hack had comprised many federal agencies and because of the attack's length and severity, the full extent of the attack will be hard to detect and be difficult to undo. The CISA has called all federal civilian agencies to review their networks for potential compromises and to disconnect SolarWinds Orion products immediately.
Microsoft (MSFT ) has since revealed that over 40 government agencies, organizations and companies have been compromised in the attack, with the majority being based in the United States. Other regions affected include North America, Europe, Asia and the Middle East. Other reports estimate that tens of thousands of servers have been compromised.
While the situation surrounding what may be the largest cybersecurity attack in history, it is expected that future governmental and corporate focus will be on enhanced cybersecurity measures to prevent malicious actors accessing sensitive data moving into the new year.
Following multiple reports of the attack, cybersecurity names like Palo Alto Networks (PANW ), Crowdstrike Holdings (CRWD ), and ZScaler (ZS ) surged as investors began to predict who will beat out SolarWinds' market share as corporations and government agencies sought to secure their networks.
Just like any industry, exchange-traded funds offer investors an easier and less risky approach to sector investing by allowing for broad exposure to the entire industry. The cybersecurity industry is also newer and quickly evolving, which brings more risk to investing in individual stocks.
There are currently four cybersecurity focused ETFs that trade on U.S. markets, gathering total assets under management (AUM) of $5.9 billion:
Global X Cybersecurity ETF (BUG )
BUG tracks the Indxx Cybersecurity Index, which is a modified market-cap-weighted global index that follows 28 stocks that are positioned to benefit from increasing adoption of cybersecurity technology. The fund has $82.07 million AUM at an the industry average expense ratio of 0.50%. The majority of its holdings are U.S. based software companies, with minority holdings coming from Japan, United Kingdom and South Korea. BUG is currently up over 75% for its year-to-date.
First Trust NASDAQ Cybersecurity ETF (CIBR )
CIBR tracks the NASDAQ CTA Cyber Security Index, which is a liquidity-weighted index that follows 41 stocks in the cybersecurity industry. Each of the fund's holdings must be classibea as a cybersecurity company by the Consumer Technology Association and have a minimum market cap of $250 million. The fund has $2.94 billion AUM and an expense ratio of 0.60%. The majority of the fund's global holdings are U.S.-based, but has minority holdings based in the U.K, Japan, France and South Korea. CIBR is currently up over 51% YTD.
iShares Cybersecurity and Tech ETF (IHAK )
IHAK tracks the NYSE FactSet Global Cyber Security Index, which is company of cybersecurity and technology stocks. The fund's 43 holdings include developers of cybersecurity hardware, software, products and services. The fund has $211 million AUM and an expense ratio of 0.47%. The majority of the fund's global holdings are U.S.-based companies, with other majority shares held by Japan, Taiwan and Malaysia. IHAK is up over 53% YTD.
ETFMG Prime Cyber Security ETF (HACK )
HACK tracks the ISE Cyber Security Index, which is a tiered and equal-weighted index that focuses on companies involved in Cybersecurity technology and services. The fund holds $1.90 billion AUM and its expense ratio is on par with CIBR's at 0.60%. The fund's 61 global holdings include companies based in U.S., U.K, Japan, Canada, Sweden, South Korea and Finland. HACK is currently up about 42% YTD.
IHAK
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Siyah-Chal (The Black Pit), in Tehran, where Baha'u'llah was first imprisoned for 4 months, and where He received the Holy Spirit.
We were consigned for four months to a place foul beyond comparison. As to the dungeon in which this Wronged One and others similarly wronged were confined, a dark and narrow pit were preferable. Upon Our arrival We were first conducted along a pitch-black corridor, from whence We descended three steep flights of stairs to the place of confinement assigned to Us. The dungeon was wrapped in thick darkness, and Our fellow prisoners numbered nearly a hundred and fifty souls: thieves, assassins and highwaymen. Though crowded, it had no other outlet than the passage by which We entered. No pen can depict that place, nor any tongue describe its loathsome smell. Most of these men had neither clothes nor bedding to lie on. God alone knoweth what befell Us in that most foul-smelling and gloomy place!
While engulfed in tribulations I heard a most wondrous, a most sweet voice, calling above My head. Turning My face, I beheld a Maiden — the embodiment of the remembrance of the name of My Lord — suspended in the air before Me. So rejoiced was she in her very soul that her countenance shone with the ornament of the good pleasure of God, and her cheeks glowed with the brightness of the All-Merciful. Betwixt earth and heaven she was raising a call which captivated the hearts and minds of men. She was imparting to both My inward and outer being tidings which rejoiced My soul, and the souls of God's honoured servants.
By these accounts from the Pen of Baha'u'llah, the seeker has direct access to these moments of Awakening of the Manifestation of God for our Day. Through the Baha'i Firesides, the seeker can confirm, through scientific and revelatory proof, that Baha'u'llah fulfills the prophecies as that great Promised One awaited by all people, and spoken of in all the Holy Books from both east and west. He comes in the prophesied Name, Date, Address & Mission, proving His authenticity, which is the criteria for believability. Investigate!
-'Abdu'l-Baha, from a talk delivered on May 11, 1912 in New York.


text:
Q: `gem install zookeeper -v '1.4.4'` on osx 10.8.4 fail (with error related to C99 mode) My system is osx 10.8.4, doing gem install zookeeper -v '1.4.4' always get the following error:

src/hashtable/hashtable_itr.c:42:1: error: redefinition of a 'extern inline' function 'hashtable_iterator_key' is not supported in C99 mode
hashtable_iterator_key(struct hashtable_itr *i)
^
src/hashtable/hashtable_itr.h:36:1: note: previous definition is here
hashtable_iterator_key(struct hashtable_itr *i)
^
src/hashtable/hashtable_itr.c:46:1: error: redefinition of a 'extern inline' function 'hashtable_iterator_value' is not supported in C99 mode
hashtable_iterator_value(struct hashtable_itr *i)
^
src/hashtable/hashtable_itr.h:45:1: note: previous definition is here
hashtable_iterator_value(struct hashtable_itr *i)
^

Does anyone happen to know the reason?
Thanks!
P.S. doing gem install zookeeper could install the zookeeper 1.4.6 with no problem.
UPDATE: doing CC=gcc-4.6 gem install zookeeper -v '1.4.4' solved my problem

A: Just to make this an answered question, I would like to supply a "proper" answer.
zookeeper appears to be meant to build on gcc.
OS X or better said Xcode (since Version 4.x) stopped using gcc as a default until they finally dropped gcc support alltogether.
They switched over to LLVM in combination with the clang frontend.
The only way to get around that issue without fiddling in the sources is to install gcc via something like homebrew - for example;
brew install gcc47
Once that is done, you may instruct your building / installation process to use that gcc by providing the matching CC (and/or CXX) environment variables;
CC=gcc-4.7 CXX=g++-4.7
The update to your question works because you had gcc4.6 installed previously. This may not be the case for more recent installations of OS X / Xcode, hence my verbose answer.
These steps should be rather generic and can be used whenever "standard" packages do not build or install properly on OS X / Xcode; simply prepend your installation/configuration instruction with the given environment variables.
As to your example that would be:
CC=gcc-4.7 CXX=g++-4.7 gem install zookeeper -v '1.4.4'
Note; there are most likely less invasive ways to get the job done, but without further try and error, the above mentioned usually does the job for all kinds of weird results in connection to clang / gcc incompatibilities.

redpajama_set_name: RedPajamaStackExchange


Hair loss isn't something that we like to talk about to others and even to our own inner self.
However, denying the reality of its existence won't help you or your hair. Rather, recognising it for what it is, reflecting upon how it is affecting us and then taking massive action to do something about it (if warranted). This is the healthy response to all potentially negative circumstances in our lives and we would encourage you to take a little time to reflect upon how your hair loss is affecting you today and how it might continue to affect you in the future.
Self reflection, self awareness and mindfulness are all wonderful traits and activities to engage in, and admittedly, in some areas of our lives it's is easier to pursue those activities. For example, reflecting upon a person we love and the positive and healthy ways they make us feel is easy and enjoyable. Reflecting upon an unhealthy relationship with someone we love is much harder as we tend to live in denial about how we really feel or about how they make us feel – it is much harder to admit we feel manipulated, abused, neglected or just hurt. Thinking this way can make us feel like we are being ungrateful, ashamed or even betraying them. Interestingly, we can feel the same way when we are losing our hair. It is often easier to live in denial about something, hoping it will go away even though it is causing us deep emotional pain. Sometimes it's so deep we don't even want to face up to it as it hurts too much.
In our experience, the pain associated for hair loss in women is deep. It is also our experience that aside of all the bravado, the upset of hair loss in men is also deep.
Hair loss affects us in many ways that we are often not aware of until we spend a some time thinking about it, reflecting and being honest and vulnerable with ourselves. "Being vulnerable with myself?" I hear you say….. yes vulnerable! Sometimes we are our own worst enemy, some of us don't feel safe with own self and our own thoughts, they can be awfully damaging, accusatory and discouraging.
We understand, sometimes it too painful to look directly into our own soul, but we also know that the 'truth shall set you free'.
Through listening to our clients and counseling them, often people have a a sense that their hair is bothering them but they spend more time trying to squash those feelings and thoughts rather than being honest and vulnerable with themselves.
Let us guide your mind and heart for the next 3-5 minutes thinking about how much hair loss may be affecting you. We think you will find it very liberating. Don't worry, there are no forms to fill out, or surveys to submit, this is an exercise for you, in the safety of your own space, mind and inner person.
Here are some important questions you need to ask yourself when deciding what to do about your hair loss.
Below we have categorised 9 areas of your life and listed one question with multiple answers to help you think through what you actually think about your situation.
Remember, there are no wrong or right answers. These answers are given to help you to uncover how you are really feeling about your hair. We know that once you understand your own mind, you will be able to make the right decision for yourself – whatever that is!
1. Appearance – How is my appearance being affected?
• I'm looking better than ever, I am a god!
2. Time – How much time do I spend thinking about my hair loss?
• Once a week or every day?
• Just when I look in the mirror, 15 mins, 30 mins a day or all the time?
• How is my life being affected by my hair loss?
4. Socially – How is my social life being affected?
6. Professionally – How is my work being affected by my hair loss?
• I feel that I am losing sales because I am aware of people looking at my hair and I am self conscious about it.
• How much will I enjoy having hair again?
• I would be relieved to have prevented or postponed future hair loss?
• I would be a much more confident person and it would change my life for the better exponentially.
9. Financial – am I willing to spend money on my hair and appearance?
We hope that you have found this exercise helpful. We know it has helped thousands of other people just like yourself to work through the internal workings of our minds and hearts.
Final Question: Hair Loss Treatments – What next?
The final question is what shall you do next?
Do you need to take massive action? A small step in the right direction? Or, nothing? (and it's OK to do nothing if that is what you want to do).
If you want to prevent further hair loss and you want to try to regrow your hair, we suggest you look at the Hairmax 82 Laserband + the Folliplus Factors (stem cell serum) for hair growth. These have been tested and trialled and proven to be effective for hair loss prevention and hair regrowth.
– look no further than the BioTHIK hair building fibres for the best cosmetic option available, they can make your hair look up to 250% thicker in 30 seconds. Truly, they are an amazing instant product. Check out the results here!
Sometimes the best thing to do is share your burden with a close friend or family member for moral support. Alternatively, you can contact us on 02-92124950 to speak with one of our hair loss specialists and they can let you know about the full suite of services and products we offer.
We hope you found this helpful, we look forward to hearing from you soon!


Dave Thomas made a challenge to have executable unit test comments in Ruby based on this Python project. I thought it was a neat idea. At the very least, I was inspired and thought it would be a fun weekend Ruby project. It was fun reading through the RDoc and RUnit code. I posted my code here for Executable Comment Unit Tests. It works with the Runit test framework and uses the parser from RDoc. It's only one file and not that big. It only took me one day to do the code and most of the time was spent reading code. Take it from it what you will. Now, on to my thesaurus project, my second weekend project.
I haven't looked at your code yet, but have you considered rewriting this to use Test::Unit (runit's successor)?


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Elias played the piano and Vilhelm sang.
Herman got out of the car on the passenger side.
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Gary and Masanobu would both like that.
I saw Bradford play tennis.
I think we should consider Guillermo's offer a little more carefully.
Trent doesn't want Harvey to go anywhere without him.
Nigel and Elisabeth have what they want.
Takayuki didn't come too soon.
Leslie told me you might be calling.
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Prakash got Pontus to help him paint the fence.
I was surprised to get a call from Jinchao.
Emil first met Chuck at a cafe in Boston.
Someone threw a rock at Prakash.
Werner filled the balloons with helium.
Lou began to remove his gloves.