The rockefeller university

Objective:Gender differences in immune response and the rate of disease progression in HIV-infected individuals have been reported but the underlying mechanism remains unclear, in part because of the lack of relevant animal models. Here, we report a novel nonhuman primate model for investigation of sex disparity in HIV disease progression.Design/methods:Viral load and rate of disease progression were evaluated in rhesus macaques infected intrarectally with lineage-related subtype C R5 simian HIVs. Cytokine/chemokine levels in rectal swab eluates, and bacterial species adherent to the swabs and in the feces were determined.Results:Simian HIV-infected female rhesus macaques progressed faster to AIDS than male macaques, recapitulating the sex bias in HIV-1 disease in humans. There were no significant differences in the levels of soluble immune mediators in the rectal mucosa of naive female and male macaques. However, an exploratory longitudinal study in six infected macaques indicates that the female macaques mounted an earlier and more robust proinflammatory skewed rectal immune response to infection. Moreover, expansion of Proteobacteria that increase in other intestinal inflammatory disorders was significantly higher in the rectal mucosa of female than male macaques during acute infection.Conclusion:These findings suggest that sex differences in local innate immune activation and compositional shifts in the gut microbiota could be the drivers of increased disease susceptibility in female macaques. Further studies with this novel nonhuman primate model of HIV infection could lead to innovative research on gender differences, which may have important therapeutic implications for controlling disease in infected men as well as women.

Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC. The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex. Linear ubiquitination and NF-kappa B activation are impaired in the patient's fibroblasts stimulated by IL-1 beta or TNF. In contrast, the patient's monocytes respond to IL-1 beta more vigorously than control monocytes. However, the activation and differentiation of the patient's B cells are impaired in response to CD40 engagement. These cellular and clinical phenotypes largely overlap those of HOIL-1-deficient patients. Clinical differences between HOIL-1- and HOIP-mutated patients may result from differences between the mutations, the loci, or other factors. Our findings show that human HOIP is essential for the assembly and function of LUBAC and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells.

Genetically encoded p-azido-phenylalanine (azF) residues in G protein-coupled receptors (GPCRs) can be targeted with dibenzocyclooctyne-modified (DIBO-modified) fluorescent probes by means of strain-promoted [3+2] azide-alkyne cycloaddition (SpAAC). Here we show that azF residues situated on the transmembrane surfaces of detergent-solubilized receptors exhibit up to 1000-fold rate enhancement relative to azF residues on water-exposed surfaces. We show that the amphipathic moment of the labeling reagent, consisting of hydrophobic DIBO coupled to hydrophilic Alexa dye, results in strong partitioning of the DIBO group into the hydrocarbon core of the detergent micelle and consequently high local reactant concentrations. The observed rate constant for the micelleenhanced SpAAC is comparable with those of the fastest bioorthogonal labeling reactions known. Targeting hydrophobic regions of membrane proteins by use of micelle-enhanced SpAAC should expand the utility of bioorthogonal labeling strategies.

A search is presented for particle dark matter produced in association with a pair of top quarks in pp collisions at a centre-of-mass energy of root s = 8TeV. The data were collected with the CMS detector at the LHC and correspond to an integrated luminosity of 19.7 fb(-1). This search requires the presence of one lepton, multiple jets, and large missing transverse energy. No excess of events is found above the SM expectation, and upper limits are derived on the production cross section. Interpreting the findings in the context of a scalar contact interaction between fermionic dark matter particles and top quarks, lower limits on the interaction scale are set. These limits are also interpreted in terms of the dark matter-nucleon scattering cross sections for the spin-independent scalar operator and they complement direct searches for dark matter particles in the low mass region.

Vocalizations are behaviorally critical sounds, and this behavioral importance is reflected in the ascending auditory system, where conspecific vocalizations are increasingly over-represented at higher processing stages. Recent evidence suggests that, in macaques, this increasing selectivity for vocalizations might culminate in a cortical region that is densely populated by vocalization-preferring neurons. Such a region might be a critical node in the representation of vocal communication sounds, underlying the recognition of vocalization type, caller and social context. These results raise the questions of whether cortical specializations for vocalization processing exist in other species, their cortical location, and their relationship to the auditory processing hierarchy. To explore cortical specializations for vocalizations in another species, we performed high-field fMRI of the auditory cortex of a vocal New World primate, the common marmoset (Callithrix jacchus). Using a sparse imaging paradigm, we discovered a caudal-rostral gradient for the processing of conspecific vocalizations in marmoset auditory cortex, with regions of the anterior temporal lobe close to the temporal pole exhibiting the highest preference for vocalizations. These results demonstrate similar cortical specializations for vocalization processing in macaques and marmosets, suggesting that cortical specializations for vocal processing might have evolved before the lineages of these species diverged.

Proteins resident in the inner nuclear membrane and underlying nuclear lamina form a network that regulates nuclear functions. This review highlights a prominent family of nuclear lamina proteins that carries the LAP2-emerin-MAN1-domain (LEM-D). LEM-D proteins share an ability to bind lamins and tether repressive chromatin at the nuclear periphery. The importance of this family is underscored by findings that loss of individual LEM-D proteins causes progressive, tissue-restricted diseases, known as laminopathies. Diverse functions of LEM-D proteins are linked to interactions with unique and overlapping partners including signal transduction effectors, transcription factors and architectural proteins. Recent investigations suggest that LEM-D proteins form hubs within the nuclear lamina that integrate external signals important for tissue homeostasis and maintenance of progenitor cell populations.

ATRX (the alpha thalassemia/mental retardation syndrome X-linked protein) is a member of the switch2/sucrose nonfermentable2 (SWI2/SNF2) family of chromatin-remodeling proteins and primarily functions at heterochromatic loci via its recognition of "repressive" histone modifications [e.g., histone H3 lysine 9 tri-methylation (H3K9me3)]. Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX's ability to recognize an activity-dependent combinatorial histone modification, histone H3 lysine 9 tri-methylation/serine 10 phosphorylation (H3K9me3S10ph), in postmitotic neurons. In neurons, this "methyl/phos" switch occurs exclusively after periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph-bound Atrx represses noncoding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction.

The dynamics of the late stages of the HIV-1 life cycle are poorly documented. Viral replication dynamics are typically measured in populations of infected cells, but asynchrony that is introduced during the early steps of HIV-1 replication complicates the measurement of the progression of subsequent steps and can mask replication dynamics and their variation in individual infected cells. We established microscopy-based methods to dynamically measure HIV-1-encoded reporter gene and antiviral gene expression in individual infected cells. We coupled these measurements with conventional analyses to quantify delays in the HIV-1 replication cycle imposed by the biphasic nature of HIV-1 gene expression and by the assembly-inhibiting property of the matrix domain of Gag. We further related the dynamics of restriction factor (APOBEC3G) removal to the dynamics of HIV-1 replication in individual cells. These studies provide a timeline for key events in the HIV-1 replication cycle, and reveal that the interval between the onset of early and late HIV-1 gene expression is only similar to 3h, but matrix causes a similar to 6-12h delay in the generation of extracellular virions. Interestingly, matrix delays particle assembly to a time at which APOBEC3G has largely been removed from the cell. Thus, a need to prepare infected cells to be efficient producers of infectious HIV-1 may provide an impetus for programmed delays in HIV-1 virion genesis. Our findings also emphasize the significant heterogeneity in the length of the HIV-1 replication cycle in homogenous cell populations and suggest that a typical infected cell generates new virions for only a few hours at the end of a 48h lifespan. Therefore, small changes in the lifespan of infected cells might have a large effect on viral yield in a single cycle and the overall clinical course in infected individuals.

Objective. A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies inflammation and joint deformation. Patients with RA rate pain relief as the highest priority; however, few studies have addressed the efficacy and safety of therapies directed specifically toward pain pathways. The -conotoxin MVIIA (ziconotide) is used in humans to alleviate persistent pain syndromes, because it specifically blocks the voltage-gated calcium 2.2 (Ca(V)2.2) channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The aims of this study were to investigate whether blockade of Ca(V)2.2 can suppress arthritis pain, and to examine the progression of induced arthritis during persistent Ca(V)2.2 blockade. Methods. Transgenic mice expressing a membrane-tethered form of MVIIA under the control of a nociceptor-specific gene (MVIIA-transgenic mice) were used in the experiments. The mice were subjected to unilateral induction of joint inflammation using a combination of antigen and collagen. Results. Ca(V)2.2 blockade mediated by tethered MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsided, MVIIA-transgenic mice showed continued inflammation, with up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. Conclusion. Taken together, our results indicate that alleviation of peripheral pain by blockade of Ca(V)2.2- mediated calcium influx and signaling in nociceptor sensory neurons impairs recovery from induced arthritis and point to the potentially devastating effects of using Ca(V)2.2 channel blockers as analgesics during inflammation.

The inclusive jet cross section for proton-proton collisions at a centre-of-mass energy of 7 TeV was measured by the CMS Collaboration at the LHC with data corresponding to an integrated luminosity of 5.0 fb(-1). The measurement covers a phase space up to 2 TeV in jet transverse momentum and 2.5 in absolute jet rapidity. The statistical precision of these data leads to stringent constraints on the parton distribution functions of the proton. The data provide important input for the gluon density at high fractions of the proton momentum and for the strong coupling constant at large energy scales. Using predictions from perturbative quantum chromodynamics at next-to-leading order, complemented with electroweak corrections, the constraining power of these data is investigated and the strong coupling constant at the Z boson mass M-Z is determined to be alpha(S)(M-Z) = 0.1185 +/- 0.0019 (exp)(-0.0037)(+0.0060) (theo), which is in agreement with the world average.