The Difficulties in Emotion Regulation Scale (DERS) is a widely used self-report measure of subjective emotion ability, as defined by a prominent clinically derived model of emotion regulation (Gratz ...and Roemer, 2004). Although the DERS is often used in treatment and research settings for adults with emotional (i.e., anxiety, mood, obsessive-compulsive, or trauma-related) disorders, its psychometric properties are not well-characterized in this population.
We examined the psychometric properties of the DERS and three popular short forms (DERS-16; DERS-18; and DERS-SF) in a large (
= 427) sample of treatment-seeking adults with one or more
emotional disorders.
For the original DERS, internal consistency was strong for all subscales except Awareness. A bifactor structure consisting of one general emotion dysregulation factor and five uncorrelated specific factors corresponding to the original DERS subscales (excluding Awareness) provided the best fit. A series of structural equation models (SEMs) demonstrated unique incremental contributions of the general factor and several specific factors to explaining concurrent clinical severity. The general factor and one specific factor (Goals) also prospectively predicted treatment outcome following a naturalistic course of outpatient cognitive-behavioral therapy (CBT) in a subset of participants (
= 202) for whom discharge data were available. Specifically, more severe emotion dysregulation at intake predicted better CBT response, while more severe impairment in goal-directed activity when distressed predicted worse CBT response. All three short forms showed a robust bifactor structure and good internal consistency and convergent validity vis-à-vis the original measure, albeit with a slight decrement in incremental utility (1-3% less variance explained in clinical severity).
With the Awareness items excluded, the DERS showed good internal consistency and a robust bifactor latent structure. The general factor and several specific factors incrementally and prospectively predicted clinical severity and treatment outcome, which suggests that the DERS may have clinical and predictive utility in treatment-seeking adults with emotional disorders. Additional research is needed to establish convergent and discriminant validity in this population. The use of a short form in lieu of the full DERS may be sufficient for many general clinical and research purposes, particularly when participant burden is a concern.
A vast array of tumor-derived genetic, proteomic and cellular components are constantly released into the circulation of cancer patients. These molecules including circulating tumor DNA and RNA, ...proteins, tumor and immune cells are emerging as convenient and accurate liquid biomarkers of cancer. Circulating cancer biomarkers provide invaluable information on cancer detection and diagnosis, prognosticate patient outcomes, and predict treatment response. In this era of effective molecular targeted treatments and immunotherapies, there is now an urgent need to implement use of these circulating biomarkers in the clinic to facilitate personalized therapy. In this review, we present recent findings in circulating melanoma biomarkers, examine the challenges and promise of evolving technologies used for liquid biomarker discovery, and discuss future directions and perspectives in melanoma biomarker research.
Dendritic cells (DCs) and macrophages are present in the tissues of the anogenital tract, where HIV-1 transmission occurs in almost all cases. These cells are both target cells for HIV-1 and ...represent the first opportunity for the virus to interfere with innate recognition. Previously we have shown that both cell types fail to produce type I interferons (IFNs) in response to HIV-1 but that, unlike T cells, the virus does not block IFN induction by targeting IFN regulatory factor 3 (IRF3) for cellular degradation. Thus, either HIV-1 inhibits IFN induction by an alternate mechanism or, less likely, these cells fail to sense HIV-1. Here we show that HIV-1 (but not herpes simplex virus 2 HSV-2 or Sendai virus)-exposed DCs and macrophages fail to induce the expression of all known type I and III IFN genes. These cells do sense the virus, and pattern recognition receptor (PRR)-induced signaling pathways are triggered. The precise stage in the IFN-inducing signaling pathway that HIV-1 targets to block IFN induction was identified; phosphorylation but not K63 polyubiquitination of TANK-binding kinase 1 (TBK1) was completely inhibited. Two HIV-1 accessory proteins, Vpr and Vif, were shown to bind to TBK1, and their individual deletion partly restored IFN-β expression. Thus, the inhibition of TBK1 autophosphorylation by binding of these proteins appears to be the principal mechanism by which HIV-1 blocks type I and III IFN induction in myeloid cells.
Dendritic cells (DCs) and macrophages are key HIV target cells. Therefore, definition of how HIV impairs innate immune responses to initially establish infection is essential to design preventative interventions, especially by restoring initial interferon production. Here we demonstrate how HIV-1 blocks interferon induction by inhibiting the function of a key kinase in the interferon signaling pathway, TBK1, via two different viral accessory proteins. Other viral proteins have been shown to target the general effects of TBK1, but this precise targeting between ubiquitination and phosphorylation of TBK1 is novel.
Herpes simplex virus type 1 (HSV-1) is a neuroinvasive human pathogen that has the ability to infect and replicate within epithelial cells and neurons and establish a life-long latent infection in ...sensory neurons. HSV-1 depends on the host cellular cytoskeleton for entry, replication, and exit. Therefore, HSV-1 has adapted mechanisms to promote its survival by exploiting the microtubule and actin cytoskeletons to direct its active transport, infection, and spread between neurons and epithelial cells during primary and recurrent infections. This review will focus on the currently known mechanisms utilized by HSV-1 to harness the neuronal cytoskeleton, molecular motors, and the secretory and exocytic pathways for efficient virus entry, axonal transport, replication, assembly, and exit from the distinct functional compartments (cell body and axon) of the highly polarized sensory neurons.
Abstract In this study we have defined protein–protein interactions between the structural proteins of herpes simplex virus type 1 (HSV-1) using a LexA yeast two-hybrid system. The majority of the ...capsid, tegument and envelope proteins of HSV-1 were screened in a matrix approach. A total of 40 binary interactions were detected including 9 out of 10 previously identified tegument–tegument interactions (Vittone, V., Diefenbach, E., Triffett, D., Douglas, M.W., Cunningham, A.L., and Diefenbach, R.J., 2005. Determination of interactions between tegument proteins of herpes simplex virus type 1. J. Virol. 79, 9566–9571). A total of 12 interactions involving the capsid protein pUL35 (VP26) and 11 interactions involving the tegument protein pUL46 (VP11/12) were identified. The most significant novel interactions detected in this study, which are likely to play a role in viral assembly, include pUL35–pUL37 (capsid–tegument), pUL46–pUL37 (tegument–tegument) and pUL49 (VP22)–pUS9 (tegument–envelope). This information will provide further insights into the pathways of HSV-1 assembly and the identified interactions are potential targets for new antiviral drugs.
PD-1 plays an important role in T cell exhaustion during HIV infection. PD-1 has two ligands: PD-L1, expressed on hematopoietic and nonhematopoietic cells, and PD-L2, limited to DCs and macrophages. ...Little is known about PD-L1 expression and regulation in human macrophages. Previous reports have found few immediate effects of macrophage exposure to HIV, suggesting that macrophages lack PRRs for this virus. Using quantitative confocal microscopy and a multiplexed cytokine bead array, we measured induction of PD-L1, PD-L2, and innate response cytokines in human MDMs in response to chemically inactivated HIV virions. Consistent with previous reports, no cytokines were induced by HIV virion exposure. Whereas PD-L1 and PD-L2 had low baseline expression, TLR ligands (LPS and CL097) up-regulated PD-L1 but not PD-L2. Unlike what we found for cytokine expression, PD-L1 and PD-L2 were up-regulated in response to exposure with inactivated HIV virions or with replication-competent HIV. Expression of PD-L1 was differentially modulated by IL-10, which induced up-regulation of PD-L1 but not of PD-L2, and IL-10 blockade enhanced only PD-L2 expression. We discuss implications for innate recognition of HIV by macrophages and potential, different roles for PD-L1 and PD-L2 in immunity and pathogenesis.
Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered ...mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging and severely so in a mouse model of Huntington’s disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared with matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate the striosomal signal-to-noise ratio, crucial for discrimination and learning.
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•Striosomal, not matrix, striatal activity is shaped with valence-based learning•Striosomal, not matrix, DREADD manipulation opposingly modulates task engagement•Striosome-selective circuit decline occurs during aging and in mouse model of HD•Interneuron-striosome connectivity modulates SNR, and this increases with learning
Friedman et al. find that specialized regions of the striatum, a key part of the brain’s movement and motivation control system, are essential for learning about the values of good and bad outcomes of decisions. The learning signals in striosomes scale according to subjective value and are vulnerable to decline with aging and in neurodegenerative disorders.
The alphaherpesviral envelope protein pUS9 has been shown to play a role in the anterograde axonal transport of herpes simplex virus 1 (HSV-1), yet the molecular mechanism is unknown. To address ...this, we used an in vitro pulldown assay to define a series of five arginine residues within the conserved pUS9 basic domain that were essential for binding the molecular motor kinesin-1. The mutation of these pUS9 arginine residues to asparagine blocked the binding of both recombinant and native kinesin-1. We next generated HSV-1 with the same pUS9 arginine residues mutated to asparagine (HSV-1pUS9KBDM) and then restored them being to arginine (HSV-1pUS9KBDR). The two mutated viruses were analyzed initially in a zosteriform model of recurrent cutaneous infection. The primary skin lesion scores were identical in severity and kinetics, and there were no differences in viral load at dorsal root ganglionic (DRG) neurons at day 4 postinfection (p.i.) for both viruses. In contrast, HSV-1pUS9KBDM showed a partial reduction in secondary skin lesions at day 8 p.i. compared to the level for HSV-1pUS9KBDR. The use of rat DRG neuronal cultures in a microfluidic chamber system showed both a reduction in anterograde axonal transport and spread from axons to nonneuronal cells for HSV-1pUS9KBDM. Therefore, the basic domain of pUS9 contributes to anterograde axonal transport and spread of HSV-1 from neurons to the skin through recruitment of kinesin-1.
Herpes simplex virus 1 and 2 cause genital herpes, blindness, encephalitis, and occasionally neonatal deaths. There is also increasing evidence that sexually transmitted genital herpes increases HIV acquisition, and the reactivation of HSV increases HIV replication and transmission. New antiviral strategies are required to control resistant viruses and to block HSV spread, thereby reducing HIV acquisition and transmission. These aims will be facilitated through understanding how HSV is transported down nerves and into skin. In this study, we have defined how a key viral protein plays a role in both axonal transport and spread of the virus from nerve cells to the skin.
Although the development of a fully protective HIV vaccine is the ultimate goal of HIV research, to date only one HIV vaccine trial, the RV144, has successfully induced a weakly protective response. ...The 31% protection from infection achieved in the RV144 trial was linked to the induction of nonneutralizing antibodies, able to mediate antibody-dependent cell-mediated cytotoxicity (ADCC), suggestive of an important role of Fc-mediated functions in protection. Similarly, Fc-mediated antiviral activity was recently shown to play a critical role in actively suppressing the viral reservoir, but the Fc effector mechanisms within tissues that provide protection from or after infection are largely unknown. Here we aimed to define the landscape of effector cells and Fc receptors present within vulnerable tissues. We found negligible Fc receptor-expressing natural killer cells in the female reproductive and gastrointestinal mucosa. Conversely, Fc receptor-expressing macrophages were highly enriched in most tissues, but neutrophils mediated superior antibody-mediated phagocytosis. Modifications in Fc domain of VRC01 antibody increased phagocytic responses in both phagocytes. These data suggest that non-ADCC-mediated mechanisms, such as phagocytosis and neutrophil activation, are more likely to play a role in preventative vaccine or reservoir-eliminating therapeutic approaches.
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