Neural activation changes following attention bias modification treatment or a selective serotonin reuptake inhibitor for social anxiety disorder.

Background: Delineation of changes in neural function associated with novel and established treatments for social anxiety disorder (SAD) can advance treatment development. We examined such changes following selective serotonin reuptake inhibitor (SSRI) and attention bias modification (ABM) variant - gaze-contingent music reward therapy (GC-MRT), a first-line and an emerging treatments for SAD.

Methods: Eighty-one patients with SAD were allocated to 12-week treatments of either SSRI or GC-MRT, or waitlist (s = 22, 29, and 30, respectively).

Attention bias vs. attention control modification for social anxiety disorder: A randomized controlled trial.

Gaze-Contingent Music Reward Therapy (GC-MRT) is an eye-tracking-based attention bias modification protocol for social anxiety disorder (SAD) with established clinical efficacy. However, it remains unclear if improvement following GC-MRT hinges on modification of threat-related attention or on more general enhancement of attention control. Here, 50 patients with SAD were randomly allocated to GC-MRT using either threat faces or shapes.

The free-viewing matrix task: A reliable measure of attention allocation in psychopathology.

Aberrant attention allocation has been implicated in the etiology and maintenance of a range of psychopathologies. However, three decades of research, relying primarily on manual response-time tasks, have been challenged on the grounds of poor reliability of its attention bias indices. Here, in a large, multisite, international study we provide reliability information for a new eye-tracking-based measure of attention allocation and its relation to psychopathology and age.

The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling.

Background: The inflammatory response is indispensable for protective immunity, yet microbial pathogens often trigger an excessive response, 'cytokine storm', harmful to the host. Full T-cell activation requires interaction of costimulatory receptors B7-1(CD80) and B7-2(CD86) expressed on antigen-presenting cells with CD28 expressed on the T cells. We created short peptide mimetics of the homodimer interfaces of the B7 and CD28 receptors and examined their ability to attenuate B7/CD28 coligand engagement and signaling through CD28 for inflammatory cytokine induction in human immune cells, and to protect from lethal toxic shock in vivo.

Functional Impact of Protein-RNA Variation in Clinical Cancer Analyses.

Comprehensive molecular characterization of tumors aims to uncover cancer vulnerabilities, drug resistance mechanisms, and biomarkers. Identification of cancer drivers was suggested as the basis for patient-tailored therapy, and transcriptomic analyses were proposed to reveal the phenotypic outcome of cancer mutations. With the maturation of the proteomic field, studies of protein-RNA discrepancies suggested that RNA analyses are insufficient to predict cellular functions.

Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short-term vs long-term survivors of glioblastoma.

Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the time of diagnosis (ie, long-term survivors [LTS]).

Attention Bias Modification Treatment Versus a Selective Serotonin Reuptake Inhibitor Or Waiting List Control for Social Anxiety Disorder: A Randomized Clinical Trial.

Objective: Social anxiety disorder is common and impairing. The efficacy of pharmacotherapy is moderate, highlighting the need for alternative therapies. This study compared the efficacy of gaze-contingent music reward therapy (GC-MRT), an eye-tracking-based attention bias modification treatment, with a selective serotonin reuptake inhibitor (SSRI) treatment or a waiting list control condition in reducing social anxiety disorder symptoms.

An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination.

Unlabelled: Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression.

Proteomic analysis of necroptotic extracellular vesicles.

Necroptosis is a regulated and inflammatory form of cell death. We, and others, have previously reported that necroptotic cells release extracellular vesicles (EVs). We have found that necroptotic EVs are loaded with proteins, including the phosphorylated form of the key necroptosis-executing factor, mixed lineage kinase domain-like kinase (MLKL).

Social Distancing During A COVID-19 Lockdown Contributes to The Maintenance of Social Anxiety: A Natural Experiment.

Background: The COVID-19 pandemic has led to extensive social distancing measures. For those suffering from social anxiety, social distancing coincides with a tendency to avoid social interactions. We used this natural experiment imposed by a COVID-19 lockdown to examine how mandated low social exposure influenced socially anxious university students, and compared their anxiety to that of socially anxious students in preceding academic years with no social distancing.

Statistical learning as a predictor of attention bias modification outcome: A preliminary study among socially anxious patients.

Attention bias modification (ABM) is a novel therapy designed to modulate attentional biases towards threat typically observed among anxious individuals. Bias modification is allegedly achieved via extraction of a statistical regularity embedded within the treatment task. However, no prior study examined prediction of ABM therapeutic response in relation to patients' capacity to extract statistical properties from the environment, a capacity known as "statistical learning".

A neuromarker of clinical outcome in attention bias modification therapy for social anxiety disorder.

Background: Attention bias modification (ABM) therapy aims to modify threat-related attention patterns via computerized tasks. Despite showing medium clinical effect sizes for anxiety disorders, underlying neural-cognitive mechanisms of change remain unclear. We used visual mismatch negativity (vMMN), an event-related potential sensitive to violations of learned statistical contingencies, to assess therapy-related contingency extraction processes in healthy participants and in patients with social anxiety disorder (SAD).

Commentary: Information-processing in anxiety and depression - novel targets for translational research, a reflection on Lau and Waters (2017).

Understanding psychopathology in the context of a developmental cognitive neuroscience approach entails the notion that specific individual differences in information processing can serve as both etiologic and maintaining factors in the development of specific disorders. It is posited that such mechanistic understanding of neurocognitive aberrations during development can then serve focused translational efforts in the form of cognitive bias modification treatments. In the review by Lau and Waters (this issue), an astute developmental model is suggested regarding the role of potential neurocognitive mechanisms in depression and anxiety in youth.

Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint.

Formation of the costimulatory axis between the B7-2 and CD28 coreceptors is critical for T-cell activation. Superantigens, Gram-positive bacterial virulence factors, cause toxic shock and sepsis by hyperinducing inflammatory cytokines. We report a novel role for costimulatory receptors CD28 and B7-2 as obligatory receptors for superantigens, rendering them therapeutic targets.

Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction.

Full T-cell activation requires interaction between the costimulatory receptors B7-2 and CD28. By binding CD28, bacterial superantigens elicit harmful inflammatory cytokine overexpression through an unknown mechanism. We show that, by engaging not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the avidity between B7-2 and CD28, inducing thereby T-cell hyperactivation.

CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis.

Background: Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mimetic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was tested for its ability to increase survival in models of polymicrobial infection and gram-negative sepsis.

Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells.

Human pluripotent stem cells (hPSCs) tend to acquire genomic aberrations in culture, the most common of which is trisomy of chromosome 12. Here we dissect the cellular and molecular implications of this trisomy in hPSCs. Global gene expression analyses reveal that trisomy 12 profoundly affects the gene expression profile of hPSCs, inducing a transcriptional programme similar to that of germ cell tumours.

CD28: direct and critical receptor for superantigen toxins.

Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on T-cells functioning as principal costimulatory receptor. Staphylococcal and streptococcal superantigen toxins hyperstimulate the T-cell-mediated immune response by orders of magnitude, inducing a lethal cytokine storm. We show that to elicit an inflammatory cytokine storm and lethality, superantigens must bind directly to CD28.

A peptide antagonist of CD28 signaling attenuates toxic shock and necrotizing soft-tissue infection induced by Streptococcus pyogenes.

Staphylococcus aureus and group A Streptococcus pyogenes (GAS) express superantigen (SAg) exotoxin proteins capable of inducing lethal shock. To induce toxicity, SAgs must bind not only to the major histocompatibility complex II molecule of antigen-presenting cells and the variable β chain of the T-cell receptor but also to the dimer interface of the T-cell costimulatory receptor CD28. Here, we show that the CD28-mimetic peptide AB103 (originally designated "p2TA") protects mice from lethal challenge with streptococcal exotoxin A, as well as from lethal GAS bacterial infection in a murine model of necrotizing soft-tissue infection.

Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock.

Bacterial superantigens, a diverse family of toxins, induce an inflammatory cytokine storm that can lead to lethal shock. CD28 is a homodimer expressed on T cells that functions as the principal costimulatory ligand in the immune response through an interaction with its B7 coligands, yet we show here that to elicit inflammatory cytokine gene expression and toxicity, superantigens must bind directly into the dimer interface of CD28. Preventing access of the superantigen to CD28 suffices to block its lethality.

Single-stranded DNA-binding protein recruits DNA polymerase V to primer termini on RecA-coated DNA.

Translesion DNA synthesis (TLS) by DNA polymerase V (polV) in Escherichia coli involves accessory proteins, including RecA and single-stranded DNA-binding protein (SSB). To elucidate the role of SSB in TLS we used an in vitro exonuclease protection assay and found that SSB increases the accessibility of 3' primer termini located at abasic sites in RecA-coated gapped DNA. The mutant SSB-113 protein, which is defective in protein-protein interactions, but not in DNA binding, was as effective as wild-type SSB in increasing primer termini accessibility, but deficient in supporting polV-catalyzed TLS.

Permeabilized mammalian cells as an experimental system for nuclear import of geminiviral karyophilic proteins and of synthetic peptides derived from their nuclear localization signal regions.

The plant-infecting geminiviruses deliver their genome and viral proteins into the host cell nucleus. Members of the family Geminiviridae possess either a bipartite genome composed of two approximately 2.6 kb DNAs or a monopartite genome of approximately 3.

Broad-spectrum immunity against superantigens is elicited in mice protected from lethal shock by a superantigen antagonist peptide.

Bypassing the restricted presentation of conventional antigens, superantigens trigger an excessive cellular immune response leading to toxic shock. Antagonist peptides that inhibit the induction of human Th1 cytokine gene expression by a variety of bacterial superantigens protect mice from lethal toxic shock. We show that the surviving mice rapidly develop a broad-spectrum, protective immunity against further lethal toxin challenges with the same superantigen and even with superantigen toxins that they have not encountered before.

Defense against biologic warfare with superantigen toxins.

Background: Superantigens produced by Staphylococcus aureus and Streptococcus pyogenes are among the most lethal of toxins. Toxins in this family trigger an excessive cellular immune response leading to toxic shock.

Objectives: To design an antagonist that is effective in vivo against a broad spectrum of superantigen toxins.