Simulating the computational mechanisms of cognitive and behavioral psychotherapeutic interventions: insights from active inference

Cognitive-behavioral therapy (CBT) leverages interactions between thoughts, feelings, and behaviors. To deepen understanding of these interactions, we present a computational (active inference) model of CBT that allows formal simulations of interactions between cognitive interventions (i.e., cognitive restructuring) and behavioral interventions (i.e., exposure) in producing adaptive behavior change (i.e., reducing maladaptive avoidance behavior). Using spider phobia as a concrete example of maladaptive avoidance more generally, we show simulations indicating that when conscious beliefs about safety/danger have strong interactions with affective/behavioral outcomes, behavioral change during exposure therapy is mediated by changes in these beliefs, preventing generalization. In contrast, when these interactions are weakened, and cognitive restructuring only induces belief uncertainty (as opposed to strong safety beliefs), behavior change leads to generalized learning (i.e., “over-writing” the implicit beliefs about action-outcome mappings that directly produce avoidance). The individual is therefore equipped to face any new context, safe or dangerous, remaining in a content state without the need for avoidance behavior—increasing resilience from a CBT perspective. These results show how the same changes in behavior during CBT can be due to distinct underlying mechanisms; they predict lower rates of relapse when cognitive interventions focus on inducing uncertainty and on reducing the effects of automatic negative thoughts on behavior

Law School Based Incubators and Access to Justice – Perspectives from Deans

At the end of February 2015, law professors, law deans, incubator staff and attorneys, and self-selected others gathered at California Western School of Law for the Second Annual Conference on Law School Incubators and Residency Programs. The incubators that are the subject of this article tend to focus on transition to law practice and access to justice, and some are also working to incorporate technology for the practice of law as a means of enhancing access to justice. As more law schools decide to host, sponsor or offer an incubator, and following our panel discussion at the February 2015 incubator conference, we thought it would be helpful to consider fundamental issues deans grapple with when asked to launch an incubator. This list may not be exhaustive, but it will certainly more quickly advance the conversation, and offers a roadmap of sorts for an incubator business plan

Law School Based Incubators and Access to Justice – Perspectives from Deans

At the end of February 2015, law professors, law deans, incubator staff and attorneys, and self-selected others gathered at California Western School of Law for the Second Annual Conference on Law School Incubators and Residency Programs. The incubators that are the subject of this article tend to focus on transition to law practice and access to justice, and some are also working to incorporate technology for the practice of law as a means of enhancing access to justice. As more law schools decide to host, sponsor or offer an incubator, and following our panel discussion at the February 2015 incubator conference, we thought it would be helpful to consider fundamental issues deans grapple with when asked to launch an incubator. This list may not be exhaustive, but it will certainly more quickly advance the conversation, and offers a roadmap of sorts for an incubator business plan

The connection analysis between the dilution of the deposited Fe-Cr-V-Mo-C layer by the basic metal and the parameters of its microstructure

In this work, the structure of the Fe-Cr-V-Mo-C coatings received by plasma transferred arc cladding was investigated. Coatings were deposited on plates with a thickness of 10 mm and made from constructional steel (steel 20). The correlation analysis of relationships between dilution of the deposited layers by the basic metal and the parameters of their microstructure was carried out. The parameters were as follows: volume fraction, a size, a shape factor, the distance between particles, the number of particles of vanadium carbide, volume fraction of the eutectic on the basis of carbide M[7]C[3] and the distances between its colonies, as well as the volume fraction of the [alpha]-phase in the alloy matrix

Plasma surface engineering to biofunctionalise polymers for β-cell adhesion

Implant devices containing insulin-secreting β-cells hold great promise for the treatment of diabetes. Using in vitro cell culture, long-term function and viability are enhanced when β-cells are cultured with extracellular matrix (ECM) proteins. Here, our goal is to engineer a favorable environment within implant devices, where ECM proteins are stably immobilized on polymer scaffolds, to better support β-cell adhesion. Four different polymer candidates (low-density polyethylene (LDPE), polystyrene (PS), polyethersulfone (PES) and polysulfone (PSU)) were treated using plasma immersion ion implantation (PIII) to enable the covalent attachment of laminin on their surfaces. Surface characterisation analysis shows the increased hydrophilicity, polar groups and radical density on all polymers after the treatment. Among the four polymers, PIII-treated LDPE has the highest water contact angle and the lowest radical density which correlate well with the non-significant protein binding improvement observed after 2 months of storage. The study found that the radical density created by PIII treatment of aromatic polymers was higher than that created by the treatment of aliphatic polymers. The higher radical density significantly improves laminin attachment to aromatic polymers, making them better substrates for β-cell adhesion

Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice.

UNLABELLED: Vasoactive intestinal peptide (VIP) mediates a broad range of biological responses by activating two related receptors, VIP receptor 1 and 2 (VIPR1 and VIPR2). Although the use of native VIP facilitates neuroprotection, clinical application of the hormone is limited due to VIP\u27s rapid metabolism and inability to distinguish between VIPR1 and VIPR2 receptors. In addition, activation of both receptors by therapeutics may increase adverse secondary toxicities. Therefore, we developed metabolically stable and receptor-selective agonists for VIPR1 and VIPR2 to improve pharmacokinetic and pharmacodynamic therapeutic end points. Selective agonists were investigated for their abilities to protect mice against MPTP-induced neurodegeneration used to model Parkinson\u27s disease (PD). Survival of tyrosine hydroxylase neurons in the substantia nigra was determined by stereological tests after MPTP intoxication in mice pretreated with either VIPR1 or VIPR2 agonist or after adoptive transfer of splenic cell populations from agonist-treated mice administered to MPTP-intoxicated animals. Treatment with VIPR2 agonist or splenocytes from agonist-treated mice resulted in increased neuronal sparing. Immunohistochemical tests showed that agonist-treated mice displayed reductions in microglial responses, with the most pronounced effects in VIPR2 agonist-treated, MPTP-intoxicated mice. In parallel studies, we observed reductions in proinflammatory cytokine release that included IL-17A, IL-6, and IFN-γ and increases in GM-CSF transcripts in CD4(+) T cells recovered from VIPR2 agonist-treated animals. Moreover, a phenotypic shift of effector to regulatory T cells was observed. These results support the use of VIPR2-selective agonists as neuroprotective agents for PD treatment. SIGNIFICANCE STATEMENT: Vasoactive intestinal peptide receptor 2 can elicit immune transformation in a model of Parkinson\u27s disease (PD). Such immunomodulatory capabilities can lead to neuroprotection by attenuating microglial activation and by slowing degradation of neuronal cell bodies and termini in MPTP-intoxicated mice. The protective mechanism arises from altering a Th1/Th2 immune cytokine response into an anti-inflammatory and neuronal sparing profile. These results are directly applicable for the development of novel PD therapies

Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote Tuberculosis Infection

Rationale: Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment. Objectives: To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. Methods: South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion 1 yr) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ+ TNF+ Mycobacterium tuberculosis-specific T cells and total CD3+ T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease and by unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (nonprogressors) or who progressed to microbiologically confirmed disease (progressors). Measurements and Main Results: In the test cohorts, frequencies of Mycobacterium tuberculosis-specific T cells differentiated between QuantiFERON-TB- (n = 25) and QuantiFERON-TB+ (n = 47) individuals (area under the receiver operating characteristic curve, 0.94; 95% confidence interval, 0.87-1.00). ΔHLA-DR significantly discriminated between recent (n = 20) and persistent (n = 22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n = 19; 0.99; 0.96-1.00); and tuberculosis progressors (n = 22) and nonprogressors (n = 34; 0.75; 0.63-0.87). However, ΔHLA-DR median fluorescent intensity could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50-0.84). Conclusions: The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted

Seismogenic zone structure of the southern Middle America Trench, Costa Rica

The shallow seismogenic portion of subduction zones generates damaging large and great earthquakes. This study provides structural constraints on the seismogenic zone of the Middle America Trench offshore central Costa Rica and insights into the physical and mechanical characteristics controlling seismogenesis. We have located ~300 events that occurred following the MW 6.9, 20 August 1999, Quepos, Costa Rica, underthrusting earthquake using a three-dimensional velocity model and arrival time data recorded by a temporary local network of land and ocean bottom seismometers. We use aftershock locations to define the geometry and characteristics of the seismogenic zone in this region. These events define a plane dipping at 19° that marks the interface between the Cocos Plate and the Panama Block. The majority of aftershocks occur below 10 km and above 30 km depth below sea level, corresponding to 30–35 km and 95 km from the trench axis, respectively. Relative event relocation produces a seismicity pattern similar to that obtained using absolute locations, increasing confidence in the geometry of the seismogenic zone. The aftershock locations spatially correlate with the downdip extension of the oceanic Quepos Plateau and reflect the structure of the main shock rupture asperity. This strengthens an earlier argument that the 1999 Quepos earthquake ruptured specific bathymetric highs on the downgoing plate. We believe that subduction of this highly disrupted seafloor has established a set of conditions which presently limit the seismogenic zone to be between 10 and 35 km below sea level

Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKTlike subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection