Thalamocortical rhythms during a vibrotactile detection task

To explore the role of oscillatory dynamics of the somatosensory thalamocortical network in perception and decision making, we recorded the simultaneous neuronal activity in the ventral posterolateral nucleus (VPL) of the somatosensory thalamus and primary somatosensory cortex (S1) in two macaque monkeys performing a vibrotactile detection task. Actively detecting a vibrotactile stimulus and reporting its perception elicited a sustained poststimulus beta power increase in VPL and an alpha power decrease in S1, in both stimulus-present and stimulus-absent trials. These oscillatory dynamics in the somatosensory thalamocortical network depended on the behavioral context: they were stronger for the active detection condition than for a passive stimulation condition. Furthermore, contrasting stimulus-present vs. stimulus-absent responses, we found that poststimulus theta power increased in both VPL and S1, and alpha/beta power decreased in S1, reflecting the monkey’s perceptual decision but not the motor response per se. Additionally, higher prestimulus alpha power in S1 correlated with an increased probability of the monkey reporting a stimulus, regardless of the actual presence of a stimulus. Thus, we found task-related modulations in oscillatory activity, not only in the neocortex but also in the thalamus, depending on behavioral context. Furthermore, oscillatory modulations reflected the perceptual decision process and subsequent behavioral response. We conclude that these early sensory regions, in addition to their primary sensory functions, may be actively involved in perceptual decision making.Presenting a subject with a (weak) sensory stimulus sometimes leads to perception and sometimes not. What exactly determines the detection of a stimulus has been a central question in the study of sensory perception (1). The neural correlates of somatosensory perceptual detection have been studied extensively in both human and nonhuman primates (2–6). Spike recordings in nonhuman primates showed the contribution of a distributed network of sensorimotor regions to somatosensory decision making, including primary and secondary somatosensory cortices and prefrontal, premotor, and motor areas (7, 8). It was suggested that the neuronal correlates of subjective sensory perception progressively build up as information traverses the cortical circuits, gradually transforming the encoded sensory information into a perceptual decision (5, 9). Crucially, a spike firing rate reflecting the decision process has been detected in secondary somatosensory cortex (S2) and frontal areas, but not in the primary somatosensory cortex (S1) (8, 9).Previous work focused mainly on the role of the sensorimotor cortex, whereas only a few studies explored the role of the somatosensory thalamus. Most thalamic recordings have been either in tissue slices (10, 11) or in anesthetized animals (12, 13). With only a few studies in awake, behaving animals (14, 15), the thalamic contribution to somatosensory detection performance remained largely unknown. We recently conducted an experiment in which we recorded the simultaneous neuronal activity across the ventral posterolateral nucleus (VPL) and S1 in two monkeys (Macaca mulatta) performing a vibrotactile detection task (6, 16). These recordings of single-unit activity in VPL of awake, behaving monkeys showed that neural activity in these nuclei reflects stimulus properties but not the animal’s percept (6). Similarly, studies in the lateral geniculate nucleus (LGN), the visual equivalent of VPL, found that spike activity reflects retinal input rather than subjective perception (17, 18). Nevertheless, a study in which spikes were recorded in monkey LGN, showed an enhanced response to attended stimuli compared with nonattended stimuli (19).Although these studies focusing on single-unit spikes led to many important insights, additional understanding of perceptual decision processes may be gained by studying neuronal population dynamics as reflected by the local field potential (LFP). Several studies in humans (using EEG/magnetoencephalography) showed that cortical oscillatory dynamics influence somatosensory detection performance by setting the state of the brain networks involved (20, 21). Importantly, these studies showed that fluctuations in (anticipatory) prestimulus activity in early sensory areas, predominantly in the alpha (8–14 Hz) and beta bands (15–30 Hz), modulate the likelihood of subsequent stimulus detection (2–4, 22–26).Here, we report on the oscillatory dynamics in the somatosensory thalamocortical network. We studied LFPs that were recorded concurrently in the aforementioned detection experiments (6, 16) and asked how oscillatory activity contributes to perceptual decision making. To assess the context dependency of stimulus processing, we compared active stimulus detection with a passive control condition. This was done by investigating oscillatory activity in the LFPs of VPL and S1 and by exploring the influence of the observed oscillatory dynamics on task performance.     

Hard sphere-like glass transition in eye lens α-crystallin solutions

We study the equilibrium liquid structure and dynamics of dilute and concentrated bovine eye lens α-crystallin solutions, using small-angle X-ray scattering, static and dynamic light scattering, viscometry, molecular dynamics simulations, and mode-coupling theory. We find that a polydisperse Percus–Yevick hard-sphere liquid-structure model accurately reproduces both static light scattering data and small-angle X-ray scattering liquid structure data from α-crystallin solutions over an extended range of protein concentrations up to 290 mg/mL or 49% vol fraction and up to ca. 330 mg/mL for static light scattering. The measured dynamic light scattering and viscosity properties are also consistent with those of hard-sphere colloids and show power laws characteristic of an approach toward a glass transition at α-crystallin volume fractions near 58%. Dynamic light scattering at a volume fraction beyond the glass transition indicates formation of an arrested state. We further perform event-driven molecular dynamics simulations of polydisperse hard-sphere systems and use mode-coupling theory to compare the measured dynamic power laws with those of hard-sphere models. The static and dynamic data, simulations, and analysis show that aqueous eye lens α-crystallin solutions exhibit a glass transition at high concentrations that is similar to those found in hard-sphere colloidal systems. The α-crystallin glass transition could have implications for the molecular basis of presbyopia and the kinetics of molecular change during cataractogenesis.The cytoplasm of the tightly packed fiber cells of the eye lens contains concentrated aqueous protein mixtures that have high refractive indexes, while normally remaining clear enough for vision. Lens clarity depends on short-range order between lens proteins (1, 2) and can be disrupted by both protein aggregation and liquid–liquid phase separation in cataract, a leading cause of blindness. At the high protein concentrations of lens cytoplasm, 25–60% by weight in mammals, small changes in interprotein interactions can disrupt transparency. For human lens proteins with cataractogenic point mutations, and for high-concentration lens protein mixtures, protein interaction changes as small as a fraction of thermal energy, k_BT, can induce phase separation and thus lead to opacification (3–7).In addition to equilibrium phase transitions, dynamical transitions including glass formation and gelation can also occur at high protein concentrations like those of the eye lens (8, 9). Relatively abrupt viscoelastic changes associated with glass formation or gelation could harden the lens and contribute to presbyopia and could alter cataract formation rates by affecting aggregation and phase separation kinetics.Here we study the equilibrium liquid structure and dynamics of concentrated solutions of eye-lens α-crystallin protein solutions, using small-angle X-ray scattering (SAXS), static light scattering (SLS) and dynamic light scattering (DLS), viscometry, liquid-state theory, event-driven molecular dynamics (MD) simulations, and mode-coupling theory (MCT). α-Crystallin is a polydisperse protein with about 40 subunits of two types, αA and αB, and accounts for up to 50% of lens protein mass. The forward scattering intensity from SAXS and light scattering experiments with concentrated α-crystallin solutions can be well represented by monodisperse hard-sphere liquid-structure models that have been key for understanding short-range order needed for lens transparency (1, 2). However, in physiological conditions α-crystallin ranges in molecular weight from 3 × 10⁵ to 2 × 10⁶, with an average near 8 × 10⁵ (10). There have indeed been reports that structure factors obtained from SAXS and small-angle neutron scattering data deviate from predictions for monodisperse hard spheres (11, 12).Accordingly, we first show that a polydisperse hard-sphere liquid-structure model (PHSM) based on the Percus–Yevick (PY) approximation (13) can accurately model SAXS data obtained from the present bovine α-crystallin preparations for volume fractions up to 49%, using a polydispersity of 20%. In contrast, polydispersity did not strongly influence model predictions for the observed SLS, which unlike SAXS probes length scales much larger than molecular sizes.We then test for glassy dynamics of α-crystallin solutions, using DLS and viscometry, and find glass transition features like those previously found for hard spheres. In particular, with increasing α-crystallin concentration, DLS intermediate scattering functions show expected progressively slower relaxations along with fast decays, and the viscosity diverges, both when approaching volume fractions in the vicinity of 58%. Using MCT (14), we obtain semiquantitative models of DLS data and corresponding data from MD simulations of high-concentration polydisperse sphere systems, in which MD polydispersity values were obtained from fits of the PHSM to the SAXS data. We note that for MCT we have used the theory for monodisperse systems, because the majority of the MCT work to date has focused on such systems. Recent results for polydisperse systems (15) support a similar overall picture.In brief, the data show that the present α-crystallin solutions have liquid structure and glassy dynamics similar to those of polydisperse hard-sphere solutions. Thus, eye lens protein solutions show analogs to ordinary glass in linking short-range order, transparency, and arrested dynamics.     

Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

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Understanding the Usage of Content in a Mental Health Intervention for Depression: An Analysis of Log Data

Background

Web-based interventions for the early treatment of depressive symptoms can be considered effective in reducing mental complaints. However, there is a limited understanding of which elements in an intervention contribute to effectiveness. For efficiency and effectiveness of interventions, insight is needed into the use of content and persuasive features.

Objective

The aims of this study were (1) to illustrate how log data can be used to understand the uptake of the content of a Web-based intervention that is based on the acceptance and commitment therapy (ACT) and (2) to discover how log data can be of value for improving the incorporation of content in Web-based interventions.

Methods

Data from 206 participants (out of the 239) who started the first nine lessons of the Web-based intervention, Living to the Full, were used for a secondary analysis of a subset of the log data of the parent study about adherence to the intervention. The log files used in this study were per lesson: login, start mindfulness, download mindfulness, view success story, view feedback message, start multimedia, turn on text-message coach, turn off text-message coach, and view text message. Differences in usage between lessons were explored with repeated measures ANOVAs (analysis of variance). Differences between groups were explored with one-way ANOVAs. To explore the possible predictive value of the login per lesson quartiles on the outcome measures, four linear regressions were used with login quartiles as predictor and with the outcome measures (Center for Epidemiologic Studies—Depression [CES-D] and the Hospital Anxiety and Depression Scale—Anxiety [HADS-A] on post-intervention and follow-up) as dependent variables.

Results

A significant decrease in logins and in the use of content and persuasive features over time was observed. The usage of features varied significantly during the treatment process. The usage of persuasive features increased during the third part of the ACT (commitment to value-based living), which might indicate that at that stage motivational support was relevant. Higher logins over time (9 weeks) corresponded with a higher usage of features (in most cases significant); when predicting depressive symptoms at post-intervention, the linear regression yielded a significant model with login quartile as a significant predictor (explained variance is 2.7%).

Conclusions

A better integration of content and persuasive features in the design of the intervention and a better intra-usability of features within the system are needed to identify which combination of features works best for whom. Pattern recognition can be used to tailor the intervention based on usage patterns from the earlier lessons and to support the uptake of content essential for therapy. An adaptable interface for a modular composition of therapy features supposes a dynamic approach for Web-based treatment; not a predefined path for all, but a flexible way to go through all features that have to be used.     

ImmunoGlobulin galaxy (IGGalaxy) for simple determination and quantitation of immunoglobulin heavy chain rearrangements from NGS

Background

Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS.

Methods

Effects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 μg of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 μg) in HLA-DR4 transgenic mice.

Results

Despite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNγ, failed to improve survival in experimental TSS.

Conclusions

Our results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.     

Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.