Double electron-electron resonance in conjunction with site-directed spin labeling has been used to probe natural conformational sampling of the human tumor necrosis factor α trimer. We suggest a ...previously unreported, predeoligomerization conformation of the trimer that has been shown to be sampled at low frequency. A model of this trimeric state has been constructed based on crystal structures using the double-electron-electron-resonance distances. The model shows one of the protomers to be rotated and tilted outward at the tip end, leading to a breaking of the trimerous symmetry and distortion at a receptor-binding interface. The new structure offers opportunities to modulate the biological activity of tumor necrosis factor α through stabilization of the distorted trimer with small molecules.
Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. ...While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions.
Incumbent political leaders risk deposition by challengers within the existing political rules and by revolutionary threats. Building on Bueno de Mesquita, Smith, Siverson, and Morrow's selectorate ...theory, the model here examines the policy responses of office-seeking leaders to revolutionary threats. Whether leaders suppress public goods such as freedom of assembly and freedom of information to hinder the organizational ability of potential revolutionaries or appease potential revolutionaries by increasing the provision of public goods depends, in part, on the sources of government revenues. Empirical tests show that governments with access to revenue sources that require few labor inputs by the citizens, such as natural resource rents or foreign aid, reduce the provision of public goods and increase the odds of increased authoritarianism in the face of revolutionary pressures. In contrast, without these sources of unearned revenues, governments respond to revolutionary pressures by increasing the provision of public goods and democratizing.
Bioluminescence imaging (BLI) is ubiquitous in scientific research for the sensitive tracking of biological processes in small animal models. However, due to the attenuation of visible light by ...tissue, and the limited set of near-infrared bioluminescent enzymes, BLI is largely restricted to monitoring single processes in vivo. Here we show, that by combining stabilised colour mutants of firefly luciferase (FLuc) with the luciferin (LH
) analogue infraluciferin (iLH
), near-infrared dual BLI can be achieved in vivo. The X-ray crystal structure of FLuc with a high-energy intermediate analogue, 5'-O-N-(dehydroinfraluciferyl)sulfamoyl adenosine (iDLSA) provides insight into the FLuc-iLH
reaction leading to near-infrared light emission. The spectral characterisation and unmixing validation studies reported here established that iLH
is superior to LH
for the spectral unmixing of bioluminescent signals in vivo; which led to this novel near-infrared dual BLI system being applied to monitor both tumour burden and CAR T cell therapy within a systemically induced mouse tumour model.
IMPORTANCE: Psychotic depression is a severely disabling and potentially lethal disorder. Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with ...psychotic depression in remission. OBJECTIVE: To determine the clinical effects of continuing antipsychotic medication once an episode of psychotic depression has responded to combination treatment with an antidepressant and antipsychotic agent. DESIGN, SETTING, AND PARTICIPANTS: Thirty-six week randomized clinical trial conducted at 4 academic medical centers. Patients aged 18 years or older had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks and met criteria for remission of psychosis and remission or near-remission of depressive symptoms for 8 weeks before entering the clinical trial. The study was conducted from November 2011 to June 2017, and the final date of follow-up was June 13, 2017. INTERVENTIONS: Participants were randomized either to continue olanzapine (n = 64) or switch from olanzapine to placebo (n = 62). All participants continued sertraline. MAIN OUTCOMES AND MEASURES: The primary outcome was risk of relapse. Main secondary outcomes were change in weight, waist circumference, lipids, serum glucose, and hemoglobin A1c (HbA1c). RESULTS: Among 126 participants who were randomized (mean SD age, 55.3 years 14.9 years; 78 women 61.9%), 114 (90.5%) completed the trial. At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range IQR, 150-200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10-20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P < .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb; 95% CI, 0.11 to 0.15), waist circumference (0.009 inches; 95% CI, 0.004 to 0.014), and total cholesterol (0.29 mg/dL; 95% CI, 0.13 to 0.45) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, −0.01 to 0.10), high-density lipoprotein cholesterol (−0.01 mg/dL; 95% CI, −0.03 to 0.01), triglyceride (−0.153 mg/dL; 95% CI, −0.306 to 0.004), glucose (−0.02 mg/dL; 95% CI, −0.12 to 0.08), or HbA1c levels (−0.0002 mg/dL; 95% CI, −0.0021 to 0.0016). CONCLUSIONS AND RELEVANCE: Among patients with psychotic depression in remission, continuing sertraline plus olanzapine compared with sertraline plus placebo reduced the risk of relapse over 36 weeks. This benefit needs to be balanced against potential adverse effects of olanzapine, including weight gain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01427608
Foreign Aid and Policy Concessions de Mesquita, Bruce Bueno; Smith, Alastair
The Journal of conflict resolution,
04/2007, Letnik:
51, Številka:
2
Journal Article
Recenzirano
We model foreign-aid-for-policy deals, assuming that leaders want to maximize their time in office. Their actions are shaped by two political institutions, their selectorate and winning coalition. ...Leaders who depend on a large coalition, a relatively small selectorate, and who extract valuable policy concessions from prospective recipients are likely to give aid. Prospective recipients are likely to get aid if they have few resources, depend on a small coalition and a large selectorate, and the policy concession sought by the donor is not too politically costly. The amount of aid received, if any, increases as the recipient leader's coalition increases, the selectorate decreases, the issue's salience increases, and the domestic resources increase. The theory explains why many Third World people hate the United States and he want to live there. Empirical tests using the U.S, Agency for International Development data for the post—World War II years support the model's predictions.
Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a ...distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors.
It is well established that children with autism often show outstanding visual search skills. To date, however, no study has tested whether these skills, usually assessed on a table-top or computer, ...translate to more true-to-life settings. One prominent account of autism, Baron-Cohen's "systemizing" theory, gives us good reason to suspect that they should. In this study, we tested whether autistic children's exceptional skills at small-scale search extend to a large-scale environment and, in so doing, tested key claims of the systemizing account. Twenty school-age children with autism and 20 age- and ability-matched typical children took part in a large-scale search task in the "foraging room": a purpose-built laboratory, with numerous possible search locations embedded into the floor. Children were instructed to search an array of 16 (green) locations to find the hidden (red) target as quickly as possible. The distribution of target locations was manipulated so that they appeared on one side of the midline for 80% of trials. Contrary to predictions of the systemizing account, autistic children's search behavior was much less efficient than that of typical children: they showed reduced sensitivity to the statistical properties of the search array, and furthermore, their search patterns were strikingly less optimal and less systematic. The nature of large-scale search behavior in autism cannot therefore be explained by a facility for systemizing. Rather, children with autism showed difficulties exploring and exploiting the large-scale space, which might instead be attributed to constraints (rather than benefits) in their cognitive repertoire.
Almost half of older patients with major depressive disorder (MDD) present with cognitive impairment, and one-third meet diagnostic criteria for mild cognitive impairment (MCI). However, mechanisms ...linking MDD and MCI remain unclear. We investigated multivariate associations between brain structural alterations and cognition in 3 groups of older patients at risk for dementia, remitted MDD (rMDD), MCI, and rMDD+MCI, as well as cognitively healthy nondepressed control participants.
We analyzed magnetic resonance imaging data and cognitive domain scores in participants from the PACt-MD (Prevention of Alzheimer’s Disease With Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression) study. Following quality control, we measured cortical thickness and subcortical volumes of selected regions from 283 T1-weighted scans and fractional anisotropy of white matter tracts from 226 diffusion-weighted scans. We assessed brain-cognition associations using partial least squares regressions in the whole sample and in each subgroup.
In the entire sample, atrophy in the medial temporal lobe and subregions of the motor and prefrontal cortex was associated with deficits in verbal and visuospatial memory, language skills, and, to a lesser extent, processing speed (p < .0001; multivariate r = 0.30, 0.34, 0.26, and 0.18, respectively). Widespread reduced white matter integrity was associated with deficits in executive functioning, working memory, and processing speed (p = .008; multivariate r = 0.21, 0.26, 0.35, respectively). Overall, associations remained significant in the MCI and rMDD+MCI groups, but not the rMDD or healthy control groups.
We confirm findings of brain-cognition associations previously reported in MCI and extend them to rMDD+MCI, but similar associations in rMDD are not supported. Early-onset and treated MDD might not contribute to structural alterations associated with cognitive impairment.
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