Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the ...potential role of task-related deactivation.
Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups.
The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent.
Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.
Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and ...quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity-a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.
Scale holography Cembranos, José A. R.; Ciarreta, Salvador E. R.; Garay, Luis J.
The European physical journal. C, Particles and fields,
09/2018, Letnik:
78, Številka:
9
Journal Article
Recenzirano
Odprti dostop
We present a new correspondence between a
d
-dimensional dynamical system and a family of higher-order derivative
(
d
+
1
)
-dimensional systems. This new scale-holographic relation is built by the ...explicit introduction of a dimensionful constant which determines the size of the additional dimension.
Scale holography
is particularly useful for studying non-local theories, since the equivalent dual system on the higher dimensional manifold can be made to be local, as we illustrate with the specific examples of the
p
-adic string theory and the free particle.
Many key features in photovoltaic perovskites occur in relatively long time scales and involve mixed compositions. This requires realistic but also numerically simple models. In this work we present ...a transferable classical force field to describe the mixed hybrid perovskite MA x FA1–x Pb(Br y I1–y )3 for variable composition (∀x, y ∈ 0, 1). The model includes Lennard-Jones and Buckingham potentials to describe the interactions between the atoms of the inorganic lattice and the organic molecule, and the AMBER model to describe intramolecular atomic interactions. Most of the parameters of the force field have been obtained by means of a genetic algorithm previously developed to parametrize the CsPb(Br x I1–x )3 perovskite (Balestra et al. J. Mater. Chem. A. 2020, DOI: 10.1039/d0ta03200j). The algorithm finds the best parameter set that simultaneously fits the DFT energies obtained for several crystalline structures with moderate degrees of distortion with respect to the equilibrium configuration. The resulting model reproduces correctly the XRD patterns, the expansion of the lattice upon I/Br substitution, and the thermal expansion coefficients. We use the model to run classical molecular dynamics simulations with up to 8600 atoms and simulation times of up to 40 ns. From the simulations we have extracted the ion diffusion coefficient of the pure and mixed perovskites, presenting for the first time these values obtained by a fully dynamical method using a transferable model fitted to first-principles calculations. The values here reported can be considered as the theoretical upper limit, that is, without grain boundaries or other defects, for ion migration dynamics induced by halide vacancies in photovoltaic perovskite devices under operational conditions.
Despite that early integration of palliative care is recommended in advanced cancer patients, referrals to outpatient specialised palliative care (SPC) frequently occur late. Well-defined referral ...criteria are still missing. We analysed indicators associated with early (ER) and late referral (LR) to SPC of an high volume outpatient unit of a comprehensive cancer center.
Characteristics, laboratory parameters and symptom burden of 281 patients at first SPC referral were analysed. Timing of referral was categorized as early, intermediate and late (> 12, 3-12 and < 3 months before death). Ordinal logistic regression analysis was used to identify factors related to referral timing. Kruskal-Wallis test was used to determine symptom severity and laboratory parameter in each referral category.
LRs (50.7%) had worse scores of weakness, loss of appetite, drowsiness, assistance of daily living (all p < 0.001) and organisation of care (p < 0.01) in contrast to ERs. The mean symptom sum score was significantly higher in LRs than ERs (13.03 vs. 16.08; p < 0.01). Parameters indicative of poor prognosis, such as elevated LDH, CRP and neutrophil-to-lymphocyte ratio (NLR) (p < 0.01) as well as the presence of ascites (p < 0.05), were significantly higher (all p < 0.001) in LRs. In univariable analyses, psychological distress (p < 0.05) and female gender (p < 0.05) were independently associated with an ER.
A symptom sum score and parameters of poor prognosis like NLR or LDH might be useful to integrate into palliative care screening tools.
Molecular valves are becoming popular for potential biomedical applications. However, little is known concerning their performance in energy and environmental areas. Zeolite RHO shows unique pore ...deformations upon changes in hydration, cation siting, cation type, or temperature–pressure conditions. By varying the level of distortion of double eight-rings, it is possible to control the adsorption properties, which confer a molecular valve behavior to this material. We have employed interatomic potentials-based simulations to obtain a detailed atomistic view of the structural distortion mechanisms of zeolite RHO, in contrast with the averaged and space group restricted information provided by diffraction studies. We have modeled four aluminosilicate structures, containing Li+, Na+, K+, Ca2+ cations. The distortions of the three different zeolite rings are coupled, and the six- and eight-membered rings are largely flexible. A large dependence on the polarizing power of the extra-framework cations and with the loading of water has been found for the minimum aperture of the eight-membered rings that control the nanovalve effect. The calculated energy barriers for moving the cations across the eight-membered rings are very high, which explains the experimentally observed slow kinetics of the phase transition as well as the appearance of metastable phases.
Treatment decision-making regarding immunosuppressive therapy is challenging for individuals with lupus. We assessed the effectiveness of a decision aid for immunosuppressive therapy in lupus ...nephritis.
In a United States multicenter, open-label, randomized controlled trial (RCT), adult women with lupus nephritis, mostly from racial/ethnic minority backgrounds with low socioeconomic status (SES), seen in in- or outpatient settings, were randomized to an individualized, culturally tailored, computerized decision aid versus American College of Rheumatology (ACR) lupus pamphlet (1:1 ratio), using computer-generated randomization. We hypothesized that the co-primary outcomes of decisional conflict and informed choice regarding immunosuppressive medications would improve more in the decision aid group. Of 301 randomized women, 298 were analyzed; 47% were African-American, 26% Hispanic, and 15% white. Mean age (standard deviation SD) was 37 (12) years, 57% had annual income of <$40,000, and 36% had a high school education or less. Compared with the provision of the ACR lupus pamphlet (n = 147), participants randomized to the decision aid (n = 151) had (1) a clinically meaningful and statistically significant reduction in decisional conflict, 21.8 (standard error SE, 2.5) versus 12.7 (SE, 2.0; p = 0.005) and (2) no difference in informed choice in the main analysis, 41% versus 31% (p = 0.08), but clinically meaningful and statistically significant difference in sensitivity analysis (net values for immunosuppressives positive in favor versus negative against), 50% versus 35% (p = 0.006). Unresolved decisional conflict was lower in the decision aid versus pamphlet groups, 22% versus 44% (p < 0.001). Significantly more patients in the decision aid versus pamphlet group rated information to be excellent for understanding lupus nephritis (49% versus 33%), risk factors (43% versus 27%), medication options (50% versus 33%; p ≤ 0.003 for all); and the ease of use of materials was higher in the decision aid versus pamphlet groups (51% versus 38%; p = 0.006). Key study limitations were the exclusion of men, short follow-up, and the lack of clinical outcomes, including medication adherence.
An individualized decision aid was more effective than usual care in reducing decisional conflict for choice of immunosuppressive medications in women with lupus nephritis.
Clinicaltrials.gov, NCT02319525.
Recent advances in available percutaneous device technology require accurate measurements and quantification of relationships between right ventricular outflow tract (RVOT) structures in children ...with and without congenital heart disease to determine device suitability. To date, no population study has described normal reference ranges of these measurements by computed tomography (CT). We aimed to establish normative values for four CT-derived measurements between RVOT structures from a heterogeneous population without heart disease and develop z scores useful for clinical practice. Patients without heart disease who underwent cardiac CT between April 2014 and February 2021 at Children's Hospital Colorado were included. Distance between the right ventricular (RV) apex to pulmonary valve (PV), PV to pulmonary trunk bifurcation, and bifurcation to the right and left pulmonary artery was measured. Previously validated models were used to normalize the measurements and calculate Z scores. Each measurement was plotted against BSA and Z scores distributions were used as reference lines. Three-hundred and sixty-four healthy patients with a mean age of 8.8 years (range 1-21), 58% male, and BSA of 1 m
(range 0.4-2.1) were analyzed. The Haycock formula was used to present data as predicted values for a given BSA and within equations relating each measurement to BSA. Predicted values and Z-score boundaries for all measurements are presented.We report CT-derived normative data for four measurements between RVOT structures from a heterogeneous cohort of healthy children. Knowledge of this normative data will be useful in both determining device fit and customizing future devices to accommodate the diverse pediatric size range.
A series of new imidazole carboxylic esters (carbamates) and
N-acylimidazole derivatives of betulin and betulinic acid (
14–
29) have been synthesized. The new compounds were screened for in vitro ...cytotoxicity activity against human cancer cell lines HepG2, Jurkat and HeLa. A number of compounds have shown IC
50 values lower than 2
μM against the cancer cell lines tested and the vast majority has shown a better cytotoxicity profile than betulinic acid, including the betulin derivatives.
N-Acylimidazole derivatives
26 and
27 (IC
50 0.8 and 1.7
μM in HepG2 cells) and the C-3 carbamate derivative
16 (IC
50 2.0
μM in HepG2 cells) were the most promising compounds. Based on the observed cytotoxicity, structure–activity relationships have been established.
Introduction Existing models of non-invasive brain stimulation focus almost exclusively on the calculation and analysis the electric field distribution. This information is necessary but insufficient ...to predict the effect of the stimulation, which also depends on the response of neurons and neuronal networks to the applied electric field. Objectives To determine the current status of models of neuronal response to suprathreshold electric fields induced by transcranial magnetic stimulation (TMS) and point out limitations and future perspectives. Materials & methods Presentation of a critical overview of studies that model the effect of TMS on neurons and neuronal networks. Results In neuronal stimulation, changes in membrane potential are driven by ionic currents through membrane channels. Action potentials are due to the response of voltage-dependent channels to suprathreshold stimuli. It is well established that only the component of the electric field tangent to the trajectory of a neuron, Es , can alter its membrane potential. In TMS, changes in membrane polarization are most pronounced at terminations and bends, and are proportional to Es and the membrane length constant, λ . These results are usually modelled in terms of Hodgkin–Huxley (HH) type models for the membrane, and the cable model for elongated neuronal structures. The few published studies modelling suprathreshold neuronal responses to TMS vary considerably in their approach. Studies trying to identify stimulation sites looked in more detail at the distribution of the induced electric field and at the neuronal paths within that field. Another study included a detailed description of the morphology and the electrophysiological parameters of a single neuron to investigate the characteristics of the neuronal response to TMS. In the best known study, a detailed model of the motor thalamocortical system implemented. This model could reproduced the generation of I-waves and paired pulse responses. Conclusion Investigating different features of neuronal responses to suprathreshold stimuli requires modelling at different scales, from single neuron to complex networks. The choice of an appropriate scale will depend on the question to be addressed.
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