Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

We describe a computational protocol to aid the design of small molecule and peptide drugs that target protein-protein interactions, particularly for anti-cancer therapy. To achieve this goal, we explore multiple strategies, including finding binding hot spots, incorporating chemical similarity and bioactivity data, and sampling similar binding sites from homologous protein complexes. We demonstrate how to combine existing interdisciplinary resources with examples of semi-automated workflows. Finally, we discuss several major problems, including the occurrence of drug-resistant mutations, drug promiscuity, and the design of dual-effect inhibitors.Fil: Goncearenco, Alexander. National Institutes of Health; Estados UnidosFil: Li, Minghui. Soochow University; China. National Institutes of Health; Estados UnidosFil: Simonetti, Franco Lucio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Shoemaker, Benjamin A. National Institutes of Health; Estados UnidosFil: Panchenko, Anna R. National Institutes of Health; Estados Unido

The role of metacognition in self-critical rumination: an investigation in individuals presenting with low self-esteem

Background: No research, to date, has directly investigated the role of metacognition in self-critical rumination and low self-esteem. Aim: To investigate the presence of metacognitive beliefs about self-critical rumination; the goal of self-critical rumination and its stop signal; and the degree of detachment from intrusive self-critical thoughts. Method: Ten individuals reporting both a self-acknowledged tendency to judge themselves critically and having low self-esteem were assessed using metacognitive profiling, a semi-structured interview. Results: All participants endorsed both positive and negative metacognitive beliefs about self-critical rumination. Positive metacognitive beliefs concerned the usefulness of self-critical rumination as a means of improving cognitive performance and enhancing motivation. Negative metacognitive beliefs concerned the uncontrollability of self-critical rumination and its negative impact on mood, motivation and perception of self-worth. The primary goal of engaging in self-critical rumination was to achieve a better or clearer understanding of a given trigger situation or to feel more motivated to resolve it. However, only four participants were able to identify when this goal had been achieved, which was if the trigger situation were not to occur again. Participants unanimously stated that they were either unable to detach from their self-critical thoughts or could do so some of the time with varying degrees of success. More often than not, though, self-critical thoughts were viewed as facts, would rarely be seen as distorted or biased, and could take hours or days to dissipate. Conclusions: These findings provide preliminary evidence that specific facets of metacognition play a role in the escalation and perseveration of self-critical rumination

The contribution of metacognitions and attentional control to decisional procrastination

Earlier research has implicated metacognitions and attentional control in procrastination and self-regulatory failure. This study tested several hypotheses: (1) that metacognitions would be positively correlated with decisional procrastination; (2) that attentional control would be negatively correlated with decisional procrastination; (3) that metacognitions would be negatively correlated with attentional control; and (4) that metacognitions and attentional control would predict decisional procrastination when controlling for negative affect. One hundred and twenty-nine participants completed the Depression Anxiety Stress Scale 21, the Meta-Cognitions Questionnaire 30, the Attentional Control Scale, and the Decisional Procrastination Scale. Significant relationships were found between all three attentional control factors (focusing, shifting, and flexible control of thought) and two metacognitions factors (negative beliefs concerning thoughts about uncontrollability and danger, and cognitive confidence). Results also revealed that decisional procrastination was significantly associated with negative affect, all measured metacognitions factors, and all attentional control factors. In the final step of a hierarchical regression analysis only stress, cognitive confidence, and attention shifting were independent predictors of decisional procrastination. Overall these findings support the hypotheses and are consistent with the Self-Regulatory Executive Function model of psychological dysfunction. The implications of these findings are discussed

Imaging the paediatric lung: what does nanotechnology have to offer?

This review will provide an overview of current research into lung imaging with nanoparticles, with a focus on the use of nanoparticles as molecular imaging agents to observe pathological processes and to monitor the effectiveness of nanoparticulate drug delivery systems. Various imaging modalities together with their advantages and limitations for lung imaging will be discussed. We will also explore the range of nanoparticles used, as well as active or passive targeting of nanoparticles

Clearance of technetium-99m-DTPA and HRCT findings in the evaluation of patients with Idiopathic Pulmonary Fibrosis

BACKGROUND: Clearance of inhaled technetium-labeled diethylenetriamine pentaacetate ((99m)Tc-DTPA) is a marker of epithelial damage and an index of lung epithelial permeability. The aim of this study was to investigate the role of (99m)Tc-DTPA scan in patients with Idiopathic Pulmonary Fibrosis (IPF). Our hypothesis is that the rate of pulmonary (99m)Tc-DTPA clearance could be associated with extent of High Resolution Computed Tomography (HRCT) abnormalities, cell differential of bronchoalveolar lavage fluid (BALF) and pulmonary function tests (PFTs) in patients with IPF. METHODS: We studied prospectively 18 patients (14 male, 4 female) of median age 67yr (range 55–81) with histologically proven IPF. HRCT scoring included the mean values of extent of disease. Mean values of these percentages represented the Total Interstitial Disease Score (TID). DTPA clearance was analyzed according to a dynamic study using a Venticis II radioaerosol delivery system. RESULTS: The mean (SD) TID score was 36 ± 12%, 3 patients had mild, 11 moderate and 4 severe TID. Abnormal DTPA clearance half-time (t(1/2)<40 min) was found in 17/18 (94.5%) [mean (SD) 29.1 ± 8.6 min]. TID was weakly correlated with the DTPA clearance (r = -0.47, p = 0.048) and with % eosinophils (r = 0.475, p = 0.05). No correlation was found between TID score or DTPA and PFTs in IPF patients. CONCLUSION: Our data suggest that (99m)Tc-DTPA lung scan is not well associated with HRCT abnormalities, PFTs, and BALF cellularity in patients with IPF. Further studies in large scale of patients are needed to define the role of this technique in pulmonary fibrosis

Atomic excitation during recollision-free ultrafast multi-electron tunnel ionization

Modern intense ultrafast pulsed lasers generate an electric field of sufficient strength to permit tunnel ionization of the valence electrons in atoms. This process is usually treated as a rapid succession of isolated events, in which the states of the remaining electrons are neglected. Such electronic interactions are predicted to be weak, the exception being recollision excitation and ionization caused by linearly-polarized radiation. In contrast, it has recently been suggested that intense field ionization may be accompanied by a two-stage `shake-up' reaction. Here we report a unique combination of experimental techniques that enables us to accurately measure the tunnel ionization probability for argon exposed to 50 femtosecond laser pulses. Most significantly for the current study, this measurement is independent of the optical focal geometry, equivalent to a homogenous electric field. Furthermore, circularly-polarized radiation negates recollision. The present measurements indicate that tunnel ionization results in simultaneous excitation of one or more remaining electrons through shake-up. From an atomic physics standpoint, it may be possible to induce ionization from specific states, and will influence the development of coherent attosecond XUV radiation sources. Such pulses have vital scientific and economic potential in areas such as high-resolution imaging of in-vivo cells and nanoscale XUV lithography.Comment: 17 pages, 4 figures, original format as accepted by Nature Physic

Metacognitions about desire thinking predict the severity of binge eating in a sample of Italian women

In this study, our principal aim was to investigate whether metacognitions about desire thinking predict the severity of binge eating in women and, if so, whether this relationship is independent of age, self-reported body mass index (BMI), negative affect, irrational food beliefs and craving. One hundred and four women, consisting of 32 consecutive patients with binge eating disorder undergoing initial assessment for cognitive therapy for eating disorders, 39 moderate binge eaters, and 33 non-binge eaters (both from the general population), completed the following measures: Self-reported BMI, Hospital Anxiety and Depression Scale, Irrational Food Beliefs Scale, General Craving Scale, Metacognitions about Desire Thinking Questionnaire, and Binge Eating Scale. A series of Spearman's rho correlation analyses revealed that self-reported BMI, anxiety, depression, irrational food beliefs, craving, and all three factors of the metacognitions about desire thinking questionnaire were significantly associated with the severity of binge eating. A stepwise regression analysis identified self-reported BMI, craving, and negative metacognitions about desire thinking as significant predictors of the severity of binge eating. These results, taken together, highlight the possible role of metacognitions about desire thinking in predicting the severity of binge eating. The clinical implications of these findings are discussed

Vertical Distribution and Migration Patterns of Nautilus pompilius

Vertical depth migrations into shallower waters at night by the chambered cephalopod Nautilus were first hypothesized early in the early 20th Century. Subsequent studies have supported the hypothesis that Nautilus spend daytime hours at depth and only ascend to around 200 m at night. Here we challenge this idea of a universal Nautilus behavior. Ultrasonic telemetry techniques were employed to track eleven specimens of Nautilus pompilius for variable times ranging from one to 78 days at Osprey Reef, Coral Sea, Australia. To supplement these observations, six remotely operated vehicle (ROV) dives were conducted at the same location to provide 29 hours of observations from 100 to 800 meter depths which sighted an additional 48 individuals, including five juveniles, all deeper than 489 m. The resulting data suggest virtually continuous, nightly movement between depths of 130 to 700 m, with daytime behavior split between either virtual stasis in the relatively shallow 160–225 m depths or active foraging in depths between 489 to 700 m. The findings also extend the known habitable depth range of Nautilus to 700 m, demonstrate juvenile distribution within the same habitat as adults and document daytime feeding behavior. These data support a hypothesis that, contrary to previously observed diurnal patterns of shallower at night than day, more complex vertical movement patterns may exist in at least this, and perhaps all other Nautilus populations. These are most likely dictated by optimal feeding substrate, avoidance of daytime visual predators, requirements for resting periods at 200 m to regain neutral buoyancy, upper temperature limits of around 25°C and implosion depths of 800 m. The slope, terrain and biological community of the various geographically separated Nautilus populations may provide different permutations and combinations of the above factors resulting in preferred vertical movement strategies most suited for each population

Neutron Scattering and Its Application to Strongly Correlated Systems

Neutron scattering is a powerful probe of strongly correlated systems. It can directly detect common phenomena such as magnetic order, and can be used to determine the coupling between magnetic moments through measurements of the spin-wave dispersions. In the absence of magnetic order, one can detect diffuse scattering and dynamic correlations. Neutrons are also sensitive to the arrangement of atoms in a solid (crystal structure) and lattice dynamics (phonons). In this chapter, we provide an introduction to neutrons and neutron sources. The neutron scattering cross section is described and formulas are given for nuclear diffraction, phonon scattering, magnetic diffraction, and magnon scattering. As an experimental example, we describe measurements of antiferromagnetic order, spin dynamics, and their evolution in the La(2-x)Ba(x)CuO(4) family of high-temperature superconductors.Comment: 31 pages, chapter for "Strongly Correlated Systems: Experimental Techniques", edited by A. Avella and F. Mancin

Disposition of Federally Owned Surpluses

PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein-protein interactions