Piii‐37

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109838/1/cptclpt2006257.pd

Comorbid anxiety increases cognitive control activation in Major Depressive Disorder

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134086/1/da22541.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134086/2/da22541_am.pd

No association between chronic musculoskeletal complaints and Val158Met polymorphism in the Catechol-O-methyltransferase gene. The HUNT study

BACKGROUND: The Catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met, that has been found to influence human pain perception. In one study fibromyalgia was less likely among those with Val/Val genotype. METHODS: In the 1995–97 Nord-Trøndelag Health Study (HUNT), the association between Val/Met polymorphism at the COMT gene and chronic musculoskeletal complaints (MSCs) was evaluated in a random sample of 3017 individuals. RESULTS: The distribution of the COMT Val158Met genotypes and alleles were similar between controls and the twelve different chronic MSCs groups. Even when the Met/Met and Val/Met genotypes were pooled, the distribution of the Val/Val genotype and other genotypes were similar between controls and the chronic MSCs groups. CONCLUSION: In this population-based study, no significant association was found between Val/Met polymorphism at the COMT gene and chronic MSCs

PySAGES: flexible, advanced sampling methods accelerated with GPUs

Molecular simulations are an important tool for research in physics, chemistry, and biology. The capabilities of simulations can be greatly expanded by providing access to advanced sampling methods and techniques that permit calculation of the relevant underlying free energy landscapes. In this sense, software that can be seamlessly adapted to a broad range of complex systems is essential. Building on past efforts to provide open-source community supported software for advanced sampling, we introduce PySAGES, a Python implementation of the Software Suite for Advanced General Ensemble Simulations (SSAGES) that provides full GPU support for massively parallel applications of enhanced sampling methods such as adaptive biasing forces, harmonic bias, or forward flux sampling in the context of molecular dynamics simulations. By providing an intuitive interface that facilitates the management of a system's configuration, the inclusion of new collective variables, and the implementation of sophisticated free energy-based sampling methods, the PySAGES library serves as a general platform for the development and implementation of emerging simulation techniques. The capabilities, core features, and computational performance of this new tool are demonstrated with clear and concise examples pertaining to different classes of molecular systems. We anticipate that PySAGES will provide the scientific community with a robust and easily accessible platform to accelerate simulations, improve sampling, and enable facile estimation of free energies for a wide range of materials and processes

Protein crystals in adenovirus type 5-infected cells: requirements for intranuclear crystallogenesis, structural and functional analysis

Intranuclear crystalline inclusions have been observed in the nucleus of epithelial cells infected with Adenovirus serotype 5 (Ad5) at late steps of the virus life cycle. Using immuno-electron microscopy and confocal microscopy of cells infected with various Ad5 recombinants modified in their penton base or fiber domains, we found that these inclusions represented crystals of penton capsomers, the heteromeric capsid protein formed of penton base and fiber subunits. The occurrence of protein crystals within the nucleus of infected cells required the integrity of the fiber knob and part of the shaft domain. In the knob domain, the region overlapping residues 489–492 in the FG loop was found to be essential for crystal formation. In the shaft, a large deletion of repeats 4 to 16 had no detrimental effect on crystal inclusions, whereas deletion of repeats 8 to 21 abolished crystal formation without altering the level of fiber protein expression. This suggested a crucial role of the five penultimate repeats in the crystallisation process. Chimeric pentons made of Ad5 penton base and fiber domains from different serotypes were analyzed with respect to crystal formation. No crystal was found when fiber consisted of shaft (S) from Ad5 and knob (K) from Ad3 (heterotypic S5-K3 fiber), but occurred with homotypic S3K3 fiber. However, less regular crystals were observed with homotypic S35-K35 fiber. TB5, a monoclonal antibody directed against the Ad5 fiber knob was found by immunofluorescence microscopy to react with high efficiency with the intranuclear protein crystals in situ. Data obtained with Ad fiber mutants indicated that the absence of crystalline inclusions correlated with a lower infectivity and/or lower yields of virus progeny, suggesting that the protein crystals might be involved in virion assembly. Thus, we propose that TB5 staining of Ad-infected 293 cells can be used as a prognostic assay for the viability and productivity of fiber-modified Ad5 vectors

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Trust predicts COVID-19 prescribed and discretionary behavioral intentions in 23 countries

The worldwide spread of a new coronavirus (SARS-CoV-2) since December 2019 has posed a severe threat to individuals well-being. While the world at large is waiting that the released vaccines immunize most citizens, public health experts suggest that, in the meantime, it is only through behavior change that the spread of COVID-19 can be controlled. Importantly, the required behaviors are aimed not only at safeguarding one s own health. Instead, individuals are asked to adapt their behaviors to protect the community at large. This raises the question of which social concerns and moral principles make people willing to do so. We considered in 23 countries (N = 6948) individuals willingness to engage in prescribed and discretionary behaviors, as well as country-level and individual-level factors that might drive such behavioral intentions. Results from multilevel multiple regressions, with country as the nesting variable, showed that publicized number of infections were not significantly related to individual intentions to comply with the prescribed measures and intentions to engage in discretionary prosocial behaviors. Instead, psychological differences in terms of trust in government, citizens, and in particular toward science predicted individuals behavioral intentions across countries. The more people endorsed moral principles of fairness and care (vs. loyalty and authority), the more they were inclined to report trust in science, which, in turn, statistically predicted prescribed and discretionary behavioral intentions. Results have implications for the type of intervention and public communication strategies that should be most effective to induce the behavioral changes that are needed to control the COVID-19 outbreak

High-Sensitivity Cardiac Troponin-I Is Elevated in Patients with Rheumatoid Arthritis, Independent of Cardiovascular Risk Factors and Inflammation

We examined the hypothesis that cardiac-specific troponin-I (cTn-I), a biomarker of myocardial injury, is elevated in patients with rheumatoid arthritis (RA).RA patients have an increased incidence of heart failure (HF). Chronic myocardial injury in RA may be a mechanism for the development of HF.We compared cTn-I concentrations measured by high-sensitivity immunoassay in 164 patients with RA and 90 controls, excluding prior or active heart failure. We examined the relationship between cTn-I concentrations and cardiovascular risk factors, inflammation, and coronary artery calcium score (CACS), a measure of coronary atherosclerosis.cTn-I concentrations were 49% higher in patients with RA (median 1.15 pg/mL [IQR 0.73–1.92] than controls (0.77 pg/mL [0.49–1.28](P<0.001). The difference remained statistically significant after adjustment for demographic characteristics (P = 0.002), further adjustment for cardiovascular (CV) risk factors (P = 0.004), inflammatory markers (P = 0.008), and in a comprehensive model of CV risk factors and inflammatory markers (P = 0.03). In patients with RA, cTn-I concentrations were positively correlated with age (rho = 0.359), Framingham risk score (FRS) (rho = 0.366), and systolic blood pressure (rho = 0.248 (all P values ≤0.001)), but not with measures of inflammation or RA drug therapies. cTn-I was significantly correlated with CACS in RA in univariate analysis, but not after adjustment for age, race, sex and FRS (P = 0.79). Further model adjustments for renal function and coronary artery disease confirmed the significance of the findings.High-sensitivity cTn-I concentrations are elevated in patients with RA without heart failure, independent of cardiovascular risk profile and inflammatory markers. Elevated troponin concentrations in RA may indicate subclinical, indolent myocardial injury

Sex differences in rheumatoid arthritis: more than meets the eye...

Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well described, but the literature is not as clear about sex differences in RA disease course and prognosis. A recent study from a very large cross-sectional international cohort demonstrated slightly worse levels of disease activity and function in female patients with RA, compared with men. These findings are discussed in the context of our evolving knowledge of sex differences in the expression of this prototypic autoimmune disease, both in terms of the actual disease activity level, the effects that the disease has on physical function, and our ability accurately to measure these aspects

Placebo and other psychological interactions in headache treatment

We present a theory according which a headache treatment acts through a specific biological effect (when it exists), a placebo effect linked to both expectancy and repetition of its administration (conditioning), and a non-specific psychological effect. The respective part of these components varies with the treatments and the clinical situations. During antiquity, suggestions and beliefs were the mainstays of headache treatment. The word placebo appeared at the beginning of the eighteenth century. Controversies about its effect came from an excessive interpretation due to methodological bias, inadequate consideration of the variation of the measure (regression to the mean) and of the natural course of the disease. Several powerful studies on placebo effect showed that the nature of the treatment, the associated announce, the patients’ expectancy, and the repetition of the procedures are of paramount importance. The placebo expectancy is associated with an activation of pre-frontal, anterior cingular, accumbens, and periacqueducal grey opioidergic neurons possibly triggered by the dopaminergic meso-limbic system. In randomized control trials, several arms design could theoretically give information concerning the respective part of the different component of the outcome and control the natural course of the disease. However, for migraine and tension type headache attacks treatment, no three arm (verum, placebo, and natural course) trial is available in the literature. Indirect evidence of a placebo effect in migraine attack treatment, comes from the high amplitude of the improvement observed in the placebo arms (28% of the patients). This figure is lower (6%) when using the harder criterium of pain free at 2 h. But these data disregard the effect of the natural course. For prophylactic treatment with oral medication, the trials performed in the last decades report an improvement in 21% of the patients in the placebo arms. However, in these studies the duration of administration was limited, the control of attacks uncertain as well as the evolution of the co-morbid psycho-pathology. Considering the reviews and meta-analysis of complex prophylactic procedures, it must be concluded that their effect is mostly linked to a placebo and non-specific psychological effects. Acupuncture may have a slight specific effect on tension type headache, but not on migraine. Manual therapy studies do not exhibit difference between manipulation, mobilization, and controls; touch has no proven specific effect. A comprehensive efficacy review of biofeedback studies concludes to a small specific effect on tension type headache but not on migraine. A review of behavioral treatment conclude to an interesting mean improvement but did not demonstrated a specific effect with the exception of a four arm study including a pseudo meditation control group. Expectation-linked placebo, conditioning, and non-specific psychological effects vary according clinical situations and psychological context; likely low in RCT, high after anempathic medical contact, and at its maximum with a desired charismatic healer. The announcements of doctors strongly influence the beliefs of patients, and in consequence their pain and anxiety sensibilities; this modulates the amplitude of the placebo and the non-specific psychological effects and is therefore a major determinant of the therapeutic success. Furthermore, any repetitive contact, even through a placebo, may interfere positively with the psychopathological co-morbidity. One has to keep in mind that the non-specific psychological interactions play a major role in the improvement of the majority of the headache sufferers