Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, ...we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
Object-constraint programming provides a design to integrate constraints with dynamic, object-oriented programming languages. It allows developers to encode multi-way constraints over objects and ...object collections using existing, object-oriented abstractions. These constraints are automatically maintained at run-time. One original goal of the Babelsberg-family of object-constraint programming languages was to allow users familiar with the imperative paradigm to quickly and efficiently make use of constraint solver capabilities. Yet, practical problems often require careful selection of solvers to find good solutions (or any at all). Furthermore, solver performance can vary and while most solvers come with various optimizations, developers have to have a good understanding of the solving process to use these optimizations effectively. This, however, is difficult to achieve if the solver is automatically selected by the system. In this work, we discuss three different implementations for automatic solver selection that we used in Babelsberg implementations. As a second step, we look at the performance potential of edit constraints that are available in some solvers such as Cassowary or DeltaBlue, and how they can be applied automatically to improve solver performance. We argue that these techniques make object-constraint programming more practical by improving the quality and performance of solutions.
BACKGROUND AND PURPOSE—Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple ...types of small vessel disease–related brain changes and examined their individual and combined predictive value on cognitive and functional abilities.
METHODS—Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network–based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years.
RESULTS—The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (P<0.001 for global cognitive function, processing speed, executive functions, and memory and P<0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on Z scores strongly predicted cognitive and functional outcomes (P<0.001) even above the contribution of the individual brain changes.
CONCLUSIONS—Global burden of small vessel disease–related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.
Actinobacteria provide a rich spectrum of bioactive natural products and therefore display an invaluable source towards commercially valuable pharmaceuticals and agrochemicals. Here, we studied the ...use of inorganic talc microparticles (hydrous magnesium silicate, 3MgO·4SiO2·H2O, 10 µm) as a general supplement to enhance natural product formation in this important class of bacteria. Added to cultures of recombinant Streptomyces lividans, talc enhanced production of the macrocyclic peptide antibiotic bottromycin A2 and its methylated derivative Met‐bottromycin A2 up to 109 mg L−1, the highest titer reported so far. Hereby, the microparticles fundamentally affected metabolism. With 10 g L−1 talc, S. lividans grew to 40% smaller pellets and, using RNA sequencing, revealed accelerated morphogenesis and aging, indicated by early upregulation of developmental regulator genes such as ssgA, ssgB, wblA, sigN, and bldN. Furthermore, the microparticles re‐balanced the expression of individual bottromycin cluster genes, resulting in a higher macrocyclization efficiency at the level of BotAH and correspondingly lower levels of non‐cyclized shunt by‐products, driving the production of mature bottromycin. Testing a variety of Streptomyces species, talc addition resulted in up to 13‐fold higher titers for the RiPPs bottromycin and cinnamycin, the alkaloid undecylprodigiosin, the polyketide pamamycin, the tetracycline‐type oxytetracycline, and the anthramycin‐analogs usabamycins. Moreover, talc addition boosted production in other actinobacteria, outside of the genus of Streptomyces: vancomycin (Amycolatopsis japonicum DSM 44213), teicoplanin (Actinoplanes teichomyceticus ATCC 31121), and the angucyclinone‐type antibiotic simocyclinone (Kitasatospora sp.). For teicoplanin, the microparticles were even crucial to activate production. Taken together, the use of talc was beneficial in 75% of all tested cases and optimized natural and heterologous hosts forming the substance of interest with clusters under native and synthetic control. Given its simplicity and broad benefits, microparticle‐supplementation appears as an enabling technology in natural product research of these most important microbes.
Kuhl and co‐authors demonstrate enhanced natural product formation in actinobacteria. Supplementation of talc microparticles to cultures of Streptomyces, Amycolatopsis, Kitasatospora, and Actinoplanes accelerates morphogenesis and boosts secondary metabolism. The use of talc boosts the production of various molecules of clinical relevance and newly emerging high‐potential candidates. Given its simplicity and broad benefits, microparticle‐supplementation appears as an enabling technology in natural product research of these most important microbes.
Applied Relaxation (AR) is an established behavioral mental health intervention, but its efficacy in real life contexts remains unclear. Using randomized controlled trial data, we examined whether AR ...can effectively reduce mental health problems in daily life. A sample of 277 adults with increased psychopathological symptoms but without 12-month DSM-5 mental disorders at study entry was randomly assigned to an intervention group receiving AR training (n = 139) and an assessment-only control group (n = 138). Ecological momentary assessments were used to assess psychological outcomes in daily life over a period of seven days at baseline, post, and 12-month follow-up, respectively. Multilevel analyses indicated that all psychopathological symptoms decreased more in the intervention group than in the control group from baseline to post (range β = -0.31 for DASS-depression to β = -0.06 for PROMIS-anger). However, from post to follow-up, psychopathological symptoms decreased more in the control group than in the intervention group, so that only the intervention effects for PROMIS-depression (β = -0.10) and PROMIS-anger (β = -0.09) remained until follow-up. Moreover, positive affect (β = 0.19), internal control beliefs (β = 0.15), favorable coping (β = 0.60), and unfavorable coping (β = -0.41) improved more in the intervention group than in the control group, and these effects were mostly maintained in the long term. Some effects were stronger among women, older individuals, and individuals with higher initial symptoms. These findings suggest that AR can effectively reduce mental health problems in daily life. Trial registration. The trial has been registered at ClinicalTrials.gov (NCT03311529).
Magnetic nanoparticles (MNPs) have been adapted for many applications, e.g., bioassays for the detection of biomarkers such as antibodies, by controlled engineering of specific surface properties. ...Specific measurement of such binding states is of high interest but currently limited to highly sensitive techniques such as ELISA or flow cytometry, which are relatively inflexible, difficult to handle, expensive and time-consuming. Here we report a method named COMPASS (Critical-Offset-Magnetic-Particle-SpectroScopy), which is based on a critical offset magnetic field, enabling sensitive detection to minimal changes in mobility of MNP ensembles, e.g., resulting from SARS-CoV-2 antibodies binding to the S antigen on the surface of functionalized MNPs. With a sensitivity of 0.33 fmole/50 µl (≙7 pM) for SARS-CoV-2-S1 antibodies, measured with a low-cost portable COMPASS device, the proposed technique is competitive with respect to sensitivity while providing flexibility, robustness, and a measurement time of seconds per sample. In addition, initial results with blood serum demonstrate high specificity.
Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort ...study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology.
We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid(1-42) (Aβ(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models.
We included 110 subjects with MCI with abnormal CSF Aβ(1-42) and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio HR 2.3, 95% confidence interval CI 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score.
In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline.
Abstract Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid ...(CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (Aβ)1–42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF Aβ1–42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aβ1–42/tau increased predictive accuracy in subjects with normal HCV ( p < 0.001) and abnormal HCV ( p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF Aβ1–42/tau ( p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.
Most of the observed associations of generalized anxiety disorder (GAD), social anxiety disorder (SAD) and major depressive disorder (MDD) with cortisol concentrations came from clinical and adult ...study samples, with inconsistent findings, partly due to method variance. We examined cross-sectional and longitudinal associations between GAD, SAD and MDD with saliva and hair cortisol as well as hair cortisol change in a population-based sample of adolescents and young adults, considering relevant co-factors.
Epidemiological cohort study in Dresden, Germany. Data of 1050 individuals (mean age: 17.2 years) assessed at baseline (11/2015–12/2016) and of 605 individuals assessed at 1-year follow-up (FU1) are used.
Multivariable regression models were implemented to assess cross-sectional and longitudinal associations of DSM-5 defined 12-month diagnoses of GAD, SAD, and MDD, with short-term (saliva cortisol: cortisol awakening response (CAR) and area under the curve (AUC) as total cortisol) and long-term (hair cortisol) cortisol indices. Multivariable models were adjusted for age or “tanner” stage, waist circumference, tobacco and alcohol consumption, physical inactivity, and hair cortisol dependent confounder. Sex-specific analyses were additionally conducted.
Cross-sectional analyses revealed positive associations between SAD and baseline saliva cortisol in multivariable models (CAR: β-coefficient: 0.12; 95% CI: 0.01; 0.23) but could not be confirmed after adjusting for “tanner” stage or comorbid depression. Cross-sectional analyses concerning GAD and MDD in the full baseline sample yielded no significant associations. Sex-specific linear models revealed a significant inverse cross-sectional association between MDD (β-coefficient: − 2.21; 95% CI: − 3.64; − 0.79) as well as SAD (β-coefficient: − 2.21; 95% CI: − 4.03; − 0.38) with baseline hair cortisol in males, but not in females. In longitudinal analyses, no significant associations were found in the fully adjusted model, except for a positive association between hair cortisol change between baseline and FU1 and FU1-SAD (OR: 1.07; 95% CI: 1.02; 1.12).
Results confirmed sex-specificity and the role of pubertal development in the association between cortisol with SAD and MDD, while no association emerged regarding cortisol and GAD. Future research in adolescents focusing on the role of cortisol in the pathogenesis of anxiety and depressive disorders would benefit from considering factors like sex-specificity and puberty development as well as comorbidity.
•Positive association between social anxiety and cortisol in adolescents.•Sex-specific association between depression and cortisol.•Puberty might influence the link between depression/social anxiety and cortisol.•No significant association between generalized anxiety disorder and cortisol.
PDF
