Programmed connection of amino acids or nucleotides into chains introduced a revolution in control of biological function. Reacting proteins together is more complex because of the number of reactive ...groups and delicate stability. Here we achieved sequence-programmed irreversible connection of protein units, forming polyprotein teams by sequential amidation and transamidation. SpyTag peptide is engineered to spontaneously form an isopeptide bond with SpyCatcher protein. By engineering the adhesin RrgA from Streptococcus pneumoniae, we developed the peptide SnoopTag, which formed a spontaneous isopeptide bond to its protein partner SnoopCatcher with >99% yield and no cross-reaction to SpyTag/SpyCatcher. Solid-phase attachment followed by sequential SpyTag or SnoopTag reaction between building-blocks enabled iterative extension. Linear, branched, and combinatorial polyproteins were synthesized, identifying optimal combinations of ligands against death receptors and growth factor receptors for cancer cell death signal activation. This simple and modular route to programmable “polyproteams” should enable exploration of a new area of biological space.
Measures of emotion: A review Mauss, Iris B.; Robinson, Michael D.
Cognition and emotion,
02/2009, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Odprti dostop
A consensual, componential model of emotions conceptualises them as experiential, physiological, and behavioural responses to personally meaningful stimuli. The present review examines this model in ...terms of whether different types of emotion-evocative stimuli are associated with discrete and invariant patterns of responding in each response system, how such responses are structured, and if such responses converge across different response systems. Across response systems, the bulk of the available evidence favours the idea that measures of emotional responding reflect dimensions rather than discrete states. In addition, experiential, physiological, and behavioural response systems are associated with unique sources of variance, which in turn limits the magnitude of convergence across measures. Accordingly, the authors suggest that there is no "gold standard" measure of emotional responding. Rather, experiential, physiological, and behavioural measures are all relevant to understanding emotion and cannot be assumed to be interchangeable.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB).
Adult patients ...enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available.
A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses.
Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.
Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and ...in some instances individual genetic aberrations such as
MYC
and
MYCN
amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including
MYC
and
MYCN
gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75–90 % survival), high risk (50–75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or
MYCN
-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with
TP53
mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.
In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and ...clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.
Expression of interest for the CODEX-b detector Aielli, Giulio; Ben-Haim, Eli; Cardarelli, Roberto ...
European physical journal. C, Particles and fields,
12/2020, Letnik:
80, Številka:
12
Journal Article
Recenzirano
Odprti dostop
This document presents the physics case and ancillary studies for the proposed CODEX-b long-lived particle (LLP) detector, as well as for a smaller proof-of-concept demonstrator detector, CODEX-
β
, ...to be operated during Run 3 of the LHC. Our development of the CODEX-b physics case synthesizes ‘top-down’ and ‘bottom-up’ theoretical approaches, providing a detailed survey of both minimal and complete models featuring LLPs. Several of these models have not been studied previously, and for some others we amend studies from previous literature: In particular, for gluon and fermion-coupled axion-like particles. We moreover present updated simulations of expected backgrounds in CODEX-b’s actively shielded environment, including the effects of shielding propagation uncertainties, high-energy tails and variation in the shielding design. Initial results are also included from a background measurement and calibration campaign. A design overview is presented for the CODEX-
β
demonstrator detector, which will enable background calibration and detector design studies. Finally, we lay out brief studies of various design drivers of the CODEX-b experiment and potential extensions of the baseline design, including the physics case for a calorimeter element, precision timing, event tagging within LHCb, and precision low-momentum tracking.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Emotionally intelligent people are thought to be more skilled in recognizing, thinking about, using, and regulating emotions. This construct has garnered considerable interest, but initial enthusiasm ...has faded and it is time to take stock. There is consensus that ability-related measures of emotional intelligence (EI) can be favored to self-report tests, in part because the resulting scores cannot be equated with personality traits. However, there are questions surrounding measurement as well as predictive value. Experts in the field were encouraged to chart new directions, with the idea that these new directions could reinvigorate EI scholarship. Special Issue papers speak to theory, mechanism, measurement, and training. In addition, these papers seek to forge links with research traditions focused on interpersonal perception, emotional awareness, and emotion regulation. As a result of these efforts, new insights into what EI is and how it works can be anticipated in upcoming years.
Purpose
This paper aims to examine whether work-related emotional intelligence (W-EI) benefits job performance among knowledge-intensive workers.
Design/methodology/approach
Postdoctoral researchers ...(Study 1) and industry researchers (Study 2) were recruited (total N = 304). These knowledge workers completed an ability-based emotional intelligence (EI) test and characterized their work-related performance. Potential moderators were also assessed.
Findings
There were positive relations between W-EI scores and both task performance and creative performance. In addition, these relationships were stronger in the context of higher levels of job negative affect and/or role overload.
Originality/value
To the best of the authors’ knowledge, these findings are among the first to demonstrate the value of the EI construct within a knowledge-intensive workforce.
Mindfulness, defined in terms of greater attention to and awareness of the present moment, may benefit equanimity both outside and inside the workplace. Two studies (total N = 224) of part-time ...employees supported this idea. Employees who were higher in dispositional mindfulness were less Machiavellian (Study 1), and they engaged in fewer counterproductive work behaviors (CWBs; Study 2). Furthermore, and consistent with an emotion-related theory of mindfulness, these inverse relationships were mediated by hostile feelings such as irritation and anger. That is, mindful people were less hostile in their behaviors in part because they were less prone to hostile feelings. The results suggest that mindfulness may be an efficacious state in reducing hostile feelings and behaviors at work. More generally, they contribute to an emotion-related perspective of mindfulness and some of its behavioral consequences.
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