Cascades of multisite phosphorylation control Sic1 destruction at the onset of S phase.

Multisite phosphorylation of proteins has been proposed to transform a graded protein kinase signal into an ultrasensitive switch-like response. Although many multiphosphorylated targets have been identified, the dynamics and sequence of individual phosphorylation events within the multisite phosphorylation process have never been thoroughly studied. In Saccharomyces cerevisiae, the initiation of S phase is thought to be governed by complexes of Cdk1 and Cln cyclins that phosphorylate six or more sites on the Clb5-Cdk1 inhibitor Sic1, directing it to SCF-mediated destruction. The resulting Sic1-free Clb5-Cdk1 complex triggers S phase. Here, we demonstrate that Sic1 destruction depends on a more complex process in which both Cln2-Cdk1 and Clb5-Cdk1 act in processive multiphosphorylation cascades leading to the phosphorylation of a small number of specific phosphodegrons. The routes of these phosphorylation cascades are shaped by precisely oriented docking interactions mediated by cyclin-specific docking motifs in Sic1 and by Cks1, the phospho-adaptor subunit of Cdk1. Our results indicate that Clb5-Cdk1-dependent phosphorylation generates positive feedback that is required for switch-like Sic1 destruction. Our evidence for a docking network within clusters of phosphorylation sites uncovers a new level of complexity in Cdk1-dependent regulation of cell cycle transitions, and has general implications for the regulation of cellular processes by multisite phosphorylation

The role of illness acuity on the association between frailty and mortality in emergency department patients referred to internal medicine.

Background: we investigated whether two frailty tools predicted mortality among emergency department (ED) patients referred to internal medicine and how the level of illness acuity influenced any association between frailty and mortality.Methods: two tools, embedded in a Comprehensive Geriatric Assessment (CGA), were the clinical frailty scale (CFS) and a 57-item deficit accumulation frailty index (FI-CGA). Illness acuity was assessed using the Canadian Triage and Acuity Scale (CTAS). We examined all-cause 30-day and 6-month mortality and time to death.Results: in 808 ED patients (mean age ± SD 80.8 ± 8.8, 54.4% female), the mean FI-CGA score was 0.44 ± 0.14, and the CFS was 5.6 ± 1.6. A minority (307; 38%) were classified as having high acuity (CTAS: 1-2). The 30-day mortality rate was 17%; this increased to 34% at 6 months. Compared to well patients with low acuity, the risk of 30-day mortality was 22.5 times (95% CI: 9.35-62.12) higher for severely frail patients with high acuity; 53% of people with very severe frailty (CFS = 8) and high acuity died within 30 days. When acuity was low, the risk for 30-day mortality was significantly higher only among those with very high levels of frailty (CFS 7-9, FI-CGA > 0.5). When acuity was high, even lower levels of frailty (CFS 5-6, FI-CGA 0.4-0.5) were associated with higher 30-day mortality.Conclusions: across levels of frailty, higher acuity increased mortality risk. When acuity was low, the risk was significant only when the degree of frailty was high, whereas when acuity was high, even lower levels of frailty were associated with greater mortality risk

Effect of prevention measures on incidence of human listeriosis, France, 1987-1997.

To assess the impact of preventive measures by the food industry, we analyzed food monitoring data as well as trends in the incidence of listeriosis estimated through three independent sources: the National Reference Center of Listeriosis; a laboratory-based active surveillance network; and two consecutive nationwide surveys of public hospital laboratories. From 1987 to 1997, the incidence of listeriosis decreased by an estimated 68%. A substantial reduction in the proportion of Listeria monocytogenes-contaminated products was observed at the retail level. The temporal relationship between prevention measures by the food industry, reduction in L. monocytogenes-contaminated foodstuffs, and reduction in listeriosis incidence suggests a causal relationship and indicates that a substantial part of the reduction in illness is related to prevention efforts

Rapid real-time PCR detection of Listeria monocytogenes in enriched food samples based on the ssrA gene, a novel diagnostic target

A real-time PCR assay was designed to detect a 162-bp fragment of the ssrA gene in Listeria monocytogenes. The specificity of the assay for L. monocytogenes was confirmed against a panel of 6 Listeria species and 26 other bacterial species. A detection limit of 1-10 genome equivalents was determined for the assay. Application of the assay in natural and artificially contaminated culture enriched foods, including soft cheese, meat, milk, vegetables and fish, enabled detection of 1-5 CFU L. monocytogenes per 25g/ml of food sample in 30h. The performance of the assay was compared with the Roche Diagnostics 'LightCycler foodproof Listeria monocytogenes Detection Kit'. Both methods detected L. monocytogenes in all artificially contaminated retail samples (n=27) and L. monocytogenes was not detected by either system in 27 natural retail food samples. The method developed in this study has the potential to enable the specific detection of L. monocytogenes in a variety of food types in a time-frame considerably faster than current standard methods. The potential of the ssrA gene as a nucleic acid diagnostic (NAD) target has been demonstrated in L. monocytogenes. We are currently developing NAD tests based on the ssrA gene for a range of common foodborne and clinically relevant bacterial pathogens

BrainStat: A toolbox for brain-wide statistics and multimodal feature associations

Analysis and interpretation of neuroimaging datasets has become a multidisciplinary endeavor, relying not only on statistical methods, but increasingly on associations with respect to other brain-derived features such as gene expression, histological data, and functional as well as cognitive architectures. Here, we introduce BrainStat - a toolbox for (i) univariate and multivariate linear models in volumetric and surface-based brain imaging datasets, and (ii) multidomain feature association of results with respect to spatial maps of post-mortem gene expression and histology, task-based fMRI meta-analysis, as well as resting-state fMRI motifs across several common surface templates. The combination of statistics and feature associations into a turnkey toolbox streamlines analytical processes and accelerates cross-modal research. The toolbox is implemented in both Python and MATLAB, two widely used programming languages in the neuroimaging and neuroinformatics communities. BrainStat is openly available and complemented by an expandable documentation

Tracheobronchomalacia due to amyloidosis in a patient with rheumatoid arthritis

In this case report, we describe a patient with longstanding rheumatoid arthritis who developed tracheobronchomalacia with fatal outcome. Despite negative antemortem biopsies of abdominal fat and tongue, amyloid was found postmortem in the trachea and appeared to be associated with tracheobronchomalacia

Parallel development of five partnerships to promote sustainable soy in brazil: solution or part of wicked problems?

The central question of this paper is how to understand and characterize the parallel development of global private partnerships and other partnerships at the global level or national level, that all aim to promote sustainability of a global commodity. The aim of this paper is to contribute to the discussion on the role and use of global private partnerships in coping with sustainability as a wicked problem. For this purpose we have constructed and used a theoretical framework on complex decision-making processes with a grounded theory that explains diversity of private governance networks in terms of rivalry and exclusion. Focusing on five partnerships that promote sustainable production of soy in Brazil, the paper concludes that their development is highly interdependent and dialectical. One of the five partnerships is the Round Table on Responsible Soy. Both the start and development of this global private partnership have not ended but fuelled rivalry between different partnerships, herewith reproducing the wickedness of governance of sustainable production of soy. Managing sustainability as a wicked problem requires an understanding of the dialectical development of partnerships. Instead of embracing one partnership as the best or the benchmark, it may be wiser for policymakers to invest in managing interactions and articulating relationships between different partnerships at the global and national level. Key words: Private partnerships, rivalry, wicked problems, sustainable soy, Brazi

Convergence of cortical types and functional motifs in the human mesiotemporal lobe

The mesiotemporal lobe (MTL) is implicated in many cognitive processes, is compromised in numerous brain disorders, and exhibits a gradual cytoarchitectural transition from six-layered parahippocampal isocortex to three-layered hippocampal allocortex. Leveraging an ultra-high-resolution histological reconstruction of a human brain, our study showed that the dominant axis of MTL cytoarchitectural differentiation follows the iso-to-allocortical transition and depth-specific variations in neuronal density. Projecting the histology-derived MTL model to in-vivo functional MRI, we furthermore determined how its cytoarchitecture underpins its intrinsic effective connectivity and association to large-scale networks. Here, the cytoarchitectural gradient was found to underpin intrinsic effective connectivity of the MTL, but patterns differed along the anterior-posterior axis. Moreover, while the iso-to-allocortical gradient parametrically represented the multiple-demand relative to task-negative networks, anterior-posterior gradients represented transmodal versus unimodal networks. Our findings establish that the combination of micro- and macrostructural features allow the MTL to represent dominant motifs of whole-brain functional organisation