Embedding a Native State into a Random Heteropolymer Model: The Dynamic Approach

We study a random heteropolymer model with Langevin dynamics, in the supersymmetric formulation. Employing a procedure similar to one that has been used in static calculations, we construct an ensemble in which the affinity of the system for a native state is controlled by a "selection temperature" T0. In the limit of high T0, the model reduces to a random heteropolymer, while for T0-->0 the system is forced into the native state. Within the Gaussian variational approach that we employed previously for the random heteropolymer, we explore the phases of the system for large and small T0. For large T0, the system exhibits a (dynamical) spin glass phase, like that found for the random heteropolymer, below a temperature Tg. For small T0, we find an ordered phase, characterized by a nonzero overlap with the native state, below a temperature Tn \propto 1/T0 > Tg. However, the random-globule phase remains locally stable below Tn, down to the dynamical glass transition at Tg. Thus, in this model, folding is rapid for temperatures between Tg and Tn, but below Tg the system can get trapped in conformations uncorrelated with the native state. At a lower temperature, the ordered phase can also undergo a dynamical glass transition, splitting into substates separated by large barriers.Comment: 19 pages, revtex, 6 figure

Kawasaki Disease Shock Syndrome vs Classical Kawasaki Disease: A Meta-analysis and Comparison With SARS-CoV-2 Multisystem Inflammatory Syndrome.

BACKGROUND: The emergence of increasing reports worldwide of a severe inflammatory process and shock in pediatric patients resembling Kawasaki disease (KD) and more specifically Kawasaki disease shock syndrome (KDSS), prompted us to explore KDSS in a preamble of a systematic comparison between the two conditions. METHODS: We completed a systematic review of KDSS and performed a meta-analysis comparison between reported KDSS cases and KD controls. RESULTS: A total of ten case-control series were included in the meta-analysis. KDSS patients were older (38.4 ± 30.6 vs. 21.9±19.5 months; P<0.001) compared to standard KD with equal sex distribution and completeness of clinical diagnostic criteria. KDSS present higher CRP (59.4±29.2 mg/dL vs. 20.8±14.8 mg/dL; p<0.001), lower albumin (2.7±0.5 g/dL vs. 3.3±0.5 g/dL; p<0.01), and lower platelets (255±149 109/L vs. 394±132 109/L; p<0.001) but only borderline higher WBC's (p=0.06). Differences in ALT, AST and ESR were non-significant. The odds of IVIG resistance (44.4% vs. 9.6%; (p<0.001) and the hospital length of stay (10.9±5.8 vs. 5.0±3.0 days; p<0.001) were higher in KDSS as were the odds of coronary artery abnormalities (33.9% vs. 8.6%; p<0.001). CONCLUSION: This first meta-analysis on KDSS versus KD represents a basis for future works on KDSS and opens the opportunity for future multicenter studies in the search of causal relationships between presenting elements and the eventual complications of KDSS. The similarities between SARS-CoV-2 multisystem inflammatory syndrome in children (MIS-C) and KDSS open new horizons to the understanding of the etiology and pathophysiology related to KDSS

Radiobiological experiments with plant seeds aboard the biosatellite Cosmos 1887

The effects of spaceflight factors on the seeds of Arabidopsis thaliana and Crepis capillaris were studied. The seeds were located inside the satellite in an open space, protected with aluminum foil and also exposed without the foil cover. When the seeds were in open space without any protection, their viability was found to be suppressed; the survival rate and fertility of plants grown from these seeds were also diminished. An increase in the frequency of chromosome aberrations (CA) and in the number of multiple injuries was registered in this case. Experiments with the aluminum foil shielding showed a decrease in the suppression of the seeds' viability, but mutational changes were found to be even more increased, while the survival rate and fertility of the plants decreased. An increase in the thickness of shielding resulted in a decrease in the effects up to the level of the control, except for the effects connected with CA and fertility of the plants. Analysis of the results shows that these impairments can be ascribed to the action of single heavy charged particles (HCP). The seeds can thus be regarded as an integral biological 'dosimeter' which allows estimation of the total effects of radiation, ecological and biological factors

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page

A practical, bioinformatic workflow system for large data sets generated by next-generation sequencing

Transcriptomics (at the level of single cells, tissues and/or whole organisms) underpins many fields of biomedical science, from understanding the basic cellular function in model organisms, to the elucidation of the biological events that govern the development and progression of human diseases, and the exploration of the mechanisms of survival, drug-resistance and virulence of pathogens. Next-generation sequencing (NGS) technologies are contributing to a massive expansion of transcriptomics in all fields and are reducing the cost, time and performance barriers presented by conventional approaches. However, bioinformatic tools for the analysis of the sequence data sets produced by these technologies can be daunting to researchers with limited or no expertise in bioinformatics. Here, we constructed a semi-automated, bioinformatic workflow system, and critically evaluated it for the analysis and annotation of large-scale sequence data sets generated by NGS. We demonstrated its utility for the exploration of differences in the transcriptomes among various stages and both sexes of an economically important parasitic worm (Oesophagostomum dentatum) as well as the prediction and prioritization of essential molecules (including GTPases, protein kinases and phosphatases) as novel drug target candidates. This workflow system provides a practical tool for the assembly, annotation and analysis of NGS data sets, also to researchers with a limited bioinformatic expertise. The custom-written Perl, Python and Unix shell computer scripts used can be readily modified or adapted to suit many different applications. This system is now utilized routinely for the analysis of data sets from pathogens of major socio-economic importance and can, in principle, be applied to transcriptomics data sets from any organism

A practical, bioinformatic workflow system for large data sets generated by next-generation sequencing

Transcriptomics (at the level of single cells, tissues and/or whole organisms) underpins many fields of biomedical science, from understanding the basic cellular function in model organisms, to the elucidation of the biological events that govern the development and progression of human diseases, and the exploration of the mechanisms of survival, drug-resistance and virulence of pathogens. Next-generation sequencing (NGS) technologies are contributing to a massive expansion of transcriptomics in all fields and are reducing the cost, time and performance barriers presented by conventional approaches. However, bioinformatic tools for the analysis of the sequence data sets produced by these technologies can be daunting to researchers with limited or no expertise in bioinformatics. Here, we constructed a semi-automated, bioinformatic workflow system, and critically evaluated it for the analysis and annotation of large-scale sequence data sets generated by NGS. We demonstrated its utility for the exploration of differences in the transcriptomes among various stages and both sexes of an economically important parasitic worm (Oesophagostomum dentatum) as well as the prediction and prioritization of essential molecules (including GTPases, protein kinases and phosphatases) as novel drug target candidates. This workflow system provides a practical tool for the assembly, annotation and analysis of NGS data sets, also to researchers with a limited bioinformatic expertise. The custom-written Perl, Python and Unix shell computer scripts used can be readily modified or adapted to suit many different applications. This system is now utilized routinely for the analysis of data sets from pathogens of major socio-economic importance and can, in principle, be applied to transcriptomics data sets from any organism

Learning from the challenges of undertaking an evaluation of a multi-partner housing support initiative delivered within a hospital setting

Objectives We present learning from a mixed-methods evaluation of a housing support initiative for hospital inpatients. Study design A mixed-methods process evaluation. Methods A social housing provider delivered a housing support service in two hospitals (mental health unit and general hospital). Healthcare providers, the social housing provider and academic researchers designed and undertook a co-produced, mixed-methods process evaluation of the intervention. The evaluation included questionnaires, semi-structured interviews, analysis of routinely collected data and economic analysis. Despite commitment from the partners, the evaluation faced challenges. We reflect on the lessons learnt within our discussion paper. Results Despite the commitment of the partners, we faced several challenges. We took an iterative approach to the design and processes of the evaluation to respond to arising challenges. Recruitment of service-users was more difficult than anticipated, requiring additional staff resources. Given the small-scale nature of the intervention, and the quality of data recorded in hospital records, the planned economic analysis was not feasible. Positive factors facilitating evaluation included involvement of staff delivering the intervention, as well as managers. Being able to offer payment to partner organisations for staff time also facilitated ongoing engagement. Conclusions Multi-partner evaluations are useful, however, researchers and partners need to be prepared to take an iterative, resource intensive approach. Both availability and quality of routine data, and the resources required to support data collection, may limit feasibility of specific methods when evaluating small-scale cross-sector initiatives. Thus, this necessitates a flexible approach to design and analysis

The Science of Marine Protected Areas (3rd edition, Mediterranean)

The main purpose of the booklet is to present the latest scientific information about the effects of MPAs in the Mediterranean in order to inform current management dialogues. This is particularly relevant given the increasing legislative frameworks and political initiatives to implement networks of MPAs in countries across the Mediterranean Sea. Importantly, this Edition does much more than simply tailor the earlier content for the Mediterranean region. The edition update the basic content of the booklet, drawing on the wealth of new published scientific literature, highlighting case studies from the Mediterranean Sea