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Information technology (IT) service management is considered a collection of frameworks that support organizations managing services. The implementation of these kinds of frameworks is constantly increasing in the IT service provider domain. The main objective is to define and manage IT services through its life cycle. However, from observing the literature, scarcely any research exists describing the main concepts of ITSM. Many organizations still struggle in several contexts in this domain, mainly during implementation. This research aims to develop a reference study detailing the main concepts related with ITSM. Thus, a systematic literature review is performed. In total, 47 articles were selected from top journals and conferences. The benefits, challenges, opportunities, and practices for ITSM implementation were extracted, critically analysed, and then discussed.

The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models. In contrast with natural IL-4, Neo-4 is hyperstable and signals exclusively through the type I IL-4 receptor complex, providing previously inaccessible insights into differential IL-4 signaling through type I versus type II receptors. Because of their hyperstability, our computationally designed mimetics can directly incorporate into sophisticated biomaterials that require heat processing, such as three-dimensional-printed scaffolds. Neo-4 should be broadly useful for interrogating IL-4 biology, and the design workflow will inform targeted cytokine therapeutic development.

The chemical control of weeds stands out as an important tool for obtaining high yields in cassava crops. This study aimed at evaluating the selectivity and efficiency of pre-emergent herbicides on cassava ('Cascuda' cultivar) crop. The experimental design was randomized blocks, with ten treatments and four replications. The treatments consisted of clomazone (900 g ha-1 and 1,080 g ha-1), flumioxazin (60 g ha-1), sulfentrazone (600 g ha-1), S-metolachlor (1,920 g ha-1), clomazone + flumioxazin (900 + 50 g ha-1), clomazone + sulfentrazone (900 + 500 g ha-1) and clomazone + S-metolachlor (900 + 1,440 g ha-1), as well as a weeded and a non-weeded control. The weed community was composed by 9 families and 12 species, with the Asteraceae and Poaceae families presenting the highest number of species. The pre-emergent herbicides were selective for 'Cascuda' cultivar cassava plants. The herbicides were effective in controlling weeds, with flumioxazin (60 g ha-1), sulfentrazone (600 g ha-1), S-metolachlor (1,920 g ha-1) and the mixtures of clomazone + flumioxazin (900 + 50 g ha-1), clomazone + sulfentrazone (900 + 500 g ha-1) and clomazone + S-metolachlor (900 + 1,440 g ha-1) presenting the highest residual effect.

The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.

Recent advances in computational protein design now enable the massively parallel de novo design and experimental characterization of small hyperstable binding proteins with potential therapeutic activity. By providing experimental feedback on tens of thousands of designed proteins, the design-build-test-learn pipeline provides a unique opportunity to systematically improve our understanding of protein folding and binding. Here, we review the structures of mini-protein binders in complex with Influenza hemagglutinin and Bot toxin, and illustrate in the case of disulfide bond placement how analysis of the large datasets of computational models and experimental data can be used to identify determinants of folding and binding.

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.

ABSTRACT Introduction: Socioeconomic and demographic diversity in the educational environment and the development of professional attitudes enhance the quality of health care delivery. Despite the importance of diversity for equity and accessibility to health care, its repercussions for students’ attitudinal learning have not been adequately evaluated. Purpose: Evaluate the influence of academic sociodemographic diversity and curricular organization in the development of professional attitudes in different phases of the undergraduate medical curriculum. Method: In 2012, the attitudinal performance of 310 socioeconomically diverse medical students was evaluated by the administration of a five-point professional attitudes scale. The participants were at different points in their education at a Brazilian public school of medicine in Brasília, Federal District. The scale comprised 6 factors: communication, ethics, professional excellence, self-assessment, beliefs, social determinants; and a general factor called medical professionalism and was validated for the purpose of this research. The reliability coefficients (aCronbach) ranged from 0.65 to 0.87, according to different scale dimensions. Student diversity was analyzed according to differences in gender, age, religious affiliation, system of student selection and socioeconomic background. Results: The authors observed a decline in the mean attitude scores during the clinical phase compared to the preclinical phase of the curriculum. Female students displayed more positive attitudes than male students, and the students who declared a religious affiliation recorded higher attitude scores compared to those who declared themselves atheist, agnostic or non-religious. There was no correlation between family income or the system of student selection and the students’ attitude scores. The students who had attended public schools expressed a greater interest in working in the public health system compared to the other students. Age and marital status had no relevant effect on attitude scores. Conclusions: The attitude scores of medical students declined as the curriculum progressed. Female students had more positive attitudes than male students. Religious affiliation appeared to positively influence the observed attitude scores.

The folding of natural proteins typically relies on hydrophobic packing, metal binding, or disulfide bond formation in the protein core. Alternatively, a 3D structure can be defined by incorporating a multivalent cross-linking agent, and this approach has been successfully developed for the selection of bicyclic peptides from large random-sequence libraries. By contrast, there is no general method for the de novo computational design of multicross-linked proteins with predictable and well-defined folds, including ones not found in nature. Here we use Rosetta and Tertiary Motifs (TERMs) to design small proteins that fold around multivalent cross-linkers. The hydrophobic cross-linkers stabilize the fold by macrocyclic restraints, and they also form an integral part of a small apolar core. The designed CovCore proteins were prepared by chemical synthesis, and their structures were determined by solution NMR or X-ray crystallography. These mesosized proteins, lying between conventional proteins and small peptides, are easily accessible either through biosynthetic precursors or chemical synthesis. The unique tertiary structures and ease of synthesis of CovCore proteins indicate that they should provide versatile templates for developing inhibitors of protein-protein interactions.

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

The dynamics of the RNA polymerase II (Pol II) backtracking process is poorly understood. We built a Markov State Model from extensive molecular dynamics simulations to identify metastable intermediate states and the dynamics of backtracking at atomistic detail. Our results reveal that Pol II backtracking occurs in a stepwise mode where two intermediate states are involved. We find that the continuous bending motion of the Bridge helix (BH) serves as a critical checkpoint, using the highly conserved BH residue T831 as a sensing probe for the 3'-terminal base paring of RNA:DNA hybrid. If the base pair is mismatched, BH bending can promote the RNA 3'-end nucleotide into a frayed state that further leads to the backtracked state. These computational observations are validated by site-directed mutagenesis and transcript cleavage assays, and provide insights into the key factors that regulate the preferences of the backward translocation.

The RNA polymerase II (Pol II) is a eukaryotic enzyme that catalyzes the synthesis of the messenger RNA using a DNA template. Despite numerous biochemical and biophysical studies, it remains elusive whether the "secondary channel" is the only route for NTP to reach the active site of the enzyme or if the "main channel" could be an alternative. On this regard, crystallographic structures of Pol II have been extremely useful to understand the structural basis of transcription, however, the conformation of the unpaired non-template DNA part of the full transcription bubble (TB) is still unknown. Since diffusion routes of the nucleoside triphosphate (NTP) substrate through the main channel might overlap with the TB region, gaining structural information of the full TB is critical for a complete understanding of Pol II transcription process. In this study, we have built a structural model of Pol II with a complete transcription bubble based on multiple sources of existing structural data and used Molecular Dynamics (MD) simulations together with structural analysis to shed light on NTP entry pathways. Interestingly, we found that although both channels have enough space to allow NTP loading, the percentage of MD conformations containing enough space for NTP loading through the secondary channel is twice higher than that of the main channel. Further energetic study based on MD simulations with NTP loaded in the channels has revealed that the diffusion of the NTP through the main channel is greatly disfavored by electrostatic repulsion between the NTP and the highly negatively charged backbones of nucleotides in the non-template DNA strand. Taken together, our results suggest that the secondary channel is the major route for NTP entry during Pol II transcription.

Online citizen science projects such as GalaxyZoo.sup.1, Eyewire.sup.2 and Phylo.sup.3 have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity. An exception is the game EteRNA.sup.4, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of Watson-Crick base pairing possibilities. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. We posed the challenge of de novo protein design in the online protein-folding game Foldit.sup.5. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can now--starting from an extended polypeptide chain--generate a diversity of protein structures and sequences that encode them in silico. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. The diversity of these structures is unprecedented in de novo protein design, representing 20 different folds--including a new fold not observed in natural proteins. High-resolution structures were determined for four of the designs, and are nearly identical to the player models. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem. Proteins designed de novo by players of the online protein-folding game Foldit can be expressed in Escherichia coli and adopt the designed structure in solution., Author(s): Brian Koepnick [sup.1] [sup.2] , Jeff Flatten [sup.3] , Tamir Husain [sup.3] , Alex Ford [sup.1] [sup.2] , Daniel-Adriano Silva [sup.1] [sup.2] , Matthew J. Bick [sup.1] [sup.2] , [...]

RNA Polymerase II can detect and cleave mis-incorporated nucleotides by a proofreading mechanism that requires backtracking of the enzyme. Here the authors show that Pol II backtracking occurs in a stepwise mode that involves two intermediate states where the fraying of the terminal RNA nucleotide is a prerequisite.