Cooperative "folding transition" in the sequence space facilitates function-driven evolution of protein families

In the protein sequence space, natural proteins form clusters of families which are characterized by their unique native folds whereas the great majority of random polypeptides are neither clustered nor foldable to unique structures. Since a given polypeptide can be either foldable or unfoldable, a kind of "folding transition" is expected at the boundary of a protein family in the sequence space. By Monte Carlo simulations of a statistical mechanical model of protein sequence alignment that coherently incorporates both short-range and long-range interactions as well as variable-length insertions to reproduce the statistics of the multiple sequence alignment of a given protein family, we demonstrate the existence of such transition between natural-like sequences and random sequences in the sequence subspaces for 15 domain families of various folds. The transition was found to be highly cooperative and two-state-like. Furthermore, enforcing or suppressing consensus residues on a few of the well-conserved sites enhanced or diminished, respectively, the natural-like pattern formation over the entire sequence. In most families, the key sites included ligand binding sites. These results suggest some selective pressure on the key residues, such as ligand binding activity, may cooperatively facilitate the emergence of a protein family during evolution. From a more practical aspect, the present results highlight an essential role of long-range effects in precisely defining protein families, which are absent in conventional sequence models.Comment: 13 pages, 7 figures, 2 tables (a new subsection added

Streamlined HPC Environments with CVMFS and CyberGIS-Compute

High-Performance Computing (HPC) resources provide the potential for complex, large-scale modeling and analysis, fueling scientific progress over the last few decades, but these advances are not equally distributed across disciplines. Those in computational disciplines are often trained to have the necessary technical skills to utilize HPC (e.g. familiarity with the terminal), but many disciplines face technical hurdles when trying to apply HPC resources to their work. This unequal familiarity with HPC is increasingly a problem as cross-discipline teams work to tackle critical interdisciplinary issues like climate change and sustainability. CyberGIS-Compute is middle-ware designed to democratize to HPC services with the goal of empowering domain scientists, but a key challenge facing model developers on CyberGIS-Compute is creating a containerized software environment for their models. In this paper, we discuss our work to integrate the Cern Virtual Machine File System (CVMFS) into CyberGIS-Compute to provide consistent software environments across science gateways and HPC resources

Análisis de tensión de los incisivos centrales superiores tratados endodónticamente con diferentes alturas de férula y tres materiales diferentes de clavija posterior: un análisis de elementos finitos.

Indicación del problema: la fractura de los dientes tratados endodónticamente se reduce mediante el uso de un poste con férula, pero el efecto de diferentes configuraciones de férula y materiales de clavija no está claro. Propósito: evaluar el efecto de los casquillos con diferentes configuraciones y alturas sobre el estrés de los dientes tratados endodónticamente restaurados con tres materiales diferentes de postes y tacos. materiales y métodos: quince modelos de incisivos centrales superiores restaurados con porcelana fundida a coronas de metal se obtuvieron con el software Pro Engineer. Los modelos se dividieron en tres grupos, cada uno de los cuales consta de cinco modelos con alturas de casquillo de 0mm, 2mm, 4mm, 2mm con fractura oblicua, 4mm con fractura oblicua. los modelos del grupo GFR fueron restaurados con poste reforzado con fibra de vidrio (GFR) y acumulación de núcleo compuesto, grupo nicr con una aleación de metal de poste fundido personalizado (NiCr) y grupo Zr con poste de zirconia (Zr) y acumulación de núcleo compuesto. se aplicó una carga oblicua de 100N y 150N en un ángulo de 135º a la superficie palatina del diente. se aplicó una carga vertical de 100N y 150N en un ángulo de 90º a la punta incisal del diente. la tensión principal máxima y la tensión de von mises se calcularon para la estructura dental restante y después del vértice utilizando el software de análisis de elementos finitos (FEA). Resultados: el estrés máximo de von falta se observó en el vértice de la publicación (p<0.05). El grupo Zr mostró el mayor estrés medio (6.39Mpa) seguido del grupo NiCr (5.65Mpa). Hubo una diferencia significativa entre la publicación NiCr y Zr para la altura de la férula de 2mm y 4mm, mientras que para la férula de 0mm hubo una diferencia significativa entre los grupos GFR y NiCr (p<0,05), bajo la carga oblicua, la tensión media máxima en las estructuras dentales restantes, mientras que para la carga vertical, se observó en el vértice del poste. En cuanto a las alturas de la férula, hubo diferencias significativas entre la férula uniforme de 0mm-2mm y de 0mm-4mm en el post-apex en el caso de los postes de NiCr (p<0.05), la ausencia de férula dio como resultado un mayor estrés para el grupo NiCr. Conclusión: las cargas más altas que llevaron a la fractura se observaron solo en el vértice del poste; Los postes de zirconia (grupo Zr) tuvieron mayores cargas de fractura, mientras que la ausencia de férula dio como resultado una mayor carga de fractura con postes moldeados personalizados (NiCr de grupo). Los umbrales de fractura fueron altos en la estructura dental restante para todos los sistemas de clavijas, especialmente para la acumulación de núcleos compuestos independientemente de la altura y configuración de la férula. Implicaciones clínicas: la selección adecuada de materiales de postes y tacos en diferentes configuraciones de alturas de férulas asegura el éxito clínico.Statement of problem : fracture of endodontically treated teeth is reduced by the use of a post with ferrule, but the effect of different ferrule configurations and dowel materials is not clear. Purpose: to evaluate the effect of ferrules with different configurations and heights on the stress of endodontically treated teeth restored with three different post and dowel materials. Materials and Methods: fifteen models of maxillary central incisors restored with porcelain fused to metal crowns were obtained using pro engineer software. the models were divided into three groups, each consisting of five models with ferrule heights of 0mm, 2mm, 4mm, 2mm with oblique fracture, 4mm with oblique fracture, the models under group GFR were restored with fiberglass reinforced post (GFR) and composite core build-up, group NiCr with a custom cast post metal alloy (NiCr), and group Zr with zirconia post (Zr) and composite core build-up. an oblique load of 100N and 150N at an angle of 135 degrees was applied to the palatal surface of the tooth, a vertical load of 100N and 150N at an angle of 90 degrees was applied to the incisal tip of the tooth. The maximum principal stress and the von mises stress was calculated for the remaining tooth structure and post apex using the finite element analysis (FEA) software. Results: the maximum von misses stress was observed in the apex of the post (p<0.05). Group Zr showed the highest mean stress (6.39Mpa) followed by group NiCr (5.65Mpa). There was a significant difference between post and between NiCr and Zr post for 2mm and 4mm ferrule height, while for 0mm ferrule there was a significant difference between the GFR and NiCr groups (p<0.05). Under oblique load, the maximum mean stress was observed in remaining tooth structures while for vertical load, it was observed at the apex of the post. Regarding ferrule heights, there were significant differences between 0mm-2mm, and 0mm-4mm uniform ferrule in post apex in the case of NiCr posts (p<0.05). Absence of ferrule resulted in higher stress for the NiCr group. Conclusion: higher loads that led to fracture were observed only at the apex of the post. Zirconia posts (group Zr) had higher fracture loads, whereas absence of ferrule resulted in higher fracture load with custom cast posts (group NiCr). Fracture thresholds were high on the remaining tooth structure for all the dowel systems especially for composite core build up irrespective of ferrule height and configuration. Clinical implications: appropriate selection of post and dowel materials in different configurations of ferrule heights ensures clinical success

Scaling Smart Appliances for Spatial Data Synthesis

International audienceWith the rapidly growing number of dynamic data streams produced by sensing and experimental devices as well as social networks, scientists are given an unprecedented opportunity to explore a variety of environmental and social phenomena ranging from understanding of weather and climate to population dynamics. One of the main challenges is that dynamic data streams and their computation requirements are volatile: sensors or social networks may generate data at highly variable rates, processing time in an application may significantly change from one stage to the next one, or different phenomena may simply generate different levels of interest. Cloud computing is a promising platform allowing us to cope with such volatility because it enables us to allocate computational resources on demand, for short periods of time, and at an acceptable cost. At the same time using clouds for this purpose is challenging because an application may yield a very different performance depending on the hosting infrastructure, requiring us to pay special attention to how and where we schedule resources. In this poster, we describe our experiences using an application relying on input from social networks, notably geo-located tweets, to discover correlation between users’ work and home locations, with focus in the Illinois area. Our overall intent is to assess the impact of running the same application in offerings from different providers; to this end, we execute data filtering and per-user classification applications in two flavors of Chameleon cloud instances, namely bare-metal and KVM. Also, we analyze specific configuration parameters, such as data block size, replication factor and parallel processing, towards statistically modeling the application performance in a given infrastructure. We then identify and discuss the key parameters that influence the execution time. Finally, we look into the gains brought by accounting for data proximity when scheduling a resource in a multi-site environment

Exceptional molecular and coreceptor-requirement properties of molecular clones isolated from an Human Immunodeficiency Virus Type-1 subtype C infection

<p>Abstract</p> <p>Background</p> <p>The pathogenic significance of coreceptor switch in the viral infection of HIV-1 is not completely understood. This situation is more complex in subtype C infection where coreceptor switch is either absent or extremely rare. To gain insights into the mechanisms that underlie coreceptor requirement of subtype C, we screened several primary viral isolates and identified a clinical sample that demonstrated a potential to grow on standard T-cell lines with no detectable CCR5 expression. The subject was diagnosed with HIV-1 associated dementia in the absence of opportunistic infections of the brain. To isolate molecular clones from this virus, we devised a novel strategy based on anchor primers that target a sequence in the reverse transcriptase, highly conserved among diverse subtypes of HIV-1.</p> <p>Results</p> <p>Using this strategy, we isolated 8 full-length molecular clones from the donor. Two of the eight molecular clones, 03In94_D17 and 03In94_D24, (D17 and D24) generated replication-competent viruses. Phylogenetic analysis of the full-length viral sequences revealed that both clones were non-recombinant subtype C viruses. They contain intact open reading frames in all the viral proteins. Both the viral clones are endowed with several unique molecular and biological properties. The viral promoter of the clones is characterized by the presence of four NF-kB binding elements, a feature rarely seen in the subtype C HIV-1 LTR. Interestingly, we identified the coexistence of two different forms of Rev, a truncated form common to subtype C and a full-length form less common for this subtype, in both proviral and plasma virus compartments. An exceptional property of the viruses, atypical of subtype C, is their ability to use a wide range of coreceptors including CCR5, CXCR4, and several others tested. Sequence analysis of Env of D17 and D24 clones identified differences within the variable loops providing important clues for the expanded coreceptor use. The V1, V2 and V4 loops in both of the molecular clones are longer due to the insertion of several amino acid residues that generated potential N-linked glycosylation sites.</p> <p>Conclusion</p> <p>The exceptional biological and molecular properties of these clones make them invaluable tools to understand the unique pathogenic characteristics of subtype C.</p

Understanding thrombosis with thrombocytopenia syndrome after COVID-19 vaccination

Safety and efficacy of vaccines against the SARS-CoV-2 coronavirus has been demonstrated in clinical trials and next by their real world use through the course of the ongoing COVID-19 pandemic. However, very rare adverse events have been detected post-authorization in certain parts of the world. This meeting report summarizes an EMA workshop’s discussion on the epidemiology, clinical presentation and biology of thrombosis with thrombocytopenia syndrome after adenovirus vector COVID-19 vaccination. General agreement was reached by international regulators, scientists and developers on the steps needed to fill the gaps in the characterization of this new syndrome. In particular, actions should be taken to improve the post-vaccination surveillance activities in low and middle income countries and investigate potential genetic predisposition factors