The analytical framework for optimizing TCP retransmission algorithm based on adjustment of its EWMA parameters.

In this paper we derive mathematical description of TCP (Transmission Control Protocol) retransmission probability based on Jacobson’s smoothing algorithm that belongs to EWMA (Exponentially Weighted Moving Average) category. This description is parametrized on the probability density function (pdf) of RTT (Round Trip Time) samples and α, β – two primary parameters of Jacobson’s algorithm. Although it is not a close form expression, it is formulated as an effective algorithm that let us to explicitly calculate the values of RTO (Retransmission Time Out) probability as a function of α, β and the pdf of RTT samples. We achieve the effectiveness of this approach by applying smart discretization of the state space and replacement of continuous functions with discrete approximate equivalents. In this way, we mitigate the cardinality of discrete distributions we deal with that results in linear (n+m) instead of multiplicative (n⋅m) growth of computational complexity. We provide the evaluation of RTO probability for a wide set of α, β parameter values and differently shaped Normal and Laplace pdfs the RTT samples are taken from. The obtained numerical results let us to draw some conclusions regarding the choice of optimal values of α, β parameters as well as the impact of pdf the RTT samples are taken from

Elastic analysis of shear test plate

March, 1970.CER70-71RHJ-MDV19.Includes bibliographical references

PURA syndrome : clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives T o delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotypephenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.Peer reviewe

Weight status, BMI and physical fitness in polish youth: relationships between 1986 and 2016

One of the components affecting the level of health is physical fitness and diets, which is also considered the foundation of a healthy lifestyle. Methods: Samples by survey ranged from 871 to 1,417 (boys) and from 843 to 1,326 (girls). Speed (5 m run), agility (figure-8-run), explosive power (vertical jump), flexibility (stand and reach) and cardiovascular fitness (step test) were measured. The Body Mass Index (BMI) of each student was classified as Thin, Normal weight or Overweight/Obese (Owt/Ob) relative to International Obesity Task Force (IOTF) criteria. Fitness items were compared among weight status groups and across surveys with sex-specific analyses of covariance. Regressions of each fitness item on the BMI in the four surveys were done using linear and nonlinear quadratic models. Results: Performances on all fitness tests except flexibility were poorer among Owt/Ob compared to Normal and Thin youth, but performances on fitness tests within weight status groups did not differ consistently across surveys. Conclusions: Relationships between the BMI and fitness tests varied across surveys, but suggested reasonably consistent curvilinear relationships between fitness tests and the BMI among boys more so than girls.info:eu-repo/semantics/publishedVersio

Towards a Smart Sustainable City Roadmap : Identifying Competency Gaps

This workshop of the CAP4CITY (Erasmus+ Strengthening Governance Capacity for Smart Sustainable Cities) project is to promote and stimulate the discussion and networking in the area of Digital Government. Smart Sustainable Cities and related concepts of Digital, Intelligent and Smart Cities represent a progression of how cities around the world apply digital technology to serve their populations, pursue sustainable socio-economic development, and transform themselves in the process, and require strong capacity for public governance in the digital world. In order to identify the gaps concerning missing knowledge and training needs in this area we propose to validate a Smart Sustainable Cities roadmap through a scenario-building approach.Trabajo publicado en Chen, Y. C., Salem, F., Zuiderwijk, A. (eds.). dg.o 2019: Proceedings of the 20th Annual International Conference on Digital Government Research. Association for Computing Machinery: New York, 2019.Facultad de Informátic

Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C : use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C

Amyloidogenic proteins like cystatin C and prion proteins have been shown to form dimers by exchange of subdomains of the monomeric proteins. This process, called "three-dimensional domain swapping," has also been suggested to play a part in the generation of amyloid fibrils. One variant of cystatin C, L68Q cystatin C, is highly amyloidogenic, and persons carrying the corresponding gene suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adult life. The present work describes the production of two variants of wild type and L68Q cystatin C with disulfide bridges at positions selected to inhibit domain swapping without affecting the biological function of the four cystatin C variants as cysteine protease inhibitors. The capacity of the four variant proteins to form dimers was tested and compared with that of wild type and L68Q cystatin C. In contrast to the latter two proteins, all four protein variants stabilized by disulfide bridges were resistant toward the formation of dimers. The capacity of the two stabilized variants of wild type cystatin C to form amyloid fibrils was investigated and found to be reduced by 80% compared with that of wild type cystatin C. In an effort to investigate whether exogenous agents could also suppress the formation of dimers of wild type and L68Q cystatin C, a monoclonal antibody or carboxymethylpapain, an inactivated form of a cysteine protease, was added to systems inducing dimerization of wild type and L68Q cystatin C. It was observed that catalytic amounts of both the monoclonal antibody and carboxymethylpapain could suppress dimerization

Human TRMT2A methylates tRNA and contributes to translation fidelity

5-Methyluridine (m5U) is one of the most abundant RNA modifications found in cytosolic tRNA. tRNA methyltransferase 2 homolog A (hTRMT2A) is the dedicated mammalian enzyme for m5U formation at tRNA position 54. However, its RNA binding specificity and functional role in the cell are not well understood. Here we dissected structural and sequence requirements for binding and methylation of its RNA targets. Specificity of tRNA modification by hTRMT2A is achieved by a combination of modest binding preference and presence of a uridine in position 54 of tRNAs. Mutational analysis together with cross-linking experiments identified a large hTRMT2A–tRNA binding surface. Furthermore, complementing hTRMT2A interactome studies revealed that hTRMT2A interacts with proteins involved in RNA biogenesis. Finally, we addressed the question of the importance of hTRMT2A function by showing that its knockdown reduces translation fidelity. These findings extend the role of hTRMT2A beyond tRNA modification towards a role in translation

Application of a Rational Crystal Contact Engineering Strategy on a Poly(ethylene terephthalate)-Degrading Cutinase

Industrial biotechnology offers a potential ecological solution for PET recycling under relatively mild reaction conditions via enzymatic degradation, particularly using the leaf branch compost cutinase (LCC) quadruple mutant ICCG. To improve the efficient downstream processing of this biocatalyst after heterologous gene expression with a suitable production host, protein crystallization can serve as an effective purification/capture step. Enhancing protein crystallization was achieved in recent studies by introducing electrostatic (and aromatic) interactions in two homologous alcohol dehydrogenases ( Lb / Lk ADH) and an ene reductase ( Nsp ER1-L1,5) produced with Escherichia coli . In this study, ICCG, which is difficult to crystallize, was utilized for the application of crystal contact engineering strategies, resulting in ICCG mutant L50Y (ICCGY). Previously focused on the Lys-Glu interaction for the introduction of electrostatic interactions at crystal contacts, the applicability of the engineering strategy was extended here to an Arg-Glu interaction to increase crystallizability, as shown for ICCGY T110E. Furthermore, the rationale of the engineering approach is demonstrated by introducing Lys and Glu at non-crystal contacts or sites without potential interaction partners as negative controls. These resulting mutants crystallized comparably but not superior to the wild-type protein. As demonstrated by this study, crystal contact engineering emerges as a promising approach for rationally enhancing protein crystallization. This advancement could significantly streamline biotechnological downstream processing, offering a more efficient pathway for research and industry.This research was funded by the German Research Foundation (DFG), research project WE2715/14-2, within the priority program SPP 1934 framework.German Research Foundation (DFG

Upregulation of Cyclin B1 by miRNA and its implications in cancer

It is largely recognized that microRNAs (miRNAs) function to silence gene expression by targeting 3′UTR regions. However, miRNAs have also been implicated to positively-regulate gene expression by targeting promoter elements, a phenomenon known as RNA activation (RNAa). In the present study, we show that expression of mouse Cyclin B1 (Ccnb1) is dependent on key factors involved in miRNA biogenesis and function (i.e. Dicer, Drosha, Ago1 and Ago2). In silico analysis identifies highly-complementary sites for 21 miRNAs in the Ccnb1 promoter. Experimental validation identified three miRNAs (miR-744, miR-1186 and miR-466d-3p) that induce Ccnb1 expression in mouse cell lines. Conversely, knockdown of endogenous miR-744 led to decreased Ccnb1 levels. Chromatin immunoprecipitation (ChIP) analysis revealed that Ago1 was selectively associated with the Ccnb1 promoter and miR-744 increased enrichment of RNA polymerase II (RNAP II) and trimethylation of histone 3 at lysine 4 (H3K4me3) at the Ccnb1 transcription start site. Functionally, short-term overexpression of miR-744 and miR-1186 resulted in enhanced cell proliferation, while prolonged expression caused chromosomal instability and in vivo tumor suppression. Such phenotypes were recapitulated by overexpression of Ccnb1. Our findings reveal an endogenous system by which miRNA functions to activate Ccnb1 expression in mouse cells and manipulate in vivo tumor development/growth

A Random shRNA-Encoding Library for Phenotypic Selection and Hit-Optimization

RNA interference (RNAi) is a mechanism for inhibiting gene expression through the action of small, non-coding RNAs. Most existing RNAi libraries target single genes through canonical pathways. Endogenous microRNAs (miRNAs), however, often target multiple genes and can act through non-canonical pathways, including pathways that activate gene expression. To interrogate all possible functions, we designed, synthesized, and validated the first shRNA-encoding library that is completely random at the nucleotide level. Screening in an IL3-dependent cell line, FL5.12, yielded shRNA-encoding sequences that double cell survival upon IL3 withdrawal. Using random mutagenesis and re-screening under more stringent IL3-starvation conditions, we hit-optimized one of the sequences; a specific nucleotide change and the creation of a mismatch between the two halves of the stem both contributed to the improved potency. Our library allows unbiased selection and optimization of shRNA-encoding sequences that confer phenotypes of interest, and could be used for the development of therapeutics and tools in many fields of biology