Challenges and industry practices for managing software variability in small and medium sized enterprises

Software variability is an ability to change (configure, customize, extend) software artefacts (e.g. code, product, domain requirements, models, design, documentation, test cases) for a specific context. Optimized variability management can lead a software company to 1) shorter development lead time, 2) improved customer and improved user satisfaction, 3) reduced complexity of product management (more variability, same $) and 4) reduced costs (same variability, less $). However, it is not easy for software companies, especially small and medium size of enterprises to deal with variability. In this paper we present variability challenges and used practices collected from five SMEs. Our study indicates that increased product complexity can lead growing SMEs to the time-consuming decision-making. Many of the analyzed medium size of companies also expect improved tool support to help them to boost their productivity when managing increasingly complex products and increasing amount of variants In fact, in many of the analysed SMEs, a high level of automation in design, release management and testing are or become a key factor for market success By introducing the challenges and used practices related to variability the paper deepens understanding of this highly relevant but relatively under-researched phenomenon and contributes to the literature on software product line engineering.     

Effects of training in sentence construction on the comprehension of learning disabled children.

30 learning-disabled Hispanic, White, and Black children (mean IQ 88.60 and mean age 11.73 yrs) were randomly assigned to 2 conditions focusing on sentence comprehension: a sentence anagram/word grouping treatment and a more traditional sentence study treatment. With age, IQ, and pretest comprehension (Gates-MacGinitie Reading Tests) controlled, Ss in the sentence anagram/word grouping condition had significantly higher cloze scores than Ss in the sentence study group. The greatest achievement benefits associated with the anagram treatment, however, accrued to Ss with higher initial reading achievement. As level of pretreatment achievement decreased, the magnitude of the treatment differences also tended to decrease. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Functional Modification of Fibronectin by N‐Terminal FXIIIa‐Mediated Transamidation

A straightforward strategy is presented for the site‐specific incorporation of fluorophores or reactive probes into the extracellular matrix (ECM) protein fibronectin (Fn) by using the enzyme‐catalyzed transamidation by activated factor XIII. Characterization by SDS‐PAGE, western blotting, absorption measurements, mass spectrometry, and stepwise photobleaching for labeling quantification at the single‐molecule level showed that the labeling was efficient and restricted to the N‐terminal tails. The introduction of labels did not interfere with Fn fibrillogenesis, as verified by the incorporation of fluorescently labeled Fn into ECM and manually pulled Fn fibers. Site‐specific incorporation of an azide was used to create a template for bioorthogonal click chemistry reactions in a second bioconjugation step, thus offering versatile modification and application possibilities in the context of matrix biology and tissue engineering.     

Proteomic Analysis of Marinesco–Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss

Marinesco–Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss-of-function mutations in the gene encoding the endoplasmic reticulum cochaperone SIL1. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1 mutant cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs, and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration responsible for the ataxia and muscle weakness typical of MSS. However, the cause of other more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature, and skeletal deformities, is less clear. To gain insights into the pathogenic mechanisms and/or adaptive responses to SIL1 loss, we carried out cell biological and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 R111X mutation. Despite fibroblasts not being overtly affected in MSS, we found morphological and biochemical changes indicative of UPR activation and altered cell metabolism. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dispose of misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid synthesis, an increase in beta oxidation, and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleucine, tryptophan, lysine, aspartate, and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine, and cysteine were reduced. These results indicate that, in addition to UPR activation and increased protein degradation, MSS fibroblasts have profound metabolic alterations, which may help them cope with the absence of SIL1.     

Polymeric scaffolds for cardiac tissue engineering: requirements and fabrication technologies

Cardiac tissue engineering (TE) is an emerging field, whose main goal is the development of innovative strategies for the treatment of heart diseases, with the aim of overcoming the drawbacks of traditional therapies. One of these strategies involves the implantation of three‐dimensional matrices (scaffolds) capable of supporting tissue formation. Scaffolds designed and fabricated for such application should meet several requirements, concerning both the scaffold‐forming materials and the properties of the scaffold itself. A scaffold for cardiac TE should be biocompatible and biodegradable, mimic the properties of the native cardiac tissue, provide a mechanical support to the regenerating heart and possess an interconnected porous structure to favour cell migration, nutrient and oxygen diffusion, and waste removal. Moreover, the mimesis of myocardium characteristic anisotropy is attracting increasing interest to provide engineered constructs with the possibility to be structurally and mechanically integrated in native tissue. Several conventional and non‐conventional fabrication techniques have been explored in the literature to produce polymeric scaffolds meeting all these requirements. This review describes these techniques, with a focus on their advantages and disadvantages, and their flexibility, with the final goal of providing the reader with the primal knowledge necessary to develop an effective strategy in cardiac TE. © 2013 Society of Chemical Industry     

Functional Analyses of Four CYP1A1 Missense Mutations Present in Patients with Atypical Femoral Fractures

Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF.     

Polyether Cyclization Cascade Alterations in Response to Monensin Polyketide Synthase Mutations

The targeted manipulation of polyketide synthases has in recent years led to numerous new-to-nature polyketides. For type I polyketide synthases the response of post-polyketide synthases (PKS) processing enzymes onto the most frequently polyketide backbone manipulations is so far insufficiently studied. In particular, complex processes such as the polyether cyclisation in the biosynthesis of ionophores such as monensin pose interesting objects of research. We present here a study of the substrate promiscuity of the polyether cyclisation cascade enzymes in monensin biosynthesis in the conversion of redox derivatives of the nascent polyketide chain. LC-HRMS/MS²-based studies revealed a remarkable flexibility of the post-PKS enzymes. They acted on derivatized polyketide backbones based on the three possible polyketide redox states within two different modules and gave rise to an altered polyether structure. One of these monensin derivatives was isolated and characterized by 2D-NMR spectroscopy, crystallography, and bioactivity studies.     

Stereoselective Biocatalyzed Reductions of Ginger Active Components Recovered from Industrial Wastes

Ginger is among the most widespread and widely consumed traditional medicinal plants around the world. Its beneficial effects, which comprise e. g. anticancer and anti-inflammatory activities as well as gastrointestinal regulatory effects, are generally attributed to a family of non-volatile compounds characterized by an arylalkyl long-chained alcohol, diol, or ketone moiety. In this work, ginger active components have been successfully recovered from industrial waste biomass of fermented ginger. Moreover, their recovery has been combined with the first systematic study of the stereoselective reduction of gingerol-like compounds by isolated alcohol dehydrogenases (ADHs), obtaining the enantioenriched sec-alcohol derivatives via a sustainable biocatalytic path in up to >99 % conversions and >99 % enantiomeric/diastereomeric excesses.     

CRISPR/Cas9-Mediated Allele-Specific Disruption of a Dominant COL6A1 Pathogenic Variant Improves Collagen VI Network in Patient Fibroblasts

Collagen VI-related disorders are the second most common congenital muscular dystrophies for which no treatments are presently available. They are mostly caused by dominant-negative pathogenic variants in the genes encoding α chains of collagen VI, a heteromeric network forming collagen; for example, the c.877G>A; p.Gly293Arg COL6A1 variant, which alters the proper association of the tetramers to form microfibrils. We tested the potential of CRISPR/Cas9-based genome editing to silence or correct (using a donor template) a mutant allele in the dermal fibroblasts of four individuals bearing the c.877G>A pathogenic variant. Evaluation of gene-edited cells by next-generation sequencing revealed that correction of the mutant allele by homologous-directed repair occurred at a frequency lower than 1%. However, the presence of frameshift variants and others that provoked the silencing of the mutant allele were found in >40% of reads, with no effects on the wild-type allele. This was confirmed by droplet digital PCR with allele-specific probes, which revealed a reduction in the expression of the mutant allele. Finally, immunofluorescence analyses revealed a recovery in the collagen VI extracellular matrix. In summary, we demonstrate that CRISPR/Cas9 gene-edition can specifically reverse the pathogenic effects of a dominant negative variant in COL6A1.     

Structure Prediction of Partial-Length Protein Sequences

Protein structure information is essential to understand protein function. Computational methods to accurately predict protein structure from the sequence have primarily been evaluated on protein sequences representing full-length native proteins. Here, we demonstrate that top-performing structure prediction methods can accurately predict the partial structures of proteins encoded by sequences that contain approximately 50% or more of the full-length protein sequence. We hypothesize that structure prediction may be useful for predicting functions of proteins whose corresponding genes are mapped expressed sequence tags (ESTs) that encode partial-length amino acid sequences. Additionally, we identify a confidence score representing the quality of a predicted structure as a useful means of predicting the likelihood that an arbitrary polypeptide sequence represents a portion of a foldable protein sequence (“foldability”). This work has ramifications for the prediction of protein structure with limited or noisy sequence information, as well as genome annotation.