Introduction The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (cas) is a new technology that allows easier manipulation of the genome. Its potential to edit genes opened a new door in treatment development for incurable neurological monogenic diseases (NMGDs). The aim of this systematic review was to summarise the findings on the current development of CRISPR-cas for therapeutic purposes in the most frequent NMGDs and provide critical assessment. Methods and data acquisition We searched the MEDLINE and EMBASE databases, looking for original studies on the use of CRISPR-cas to edit pathogenic variants in models of the most frequent NMGDs, until end of 2017. We included all the studies that met the following criteria: 1. Peer-reviewed study report with explicitly described experimental designs; 2. In vitro, ex vivo, or in vivo study using human or other animal biological systems (including cells, tissues, organs, organisms); 3. focusing on CRISPR as the gene-editing method of choice; and 5. featured at least one NMGD. Results We obtained 404 papers from MEDLINE and 513 from EMBASE. After removing the duplicates, we screened 490 papers by title and abstract and assessed them for eligibility. After reading 50 full-text papers, we finally selected 42 for the review. Discussion Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne’s muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington’s disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies. Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.

We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10−8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10−7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10−7, HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

In 2012, alcohol liver disease resulted in 3.3 million—5.9% of global deaths. This study introduced whey protection capacity against chronic alcohol-induced liver injury. Rats were orally administered to 12% ethanol solution in water (ad libitum, average 8.14 g of ethanol/kg body weight (b.w.)/day) alone or combined with whey (per os, 2 g/kg b.w./day). After 6-week treatment, chronic ethanol consumption induced significant histopathological liver changes: congestion, central vein dilation, hepatic portal vein branch dilation, Kupffer cells hyperplasia, fatty liver changes, and hepatocytes focal necrosis. Ethanol significantly increased liver catalase activity and glutathione reductase protein expression without significant effects on antioxidative enzymes: glutathione peroxidase (GPx), copper–zinc-containing superoxide dismutase (CuZnSOD) and manganese-containing superoxide dismutase (MnSOD). Co-treatment with whey significantly attenuated pathohistological changes induced by ethanol ingestion and increased GSH-Px and nuclear factor kappa B (NF-κB) protein expression. Our results showed positive effects of whey on liver chronically exposed to ethanol, which seem to be associated with NF-κB-GPx signaling.

In this paper, we consider the topic from the theory of cosine operator functions in 2-dimensional real vector space, which is an interplay between functional analysis and matrix theory. For the various cases of a given real matrix A= [α , β; γ , δ] we find out the appropriate cosine operator function C(t)= [a(t), b(t); c(t), d(t)], (t \in R) in a real vector space R2 as the solutions of the Cauchy problem C''(t)=AC(t), C(0)=I, C'(0)=0.

Aims The aims of this study were to establish cardiac rehabilitation availability and density, as well as the nature of programmes, and to compare these by European region (geoscheme) and with other high-income countries. Methods A survey was administered to cardiac rehabilitation programmes globally. Cardiac associations were engaged to facilitate programme identification. Density was computed using global burden of disease study ischaemic heart disease incidence estimates. Four high-income countries were selected for comparison (N = 790 programmes) to European data, and multilevel analyses were performed. Results Cardiac rehabilitation was available in 40/44 (90.9%) European countries. Data were collected in 37 (94.8% country response rate). A total of 455/1538 (29.6% response rate) programme respondents initiated the survey. Programme volumes (median 300) were greatest in western European countries, but overall were higher than in other high-income countries (P < 0.001). Across all Europe, there was on average only 1 CR spot per 7 IHD patients, with an unmet regional need of 3,449,460 spots annually. Most programmes were funded by social security (n = 25, 59.5%; with significant regional variation, P < 0.001), but in 72 (16.0%) patients paid some or all of the programme costs (or ∼18.5% of the ∼€150.0/programme) out of pocket. Guideline-indicated conditions were accepted in 70% or more of programmes (lower for stable coronary disease), with no regional variation. Programmes had a multidisciplinary team of 6.5 ± 3.0 staff (number and type varied regionally; and European programmes had more staff than other high-income countries), offering 8.5 ± 1.5/10 core components (consistent with other high-income countries) over 24.8 ± 26.0 hours (regional differences, P < 0.05). Conclusion European cardiac rehabilitation capacity must be augmented. Where available, services were consistent with guidelines, but varied regionally.

A warehouse system as a time transformation of the flows of goods plays an essential role in a complete logistics chain. The efficiency of a complete warehouse system largely depends on the efficiency of carrying out transport and handling operations. Therefore, it is essential to have adequate means of internal transport that will influence the efficiency of the warehouse system by its performance. In this paper, the evaluation and selection of side- loading forklift using the FUCOM-WASPAS model, which has been used for the first time in the literature in this paper, is performed. The FUCOM method was used to obtain the weight values of the criteria, while WASPAS was applied for the evaluation and ranking of forklifts. A possibility to apply the FUCOM method in group decision-making was presented. A comparative analysis, in which other methods of multi-criteria decision-making were applied, was carried out. The analysis showed the stability of the results obtained.

The ability to detect, in real-time, heavy hitters is beneficial to many network applications, such as DoS and anomaly detection. Through programmable languages as P4, heavy hitter detection can be implemented directly in the data-plane, allowing custom actions to be applied to packets as they are processed at a network node. This enables networks to immediately respond to changes in network traffic in the data-plane itself and allows for different QoS profiles for heavy hitter and non-heavy hitter traffic. Current interval-based methods that flush the whole counting structure are not well-suited for programmable hardware (the data-plane), because they either require more resources than available in that hardware, they do not provide good accuracy, or require too many actions from the control-plane. A sliding window approach that maintains accuracy over time would solve these issues. However, to the best of our knowledge, the concept of sliding windows in programmable hardware has not been studied yet. In this paper, we develop streaming approaches to detect heavy hitters in the data-plane. We consider the problems of (1) adopting a sliding window and (2) identifying heavy hitters separately and propose multiple memory- and processing-efficient solutions for each of them. These solutions are suitable for P4 programmable hardware and can be combined at will to solve the streaming variant of the heavy hitter detection problem.

We report a study of the relationship between oxide microstructure at the scale of tens of nanometres and resistance switching behaviour in silicon oxide. In the case of sputtered amorphous oxides, the presence of columnar structure enables efficient resistance switching by providing an initial structured distribution of defects that can act as precursors for the formation of chains of conductive oxygen vacancies under the application of appropriate electrical bias. Increasing electrode interface roughness decreases electroforming voltages and reduces the distribution of switching voltages. Any contribution to these effects from field enhancement at rough interfaces is secondary to changes in oxide microstructure templated by interface structure.

Abstract The aim of the present study was to investigate the potential of Mentha aquatica L. for phytoremediation of water contaminated with heavy metals and fecal pathogens from Bosna river. The water was treated with M. aquatica for 5, 10, and 15 days consecutively after which it was analyzed for the various physicochemical and microbiological parameters. The initial concentration of cadmium (Cd) ranged from 3.644 to 6.108 µg/l, while lead (Pb) varied between 0.1 and 1.386 µg/l. After treatment, M. aquatica accumulated significant amounts of cadmium (Cd) and lead (Pb) with the highest removal rates of 96.49% for Cd and 45.72% for Pb. Values of several physicochemical parameters were decreased after 15 days treatment period. All water samples were analyzed for enumeration of aerobic heterotrophic bacteria, total coliforms, and fecal coliforms by the membrane filtration. Removal efficiency was greater than 80% for microbiological parameters. The concentration of heavy metals was determined in different plant parts and subsequently, the translocation factor was determined. In M. aquatica plant parts, concentrations of Pb and Cd were increased after 15 days of treatment. Our results demonstrated that M. aquatica could be good candidates for the removal of fecal pathogens and heavy metals present in surface water.