Interactive gene networks with KNIT.

SUMMARY: KNIT is a web application that provides a hierarchical, directed graph on how a set of genes is connected to a particular gene of interest. Its primary aim is to aid researchers in discerning direct from indirect effects that a gene might have on the expression of other genes and molecular pathways, a very common problem in omics analysis. As such, KNIT provides deep contextual information for experiments where gene or protein expression might be changed, such as gene knock-out and overexpression experiments. AVAILABILITY AND IMPLEMENTATION: KNIT is publicly available at http://knit.ims.bio. It is implemented with Django and Nuxtjs, with all major browsers supported. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Screening for irradiation vasculopathy by intima-media thickness sonography in head and neck cancer patients.

PURPOSE: Post-irradiation vasculopathy is a severe form of atherosclerosis and affects the prognosis of head and neck cancer survivors. Sonographic intima-media thickness (IMT) precedes stenosis, plaque formation, and cerebrovascular events. Therefore, IMT may be a valuable screening marker for post-irradiation toxicity. However, the critical irradiation dose and the onset of IMT increase remain unclear. METHODS: The cross-sectional study analysed the carotid artery IMT in 96 irradiated patients and 41 controls regarding irradiation dose, post-irradiation-interval, and cardiovascular risk factors. Distinct irradiation doses to the tumour side and the contralateral hemineck enabled detection of dose depended effects within one patient and control of risk factors. RESULTS: Radiotherapy caused a dose-dependent increase in IMT. The toxicity did not have saturation effects for > 60 Gy. The IMT increase occurred in short-term following radiotherapy and the risk for a pathological value (> 0.9 mm) rose significantly. The correlation between IMT and radiotherapy was comparable to established cardiovascular risk factors. CONCLUSION: Radiotherapists should consider the additional toxicity of high doses for non-metastatic head and neck cancer. If neck metastases require radiotherapy with boost, IMT measurement is suitable for early detection of carotid artery damage.

OTTO: a new strategy to extract mental disease-relevant combinations of GWAS hits from individuals.

Despite high heritability of schizophrenia, genome-wide association studies (GWAS) have not yet revealed distinct combinations of single-nucleotide polymorphisms (SNPs), relevant for mental disease-related, quantifiable behavioral phenotypes. Here we propose an individual-based model to use genome-wide significant markers for extracting first genetic signatures of such behavioral continua. 'OTTO' (old Germanic=heritage) marks an individual characterized by a prominent phenotype and a particular load of phenotype-associated risk SNPs derived from GWAS that likely contributed to the development of his personal mental illness. This load of risk SNPs is shared by a small squad of 'similars' scattered under the genetically and phenotypically extremely heterogeneous umbrella of a schizophrenia end point diagnosis and to a variable degree also by healthy subjects. In a discovery sample of >1000 deeply phenotyped schizophrenia patients and several independent replication samples, including the general population, a gradual increase in the severity of 'OTTO's phenotype' expression is observed with an increasing share of 'OTTO's risk SNPs', as exemplified here by autistic and affective phenotypes. These data suggest a model in which the genetic contribution to dimensional behavioral traits can be extracted from combinations of GWAS SNPs derived from individuals with prominent phenotypes. Even though still in the 'model phase' owing to a world-wide lack of sufficiently powered, deeply phenotyped replication samples, the OTTO approach constitutes a conceptually novel strategy to delineate biological subcategories of mental diseases starting from GWAS findings and individual subjects.

The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43.

The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function.

Genome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia.

Higher educational attainment (EA) is negatively associated with schizophrenia (SZ). However, recent studies found a positive genetic correlation between EA and SZ. We investigate possible causes of this counterintuitive finding using genome-wide association study results for EA and SZ (N = 443,581) and a replication cohort (1169 controls; 1067 cases) with deeply phenotyped SZ patients. We find strong genetic dependence between EA and SZ that cannot be explained by chance, linkage disequilibrium, or assortative mating. Instead, several genes seem to have pleiotropic effects on EA and SZ, but without a clear pattern of sign concordance. Using EA as a proxy phenotype, we isolate FOXO6 and SLITRK1 as novel candidate genes for SZ. Our results reveal that current SZ diagnoses aggregate over at least two disease subtypes: one part resembles high intelligence and bipolar disorder (BIP), while the other part is a cognitive disorder that is independent of BIP.

Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy.

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.

Intake of vitamin C, vitamin E, selenium, zinc and polyunsaturated fatty acids and upper respiratory tract infection-a prospective cohort study.

BACKGROUND/OBJECTIVES: Antioxidants and polyunsaturated fatty acids (PUFAs) have a role in the human immune defense and may affect the susceptibility to upper respiratory tract infection (URTI). To examine dietary intake of vitamin C, vitamin E, selenium, zinc and PUFAs in relation to URTI incidence in a prospective cohort study. SUBJECTS/METHODS: A total of 1533 Swedish women and men aged 25-64 years were followed for nine months during 2011-2012. Information on dietary intake was assessed through a web-based food frequency questionnaire, and events of URTI were self-reported prospectively as they occurred. Cox proportional hazards regression was applied to obtain incidence rate ratios with 95% confidence intervals. RESULTS: The mean number of URTI events was 0.9 among all participants, 1.0 among women and 0.7 among men. In women, the incidence rate ratios (95% confidence interval) for high compared with low intake were 0.69 (0.55-0.88) for vitamin C, 0.77 (0.62-0.96) for vitamin E, 0.57 (0.39-0.83) for docosahexaenoic acid (DHA) and 0.80 (0.65-0.99) for arachidonic acid (AA). No association was found for selenium or zinc among women. In men, an increased URTI incidence was seen with medium vitamin E intake (1.42 (1.09-1.85)) and high zinc intake (1.50 (1.04-2.16)). No association was found for vitamin C, selenium or PUFAs among men. CONCLUSIONS: We found an inverse association of URTI incidence among women for vitamin C, vitamin E, DHA and AA intake and a positive association among men for vitamin E and zinc intake. The observed gender differences warrant further investigation.

[Microinvasive laparoscopic cholecystectomy with 2 mm instruments. Presentation of the method and initial results]. / Mikroinvasive laparoskopische Cholecystektomie mit 2-mm-Instrumenten. Methodenvorstellung und erste Ergebnisse.

Between September 1998 and May 1999, 498 patients underwent laparoscopic cholecystectomy. Of these, 301 patients were electively scheduled cases. Two hundred and sixty-seven patients (58.4%) patients were operated on with the standard laparoscopic technique (LC) and 34 (6.8%) with a new microinvasive technique (MLC) using self-developed 2-mm instruments. The technique of this microinvasive method is introduced and the first results are reported. These results encourage us to recommend our new method for selected cases.