Tightness of slip-linked polymer chains

We study the interplay between entropy and topological constraints for a polymer chain in which sliding rings (slip-links) enforce pair contacts between monomers. These slip-links divide a closed ring polymer into a number of sub-loops which can exchange length between each other. In the ideal chain limit, we find the joint probability density function for the sizes of segments within such a slip-linked polymer chain (paraknot). A particular segment is tight (small in size) or loose (of the order of the overall size of the paraknot) depending on both the number of slip-links it incorporates and its competition with other segments. When self-avoiding interactions are included, scaling arguments can be used to predict the statistics of segment sizes for certain paraknot configurations.Comment: 10 pages, 6 figures, REVTeX

Model of haplotype and phenotype in the evolution of a duplicated autoregulatory activator

Gene duplication is believed to play a major role in the evolution of genomic complexity. The presence of a duplicate frees a gene from the constraint of natural selection, leading to its loss of function or the gain of a novel one. Alternately, a pleiotropic gene might partition its functions among its duplicates, thus preserving both copies. Such arguments invoking duplication for novelty or specialisation are not qualitatively true of diploid genotypes, but only of haplotypes. In this paper, we study the consequences of regulatory interactions in diploid genotypes and explore how the context of allelic interactions gives rise to dynamical phenotypes that enable duplicate genes to spread in a population. The regulatory network we study is that of a single autoregulatory activator gene, and the two copies of the gene diverge either as alleles in a diploid species or as duplicates in haploids. These differences are in their transcriptional ability—either via alterations to its activating domain, or to its cis-regulatory binding repertoire. When cis-regulatory changes are introduced that partition multiple regulatory triggers among the duplicates, it is shown that mutually exclusive expression states of the duplicates that emerge are accompanied by a back-up facility: when a highly expressed gene is deleted, the previously unexpressed duplicate copy compensates for it. The diploid version of the regulatory network model can account for allele-specific expression variants, and a model of inheritance of the haplotype network enables us to trace the evolutionary consequence of heterozygous phenotypes. This is modelled for the variations in the activating domain of one copy, whereby stable as well as transiently bursting oscillations ensue in single cells. The evolutionary model shows that these phenotypic states accessible to a diploid, heterozygous genotype enable the spread of a duplicated haplotype

Optogenetic Dissection of Neuronal Circuits in Zebrafish using Viral Gene Transfer and the Tet System

The conditional expression of transgenes at high levels in sparse and specific populations of neurons is important for high-resolution optogenetic analyses of neuronal circuits. We explored two complementary methods, viral gene delivery and the iTet-Off system, to express transgenes in the brain of zebrafish. High-level gene expression in neurons was achieved by Sindbis and Rabies viruses. The Tet system produced strong and specific gene expression that could be modulated conveniently by doxycycline. Moreover, transgenic lines showed expression in distinct, sparse and stable populations of neurons that appeared to be subsets of the neurons targeted by the promoter driving the Tet-activator. The Tet system therefore provides the opportunity to generate libraries of diverse expression patterns similar to gene trap approaches or the thy-1 promoter in mice, but with the additional possibility to pre-select cell types of interest. In transgenic lines expressing channelrhodopsin-2, action potential firing could be precisely controlled by two-photon stimulation at low laser power, presumably because the expression levels of the Tet-controlled genes were high even in adults. In channelrhodopsin-2-expressing larvae, optical stimulation with a single blue LED evoked distinct swimming behaviors including backward swimming. These approaches provide new opportunities for the optogenetic dissection of neuronal circuit structure and function

Stereotactic Radiosurgery for Benign Cavernous Sinus Meningiomas: A Multicentre Study and Review of the Literature

SIMPLE SUMMARY: Meningiomas are the most common tumours of the central nervous system (CNS). Despite their benign histology, proximity to critical neurovascular structures may lead to significant morbidity with tumour growth. This is the case for cavernous sinus meningiomas (CSMs), as their growth may surround critical neuro-vascular structures and cause significant morbidity. Radical microsurgical resection carries a high risk of additional neurological deficits, as well as the risk of death. Current management of these tumours, where treatment is indicated, has moved away from radical surgery towards radiotherapy/radiosurgery. This is particularly the case for patients who have residual or recurring tumours after previous surgery. There are many reports that describe the effectiveness of using stereotactic radiosurgery (SRS) for CSMs; however, large cohort analyses are lacking. This multicentre analysis reports the outcome data of over 1000 patients with CSMs who were treated with SRS. SRS shows a high local tumour control rate with few complications. These results agree with previous reports in the literature. SRS is a valuable primary or adjuvant treatment option for CSMs. ABSTRACT: Cavernous sinus meningiomas (CSMs) remain a surgical challenge due to the intimate involvement of their contained nerves and blood vessels. Stereotactic radiosurgery (SRS) is a safe and effective minimally invasive alternative for the treatment of small- to medium-sized CSMs. Objective: To assess the medium- to long-term outcomes of SRS for CSMs with respect to tumour growth, prevention of further neurological deterioration and improvement of existing neurological deficits. This multicentric study included data from 15 European institutions. We performed a retrospective observational analysis of 1222 consecutive patients harbouring 1272 benign CSMs. All were treated with Gamma Knife stereotactic radiosurgery (SRS). Clinical and imaging data were retrieved from each centre and entered into a common database. All tumours with imaging follow-up of less than 24 months were excluded. Detailed results from 945 meningiomas (86%) were then analysed. Clinical neurological outcomes were available for 1042 patients (85%). Median imaging follow-up was 67 months (mean 73.4, range 24–233). Median tumour volume was 6.2 cc (+/−7), and the median marginal dose was 14 Gy (+/−3). The post-treatment tumour volume decreased in 549 (58.1%), remained stable in 336 (35.6%) and increased in only 60 lesions (6.3%), yielding a local tumour control rate of 93.7%. Only 27 (2.8%) of the 60 enlarging tumours required further treatment. Five- and ten-year actuarial progression-free survival (PFS) rates were 96.7% and 90.1%, respectively. Tumour control rates were higher for women than men (p = 0.0031), and also for solitary sporadic meningiomas (p = 0.0201). There was no statistically significant difference in outcome for imaging-defined meningiomas when compared with histologically proven WHO Grade-I meningiomas (p = 0.1212). Median clinical follow up was 61 months (mean 64, range 6–233). Permanent morbidity occurred in 5.9% of cases at last follow-up. Stereotactic radiosurgery is a safe and effective method for treating benign CSM in the medium term to long term