A rule-based kinetic model of RNA polymerase II C-terminal domain phosphorylation

The complexity ofmany RNA processing pathways is such that a conventional systemsmodelling approach is inadequate to represent all themolecular species involved. We demonstrate that rule-based modelling permits a detailed model of a complex RNA signalling pathway to be defined. Phosphorylation of the RNApolymerase II (RNAPII)C-terminal domain (CTD; a flexible tail-like extension of the largest subunit) couples pre-messenger RNA capping, splicing and 30 end maturation to transcriptional elongation and termination, and plays a central role in integrating these processes. The phosphorylation states of the serine residues of many heptapeptide repeats of the CTD alter along the coding region of genes as a function of distance from the promoter. From a mechanistic perspective, both the changes in phosphorylation and the location atwhich they take place on the genes are a function of the time spent byRNAPII in elongation as this interval provides the opportunity for the kinases and phosphatases to interactwith theCTD.On this basis,we synthesize the available data to create a kinetic model of the action of the known kinases and phosphatases to resolve the phosphorylation pathways and their kinetics.</p

Is neurosurgery referral warranted for small brain aneurysms?

The risk of rupture of a small cerebral aneurysm (<10 mm) is very low in asymptomatic patients who have never had a subarachnoid hemorrhage. Because the risk of morbidity and mortality from surgical intervention significantly exceeds that of nonsurgical monitoring for this group, primary care physicians do not need to refer patients with this condition to a neurosurgeon for clipping (strength of recommendation [SOR]: B, based on cohort and case-control studies). For patients managed conservatively, annual office follow-up and imaging evaluation should be considered, and is necessary if a specific symptom should arise (SOR: C, based on expert opinion)

Evaluation of enzyme immunoassays in the diagnosis of camel (Camelus dromedarius) trypanosomiasis:a preliminary investigation

Three enzyme immunoassays were used for the serodiagnosis of Trypanosoma evansi in camels in the Sudan in order to evaluate their ability to discriminate between infected and non-infected animals. Two assays were used for the detection of trypanosomal antibodies, one using specific anti-camel IgG conjugate and another using a non-specific Protein A conjugate. The third assay detected the presence of trypanosomal antigens using anti-T. evansi antibodies in a double antibody sandwich assay. Inspection of the frequency distribution of assay results suggested that the ELISA for circulating trypanosomal antibodies using specific antisera and the ELISA for circulating antigens can distinguish between non-infected camels and infected camels exhibiting patent infections or not. The ELISA using Protein A conjugate to bind non-specifically to camel immunoglobulin did not appear to discriminate between infected and non-infected animals

Identities for hyperelliptic P-functions of genus one, two and three in covariant form

We give a covariant treatment of the quadratic differential identities satisfied by the P-functions on the Jacobian of smooth hyperelliptic curves of genera 1, 2 and 3

Combination of measurements and the BLUE method

The most accurate method to combine measurement from different experiments is to build a combined likelihood function and use it to perform the desired inference. This is not always possible for various reasons, hence approximate methods are often convenient. Among those, the best linear unbiased estimator (BLUE) is the most popular, allowing to take into account individual uncertainties and their correlations. The method is unbiased by construction if the true uncertainties and their correlations are known, but it may exhibit a bias if uncertainty estimates are used in place of the true ones, in particular if those estimated uncertainties depend on measured values. In those cases, an iterative application of the BLUE method may reduce the bias of the combined measurement.Comment: 10 pages, 4 figures, proceedings of the XIIth Quark Confinement and Hadron Spectrum conference, 28/8-2/9 2016, Tessaloniki, Greec

How should we treat chronic daily headache when conservative measures fail?

For the purposes of this review, we considered conservative measures to include such therapies as nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, and acetaminophen with codeine. Amitriptyline is the best-supported option for the treatment of chronic daily headaches for those patients who have not been treated by conservative measures (strength of recommendation [SOR]: A, based on a metaanalysis of randomized controlled trials [RCTs]). For patients who overuse symptomatic headache medications, medication withdrawal is effective (SOR: B, based on a systematic review of cohort and case-control studies). Additional therapies include other tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and prophylactic treatments for migraine (SOR: B)

Do statins delay onset or slow progression of Alzheimer's dementia?

Statins (coenzyme-A reductase inhibitors) should not be used with the single intent to delay the onset or slow the progression of dementia. Large randomized control trials (RCTs) found that the administration of a statin had no significant effect on preventing or slowing all-cause cognitive decline (strength of recommendation [SOR]: A, based on large RCTs with narrow confidence interval). Specifically, there is insufficient evidence that statins delay the onset or slow the progression of Alzheimer's dementia (SOR: B, based on systematic review with heterogeneity). While 3 epidemiologic studies have found a decreased incidence of dementia among those taking statins, these studies have significant methodological shortcomings and do not show a causal relationship (SOR: C, based on poor-quality studies)

Lagrangian Framework for Systems Composed of High-Loss and Lossless Components

Using a Lagrangian mechanics approach, we construct a framework to study the dissipative properties of systems composed of two components one of which is highly lossy and the other is lossless. We have shown in our previous work that for such a composite system the modes split into two distinct classes, high-loss and low-loss, according to their dissipative behavior. A principal result of this paper is that for any such dissipative Lagrangian system, with losses accounted by a Rayleigh dissipative function, a rather universal phenomenon occurs, namely, selective overdamping: The high-loss modes are all overdamped, i.e., non-oscillatory, as are an equal number of low-loss modes, but the rest of the low-loss modes remain oscillatory each with an extremely high quality factor that actually increases as the loss of the lossy component increases. We prove this result using a new time dynamical characterization of overdamping in terms of a virial theorem for dissipative systems and the breaking of an equipartition of energy.Comment: 53 pages, 1 figure; Revision of our original manuscript to incorporate suggestions from refere

No evidence for killer sperm or other selective interactions between human spermatozoa in ejaculates of different males in vitro

This study examines one of the possible mechanisms of sperm competition, i.e. the kamikaze sperm hypothesis. This hypothesis states that sperm from different males interact to incapacitate each other in a variety of ways. We used ejaculates from human donors to compare mixes of semen in vitro from the same or different males. We measured the following parameters: (i) the degree of sperm aggregation, velocity and proportion of morphologically normal sperm after 1 and 3 h incubation in undiluted semen samples, (ii) the proportion of viable sperm plus the same parameters as in (i) in 'swim-up' sperm suspensions after 1 and 3 h incubation, (iii) the degree of self and non-self sperm aggregation using fluorescent dyes to distinguish the sperm of different males, and (iv) the extent of sperm capacitation and acrosome-reacted sperm in mixtures of sperm from the same and different males. We observed very few significant changes in sperm aggregation or performance in mixtures of sperm from different males compared with mixtures from the same male and none that were consistent with previously reported findings. The incapacitation of rival sperm therefore seems an unlikely mechanism of sperm competition in humans

Mobile Phone Radiation Induces Reactive Oxygen Species Production and DNA Damage in Human Spermatozoa In Vitro

Background: In recent times there has been some controversy over the impact of electromagnetic radiation on human health. The significance of mobile phone radiation on male reproduction is a key element of this debate since several studies have suggested a relationship between mobile phone use and semen quality. The potential mechanisms involved have not been established, however, human spermatozoa are known to be particularly vulnerable to oxidative stress by virtue of the abundant availability of substrates for free radical attack and the lack of cytoplasmic space to accommodate antioxidant enzymes. Moreover, the induction of oxidative stress in these cells not only perturbs their capacity for fertilization but also contributes to sperm DNA damage. The latter has, in turn, been linked with poor fertility, an increased incidence of miscarriage and morbidity in the offspring, including childhood cancer. In light of these associations, we have analyzed the influence of RF-EMR on the cell biology of human spermatozoa in vitro. Principal Findings: Purified human spermatozoa were exposed to radio-frequency electromagnetic radiation (RF-EMR) tuned to 1.8 GHz and covering a range of specific absorption rates (SAR) from 0.4 W/kg to 27.5 W/kg. In step with increasing SAR, motility and vitality were significantly reduced after RF-EMR exposure, while the mitochondrial generation of reactive oxygen species and DNA fragmentation were significantly elevated (P<0.001). Furthermore, we also observed highly significant relationships between SAR, the oxidative DNA damage bio-marker, 8-OH-dG, and DNA fragmentation after RF-EMRexposure. Conclusions: RF-EMR in both the power density and frequency range of mobile phones enhances mitochondrial reactive oxygen species generation by human spermatozoa, decreasing the motility and vitality of these cells while stimulating DNA base adduct formation and, ultimately DNA fragmentation. These findings have clear implications for the safety of extensive mobile phone use by males of reproductive age, potentially affecting both their fertility and the health and wellbeing of their offspring