Paternal effects in a wild‐type zebrafish implicate a role of sperm‐derived small RNAs

While the importance of maternal effects has long been appreciated, a growing body of evidence now points to the paternal environment having an important influence on offspring phenotype. Indeed, research on rodent models suggests that paternal stress leaves an imprint on the behaviour and physiology of offspring via nongenetic information carried in the spermatozoa; however, fish have been understudied with regard to these sperm‐mediated effects. Here, we investigated whether the zebrafish was subjected to heritable influences of paternal stress by exposing males to stressors (conspecific‐derived alarm cue, chasing and bright light) before mating and assessing the behavioural and endocrine responses of their offspring, including their behavioural response to conspecific‐derived alarm cue. We found that after males are exposed to stress, their larval offspring show weakened responses to stressors. Small RNA sequencing subsequently revealed that the levels of several small noncoding RNAs, including microRNAs, PIWI‐interacting RNAs and tRNA‐derived small RNAs, were altered in the spermatozoa of stressed fathers, suggesting that stress‐induced alterations to the spermatozoal RNA landscape may contribute to shaping offspring phenotype. The work demonstrates that paternal stress should not be overlooked as a source of phenotypic variation and that spermatozoal small RNAs may be important intergenerational messengers in fish

Disrupted-in-schizophrenia-1 is essential for normal hypothalamic-pituitary-interrenal (HPI) axis function

Psychiatric disorders arise due to an interplay of genetic and environmental factors, including stress. Studies in rodents have shown that mutants for Disrupted-In-Schizophrenia-1 (DISC1), a well-accepted genetic risk factor for mental illness, display abnormal behaviours in response to stress, but the mechanisms through which DISC1 affects stress responses remain poorly understood. Using two lines of zebrafish homozygous mutant for disc1, we investigated behaviour and functioning of the hypothalamic-pituitary-interrenal (HPI) axis, the fish equivalent of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we show that the role of DISC1 in stress responses is evolutionarily conserved and that DISC1 is essential for normal functioning of the HPI axis. Adult zebrafish homozygous mutant for disc1 show aberrant behavioural responses to stress. Our studies reveal that in the embryo, disc1 is expressed in neural progenitor cells of the hypothalamus, a conserved region of the vertebrate brain that centrally controls responses to environmental stressors. In disc1 mutant embryos, proliferating rx3þ hypothalamic progenitors are not maintained normally and neuronal differentiation is compromised: rx3-derived ff1bþ neurons, implicated in anxiety-related behaviours, and corticotrophin releasing hormone (crh) neurons, key regulators of the stress axis, develop abnormally, and rx3-derived pomcþ neurons are disorganised. Abnormal hypothalamic development is associated with dysfunctional behavioural and neuroendocrine stress responses. In contrast to wild type siblings, disc1 mutant larvae show altered crh levels, fail to upregulate cortisol levels when under stress and do not modulate shoal cohesion, indicative of abnormal social behaviour. These data indicate that disc1 is essential for normal development of the hypothalamus and for the correct functioning of the HPA/HPI axis

Detecting asymptomatic coronary artery disease using routine exercise testing and exercise thallium scintigraphy in patients with atherosclerotic vascular disease

ECG-monitored exercise testing has been proposed as a relatively inexpensive and effective means of screening for asymptomatic coronary artery disease in patients presenting for peripheral vascular surgery. Despite the fact that exercise thallium scintigraphy is also dependent on the patient's ability to exercise, using this test in conjunction with ECG-monitored exercise testing may enhance sensitivity and specificity of non-invasive evaluation. Thirty-two patients were subjected to ECG-monitored exercise testing, exercise thallium scintigraphy and coronary angiography. The sensitivity of ECGmonitored exercise testing for detecting coronary artery disease was calculated at 81,8% and the specificity at 87,5%, while the figures for exercise thallium scintigraphy were 73,1% and 33,3% respectively. Using these two methods in combination yielded a predictive accuracy of 90,6%. The only advantage of exercise thallium scintigraphy over exercise ECG appears to be in patients in whom the latter test could not be interpreted or was non-diagnostic

New insights into landslide processes around volcanic islands from Remotely Operated Vehicle (ROV) observations offshore Montserrat

Submarine landslide deposits have been mapped around many volcanic islands, but interpretations of their structure, composition, and emplacement are hindered by the challenges of investigating deposits directly. Here we report on detailed observations of four landslide deposits around Montserrat collected by Remotely Operated Vehicles, integrating direct imagery and sampling with sediment core and geophysical data. These complementary approaches enable a more comprehensive view of large-scale mass-wasting processes around island-arc volcanoes than has been achievable previously. The most recent landslide occurred at 11.5–14 ka (Deposit 1; 1.7 km3) and formed a radially spreading hummocky deposit that is morphologically similar to many subaerial debris-avalanche deposits. Hummocks comprise angular lava and hydrothermally altered fragments, implying a deep-seated, central subaerial collapse, inferred to have removed a major proportion of lavas from an eruptive period that now has little representation in the subaerial volcanic record. A larger landslide (Deposit 2; 10 km3) occurred at ∼130 ka and transported intact fragments of the volcanic edifice, up to 900 m across and over 100 m high. These fragments were rafted within the landslide, and are best exposed near the margins of the deposit. The largest block preserves a primary stratigraphy of subaerial volcanic breccias, of which the lower parts are encased in hemipelagic mud eroded from the seafloor. Landslide deposits south of Montserrat (Deposits 3 and 5) indicate the wide variety of debris-avalanche source lithologies around volcanic islands. Deposit 5 originated on the shallow submerged shelf, rather than the terrestrial volcanic edifice, and is dominated by carbonate debris

Study protocol; thyroid hormone replacement for untreated older adults with subclinical hypothyroidism - a randomised placebo controlled trial (TRUST)

Background: Subclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH. Methods: Participants are community-dwelling subjects aged ≥65 years with SCH, diagnosed by elevated TSH levels (≥4.6 and ≤19.9 mU/L) on a minimum of two measures ≥ three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p = 0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients. Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture. Discussion: This large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition. Trial registration: Clinicaltrials.gov NCT01660126; registered 8th June 2012

Solution of the Kwiecinski evolution equations for unintegrated parton distributions using the Mellin transform

The Kwiecinski equations for the QCD evolution of the unintegrated parton distributions in the transverse-coordinate space (b) are analyzed with the help of the Mellin-transform method. The equations are solved numerically in the general case, as well as in a small-b expansion which converges fast for b Lambda_QCD sufficiently small. We also discuss the asymptotic limit of large bQ and show that the distributions generated by the evolution decrease with b according to a power law. Numerical results are presented for the pion distributions with a simple valence-like initial condition at the low scale, following from chiral large-N_c quark models. We use two models: the Spectral Quark Model and the Nambu--Jona-Lasinio model. Formal aspects of the equations, such as the analytic form of the b-dependent anomalous dimensions, their analytic structure, as well as the limits of unintegrated parton densities at x -> 0, x -> 1, and at large b, are discussed in detail. The effect of spreading of the transverse momentum with the increasing scale is confirmed, with growing asymptotically as Q^2 alpha(Q^2). Approximate formulas for for each parton species is given, which may be used in practical applications.Comment: 18 pages, 6 figures, RevTe

Submarine deposits from pumiceous pyroclastic density currents traveling over water: an outstanding example from offshore Montserrat (IODP 340)

Pyroclastic density currents have been observed to both enter the sea, and to travel over water for tens of kilometers. Here, we identified a 1.2-m-thick, stratified pumice lapilli-ash cored at Site U1396 offshore Montserrat (Integrated Ocean Drilling Program [IODP] Expedition 340) as being the first deposit to provide evidence that it was formed by submarine deposition from pumice-rich pyroclastic density currents that traveled above the water surface. The age of the submarine deposit is ca. 4 Ma, and its magma source is similar to those for much younger Soufrière Hills deposits, indicating that the island experienced large-magnitude, subaerial caldera-forming explosive eruptions much earlier than recorded in land deposits. The deposit’s combined sedimentological characteristics are incompatible with deposition from a submarine eruption, pyroclastic fall over water, or a submarine seafloor-hugging turbidity current derived from a subaerial pyroclastic density current that entered water at the shoreline. The stratified pumice lapilli-ash unit can be subdivided into at least three depositional units, with the lowermost one being clast supported. The unit contains grains in five separate size modes and has a >12 phi range. Particles are chiefly subrounded pumice clasts, lithic clasts, crystal fragments, and glass shards. Pumice clasts are very poorly segregated from other particle types, and lithic clasts occur throughout the deposit; fine particles are weakly density graded. We interpret the unit to record multiple closely spaced (<2 d) hot pyroclastic density currents that flowed over the ocean, releasing pyroclasts onto the water surface, and settling of the various pyroclasts into the water column. Our settling and hot and cold flotation experiments show that waterlogging of pumice clasts at the water surface would have been immediate. The overall poor hydraulic sorting of the deposit resulted from mixing of particles from multiple pulses of vertical settling in the water column, attesting to complex sedimentation. Slow-settling particles were deposited on the seafloor together with faster-descending particles that were delivered at the water surface by subsequent pyroclastic flows. The final sediment pulses were eventually deflected upon their arrival on the seafloor and were deposited in laterally continuous facies. This study emphasizes the interaction between products of explosive volcanism and the ocean and discusses sedimentological complexities and hydrodynamics associated with particle delivery to water

Heavy-quark mass dependence in global PDF analyses and 3- and 4-flavour parton distributions

We study the sensitivity of our recent MSTW 2008 NLO and NNLO PDF analyses to the values of the charm- and bottom-quark masses, and we provide additional public PDF sets for a wide range of these heavy-quark masses. We quantify the impact of varying m_c and m_b on the cross sections for W, Z and Higgs production at the Tevatron and the LHC. We generate 3- and 4-flavour versions of the (5-flavour) MSTW 2008 PDFs by evolving the input PDFs and alpha_S determined from fits in the 5-flavour scheme, including the eigenvector PDF sets necessary for calculation of PDF uncertainties. As an example of their use, we study the difference in the Z total cross sections at the Tevatron and LHC in the 4- and 5-flavour schemes. Significant differences are found, illustrating the need to resum large logarithms in Q^2/m_b^2 by using the 5-flavour scheme. The 4-flavour scheme is still necessary, however, if cuts are imposed on associated (massive) b-quarks, as is the case for the experimental measurement of Z b bbar production and similar processes.Comment: 40 pages, 11 figures. Grids can be found at http://projects.hepforge.org/mstwpdf/ and in LHAPDF V5.8.4. v2: version published in EPJ

Impact of the calcium form of β-hydroxy-β-methylbutyrate upon human skeletal muscle protein metabolism

Background & aims: β-hydroxy-β-methylbutyrate (HMB) is purported as a key nutritional supplement for the preservation of muscle mass in health, disease and as an ergogenic aid in exercise. Of the two available forms of HMB (calcium (Ca-HMB) salt or free acid (FA-HMB)) – differences in plasma bioavailability have been reported. We previously reported that ∼3 g oral FA-HMB increased muscle protein synthesis (MPS) and reduced muscle protein breakdown (MPB). The objective of the present study was to quantify muscle protein metabolism responses to oral Ca-HMB. Methods: Eight healthy young males received a primed constant infusion of 1,2 13C2 leucine and 2H5 phenylalanine to assess MPS (by tracer incorporation in myofibrils) and MPB (via arterio-venous (A-V) dilution) at baseline and following provision of ∼3 g of Ca-HMB; muscle anabolic (MPS) and catabolic (MPB) signalling was assessed via immunoblotting. Results: Ca-HMB led a significant and rapid (<60 min) peak in plasma HMB concentrations (483.6 ± 14.2 μM, p < 0.0001). This rise in plasma HMB was accompanied by increases in MPS (PA: 0.046 ± 0.004%/h, CaHMB: 0.072 ± 0.004%/h, p < 0001) and suppressions in MPB (PA: 7.6 ± 1.2 μmol Phe per leg min−1, Ca-HMB: 5.2 ± 0.8 μmol Phe per leg min−1, p < 0.01). Increases in the phosphorylation of mTORc1 substrates i.e. p70S6K1 and RPS6 were also observed, with no changes detected in the MPB targets measured. Conclusions: These findings support the pro-anabolic properties of HMB via mTORc1, and show that despite proposed differences in bioavailability, Ca-HMB provides a comparable stimulation to MPS and suppression of MPB, to FA-HMB, further supporting its use as a pharmaconutrient in the modulation of muscle mass

Using behavior-analytic implicit tests to assess sexual interests among normal and sex-offender populations

The development of implicit tests for measuring biases and behavioral predispositions is a recent development within psychology. While such tests are usually researched within a social-cognitive paradigm, behavioral researchers have also begun to view these tests as potential tests of conditioning histories, including in the sexual domain. The objective of this paper is to illustrate the utility of a behavioral approach to implicit testing and means by which implicit tests can be built to the standards of behavioral psychologists. Research findings illustrating the short history of implicit testing within the experimental analysis of behavior are reviewed. Relevant parallel and overlapping research findings from the field of social cognition and on the Implicit Association Test are also outlined. New preliminary data obtained with both normal and sex offender populations are described in order to illustrate how behavior-analytically conceived implicit tests may have potential as investigative tools for assessing histories of sexual arousal conditioning and derived stimulus associations. It is concluded that popular implicit tests are likely sensitive to conditioned and derived stimulus associations in the history of the test-taker rather than 'unconscious cognitions', per se