Toxicity in mice expressing short hairpin RNAs gives new insight into RNAi

Short hairpin RNAs can provide stable gene silencing via RNA interference. Recent studies have shown toxicity in vivo that appears to be related to saturation of the endogenous microRNA pathway. Will these findings limit the therapeutic use of such hairpins

Протокол функционального обследования аноректальной зоны и классификация нарушений: международный консенсус и Российские рекомендации

This manuscript summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance, terminology used, and interpretation of anorectal function testing including anorectal manometry (focused on high-resolution manometry), the rectal sensory test, and the balloon expulsion test. Based on these measurements, a classification system for disorders of anorectal function is proposed. Aim to provide information about methods of diagnosis and new classification of functional anorectal disorders to a wide range of specialists general practitioners, therapists, gastroenterologists, coloproctologists all who face the manifestations of these diseases in everyday practice and determine the diagnostic and therapeutic algorithm. Current paper provides agreed statements of IAPWG Consensus and comments (in italics) of Russian experts on real-world practice, mainly on methodology of examination. These comments in no way intended to detract from the provisions agreed by the international group of experts. We hope that these comments will help to improve the quality of examination based on the systematization of local experience with the use of the methods discussed and the results obtained. Key recommendations: the International Anorectal Physiology Working Group protocol for the performance of anorectal function testing recommends a standardized sequence of maneuvers to test rectoanal reflexes, anal tone and contractility, rectoanal coordination, and rectal sensation. Major findings not seen in healthy controls defined by the classification are as follows: rectoanal areflexia, anal hypotension and hypocontractility, rectal hyposensitivity, and hypersensitivity. Minor and inconclusive findings that can be present in health and require additional information prior to diagnosis include anal hypertension and dyssynergia

Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria

Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF

First beta-decay spectroscopy of In-135 and new beta-decay branches of In-134

The beta decay of the neutron-rich In-134 and In-135 was investigated experimentally in order to provide new insights into the nuclear structure of the tin isotopes with magic proton number Z = 50 above the N = 82 shell. The beta-delayed gamma-ray spectroscopy measurement was performed at the ISOLDE facility at CERN, where indium isotopes were selectively laser-ionized and on-line mass separated. Three beta-decay branches of In-134 were established, two of which were observed for the first time. Population of neutron-unbound states decaying via. rays was identified in the two daughter nuclei of In-134, Sn-134 and Sn-133, at excitation energies exceeding the neutron separation energy by 1 MeV. The beta-delayed one- and two-neutron emission branching ratios of In-134 were determined and compared with theoretical calculations. The beta-delayed one-neutron decay was observed to be dominant beta-decay branch of In-134 even though the Gamow-Teller resonance is located substantially above the two-neutron separation energy of Sn-134. Transitions following the beta decay of In-135 are reported for the first time, including. rays tentatively attributed to Sn-135. In total, six new levels were identified in Sn-134 on the basis of the beta.. coincidences observed in the In-134 and In-135 beta decays. A transition that might be a candidate for deexciting the missing neutron single-particle 13/2(+) state in Sn-133 was observed in both beta decays and its assignment is discussed. Experimental level schemes of Sn-134 and Sn-135 are compared with shell-model predictions. Using the fast timing technique, half-lives of the 2(+), 4(+), and 6(+) levels in Sn-134 were determined. From the lifetime of the 4(+) state measured for the first time, an unexpectedly large B(E2; 4(+)-> 2(+)) transition strength was deduced, which is not reproduced by the shell-model calculations.Peer reviewe

Intron Evolution: Testing Hypotheses of Intron Evolution Using the Phylogenomics of Tetraspanins

BACKGROUND: Although large scale informatics studies on introns can be useful in making broad inferences concerning patterns of intron gain and loss, more specific questions about intron evolution at a finer scale can be addressed using a gene family where structure and function are well known. Genome wide surveys of tetraspanins from a broad array of organisms with fully sequenced genomes are an excellent means to understand specifics of intron evolution. Our approach incorporated several new fully sequenced genomes that cover the major lineages of the animal kingdom as well as plants, protists and fungi. The analysis of exon/intron gene structure in such an evolutionary broad set of genomes allowed us to identify ancestral intron structure in tetraspanins throughout the eukaryotic tree of life. METHODOLOGY/PRINCIPAL FINDINGS: We performed a phylogenomic analysis of the intron/exon structure of the tetraspanin protein family. In addition, to the already characterized tetraspanin introns numbered 1 through 6 found in animals, three additional ancient, phase 0 introns we call 4a, 4b and 4c were found. These three novel introns in combination with the ancestral introns 1 to 6, define three basic tetraspanin gene structures which have been conserved throughout the animal kingdom. Our phylogenomic approach also allows the estimation of the time at which the introns of the 33 human tetraspanin paralogs appeared, which in many cases coincides with the concomitant acquisition of new introns. On the other hand, we observed that new introns (introns other than 1-6, 4a, b and c) were not randomly inserted into the tetraspanin gene structure. The region of tetraspanin genes corresponding to the small extracellular loop (SEL) accounts for only 10.5% of the total sequence length but had 46% of the new animal intron insertions. CONCLUSIONS/SIGNIFICANCE: Our results indicate that tests of intron evolution are strengthened by the phylogenomic approach with specific gene families like tetraspanins. These tests add to our understanding of genomic innovation coupled to major evolutionary divergence events, functional constraints and the timing of the appearance of evolutionary novelty

The great tit HapMap project: A continental‐scale analysis of genomic variation in a songbird

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The code to reproduce the results is available on Github: https://github.com/lgs85/SpurginBosse_Hapmap. The data, including the Plink-formatted genotype files from all populations, and the downstream outputs are on Dryad: https://doi.org/10.5061/dryad.w3r2280z5.A major aim of evolutionary biology is to understand why patterns of genomic diversity vary within taxa and space. Large-scale genomic studies of widespread species are useful for studying how environment and demography shape patterns of genomic divergence. Here, we describe one of the most geographically comprehensive surveys of genomic variation in a wild vertebrate to date; the great tit (Parus major) HapMap project. We screened ca 500,000 SNP markers across 647 individuals from 29 populations, spanning ~30 degrees of latitude and 40 degrees of longitude – almost the entire geographical range of the European subspecies. Genome-wide variation was consistent with a recent colonisation across Europe from a South-East European refugium, with bottlenecks and reduced genetic diversity in island populations. Differentiation across the genome was highly heterogeneous, with clear ‘islands of differentiation’, even among populations with very low levels of genome-wide differentiation. Low local recombination rates were a strong predictor of high local genomic differentiation (FST), especially in island and peripheral mainland populations, suggesting that the interplay between genetic drift and recombination causes highly heterogeneous differentiation landscapes. We also detected genomic outlier regions that were confined to one or more peripheral great tit populations, probably as a result of recent directional selection at the species' range edges. Haplotype-based measures of selection were related to recombination rate, albeit less strongly, and highlighted population-specific sweeps that likely resulted from positive selection. Our study highlights how comprehensive screens of genomic variation in wild organisms can provide unique insights into spatio-temporal evolutionary dynamics.Natural Environment Research Council (NERC)European Research Council (ERC)Biotechnology and Biological Sciences Research Council (BBSRC

New ß-decaying state in 214Bi

A new β-decaying state in 214Bi has been identified at the ISOLDE Decay Station at the CERN-ISOLDE facility. A preferred Iπ = (8−) assignment was suggested for this state based on the β-decay feeding pattern to levels in 214Po and shell-model calculations. The half-life of the Iπ = (8−) state was deduced to be T1/2 = 9.39(10) min. The deexcitation of the levels populated in 214Po by the β decay of this state was investigated via γ -γ coincidences and a number of new levels and transitions was identified. Shell-model calculations for excited states in 214Bi and 214Po were performed using two different effective interactions: the H208 and the modified Kuo-Herling particle interaction. Both calculations agree on the interpretation of the new β-decaying state as an Iπ = 8− isomer and allow for tentative assignment of shell-model states to several high-spin states in 214Po.peerReviewe

New ß-decaying state in 214Bi

A new β-decaying state in 214Bi has been identified at the ISOLDE Decay Station at the CERN-ISOLDE facility. A preferred Iπ = (8−) assignment was suggested for this state based on the β-decay feeding pattern to levels in 214Po and shell-model calculations. The half-life of the Iπ = (8−) state was deduced to be T1/2 = 9.39(10) min. The deexcitation of the levels populated in 214Po by the β decay of this state was investigated via γ -γ coincidences and a number of new levels and transitions was identified. Shell-model calculations for excited states in 214Bi and 214Po were performed using two different effective interactions: the H208 and the modified Kuo-Herling particle interaction. Both calculations agree on the interpretation of the new β-decaying state as an Iπ = 8− isomer and allow for tentative assignment of shell-model states to several high-spin states in 214Po.peerReviewe

Change in structure between the I = 1/2 states in 181Tl and 177,179Au

The first accurate measurements of the α-decay branching ratio and half-life of the Iπ=1/2+ ground state in 181Tl have been made, along with the first determination of the magnetic moments and I=1/2 spin assignments of the ground states in 177,179Au. The results are discussed within the complementary systematics of the reduced α-decay widths and nuclear g factors of low-lying, Iπ=1/2+ states in the neutron-deficient lead region. The findings shed light on the unexpected hindrance of the 1/2+→1/2+, 181Tl→g177Aug α decay, which is explained by a mixing of π3s1/2 and π2d3/2 configurations in 177Aug, whilst 181Tlg remains a near-pure π3s1/2. This conclusion is inferred from the g factor of 177Aug which has an intermediate value between those of π3s1/2 and π2d3/2 states. A similar mixed configuration is proposed for the Iπ=1/2+ ground state of 179Au. This mixing may provide evidence for triaxial shapes in the ground states in these nuclei

Characterization of the shape-staggering effect in mercury nuclei

In rare cases, the removal of a single proton (Z) or neutron (N) from an atomic nucleus leads to a dramatic shape change. These instances are crucial for understanding the components of the nuclear interactions that drive deformation. The mercury isotopes (Z = 80) are a striking example1,2: their close neighbours, the lead isotopes (Z = 82), are spherical and steadily shrink with decreasing N. The even-mass (A = N + Z) mercury isotopes follow this trend. The odd-mass mercury isotopes 181,183,185Hg, however, exhibit noticeably larger charge radii. Due to the experimental difficulties of probing extremely neutron-deficient systems, and the computational complexity of modelling such heavy nuclides, the microscopic origin of this unique shape staggering has remained unclear. Here, by applying resonance ionization spectroscopy, mass spectrometry and nuclear spectroscopy as far as 177Hg, we determine 181Hg as the shape-staggering endpoint. By combining our experimental measurements with Monte Carlo shell model calculations, we conclude that this phenomenon results from the interplay between monopole and quadrupole interactions driving a quantum phase transition, for which we identify the participating orbitals. Although shape staggering in the mercury isotopes is a unique and localized feature in the nuclear chart, it nicely illustrates the concurrence of single-particle and collective degrees of freedom at play in atomic nuclei