Maturation of NaV and KV channel topographies in the auditory nerve spike initiator before and after developmental onset of hearing function

Auditory nerve excitation and thus hearing depend on spike-generating ion channels and their placement along the axons of auditory nerve fibers (ANFs). The developmental expression patterns and native axonal locations of voltage-gated ion channels in ANFs are unknown. Therefore, we examined the development of heminodes and nodes of Ranvier in the peripheral axons of type I ANFs in the rat cochlea with immunohistochemistry and confocal microscopy. Nodal structures presumably supporting presensory spiking formed between postnatal days 5 (P5) and P7, including Ankyrin-G, NaV1.6, and Caspr. These immature nodal structures lacked low-voltage-activated KV1.1 which was not enriched at juxtaparanodes until approximately P13, concurrent with the developmental onset of acoustic hearing function. Anatomical alignment of ANF spike-initiating heminodes relative to excitatory input from inner hair cell (IHC) ribbon synapses continued until approximately P30. High-voltage-activated KV3.1b and KV2.2 were expressed in mutually exclusive domains: KV3.1b was strictly localized to nodes and heminodes, whereas KV2.2 expression began at the juxtaparanodes and continued centrally along the first internode. At spike-initiating heminodes in the distal osseous spiral lamina, NaV1.1 partly overlapped NaV1.6 and ankyrin-G. ANFs displayed KV7.2 and KV7.3 at heminodes, nodes, internodes, and the unmyelinated synaptic terminal segments beneath IHCs in the organ of Corti. In response to sound, spikes are initiated at the heminode, which is tightly coupled to the IHC ribbon synapse ∼20–40 μm away. These results show that maturation of nodal alignment and ion channel content may underlie postnatal improvements of ANF excitability and discharge synchrony.SIGNIFICANCE STATEMENTAcoustic and electrical hearing depends on rapid, reliable, and precise spike generation in auditory nerve fibers. A limitation of current models and therapies is a lack of information on the identities and topographies of underlying ion channels. We report the developmental profile of the auditory nerve spike generator with a focus on NaV1.1, NaV1.6, KV1.1, KV2.2, KV3.1b, KV7.2, and KV7.3 in relation to the scaffold ankyrin-G. Molecular anatomy of the spike generator matures in the weeks after developmental onset of hearing function. Subcellular positioning of voltage-gated ion channels will enable multicompartmental modeling of auditory nerve responses elicited by afferent chemical neurotransmission from hair cells and modulated by efferent neurotransmitters or evoked by extracellular field stimulation from a cochlear implant.</jats:p

On the Atrophy of Moral Reasoning in the Global Financial Crisis

The Global Financial Crisis - and its human toll - can be attributed to an atypical pandemic of morally sourced market failure. This paper develops a ‘moral bubble’ understanding of the sub-prime crisis, in which ethical decision-making by economic actors is marked by expediency and crowd effects. The paper revisits Adam Smith’s Theory of Moral Sentiments and shows Smith’s theory offers a helpful corrective to the ethical atrophy behind the recent credit crisis. The need to safeguard the \u27soft\u27 (moral) infrastructure of markets has significant implications for business decision-makers, for public policy, and for the role of Christian belief in society

Detectable HIV Viral Load in Kenya: Data from a Population-Based Survey.

IntroductionAt the individual level, there is clear evidence that Human Immunodeficiency Virus (HIV) transmission can be substantially reduced by lowering viral load. However there are few data describing population-level HIV viremia especially in high-burden settings with substantial under-diagnosis of HIV infection. The 2nd Kenya AIDS Indicator Survey (KAIS 2012) provided a unique opportunity to evaluate the impact of antiretroviral therapy (ART) coverage on viremia and to examine the risks for failure to suppress viral replication. We report population-level HIV viral load suppression using data from KAIS 2012.MethodsBetween October 2012 to February 2013, KAIS 2012 surveyed household members, administered questionnaires and drew serum samples to test for HIV and, for those found to be infected with HIV, plasma viral load (PVL) was measured. Our principal outcome was unsuppressed HIV viremia, defined as a PVL ≥ 550 copies/mL. The exposure variables included current treatment with ART, prior history of an HIV diagnosis, and engagement in HIV care. All point estimates were adjusted to account for the KAIS 2012 cluster sampling design and survey non-response.ResultsOverall, 61·2% (95% CI: 56·4-66·1) of HIV-infected Kenyans aged 15-64 years had not achieved virological suppression. The base10 median (interquartile range [IQR]) and mean (95% CI) VL was 4,633 copies/mL (0-51,596) and 81,750 copies/mL (59,366-104,134), respectively. Among 266 persons taking ART, 26.1% (95% CI: 20.0-32.1) had detectable viremia. Non-ART use, younger age, and lack of awareness of HIV status were independently associated with significantly higher odds of detectable viral load. In multivariate analysis for the sub-sample of patients on ART, detectable viremia was independently associated with younger age and sub-optimal adherence to ART.DiscussionThis report adds to the limited data of nationally-representative surveys to report population- level virological suppression. We established heterogeneity across the ten administrative and HIV programmatic regions on levels of detectable viral load. Timely initiation of ART and retention in care are crucial for the elimination of transmission of HIV through sex, needle and syringe use or from mother to child. Further refinement of geospatial mapping of populations with highest risk of transmission is necessary

New PomBase Website 2017, Group Leader Survey Summary

PomBase launched a new version of its website on 25th October 2017. Shortly thereafter, 100 fission yeast research group leaders were surveyed to gauge the impact of the site redesign

Preventive measures in infancy to reduce under-five mortality: a case-control study in The Gambia.

OBJECTIVE: To investigate the relationship between child mortality and common preventive interventions: vaccination, trained birthing attendants, tetanus toxoid during pregnancy, breastfeeding and vitamin A supplementation. METHODS: Case-control study in a population under demographic surveillance. Cases (n = 141) were children under five who died. Each was age and sex-matched to five controls (n = 705). Information was gathered by interviewing primary caregivers. RESULTS: All but one of the interventions - whether the mother had received tetanus toxoid during pregnancy - were protective against child mortality after multivariate analysis. Having a trained person assisting at child birth (OR 0.2 95% CI 0.1-0.4), receiving all vaccinations by 9 months of age (OR 0.1; 95% CI 0.01-0.3), being breastfed for more than 12 months (Children breastfed between 13 and 24 months OR 0.1 95% CI 0.03-0.3, more than 25 months OR 0.1 95% CI 0.01-0.5) and receiving vitamin A supplementation at or after 6 months of age (OR 0.05; 95% CI 0.01-0.2) were protective against child death. CONCLUSIONS: This study confirms the value of at least four available interventions in the prevention of under-five death in The Gambia. It is now important to identify those who are not receiving them and why, and to intervene to improve coverage across the population

De novo draft assembly of the Botrylloides leachii genome provides further insight into tunicate evolution

Tunicates are marine invertebrates that compose the closest phylogenetic group to the vertebrates. These chordates present a particularly diverse range of regenerative abilities and life-history strategies. Consequently, tunicates provide an extraordinary perspective into the emergence and diversity of these traits. Here we describe the genome sequencing, annotation and analysis of the Stolidobranchian Botrylloides leachii. We have produced a high-quality 159 Mb assembly, 82% of the predicted 194  Mb genome. Analysing genome size, gene number, repetitive elements, orthologs clustering and gene ontology terms show that B. leachii has a genomic architecture similar to that of most solitary tunicates, while other recently sequenced colonial ascidians have undergone genome expansion. In addition, ortholog clustering has identified groups of candidate genes for the study of colonialism and whole-body regeneration. By analysing the structure and composition of conserved gene linkages, we observed examples of cluster breaks and gene dispersions, suggesting that several lineage-specific genome rearrangements occurred during tunicate evolution. We also found lineage-specific gene gain and loss within conserved cell-signalling pathways. Such examples of genetic changes within conserved cell-signalling pathways commonly associated with regeneration and development that may underlie some of the diverse regenerative abilities observed in tunicates. Overall, these results provide a novel resource for the study of tunicates and of colonial ascidians

Focusing of high-energy particles in the electrostatic field of a homogeneously charged sphere and the effective momentum approximation

The impact of the strongly attractive electromagnetic field of heavy nuclei on electrons in quasi-elastic (e,e') scattering is often accounted for by the effective momentum approximation. This method is a plane wave Born approximation which takes the twofold effect of the attractive nucleus on initial and final state electrons into account, namely the modification of the electron momentum in the vicinity of the nucleus, and the focusing of electrons towards the nuclear region leading to an enhancement of the corresponding wave function amplitudes. The focusing effect due to the attractive Coulomb field of a homogeneously charged sphere on a classical ensemble of charged particles incident on the field is calculated in the highly relativistic limit and compared to results obtained from exact solutions of the Dirac equation. The result is relevant for the theoretical foundation of the effective momentum approximation and describes the high energy behavior of the amplitude of continuum Dirac waves in the potential of a homogeneously charged sphere. Our findings indicate that the effective momentum approximation is a useful approximation for the calculation of Coulomb corrections in (e,e') scattering off heavy nuclei for sufficiently high electron energies and momentum transfer.Comment: 16 pages, 9 figures, LATEX, some references adde

Methodological Bias in Estimates of Strain Composition and Straying of Hatchery‐Produced Steelhead in Lake Michigan Tributaries

Steelhead Oncorhynchus mykiss were first introduced into the Great Lakes in the late 1800s. Subsequently, natural recruitment of steelhead from spawning runs in streams across the basin has been regularly supplemented by hatchery production of strains derived from widely dispersed locales within the species’ native range. Estimates of hatchery contributions to the spawning runs of naturalized populations may be underrepresented by observations of marked fish, as not all hatchery fish are marked prior to release. To assess the potential bias in estimates of the hatchery contribution to steelhead spawning runs in four major rivers in Michigan, we used scale pattern analysis (SPA) to identify nonmarked hatchery fish and multilocus genotypes to estimate the proportional contributions of each hatchery strain to spawning runs. The four hatchery strains currently stocked are significantly genetically distinct (mean FST = 0.077), making it possible to identify specific strains by use of likelihood‐based assignment tests. The differences between direct (mark observations) and indirect (SPA and genetic analysis) estimates of hatchery contribution were mainly due to variations in the percentage of hatchery fish marked by states prior to release and the potential for confusion between certain marks and injuries. By combining direct and indirect assessment methodologies, we estimated that the percentage of hatchery fish returning to the four rivers ranged from 13% to 31% of total spawning runs. The large contribution of hatchery fish to nonstocked rivers differed significantly from expectations of strain‐specific stocking rates across the Lake Michigan basin and for individual streams, indicating high amounts of straying into Michigan streams.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141020/1/nafm1288.pd

Improving functional annotation for industrial microbes: a case study with Pichia pastoris.

The research communities studying microbial model organisms, such as Escherichia coli or Saccharomyces cerevisiae, are well served by model organism databases that have extensive functional annotation. However, this is not true of many industrial microbes that are used widely in biotechnology. In this Opinion piece, we use Pichia (Komagataella) pastoris to illustrate the limitations of the available annotation. We consider the resources that can be implemented in the short term both to improve Gene Ontology (GO) annotation coverage based on annotation transfer, and to establish curation pipelines for the literature corpus of this organism.We gratefully acknowledge funding from the Wellcome Trust (PomBase and Canto; WT090548MA to SGO), and the EU 7th Framework Programme (BIOLEDGE Contract No: 289126 to SGO).This is the published version distributed under a Creative Commons Attribution License 2.0, which can also be found on the publisher's website at: http://www.sciencedirect.com/science/article/pii/S0167779914001061