4,017 research outputs found
PRUNE1: a disease-causing gene for secondary microcephaly
In their Letter to the Editor, Karakaya et al. (2017) present
an interesting case report describing the clinical course
involving secondary microcephaly of a 3-year-old Turkish
boy found to be homozygous for a frameshift mutation in
PRUNE1 identified through whole exome sequencing. The
child presented with congenital hypotonia, contractures and
global developmental delay with respiratory insufficiency
and seizures developing in the first year of life. The authors
note that the affected child’s head circumference plotted on
the 75th centile at birth, and that by 38 months of age he
had developed microcephaly. Neuroimaging at 14 months
revealed cerebral and cerebellar atrophy consistent with
other patients described with Prune syndrome (Karaca
et al., 2015; Costain et al., 2017; Zollo et al., 2017).
Although the child had abnormal neurology from birth,
there was a period of early developmental regression.
Peripheral spasticity in the lower extremities and optic atrophy
were not documented until 38 months. In addition to
the PRUNE1 variant, Karakaya et al. also identified a
second homozygous variant in the CCDC14 gene in the
Turkish child’s whole exome sequencing data that, while
listed to have an allele count of 108 in the current Genome
Aggregation Database (gnomAD) release, is notably absent
in homozygous fashion (Lek et al., 2016). CCDC14 is
known to be expressed in human brain, reported to negatively
regulate centriole duplication and interact with proteins
previously associated with primary microcephaly
(Firat-Karalar et al., 2014). Thus, while it seems likely
that the homozygous PRUNE1 variant is primarily responsible
for the clinical presentation in the Turkish child, it is
impossible to determine whether there may be any phenotypical
contribution from this additional homozygous
sequence variant.
Recently, Costain et al. (2017) described a homozygous
consensus splice site variant in PRUNE1 (c.521-2A4G;
NM_021222.1) in a 2-year-old Oji-Cre male who presented
with congenital hypotonia and talipes, whose head circumference
was large at birth ( +3 standard deviations), but by
2 years and 2 months plotted on the 50th centile, with a
weight and height on the 95th and 75th centiles, respectively.
However, it should be noted that the child’s father
is macrocephalic ( +4 standard deviations), the published
clinical photographs at 2 years 5 months of age illustrate
bitemporal narrowing, a sloping forehead and large ears,
consistent with a developing microcephaly, and neuroimaging revealed cortical and cerebellar atrophy. He
developed respiratory insufficiency shortly after birth, and
infantile spasms in the first year of life (Costain et al., 2017).
It remains to be determined how the phenotypical outcomes
stemming from proposed loss-of-function mutations
defined by Karakaya et al. and Costain et al., relate to
missense mutations published by Karaca et al. and also
Zollo et al., which are likely to involve at least partial
gain-of-function outcomes in PRUNE1 activity. However,
as more cases are investigated and published, the phenotype
associated with autosomal recessive Prune neurodevelopmental
disorder, and the functional outcomes of
PRUNE1 mutation, are becoming clearer. It is now apparent
that while some patients have a small head at birth and
others a head circumference in the normal range, the key
component of the microcephaly is that it is progressive, and
associated with characteristic neuroimaging findings with a
thin or hypoplastic corpus callosum and cortical and cerebellar
atrophy developing in early childhood. Although all
patients with Prune syndrome described to date are neurologically
impaired from birth, there also appears to be a
neurodegenerative component with progression of the disorder.
In our manuscript, we described clinical overlap of
Prune syndrome with the neurodegenerative condition associated
with homozygous mutations in TBCD (Zollo et al.,
2017). TBCD encodes one of the five tubulin-specific chaperones
that are required for a/b-tubulin de novo heterodimer
formation and the disorder is characterized by
developmental regression, seizures, optic atrophy and secondary
microcephaly, cortical atrophy with delayed myelination,
cerebellar atrophy and thinned corpus callosum
(Edvardson et al., 2016; Flex et al., 2016; Miyake et al.,
2016; Pode-Shakked et al., 2017). The neurodegenerative
phenotype documented in the Turkish child by Karakaya
et al. further demonstrates the similarities with the TBCD
disorder and Prune syndrome, and confirms optic atrophy
to be a feature of Prune syndrome. Interestingly, it is also
becoming clear that respiratory insufficiency is a common
feature of Prune syndrome, having been documented by
Karakaya et al. and in the Oji-Cre child, as well as the
youngest affected Omani child described in our manuscript
An unusual presentation of actinomycosis in a dairy cow
A first lactation dairy cow (in late gestation) presented with a hard round swelling of the right olecranon and slight lameness. A lateromedial radiograph of the right olecranon had a mottled appearance with indistinct borders. Bone biopsy was performed post calving. Histology showed fibrosis and reactive changes, however this sample was considered too superficial and not representative of the whole lesion. Based on the differential diagnoses treatment was not possible and the cow was culled at the end of her lactation. At slaughter the forelimb was retained for further analysis. Grossly, the olecranon was severely enlarged, irregular with multiple yellow granulomas in the cortex and medulla of the bone. Histology showed multifocal pyogranulomas containing bacteria, Splendore-Hoeppli material and surrounded by remodelled bone and fibrosis. Despite displaying biochemical properties characteristic of Actinomycesspecies this could not be confirmed by partial 16s rRNA sequencing and the organism could not be definitively speciated
PMI: A Delta Psi(m) Independent Pharmacological Regulator of Mitophagy
Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy
Evidence for equilibrium iron isotope fractionation by nitrate-reducing iron(II)-oxidizing bacteria
Iron isotope fractionations produced during chemical and biological Fe(II) oxidation are sensitive to the proportions and nature of dissolved and solid-phase Fe species present, as well as the extent of isotopic exchange between precipitates and aqueous Fe. Iron isotopes therefore potentially constrain the mechanisms and pathways of Fe redox transformations in modern and ancient environments. In the present study, we followed in batch experiments Fe isotope fractionations between Fe(II)_(aq) and Fe(III) oxide/hydroxide precipitates produced by the Fe(III) mineral encrusting, nitrate-reducing, Fe(II)-oxidizing Acidovorax sp. strain BoFeN1. Isotopic fractionation in ^(56)Fe/^(54)Fe approached that expected for equilibrium conditions, assuming an equilibrium Δ^(56)Fe_(Fe(OH)3–Fe(II)aq) fractionation factor of +3.0‰. Previous studies have shown that Fe(II) oxidation by this Acidovorax strain occurs in the periplasm, and we propose that Fe isotope equilibrium is maintained through redox cycling via coupled electron and atom exchange between Fe(II)_(aq) and Fe(III) precipitates in the contained environment of the periplasm. In addition to the apparent equilibrium isotopic fractionation, these experiments also record the kinetic effects of initial rapid oxidation, and possible phase transformations of the Fe(III) precipitates. Attainment of Fe isotope equilibrium between Fe(III) oxide/hydroxide precipitates and Fe(II)_(aq) by neutrophilic, Fe(II)-oxidizing bacteria or through abiologic Fe(II)_(aq) oxidation is generally not expected or observed, because the poor solubility of their metabolic product, i.e. Fe(III), usually leads to rapid precipitation of Fe(III) minerals, and hence expression of a kinetic fractionation upon precipitation; in the absence of redox cycling between Fe(II)_(aq) and precipitate, kinetic isotope fractionations are likely to be retained. These results highlight the distinct Fe isotope fractionations that are produced by different pathways of biological and abiological Fe(II) oxidation
Deformation of vortex patches by boundaries
The deformation of two-dimensional vortex patches in the vicinity of fluid
boundaries is investigated. The presence of a boundary causes an initially
circular patch of uniform vorticity to deform. Sufficiently far away from the
boundary, the deformed shape is well approximated by an ellipse. This leading
order elliptical deformation is investigated via the elliptic moment model of
Melander, Zabusky & Styczek [M. V. Melander, N. J. Zabusky & A. S. Styczek, J.
Fluid. Mech., 167, 95 (1986)]. When the boundary is straight, the centre of the
elliptic patch remains at a constant distance from the boundary, and the motion
is integrable. Furthermore, since the straining flow acting on the patch is
constant in time, the problem is that of an elliptic vortex patch in constant
strain, which was analysed by Kida [S. Kida, J. Phys. Soc. Japan, 50, 3517
(1981)]. For more complicated boundary shapes, such as a square corner, the
motion is no longer integrable. Instead, there is an adiabatic invariant for
the motion. This adiabatic invariant arises due to the separation in times
scales between the relatively rapid time scale associated with the rotation of
the patch and the slower time scale associated with the self-advection of the
patch along the boundary. The interaction of a vortex patch with a circular
island is also considered. Without a background flow, conservation of angular
impulse implies that the motion is again integrable. The addition of an
irrotational flow past the island can drive the patch towards the boundary,
leading to the possibility of large deformations and breakup.Comment: 19 pages, 16 figure
Perceptions of a self-management intervention for adolescents with sickle cell disease
Objective: Individuals with sickle cell disease (SCD) are at increased risk for complications from their disease during their adolescent and young adult (AYA) years. The risk of morbidity in AYAs with SCD can be decreased with improved self-management. Existing self-management interventions typically focus on one aspect of self-management (e.g., adherence) and do not address factors that activate patients (knowledge, motivation, self-efficacy, and social support) to self-manage. Sickle Cell Thrive (SCThrive) is a mixed in-person/online, technology-enhanced (use of a mobile app), group self-management intervention that targets patient activation. To determine the most clinically significant intervention components, a qualitative study was conducted. Method: Participants were 19 AYAs (Mage = 17.05) with SCD who participated in individual semistructured phone interviews after completing SCThrive. Interview content was coded using a grounded-theory approach to generate themes related to SCThrive’s feasibility, acceptability, and motivation for and impact on self-management. Results: SCThrive was reported to be highly feasible due to the mixed in-person/online format and acceptable because they learned skills to manage SCD in a group of AYAs with SCD. Action planning and pain/mood tracking appeared to be key factors in motivating AYAs for self-management. Participants reported continuing to use self-management skills post-SCThrive (self-efficacy) including applying them to other domains of their lives (e.g., educational/vocational). Conclusions: Study results provide data that can be leveraged to enhance the feasibility, acceptability, and impact of SCThrive and other self-management interventions. Findings can also inform clinical and mobile health interventions to increase self-management in this population
Universality in solar flare and earthquake occurrence
Earthquakes and solar flares are phenomena involving huge and rapid releases
of energy characterized by complex temporal occurrence. By analysing available
experimental catalogs, we show that the stochastic processes underlying these
apparently different phenomena have universal properties. Namely both problems
exhibit the same distributions of sizes, inter-occurrence times and the same
temporal clustering: we find afterflare sequences with power law temporal
correlations as the Omori law for seismic sequences. The observed universality
suggests a common approach to the interpretation of both phenomena in terms of
the same driving physical mechanism
MNS1 variant associated with situs inversus and male infertility
Ciliopathy disorders due to abnormalities of motile cilia encompass a range of autosomal recessive conditions typified by chronic otosinopulmonary disease, infertility, situs abnormalities and hydrocephalus. Using a combination of genome-wide SNP mapping and whole exome sequencing (WES), we investigated the genetic cause of a form of situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family, assuming that an autosomal recessive founder variant was responsible. This identified a single shared (2.34 Mb) region of autozygosity on chromosome 15q21.3 as the likely disease locus, in which we identified a single candidate biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)]. Genotyping of multiple family members identified randomisation of the laterality defects in other homozygous individuals, with all wild type or MNS1 c.407_410del heterozygous carriers being unaffected, consistent with an autosomal recessive mode of inheritance. This study identifies an MNS1 variant as a cause of laterality defects and male infertility in humans, mirroring findings in Mns1-deficient mice which also display male infertility and randomisation of left-right asymmetry of internal organs, confirming a crucial role for MNS1 in nodal cilia and sperm flagella formation and function.This article is freely available via Open Access. Click on the Publisher URL to access the full-text
How unique is the Asymptotic Normalisation Coefficient (ANC) method?
The asymptotic normalisation coefficients (ANC) for the vertex B
Be + p is deduced from a set of different proton transfer reactions at
different energies. This set should ensure the peripheral character of the
reaction and availability of data for the elastic channels. The problems
associated with the characteristics of the data and the analysis are discussed.
For a subgroup of the set of available data, the uniqueness property of the
extracted ANC is fulfilled. However, more measurements are needed before a
definite conclusion can be drawn.Comment: 19 pages, 11 figures, to be published in Phys Rev
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