ABSTRACT
KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic ...paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
De novo (genetic changes not transmitted from the parents) missense mutations targeting conserved residues in the motor domain of the neuron‐specific motor protein KIF1A alters its activity and cause a complex neurologic phenotype characterized by severe developmental delay and/or intellectual disability, as well as variable cerebellar atrophy, visual loss, spastic paraparesis, peripheral neuropathy and epilepsy.
Protein phosphatase 1 (PP1) binding proteins are quintessential regulators, determining substrate specificity and defining subcellular localization and activity of the latter. Here, we describe a ...novel PP1 binding protein, the nuclear membrane protein lamina associated polypeptide 1B (LAP1B), which interacts with the DYT1 dystonia protein torsinA. The PP1 binding domain in LAP1B was here identified as the REVRF motif at amino acids 55-59. The LAP1B:PP1 complex can be immunoprecipitated from cells in culture and rat cortex and the complex was further validated by yeast co-transformations and blot overlay assays. PP1, which is enriched in the nucleus, binds to the N-terminal nuclear domain of LAP1B, as shown by immunocolocalization and domain specific binding studies. PP1 dephosphorylates LAP1B, confirming the physiological relevance of this interaction. These findings place PP1 at a key position to participate in the pathogenesis of DYT1 dystonia and related nuclear envelope-based diseases.
Although alcohol consumption is a common lifestyle behavior with previous studies reporting positive effects of alcohol on chronic pain and rheumatoid arthritis, no studies to this date have examined ...alcohol consumption in patients with fibromyalgia. We examined the association between alcohol consumption and symptom severity and quality of life (QOL) in patients with fibromyalgia.
Data on self-reported alcohol consumption from 946 patients were analyzed. Subjects were grouped by level of alcohol consumption (number of drinks/week): none, low (≤ 3), moderate (>3 to 7), and heavy (>7).
Five hundred and forty-six subjects (58%) did not consume alcohol. Low, moderate, and heavy levels of alcohol consumption were reported for 338 (36%), 31 (3%), and 31 patients (3%), respectively. Employment status (P <0.001), education level (P = 0.009), body mass index (P = 0.002) and opioid use (P = 0.002) differed significantly among groups with drinkers having higher education, a lower BMI, and a lower frequency of unemployment and opioid use than nondrinkers. After adjusting for these differences, the measures including the number of tender points (P = 0.01), FIQ total score (P = 0.01), physical function (P <0.001), work missed (P = 0.005), job ability (P = 0.03), and pain (P = 0.001) differed across groups, as did the SF-36 subscales of physical functioning (P <0.001), pain index (P = 0.002), general health perception (P = 0.02), social functioning (P = 0.02), and the physical component summary (P <0.001). Pairwise comparison among the 4 groups showed that the moderate and low alcohol drinkers had lower severity of fibromyalgia symptoms and better physical QOL than nondrinkers.
Our study demonstrates that low and moderate alcohol consumption was associated with lower fibromyalgia symptoms and better QOL compared to no alcohol consumption. The reasons for these results are unclear. Since recent studies have demonstrated that γ-Aminobutyric Acid (GABA) levels are low in fibromyalgia, and alcohol is known to be a GABA-agonist, future studies should examine whether alcohol could have a salutary effect on pain and other symptoms in fibromyalgia.
Background
Preliminary work has demonstrated that background parenchymal enhancement (BPE) assessed by radiologists is predictive of future breast cancer in women undergoing high‐risk screening MRI. ...Algorithmically assessed measures of BPE offer a more precise and reproducible means of measuring BPE than human readers and thus might improve the predictive performance of future cancer development.
Purpose
To determine if algorithmically extracted imaging features of BPE on screening breast MRI in high‐risk women are associated with subsequent development of cancer.
Study Type
Case–control study.
Population
In all, 133 women at high risk for developing breast cancer; 46 of these patients developed breast cancer subsequently over a follow‐up period of 2 years.
Field Strength/Sequence
5 T or 3.0 T T1‐weighted precontrast fat‐saturated and nonfat‐saturated sequences and postcontrast nonfat‐saturated sequences.
Assessment
Automatic features of BPE were extracted with a computer algorithm. Subjective BPE scores from five breast radiologists (blinded to clinical outcomes) were also available.
Statistical Tests
Leave‐one‐out crossvalidation for a multivariate logistic regression model developed using the automatic features and receiver operating characteristic (ROC) analysis were performed to calculate the area under the curve (AUC). Comparison of automatic features and subjective features was performed using a generalized regression model and the P‐value was obtained. Odds ratios for automatic and subjective features were compared.
Results
The multivariate model discriminated patients who developed cancer from the patients who did not, with an AUC of 0.70 (95% confidence interval: 0.60–0.79, P < 0.001). The imaging features remained independently predictive of subsequent development of cancer (P < 0.003) when compared with the subjective BPE assessment of the readers.
Data Conclusion
Automatically extracted BPE measurements may potentially be used to further stratify risk in patients undergoing high‐risk screening MRI.
Level of Evidence: 3
Technical Efficacy: Stage 5
J. Magn. Reson. Imaging 2019;50:456–464.
The adverse skeletal effects of Roux-en-Y gastric bypass (RYGB) are partly caused by intestinal calcium absorption decline. Prebiotics, such as soluble corn fiber (SCF), augment colonic calcium ...absorption in healthy individuals.
We tested the effects of SCF on fractional calcium absorption (FCA), biochemical parameters, and the fecal microbiome in a post-RYGB population.
Randomized, double-blind, placebo-controlled trial of 20 postmenopausal women with history of RYGB a mean 5 years prior; a 2-month course of 20 g/day SCF or maltodextrin placebo was taken orally. The main outcome measure was between-group difference in absolute change in FCA (primary outcome) and was measured with a gold standard dual stable isotope method. Other measures included tolerability, adherence, serum calciotropic hormones and bone turnover markers, and fecal microbial composition via 16S rRNA gene sequencing.
Mean FCA ± SD at baseline was low at 5.5 ± 5.1%. Comparing SCF to placebo, there was no between-group difference in mean (95% CI) change in FCA (+3.4 -6.7, +13.6%), nor in calciotropic hormones or bone turnover markers. The SCF group had a wider variation in FCA change than placebo (SD 13.4% vs 7.0%). Those with greater change in microbial composition following SCF treatment had greater increase in FCA (r2 = 0.72, P = 0.05). SCF adherence was high, and gastrointestinal symptoms were similar between groups.
No between-group differences were observed in changes in FCA or calciotropic hormones, but wide CIs suggest a variable impact of SCF that may be due to the degree of gut microbiome alteration. Daily SCF consumption was well tolerated. Larger and longer-term studies are warranted.
The N‐Myc Downstream‐Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the ...tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4−/−) CRC models and an indirect co‐culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that the absence of Ndrg4 does not trigger any functional or morphological GI abnormalities. However, combining in vivo, in vitro, and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4−/− ENS cell secretome, which is enriched for Nidogen‐1 (Nid1) and Fibulin‐2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance migration capacities of CRC cells, and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS‐derived Nidogen‐1 and Fibulin‐2 enhance colorectal carcinogenesis.
SYNOPSIS
Loss of enteric neuronal N‐Myc Downstream‐Regulated Gene 4 (Ndrg4) increases the release of the extracellular matrix proteins, Nidogen‐1 and Fibulin‐2, which accelerates intestinal growth in vitro and promotes colorectal cancer progression in vivo.
Loss of Ndrg4 is associated with a more aggressive tumor behavior in murine models of colorectal cancer.
Medium derived from primary Ndrg4‐/‐ enteric nervous system cells accelerates the growth of murine intestinal organoids.
Ndrg4‐/‐ medium is enriched for two extracellular matrix components: Nidogen‐1 and Fibulin‐2.
Soluble Nidogen‐1 and Fibulin‐2 stimulate human intestinal organoid proliferation and CRC cell migration in vitro.
Loss of enteric neuronal N‐Myc Downstream‐Regulated Gene 4 (Ndrg4) increases the release of the extracellular matrix proteins, Nidogen‐1 and Fibulin‐2, which accelerates intestinal growth in vitro and promotes colorectal cancer progression in vivo.
Developmental pathologies may result from endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS), which oxidatively damage cellular macromolecules and/or alter signal ...transduction. This minireview focuses upon several model drugs (phenytoin, thalidomide, methamphetamine), environmental chemicals (benzoapyrene) and gamma irradiation to examine this hypothesis in vivo and in embryo culture using mouse, rat and rabbit models. Embryonic prostaglandin H synthases (PHSs) and lipoxygenases bioactivate xenobiotics to free radical intermediates that initiate ROS formation, resulting in oxidation of proteins, lipids and DNA. Oxidative DNA damage and embryopathies are reduced in PHS knockout mice, and in mice treated with PHS inhibitors, antioxidative enzymes, antioxidants and free radical trapping agents. Thalidomide causes embryonic DNA oxidation in susceptible (rabbit) but not resistant (mouse) species. Embryopathies are increased in mutant mice deficient in the antioxidative enzyme glucose-6-phosphate dehydrogenase (G6PD), or by glutathione (GSH) depletion, or inhibition of GSH peroxidase or GSH reductase. Inducible nitric oxide synthase knockout mice are partially protected. Inhibition of Ras or NF-kB pathways reduces embryopathies, implicating ROS-mediated signal transduction. Atm and p53 knockout mice deficient in DNA damage response/repair are more susceptible to xenobiotic or radiation embryopathies, suggesting a teratological role for DNA damage, consistent with enhanced susceptibility to methamphetamine in
ogg1 knockout mice with deficient repair of oxidative DNA damage. Even endogenous embryonic oxidative stress carries a risk, since untreated G6PD- or ATM-deficient mice have increased embryopathies. Thus, embryonic processes regulating the balance of ROS formation, oxidative DNA damage and repair, and ROS-mediated signal transduction may be important determinants of teratological risk.
A multidentate ligand platform is introduced that enables the isolation of both homo- and heterobimetallic complexes of divalent first-row transition metal ions such as Mn(II), Fe(II), and Co(II). By ...means of a two-step metalation strategy, five bimetallic coordination complexes were synthesized with the general formula M1M2Cl(py3tren), where py3tren is the triply deprotonated form of N,N,N-tris(2-(2-pyridylamino)ethyl)amine. The metal–metal pairings include dicobalt (1), cobalt–iron (2), cobalt–manganese (3), diiron (4), and iron–manganese (5). The bimetallic complexes have been investigated by X-ray diffraction and X-ray anomalous scattering studies, cyclic voltammetry, magnetometry, Mössbauer spectroscopy, UV–vis–NIR spectroscopy, NMR spectroscopy, combustion analyses, inductively coupled plasma optical emission spectrometry, and ab initio quantum chemical methods. Only the diiron chloride complex in this series contains a metal–metal single bond (2.29 Å). The others show weak metal–metal interactions (2.49 to 2.53 Å). The diiron complex is also distinct with a septet ground state, while the other bimetallic species have much lower spin states from S = 0 to S = 1. We propose that the diiron system has delocalized metal–metal bonding electrons, which seems to correlate with a short metal–metal bond and a higher spin state. Multiconfigurational wave function calculations revealed that, indeed, the metal–metal bonding orbitals in the diiron complex are much more delocalized than those of the dicobalt analogue.
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