Brittle cornea syndrome: A systemic review of disease-causing mutations in ZNF469 and two novel variants identified in a patient followed for 26 years

AIMS: Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder. The aim of this study was to review ZNF469 mutations associated with BCS type 1 to date and to describe an additional case of Czech/Polish background. METHODS: Whole genome sequencing was undertaken to identify the molecular genetic cause of disease in the proband. Sequence variants in ZNF469 previously reported as BCS type 1-causing were searched in the literature, manually curated and aligned to the reference sequence NM_001127464.2. RESULTS: The proband has been reviewed since childhood with progressive myopia and hearing loss. Aged 13 years had been diagnosed with Stickler syndrome. Aged 16.5 years, he developed acute hydrops in the left eye managed by corneal transplantation. At the age of 26, he experienced right corneal rupture after blunt trauma, also managed by grafting. He had a number of secondary complications and despite regular follow-up and timely management, the right eye became totally blind and the left eye had light perception at the last follow-up visit, aged 42. He was found to be a compound heterozygote for two novel mutations c.1705C>T; p.(Gln569*) and c.1402_1411del; p.(Pro468Alafs*31) in ZNF469. In total 22 disease-causing variants in ZNF469 have been identified, mainly in consanguineous families or endogamous populations. Only four probands, including the case described in the current study, harboured compound heterozygous mutations. CONCLUSION: BCS occurs very rarely in outbred populations which may cause diagnostic errors due to poor awareness of the disease. Investigation into the underlying molecular genetic cause in patients with connective tissue disorders may lead to a re-evaluation of their clinical diagnosis

The pre-main sequence binary HK Ori : Spectro-astrometry and EXPORT data

In this paper we present multi-epoch observations of the pre-main sequence binary HK Ori. These data have been drawn from the EXPORT database and are complemented by high quality spectro-astrometric data of the system. The spectroscopic data appear to be very well represented by a combination of an A dwarf star spectrum superposed on a (sub-)giant G-type spectrum. The radial velocity of the system is consistent with previous determinations, and does not reveal binary motion, as expected for a wide binary. The spectral, photometric and polarimetric properties and variability of the system indicate that the active object in the system is a T Tauri star with UX Ori characteristics. The spectro-astrometry of HK Ori is sensitive down to milli-arcsecond scales and confirms the speckle interferometric results from Leinert et al. The spectro-astrometry allows with fair certainty the identification of the active star within the binary, which we suggest to be a G-type T Tauri star based on its spectral characteristics.Comment: MNRAS in press 8 pages 7 figure

Analyzing food value chains for nutrition goals

First proposed in 2010, the use of ‘value chain analysis’ to identify opportunities for targeted nutrition interventions in food systems is still an emerging method. This review explores and summarizes the application of value chain analysis to nutrition and from this provides five insights into how to more effectively conduct value chain analysis for nutrition: 1) use a consumer perspective to inform selection of foods and chains; 2) consider the research question, available resources, and the type of chain; 3) situate consumer research at the center of the analysis; 4) assess economic trade-offs; and 5) pay attention to governance and stakeholders’ capacity for and incentives to change

Overexpression of microRNA-206 in the skeletal muscle from myotonic dystrophy type 1 patients

<p>Abstract</p> <p>Background</p> <p>MicroRNAs are highly conserved, noncoding RNAs involved in post-transcriptional gene silencing. They have been shown to participate in a wide range of biological processes, including myogenesis and muscle regeneration. The goal of this study is to test the hypothesis that myo-miRs (myo = muscle + miR = miRNA) expression is altered in muscle from patients affected by myotonic dystrophy type 1 (DM1), the most frequently inherited neuromuscular disease in adults. In order to gain better insights about the role of miRNAs in the DM1 pathogenesis, we have also analyzed the muscular expression of miR-103 and miR-107, which have been identified <it>in silico </it>as attractive candidates for binding to the <it>DMPK </it>mRNA.</p> <p>Methods</p> <p>To this aim, we have profiled the expression of miR-133 (miR-133a, miR-133b), miR-1, miR-181 (miR-181a, miR-181b, miR-181c) and miR-206, that are specifically induced during myogenesis in cardiac and skeletal muscle tissues. miR-103 and miR-107, highly expressed in brain, heart and muscle have also been included in this study. QRT-PCR experiments have been performed on RNA from vastus lateralis biopsies of DM1 patients (n = 7) and control subjects (n = 4). Results of miRNAs expression have been confirmed by Northern blot, whereas <it>in situ </it>hybridization technique have been performed to localize misexpressed miRNAs on muscle sections from DM1 and control individuals.</p> <p>Results</p> <p>Only miR-206 showed an over-expression in 5 of 7 DM1 patients (threshold = 2, fold change between 1.20 and 13.22, average = 5.37) compared to the control group. This result has been further confirmed by Northern blot analysis (3.37-fold overexpression, <it>R</it>²= 0.89). <it>In situ </it>hybridization localized miR-206 to nuclear site both in normal and DM1 tissues. Cellular distribution in DM1 tissues includes also the nuclear regions of centralized nuclei, with a strong signal corresponding to nuclear clumps.</p> <p>Conclusions</p> <p>This work provides, for the first time, evidences about miRNAs misexpression in DM1 muscle tissues, adding a new element in the pathogenesis of this complex genetic disease.</p

Timescales of transformational climate change adaptation in sub-Saharan African agriculture

Climate change is projected to constitute a significant threat to food security if no adaptation actions are taken. Transformation of agricultural systems, for example switching crop types or moving out of agriculture, is projected to be necessary in some cases. However, little attention has been paid to the timing of these transformations. Here, we develop a temporal uncertainty framework using the CMIP5 ensemble to assess when and where cultivation of key crops in sub-Saharan Africa becomes unviable. We report potential transformational changes for all major crops during the twenty-first century, as climates shift and areas become unsuitable. For most crops, however, transformation is limited to small pockets (<15% of area), and only for beans, maize and banana is transformation more widespread (â 1/430% area for maize and banana, 60% for beans). We envisage three overlapping adaptation phases to enable projected transformational changes: an incremental adaptation phase focused on improvements to crops and management, a preparatory phase that establishes appropriate policies and enabling environments, and a transformational adaptation phase in which farmers substitute crops, explore alternative livelihoods strategies, or relocate. To best align policies with production triggers for no-regret actions, monitoring capacities to track farming systems as well as climate are needed

Partial Order Optimum Likelihood (POOL): Maximum Likelihood Prediction of Protein Active Site Residues Using 3D Structure and Sequence Properties

A new monotonicity-constrained maximum likelihood approach, called Partial Order Optimum Likelihood (POOL), is presented and applied to the problem of functional site prediction in protein 3D structures, an important current challenge in genomics. The input consists of electrostatic and geometric properties derived from the 3D structure of the query protein alone. Sequence-based conservation information, where available, may also be incorporated. Electrostatics features from THEMATICS are combined with multidimensional isotonic regression to form maximum likelihood estimates of probabilities that specific residues belong to an active site. This allows likelihood ranking of all ionizable residues in a given protein based on THEMATICS features. The corresponding ROC curves and statistical significance tests demonstrate that this method outperforms prior THEMATICS-based methods, which in turn have been shown previously to outperform other 3D-structure-based methods for identifying active site residues. Then it is shown that the addition of one simple geometric property, the size rank of the cleft in which a given residue is contained, yields improved performance. Extension of the method to include predictions of non-ionizable residues is achieved through the introduction of environment variables. This extension results in even better performance than THEMATICS alone and constitutes to date the best functional site predictor based on 3D structure only, achieving nearly the same level of performance as methods that use both 3D structure and sequence alignment data. Finally, the method also easily incorporates such sequence alignment data, and when this information is included, the resulting method is shown to outperform the best current methods using any combination of sequence alignments and 3D structures. Included is an analysis demonstrating that when THEMATICS features, cleft size rank, and alignment-based conservation scores are used individually or in combination THEMATICS features represent the single most important component of such classifiers

Bacterial Chemotaxis in an Optical Trap

An optical trapping technique is implemented to investigate the chemotactic behavior of a marine bacterial strain Vibrio alginolyticus. The technique takes the advantage that the bacterium has only a single polar flagellum, which can rotate either in the counter-clock-wise or clock-wise direction. The two rotation states of the motor can be readily and instantaneously resolved in the optical trap, allowing the flagellar motor switching rate to be measured under different chemical stimulations. In this paper the focus will be on the bacterial response to an impulsive change of chemoattractant serine. Despite different propulsion apparati and motility patterns, cells of V. alginolyticus apparently use a similar response as Escherichia coli to regulate their chemotactic behavior. Specifically, we found that the switching rate of the bacterial motor exhibits a biphasic behavior, showing a fast initial response followed by a slow relaxation to the steady-state switching rate . The measured can be mimicked by a model that has been recently proposed for chemotaxis in E. coli. The similarity in the response to the brief chemical stimulation in these two different bacteria is striking, suggesting that the biphasic response may be evolutionarily conserved. This study also demonstrated that optical tweezers can be a useful tool for chemotaxis studies and should be applicable to other polarly flagellated bacteria

Human and mouse neuroinflammation markers in Niemann‐Pick disease, type C1

Niemann‐Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post‐mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C‐X‐C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL‐3, IL‐10 and IL‐13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147148/1/jimd0083.pd

Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21

The cisplatin analogue 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinumIV (DAP) is a DNA-damaging agent that will be entering clinical trials for its potent cytotoxic effects against cisplatin-resistant tumour cells. This cytotoxicity may reside in its ability to selectively activate G1-phase checkpoint response by inhibiting CDKs via the p53/p21 pathway. We have now evaluated the role of another CDK inhibitor p27 as a contributor to DAP-mediated inhibition of G1-phase CDK2 activity. Our studies in ovarian A2780 tumour cells demonstrate that p27 levels induced by DAP are comparable to or greater than those seen for p21. The induction of p27 is not through a transcriptional mechanism, but rather is due to a four-fold increase in protein stabilisation through a mechanism dependent on p21. Moreover, DAP-induced p21 promoted the selective increase of p27 in the CDK2 complex, but not in CDK4 complex, and this selective increase contributed to inhibition of the CDK2 kinase activity. The inhibited complex contained either p27 or p21, but not both, with the relative levels of cyclin E associated with p27 and p21 indicating that about 25% of the inhibition of CDK2 activity was due to p27 and 75% due to p21. This study provides the first evidence that p27 upregulation is directly attributable to activation of the p53/p21 pathway by a DNA-damaging agent, and promulgates p53/p21/p27 axis as a significant component of checkpoint response