MYCN-targeting miRNAs are predominantly downregulated during MYCN-driven neuroblastoma tumor formation

MYCN is a transcription factor that plays key roles in both normal development and cancer. In neuroblastoma, MYCN acts as a major oncogenic driver through pleiotropic effects controlled by multiple protein encoding genes as well as microRNAs (miRNAs). MYCN activity is tightly regulated at the level of transcription and protein stability through various mechanisms. Like most genes, MYCN is further controlled by miRNAs, but the full complement of all miRNAs implicated in this process has not been determined through an unbiased approach. To elucidate the role of miRNAs in regulation of MYCN, we thus explored the MYCN-miRNA interactome to establish miRNAs controlling MYCN expression levels. We combined results from an unbiased and genome-wide high-throughput miRNA target reporter screen with miRNA and mRNA expression data from patients and a murine neuroblastoma progression model. We identified 29 miRNAs targeting MYCN, of which 12 miRNAs are inversely correlated with MYCN expression or activity in neuroblastoma tumor tissue. The majority of MYCN-targeting miRNAs in neuroblastoma showed a decrease in expression during murine MYCN-driven neuroblastoma tumor development. Therefore, we provide evidence that MYCN-targeting miRNAs are preferentially downregulated in MYCN-driven neuroblastoma, suggesting that MYCN negatively controls the expression of these miRNAs, to safeguard its expression

The \u3cem\u3eChlamydomonas\u3c/em\u3e Genome Reveals the Evolution of Key Animal and Plant Functions

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the ∼120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella

The Long-term Visual Outcomes of Primary Congenital Glaucoma

Purpose: To evaluate the long-term visual outcomes of ab externo trabeculotomy for primary congenital glaucoma (PCG) at a single pediatric ophthalmology center. Methods: In this retrospective single-center case series, data from 63 eyes of 40 patients who underwent ab externo trabeculotomy between September 2006 and June 2018 were included. The data were analyzed for best corrected visual acuity (BCVA), stereopsis, and surgical success. Kaplan–Meier analysis was performed using the surgical success criteria defined as intraocular pressure (IOP) ≤ 21 mmHg and ≥ 20% below baseline without the need for additional glaucoma surgery. Results: BCVA at the time of diagnosis was 0.37 ± 0.48 logMAR, which changed to 0.51 ± 0.56 logMAR at the final follow-up (P = 0.08). Twenty-five percent of patients had BCVA equal to or better than 20/40 at the final visit. The mean refraction at baseline was –4.78 ± 5.87 diopters, which changed to less myopic refraction of –2.90 ± 3.83 diopters at the final visit. Optical correction was prescribed in 66% of eyes at the final visit. The average final stereopsis was 395.33 sec of arc. The linear regression model showed a significant association between the surgery success rate and final BCVA as well as stereoacuity (Pvalues: 0.04 and 0.03, respectively). Intraocular pressure (IOP) decreased significantly from 29.79 ± 7.67 mmHg at baseline to 16.13 ± 3.41 mmHg at the final follow-up (P = 0.001). Conclusion: Patients with PCG can achieve an acceptable visual acuity and stereoacuity, particularly in cases of timely intervention and close follow-up

Sufficient levels of 25-hydroxyvitamin D and protein intake required to increase muscle mass in sarcopenic older adults - The PROVIDE study

BACKGROUND: Inadequate nutritional intake and altered response of aging muscles to anabolic stimuli from nutrients contribute to the development of sarcopenia. Nutritional interventions show inconsistent results in sarcopenic older adults, which might be influenced by their basal nutritional status. OBJECTIVE: To test if baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations and dietary protein intake influenced changes in muscle mass and function in older adults who received nutritional intervention. METHODS AND DESIGN: Post-hoc analysis was performed in the PROVIDE study that was a randomized controlled, double blind trial among 380 sarcopenic older adults. This study showed that those who received a vitamin D and leucine-enriched whey protein medical nutrition drink for 13 weeks gained more appendicular muscle mass (aMM), and improved lower-extremity function as assessed by the chair stand test compared with controls. To define low and high groups, a baseline serum concentration of 50 nmol/L 25(OH)D and baseline dietary protein intake of 1.0 g/kg/d were used as cut offs. RESULTS: At baseline, participants with lower 25(OH)D concentrations showed lower muscle mass, strength and function compared with participants with a high 25(OH)D, while the group with lower protein intake (g/kg/day) had more muscle mass at baseline compared with the participants with higher protein intake. Participants with higher baseline 25(OH)D concentrations and dietary protein intake had, independent of other determinants, greater gain in appendicular muscle mass, skeletal muscle index (aMM/h2), and relative appendicular muscle mass (aMM/body weight × 100%) in response to the nutritional intervention. There was no effect modification of baseline 25(OH)D status or protein intake on change in chair-stand test. CONCLUSIONS: Sufficient baseline levels of 25(OH)D and protein intake may be required to increase muscle mass as a result of intervention with a vitamin D and protein supplement in sarcopenic older adults. This suggests that current cut-offs in the recommendations for vitamin D and protein intake could be considered the "minimum" for adults with sarcopenia to respond adequately to nutrition strategies aimed at attenuating muscle loss

Cystatin C or creatinine for pre-operative assessment of kidney function and risk of post-operative acute kidney injury: a secondary analysis of the METS cohort study.

BACKGROUND: Post-operative acute kidney injury (PO-AKI) is a common surgical complication consistently associated with subsequent morbidity and mortality. Prior kidney dysfunction is a major risk factor for PO-AKI, however it is unclear whether serum creatinine, the conventional kidney function marker, is optimal in this population. Serum cystatin C is a kidney function marker less affected by body composition and might provide better prognostic information in surgical patients. METHODS: This was a pre-defined, secondary analysis of a multi-centre prospective cohort study of pre-operative functional capacity. Participants were aged ≥40 years, undergoing non-cardiac surgery. We assessed the association of pre-operative estimated glomerular filtration rate (eGFR) calculated using both serum creatinine and serum cystatin C with PO-AKI within 3 days after surgery, defined by KDIGO creatinine changes. The adjusted analysis accounted for established AKI risk factors. RESULTS: A total of 1347 participants were included (median age 65 years, interquartile range 56-71), of whom 775 (58%) were male. A total of 82/1347 (6%) patients developed PO-AKI. These patients were older, had higher prevalence of cardiovascular disease and related medication, were more likely to have intra-abdominal procedures, had more intraoperative transfusion, and were more likely to be dead at 1 year after surgery 6/82 (7.3%) vs 33/1265 (2.7%) (P = .038). Pre-operative eGFR was lower in AKI than non-AKI patients using both creatinine and cystatin C. When both measurements were considered in a single age- and sex-adjusted model, eGFR-Cysc was strongly associated with PO-AKI, with increasing risk of AKI as eGFR-Cysc decreased below 90, while eGFR-Cr was no longer significantly associated. CONCLUSIONS: Data from over 1000 prospectively recruited surgical patients confirms pre-operative kidney function as major risk factor for PO-AKI. Of the kidney function markers available, compared with creatinine, cystatin C had greater strength of association with PO-AKI and merits further assessment in pre-operative assessment of surgical risk

Free-standing polyelectrolyte membranes made of chitosan and alginate

Free-standing films have increasing applications in the biomedical field as drug delivery systems for wound healing and tissue engineering. Here, we prepared free-standing membranes by the layer-by-layer assembly of chitosan and alginate, two widely used biomaterials. Our aim was to produce a thick membrane and to study the permeation of model drugs and the adhesion of muscle cells. We first defined the optimal growth conditions in terms of pH and alginate concentration. The membranes could be easily detached from polystyrene or polypropylene substrate without any postprocessing step. The dry thickness was varied over a large range from 4 to 35 μm. A 2-fold swelling was observed by confocal microscopy when they were immersed in PBS. In addition, we quantified the permeation of model drugs (fluorescent dextrans) through the free-standing membrane, which depended on the dextran molecular weight. Finally, we showed that myoblast cells exhibited a preferential adhesion on the alginate-ending membrane as compared to the chitosan-ending membrane or to the substrate side.This work was financially supported by Foundation for Science and Technology (FCT) through the Scholarship SFRH/BD/64601/2009 granted to S.G.C. C.M. is indebted to Grenoble INP for financial support via a postdoctoral fellowship. This work was supported by the European Commission (FP7 Program) via a European Research Council starting grant (BIOMIM, GA 259370 to C.P.). C.P. is also grateful to Institut Universitaire de France and to Grenoble Institute of Technology for financial support. We thank Isabelle Paintrand for her technical help with the confocal apparatus and Patrick Chaudouet for his help with SEM imaging

An interlaboratory study of TEX86 and BIT analysis of sediments, extracts and standard mixtures.

Two commonly used proxies based on the distribution of glycerol dialkyl glycerol tetraethers (GDGTs) are the TEX86 (TetraEther indeX of 86 carbon atoms) paleothermometer for sea surface temperature reconstructions and the BIT (Branched Isoprenoid Tetraether) index for reconstructing soil organic matter input to the ocean. An initial round-robin study of two sediment extracts, in which 15 laboratories participated, showed relatively consistent TEX86 values (reproducibility ±3-4°C when translated to temperature) but a large spread in BIT measurements (reproducibility ±0.41 on a scale of 0-1). Here we report results of a second round-robin study with 35 laboratories in which three sediments, one sediment extract, and two mixtures of pure, isolated GDGTs were analyzed. The results for TEX86 and BIT index showed improvement compared to the previous round-robin study. The reproducibility, indicating interlaboratory variation, of TEX86 values ranged from 1.3 to 3.0°C when translated to temperature. These results are similar to those of other temperature proxies used in paleoceanography. Comparison of the results obtained from one of the three sediments showed that TEX86 and BIT indices are not significantly affected by interlaboratory differences in sediment extraction techniques. BIT values of the sediments and extracts were at the extremes of the index with values close to 0 or 1, and showed good reproducibility (ranging from 0.013 to 0.042). However, the measured BIT values for the two GDGT mixtures, with known molar ratios of crenarchaeol and branched GDGTs, had intermediate BIT values and showed poor reproducibility and a large overestimation of the "true" (i.e., molar-based) BIT index. The latter is likely due to, among other factors, the higher mass spectrometric response of branched GDGTs compared to crenarchaeol, which also varies among mass spectrometers. Correction for this different mass spectrometric response showed a considerable improvement in the reproducibility of BIT index measurements among laboratories, as well as a substantially improved estimation of molar-based BIT values. This suggests that standard mixtures should be used in order to obtain consistent, and molar-based, BIT values

Book Reviews

Book 1 Book Title: Basic EpidemiologyBook Authors: R. Beaglehole, R. Bonita & T. KjellströmPp. viii + 174. (in English, French and Spanish in preparation). $19,40. Geneva: WHO. 1993. Order No. 1150395. ISBN 92-4-154446-5.Book 2Book Title: A Pocket Book of Social and Community PaediatricsBook Author: Jo SibertPp. viii + 164. London: Edward Arnold. 1992. ISBN 0-340-54929-7.Book 3Book Title: Knowledge Beats CancerBook Author: Albert Stegmann AlbertsPp. 226. Illustrated. R55,45. Pretoria: Haum Tertiary. 1993. ISBN 0-7986-3196-1.Book 4Book Title: AIDS and Your ResponsePp. vi + 226. R49,50. ISBN 0-620-17319-X.Book 5Book Title: Principles for Evaluating Chemical Effects on the Aged Population. Enviromnental Health Criteria. No. 144Book Author: W.H.O.Pp. 159. (English only).$20,50. Geneva: WHO. 1993. Order No. 1160144. ISBN 92-4-1571446.Book 6Book Title: The Guide to Heart Sounds: Normal and AbnormalBook Authors: Donald W. Novey, Marcia Pencak & John M. StangAudio-cassette narrated by: Donald W. Novey. pp. xi + 74. Illustrated. Florida: CRC Press. 1988. ISB J 0-8493-0153X.Book 7Book Title: Propachlor. Enviromnental Health Criteria. No. 147Book Author: W.H.O.Pp. 110. (English, French and Spanish summaries). $17,30. Geneva: WHO. 1993. Order TO. 1160147. ISBN 92-4-157147-0.Book 8Book Title: Quality Assurance in Health Care: A HandbookBook Authors: Roger Ellis & Dorothy WhittingronLondon: Edward Arnold. 1993. ISBN 0-340-55273-5.Book 9Book Title:  Rehabilitation after Cardiovascular Diseases, with Special Emphasis on Developing CountriesReport of a WHO expert committee. Technical Report Series No 831. Pp. viii + 122 (available in English, French and Spanish in preparation). Geneva: WHO. 1993. ISBN 92-4-120831-7