Translation and manipulation of silicon nanomembranes using holographic optical tweezers

We demonstrate the use of holographic optical tweezers for trapping and manipulating silicon nanomembranes. These macroscopic free-standing sheets of single-crystalline silicon are attractive for use in next-generation flexible electronics. We achieve three-dimensional control by attaching a functionalized silica bead to the silicon surface, enabling non-contact trapping and manipulation of planar structures with high aspect ratios (high lateral size to thickness). Using as few as one trap and trapping powers as low as several hundred milliwatts, silicon nanomembranes can be rotated and translated in a solution over large distances

WHEN WILL TAXONOMIC SATURATION BE ACHIEVED? A CASE STUDY IN NUNDUVA AND KYRTUTHRIX (RIVULARIACEAE, CYANOBACTERIA)1

A number of heterocytous, mat-forming, tapering cyanobacteria in Rivulariaceae have recently been observed in both the Atlantic and Pacific coasts in the rocky intertidal and supratidal zones. These belong to the genera Nunduva, Kyrtuthrix, and Phyllonema and have been the subject of several recent studies. Herein, two new species of Nunduva (N. komarkovae and N. sanagustinensis) and two new species of Kyrtuthrix (K. munecosensis and K. totonaca) are characterized and described from the coasts of Mexico. Genetic separation based on the 16S-23S ITS region was pronounced (\u3e10% in all comparisons). Morphological differences between all existing species in these two genera were also observed, but the group is morphologically complex, and these taxa are considered pseudocryptic. Nunduva and Kyrtuthrix remain morphologically and phylogenetically separate even with the addition of new species. However, how long will this remain the case? Many new genera and species of cyanobacteria have recently been described. Will the taxonomy of cyanobacteria eventually become saturated? Will we start to see multiple populations for the same cryptic species, or will future taxonomists collapse multiple species into fewer species, or multiple genera into single genera. The description of even more Nunduva and Kyrtuthrix species causes us to pause and evaluate the future of cyanobacterial taxonomy. These same questions are faced by algal taxonomists studying other phyla, and the resolution may ultimately be similar

A palaeoecological approach to understanding the past and present of Sierra Nevada, a Southwestern European biodiversity hotspot

Mediterranean mountainous environments are biodiversity hotspots and priority areas in conservation agendas. Although they are fragile and threatened by forecasted global change scenarios, their sensitivity to long-term environmental variability is still understudied. The Sierra Nevada range, located in southern Spain on the north-western European flanks of the Mediterranean basin, is a biodiversity hotspot. Consequently, Sierra Nevada provides an excellent model system to apply a palaeoecological approach to detect vegetation changes, explore the drivers triggering those changes, and how vegetation changes link to the present landscape in such a paradigmatic mountain system. A multi-proxy strategy (magnetic susceptibility, grain size, loss-on-ignition, macroremains, charcoal and palynological analyses) is applied to an 8400-year long lacustrine environmental archive from the Laguna de la Mosca (2889 masl). The long-term ecological data show how the Early Holocene pine forests transitioned towards mixed Pinus-Quercus submediterranean forests as a response to a decrease in seasonality at ~7.3 cal. kyr BP. The mixed Pinus-Quercus submediterranean forests collapsed drastically giving way to open evergreen Quercus formations at ~4.2 cal. kyr BP after a well-known aridity crisis. Under the forecasted northward expansion of the Mediterranean area due to global change-related aridity increase, mountain forests inhabiting territories adjacent to the Mediterranean Region could experience analogous responses to those detected in the Sierra Nevada forests to the Mid to Late Holocene aridification, moving from temperate to submediterranean and then Mediterranean formations

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E 04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E 02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons

RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition

Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE-1 retrotransposition. It has therefore been suggested that increased LINE-1 activity may be the cause of aberrant innate immune activation in AGS. Here, we establish that, contrary to expectations, RNase H2 is required for efficient LINE-1 retrotransposition. As RNase H1 overexpression partially rescues the defect in RNase H2 null cells, we propose a model in which RNase H2 degrades the LINE-1 RNA after reverse transcription, allowing retrotransposition to be completed. This also explains how LINE-1 elements can retrotranspose efficiently without their own RNase H activity. Our findings appear to be at odds with LINE-1-derived nucleic acids driving autoinflammation in AGS.M.B.-G. is funded by a “Formacion Profesorado Universitario” (FPU) PhD fellowship from the Government of Spain (MINECO, Ref FPU15/03294), and this paper is part of her thesis project (“Epigenetic control of the mobility of a human retrotransposon”). R.V.-A. is funded by a PFIS Fellowship from the Government of Spain (ISCiii, FI16/00413). O.M. is funded by an EMBO Long-Term Fellowship (ALTF 7-2015), the European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409) and the Swiss National Science Foundation (P2ZHP3_158709). S.R.H. is funded by the Government of Spain (MINECO, RYC-2016-21395 and SAF2015-71589-P). A.P.J’s laboratory is supported by the UK Medical Research Council (MRC University Unit grant U127527202). J.L.G.P’s laboratory is supported by CICEFEDER- P12-CTS-2256, Plan Nacional de I+D+I 2008-2011 and 2013-2016 (FISFEDER- PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), by The Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund (ISFF2) and by a private donation from Ms Francisca Serrano (Trading y Bolsa para Torpes, Granada, Spain)

Engineered LINE-1 retrotransposition in nondividing human neurons

Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80-100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought.We thank current members of the J.L.G.-P. laboratory for helpful discussions. We also thank Drs. Geoffrey Faulkner (Mater Research, Australia) and John V. Moran (University of Michigan) for sharing unpublished data and for critical input during the project; Ms. Raquel Marrero (Microscopy Unit, Genyo) for technical support; Simon Mendez-Ferrer (CNIC, Spain) for providing total RNA isolated from human mesenspheres; Dr. Oliver Weichenrieder (Max-Planck, Tubingen, Germany) for providing a polyclonal L1-ORF1p antibody; and Dr. Aurelien Doucet (IRCAN, Nice, France) for providing a plasmid containing an UBC-driven EGFP retrotransposition indicator cassette. J.L.G. was funded by the US Department of Defense, Breast Cancer Research Program (award #BC051386), the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (1R03NS087290-01), and the ALS Therapy Alliance (2013-F-067). A.M. has been partially funded by a Marie Curie IRG project (FP7-PEOPLE-2007-4-3-IRG: SOMATIC LINE-1). J.L.G.-P's laboratory is supported by CICE-FEDER-P09-CTS-4980, CICE-FEDER-P12-CTS-2256, Plan Nacional de I+D+I 2008–2011 and 2013–2016 (FIS-FEDER-PI11/01489 and FIS-FEDER-PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764), by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420), and by The Wellcome Trust–University of Edinburgh Institutional Strategic Support Fund (ISFF2).S

Automatic Selection of Molecular Descriptors using Random Forest: Application to Drug Discovery

The optimal selection of chemical features (molecular descriptors) is an essential pre-processing step for the efficient application of computational intelligence techniques in virtual screening for identification of bioactive molecules in drug discovery. The selection of molecular descriptors has key influence in the accuracy of affinity prediction. In order to improve this prediction, we examined a Random Forest (RF)-based approach to automatically select molecular descriptors of training data for ligands of kinases, nuclear hormone receptors, and other enzymes. The reduction of features to use during prediction dramatically reduces the computing time over existing approaches and consequently permits the exploration of much larger sets of experimental data. To test the validity of the method, we compared the results of our approach with the ones obtained using manual feature selection in our previous study (Perez-Sanchez et al., 2014). The main novelty of this work in the field of drug discovery is the use of RF in two different ways: feature ranking and dimensionality reduction, and classification using the automatically selected feature subset. Our RF-based method out-performs classification results provided by Support Vector Machine (SVM) and Neural Networks (NN) approaches

LITIO COMO TERAPIA NEUROPROTECTORA EN EL MODELO APPSL/PS1M146L DE LA ENFERMEDAD DE ALZHEIMER

El litio se utiliza desde hace varias décadas en el tratamiento de trastornos bipolares y la depresión, y recientemente se debate su uso potencial en patologías neurodegenerativas como la enfermedad de Alzheimer (AD). Diversos estudios han puesto de manifiesto su efecto positivo como potente inhibidor de GSK3beta disminuyendo la fosforilación de tau, la producción de Abeta e incrementando plasticidad sináptica. Sin embargo, su posible efecto neuroprotector previniendo la muerte neuronal in vivo no ha sido aun demostrado ya que la mayoría de los modelos transgénicos de AD no presentan pérdida neuronal. Nuestro modelo APPSL/PS1M146L sufre una pérdida significativa de neuronas SOM/NPY en hipocampo y corteza entorrinal desde edades tempranas (6 meses) con un marcado desarrollo de distrofias axonales. En este trabajo hemos estudiado el posible efecto neuroprotector del litio en este modelo animal mediante tratamiento crónico en la dieta desde los 3 hasta los 9 meses de edad. Se han utilizado técnicas imnunohistoquímicas, western blots y análisis por RT-PCR, y además se ha determinado la carga amiloide, el grado de compactación y el tamaño de las placas. El resultado más relevante de este estudio fue la preservación de la población de interneuronas SOM/NPY tanto en hipocampo como corteza entorrinal en los animales tratados, mientras que en los no tratados existió una pérdida significativa de esta supoblación neuronal. El efecto neuroprotector del litio se manifestó también en una marcada disminución de tau fosforilado, distrofias axonales y marcadores sinápticos, junto con una mejora cognitiva de los animales utilizando el test de reconocimiento de objetos. Este efecto preventivo del litio parece estar asociado con cambios en la formación de placas de Abeta que podrían afectar a su toxicidad, ya que los animales tratados presentaron placas más pequeñas y apariencia más compacta. Financiación: FIS PI12/01431 (AG) y FIS PI12/01439 (JV).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Surgical treatment for colorectal cancer: Analysis of the influence of an enhanced recovery programme on long-term oncological outcomes-a study protocol for a prospective, multicentre, observational cohort study

Introduction The evidence currently available from enhanced recovery after surgery (ERAS) programmes concerns their benefits in the immediate postoperative period, but there is still very little evidence as to whether their correct implementation benefits patients in the long term. The working hypothesis here is that, due to the lower response to surgical aggression and lower rates of postoperative complications, ERAS protocols can reduce colorectal cancer-related mortality. The main objective of this study is to analyse the impact of an ERAS programme for colorectal cancer on 5-year survival. As secondary objectives, we propose to analyse the weight of each of the predefined items in the oncological results as well as the quality of life. Methods and analysis A multicentre prospective cohort study was conducted in patients older than 18 years of age who are scheduled to undergo surgery for colorectal cancer. The study involved 12 hospitals with an implemented enhanced recovery protocol according to the guidelines published by the Spanish National Health Service. The intervention group includes patients with a minimum implementation level of 70%, and the control group includes those who fail to reach this level. Compliance will be studied using 18 key performance indicators, and the results will be analysed using cancer survival indicators, including overall survival, cancer-specific survival and relapse-free survival. The time to recurrence, perioperative morbidity and mortality, hospital stay and quality of life will also be studied, the latter using the validated EuroQol Five questionnaire. The propensity index method will be used to create comparable treatment and control groups, and a multivariate regression will be used to study each variable. The Kaplan-Meier estimator will be used to estimate survival and the log-rank test to make comparisons. A p value of less than 0.05 (two-tailed) will be considered to be significant. Ethics and dissemination Ethical approval for this study was obtained from the Aragon Ethical Committee (C.P.-C.I. PI20/086) on 4 March 2020. The findings of this study will be submitted to peer-reviewed journals (BMJ Open, JAMA Surgery, Annals of Surgery, British Journal of Surgery). Abstracts will be submitted to relevant national and international meetings.The present research study was awarded a Ministerio de Ciencia e Innovación health research project grant (PI19/00291) from the Carlos III Institute of the Spanish National Health Service as part of the 2019 call for Strategic Action in Health