Shower Thoughts: Why Scientists Should Spend More Time in the Rain

Stormwater is a vital resource and dynamic driver of terrestrial ecosystem processes. However, processes controlling interactions during and shortly after storms are often poorly seen and poorly sensed when direct observations are substituted with technological ones. We discuss how human observations complement technological ones and the benefits of scientists spending more time in the storm. Human observation can reveal ephemeral storm-related phenomena such as biogeochemical hot moments, organismal responses, and sedimentary processes that can then be explored in greater resolution using sensors and virtual experiments. Storm-related phenomena trigger lasting, oversized impacts on hydrologic and biogeochemical processes, organismal traits or functions, and ecosystem services at all scales. We provide examples of phenomena in forests, across disciplines and scales, that have been overlooked in past research to inspire mindful, holistic observation of ecosystems during storms. We conclude that technological observations alone are insufficient to trace the process complexity and unpredictability of fleeting biogeochemical or ecological events without the shower thoughts produced by scientists\u27 human sensory and cognitive systems during storms

The Hamiltonian formulation of General Relativity: myths and reality

A conventional wisdom often perpetuated in the literature states that: (i) a 3+1 decomposition of space-time into space and time is synonymous with the canonical treatment and this decomposition is essential for any Hamiltonian formulation of General Relativity (GR); (ii) the canonical treatment unavoidably breaks the symmetry between space and time in GR and the resulting algebra of constraints is not the algebra of four-dimensional diffeomorphism; (iii) according to some authors this algebra allows one to derive only spatial diffeomorphism or, according to others, a specific field-dependent and non-covariant four-dimensional diffeomorphism; (iv) the analyses of Dirac [Proc. Roy. Soc. A 246 (1958) 333] and of ADM [Arnowitt, Deser and Misner, in "Gravitation: An Introduction to Current Research" (1962) 227] of the canonical structure of GR are equivalent. We provide some general reasons why these statements should be questioned. Points (i-iii) have been shown to be incorrect in [Kiriushcheva et al., Phys. Lett. A 372 (2008) 5101] and now we thoroughly re-examine all steps of the Dirac Hamiltonian formulation of GR. We show that points (i-iii) above cannot be attributed to the Dirac Hamiltonian formulation of GR. We also demonstrate that ADM and Dirac formulations are related by a transformation of phase-space variables from the metric $g_{\mu\nu}$ to lapse and shift functions and the three-metric $g_{km}$, which is not canonical. This proves that point (iv) is incorrect. Points (i-iii) are mere consequences of using a non-canonical change of variables and are not an intrinsic property of either the Hamilton-Dirac approach to constrained systems or Einstein's theory itself.Comment: References are added and updated, Introduction is extended, Subsection 3.5 is added, 83 pages; corresponds to the published versio

Dark Energy and Gravity

I review the problem of dark energy focusing on the cosmological constant as the candidate and discuss its implications for the nature of gravity. Part 1 briefly overviews the currently popular `concordance cosmology' and summarises the evidence for dark energy. It also provides the observational and theoretical arguments in favour of the cosmological constant as the candidate and emphasises why no other approach really solves the conceptual problems usually attributed to the cosmological constant. Part 2 describes some of the approaches to understand the nature of the cosmological constant and attempts to extract the key ingredients which must be present in any viable solution. I argue that (i)the cosmological constant problem cannot be satisfactorily solved until gravitational action is made invariant under the shift of the matter lagrangian by a constant and (ii) this cannot happen if the metric is the dynamical variable. Hence the cosmological constant problem essentially has to do with our (mis)understanding of the nature of gravity. Part 3 discusses an alternative perspective on gravity in which the action is explicitly invariant under the above transformation. Extremizing this action leads to an equation determining the background geometry which gives Einstein's theory at the lowest order with Lanczos-Lovelock type corrections. (Condensed abstract).Comment: Invited Review for a special Gen.Rel.Grav. issue on Dark Energy, edited by G.F.R.Ellis, R.Maartens and H.Nicolai; revtex; 22 pages; 2 figure

The delivery of personalised, precision medicines via synthetic proteins

Introduction: The design of advanced drug delivery systems based on synthetic and su-pramolecular chemistry has been very successful. Liposomal doxorubicin (Caelyx®), and liposomal daunorubicin (DaunoXome®), estradiol topical emulsion (EstrasorbTM) as well as soluble or erodible polymer systems such as pegaspargase (Oncaspar®) or goserelin acetate (Zoladex®) represent considerable achievements. The Problem: As deliverables have evolved from low molecular weight drugs to biologics (currently representing approximately 30% of the market), so too have the demands made of advanced drug delivery technology. In parallel, the field of membrane trafficking (and endocytosis) has also matured. The trafficking of specific receptors i.e. material to be recycled or destroyed, as well as the trafficking of protein toxins has been well characterized. This, in conjunction with an ability to engineer synthetic, recombinant proteins provides several possibilities. The Solution: The first is using recombinant proteins as drugs i.e. denileukin diftitox (Ontak®) or agalsidase beta (Fabrazyme®). The second is the opportunity to use protein toxin architecture to reach targets that are not normally accessible. This may be achieved by grafting regulatory domains from multiple species to form synthetic proteins, engineered to do multiple jobs. Examples include access to the nucleocytosolic compartment. Herein the use of synthetic proteins for drug delivery has been reviewed

Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a C. elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients. This article is protected by copyright. All rights reserved

First-order formalism for dark energy and dust

This work deals with first-order formalism for dark energy and dust in standard cosmology, for models described by real scalar field in the presence of dust in spatially flat space. The field dynamics may be standard or tachyonic, and we show how the equations of motion can be solved by first-order differential equations. We investigate a model to illustrate how the dustlike matter may affect the cosmic evolution using this framework.Comment: 5 pages, 1 figure; title changed, new author included, discussions extended, references added, version to appear in EPJ

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes

Loxoscelismo en Chile: estudios epidemiológicos, clínicos y experimentales

Se presenta un enfoque panorámico de estudios epidemiológicos, clínicos y experimentales referentes a Loxosceles laeta y loxoscelismo efectuados en 1955-1988 en Santiago, Chile. Se estudiaron 216 casos de loxoscelismo. Los hechos más relevantes fueron: 52,8% correspondió a mujeres; edad entre 7 meses y 78 años; 84,3% fué loxoscelismo cutáneo (LO y 15,7% loxoscelismo cutáneo-visceral (LCV); 73,6% sucedió en época calurosa; en 86,6% el accidente ocurrió en la vivienda, especialmente en dormitorios, mientras la persona dormía o se vestía. La araña fué vista en 60,2% de los casos e identificada en laboratorio como L. laeta en 17,7% (10,6% de los 216 casos). Los sitios más frecuen temente afectados fueron las extremidades con 67,6%, lancetazo urente fué el síntoma inicial más frecuente. Dolor, edema y placa livedoide, la cual posteriormente se transformaría en escara necrótica, fueron las manifestaciones locales predominantes. En LCV hematuria y hemoglobinuria fueron constantes, ictericia, fiebre y compromiso de conciencia se presentaron en la mayoría de los casos. Tratamiento: LC con antihistamínicos o corticoides inyectables, LCV con corti-coides inyectables. La condición de los pacientes en el último control fué: curación completa en 75,5%, curación con secuela cicatrizal en 8,3%, muerte en 3,7% (todos con LCV) y abandono en 12,5%. Adicionalmente, se ha efectuado una serie de estudios experimentales, tanto in vivo como in vitro para esclarecer aspectos básicos sobre el veneno de L. laeta y el tratamiento del loxoscelismo.A panoramic sight of epidemiological, clinical and experimental studies, referring to Loxosceles laeta and loxoscelism, carried out in 1955-1988, in Santiago, Chile is presented. Two-hundred and sixteen cases of loxosce lism were studied. The most relevant features were: 84.3% corresponded to cutaneous loxosce lism (CD and 15.7% to viscerocutaneous loxos celism (VCD; 73.6% ocurred in hot season; in 86.6% of cases the accident happened in the hou se, particularly in bedrooms, while the people were sleeping or dressing. The spider was seen in 60.2%r of cases and identified in the laboratory as L. laeta in 10.69c of all cases. The sites more frequently bitten were the limbs with 67.6% ; a burning stinging was the most frequent initial symptom. Pain, edema and livedoid plaque, which developed later into a necrotic eschar, we re the predominant local manifestations. In VCL, hematuria and hemoglobinuria were cons tant, while jaundice, fever and sensorial involve ment were present in most of the cases. CL patients were parenterally treated with antihistamine drugs or corticoids, while VCL ones were treated with corticoids by injection. The condition of patients in the last follow up was: complete cure in 75.5% , cure with a scarfed sequela in 8.3%, death in 3.7% (all VCL) and abandonment in 12.5%. Additionally, a series of experimental studies, both in vivo and in vitro, has been performed in order to clarify basic aspects on L. laeta venom and the treatment of loxoscelism