Faint young Sun paradox remains

The Sun was fainter when the Earth was young, but the climate was generally at least as warm as today; this is known as the `faint young Sun paradox'. Rosing et al. [1] claim that the paradox can be resolved by making the early Earth's clouds and surface less reflective. We show that, even with the strongest plausible assumptions, reducing cloud and surface albedos falls short by a factor of two of resolving the paradox. A temperate Archean climate cannot be reconciled with the low level of CO2 suggested by Rosing et al. [1]; a stronger greenhouse effect is needed.Comment: 3 pages, no figures. In press in Nature. v2 corrects typo in author list in original submissio

Statistically Motivated Second Order Pooling

Second-order pooling, a.k.a.~bilinear pooling, has proven effective for deep learning based visual recognition. However, the resulting second-order networks yield a final representation that is orders of magnitude larger than that of standard, first-order ones, making them memory-intensive and cumbersome to deploy. Here, we introduce a general, parametric compression strategy that can produce more compact representations than existing compression techniques, yet outperform both compressed and uncompressed second-order models. Our approach is motivated by a statistical analysis of the network's activations, relying on operations that lead to a Gaussian-distributed final representation, as inherently used by first-order deep networks. As evidenced by our experiments, this lets us outperform the state-of-the-art first-order and second-order models on several benchmark recognition datasets.Comment: Accepted to ECCV 2018. Camera ready version. 14 page, 5 figures, 3 table

Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

Objective: Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. Design: Mutational analysis of MC2R by direct sequencing. Patients: Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). Results: MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. Conclusions: MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosi

Siglec receptors impact mammalian lifespan by modulating oxidative stress.

Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan

The hidden perils of read mapping as a quality assessment tool in genome sequencing

This article provides a comparative analysis of the various methods of genome sequencing focusing on verification of the assembly quality. The results of a comparative assessment of various de novo assembly tools, as well as sequencing technologies, are presented using a recently completed sequence of the genome of Lactobacillus fermentum 3872. In particular, quality of assemblies is assessed by using CLC Genomics Workbench read mapping and Optical mapping developed by OpGen. Over-extension of contigs without prior knowledge of contig location can lead to misassembled contigs, even when commonly used quality indicators such as read mapping suggest that a contig is well assembled. Precautions must also be undertaken when using long read sequencing technology, which may also lead to misassembled contigs

Single-Atom Gating of Quantum State Superpositions

The ultimate miniaturization of electronic devices will likely require local and coherent control of single electronic wavefunctions. Wavefunctions exist within both physical real space and an abstract state space with a simple geometric interpretation: this state space--or Hilbert space--is spanned by mutually orthogonal state vectors corresponding to the quantized degrees of freedom of the real-space system. Measurement of superpositions is akin to accessing the direction of a vector in Hilbert space, determining an angle of rotation equivalent to quantum phase. Here we show that an individual atom inside a designed quantum corral can control this angle, producing arbitrary coherent superpositions of spatial quantum states. Using scanning tunnelling microscopy and nanostructures assembled atom-by-atom we demonstrate how single spins and quantum mirages can be harnessed to image the superposition of two electronic states. We also present a straightforward method to determine the atom path enacting phase rotations between any desired state vectors. A single atom thus becomes a real space handle for an abstract Hilbert space, providing a simple technique for coherent quantum state manipulation at the spatial limit of condensed matter.Comment: Published online 6 April 2008 in Nature Physics; 17 page manuscript (including 4 figures) + 3 page supplement (including 2 figures); supplementary movies available at http://mota.stanford.ed

Sterol O-Acyltransferase 1 (SOAT1, ACAT) Is a Novel Target of Steroidogenic Factor-1 (SF-1, NR5A1, Ad4BP) in the Human Adrenal

Context: Steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) is a master regulator of adrenal development and steroidogenesis. Defects in several known targets of SF-1 can cause adrenal disorders in humans.Objective: We aimed to identify novel targets of SF-1 in the human adrenal. These factors could be important regulators of adrenal development and steroidogenesis and potential candidates for adrenal dysfunction.Design: A gene discovery strategy was developed based on bidirectional manipulation of SF-1. Overexpression or knockdown of SF-1 in NCI-H295R human adrenocortical cells was used to identify a subset of positively-regulated SF-1 targets.Results: This approach identified well-established SF-1 target genes (STAR, CYP11A) and several novel genes (VSNL1, ZIM2, PEG3, SOAT1, and MTSS1). Given its role in cholesterol metabolism, sterol O-acyltransferase 1 (SOAT1, previously referred to as acyl-Coenzyme A: cholesterol acyltransferase 1, ACAT) was studied further and found to be expressed in the developing human fetal adrenal cortex. We hypothesized that impaired SOAT1 activity could result in adrenal insufficiency through reduced cholesteryl ester reserves or through toxic destruction of the adrenal cells during development. Therefore, mutational analysis of SOAT1 in a cohort of 43 patients with unexplained adrenal insufficiency was performed but failed to reveal significant coding sequence changes.Conclusions: Our reverse discovery approach led to the identification of novel SF-1 targets and defined SOAT1 as an important factor in human adrenal steroidogenesis. SF-1-dependent upregulation of SOAT1 may be important for maintaining readily-releasable cholesterol reserves needed for active steroidogenesis and during episodes of recurrent stress. (J Clin Endocrinol Metab 96: E663-E668, 2011

Observation of Bose-Einstein Condensation in a Strong Synthetic Magnetic Field

Extensions of Berry's phase and the quantum Hall effect have led to the discovery of new states of matter with topological properties. Traditionally, this has been achieved using gauge fields created by magnetic fields or spin orbit interactions which couple only to charged particles. For neutral ultracold atoms, synthetic magnetic fields have been created which are strong enough to realize the Harper-Hofstadter model. Despite many proposals and major experimental efforts, so far it has not been possible to prepare the ground state of this system. Here we report the observation of Bose-Einstein condensation for the Harper-Hofstadter Hamiltonian with one-half flux quantum per lattice unit cell. The diffraction pattern of the superfluid state directly shows the momentum distribution on the wavefuction, which is gauge-dependent. It reveals both the reduced symmetry of the vector potential and the twofold degeneracy of the ground state. We explore an adiabatic many-body state preparation protocol via the Mott insulating phase and observe the superfluid ground state in a three-dimensional lattice with strong interactions.Comment: 6 pages, 5 figures. Supplement: 6 pages, 4 figure

Mycolactone-dependent depletion of endothelial cell thrombomodulin is strongly associated with fibrin deposition in Buruli ulcer lesions

A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin's substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells' ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone's effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tisischemia could contribute to the development of the tissue necrosis seen in BU lesions

N = 2 SCFTs: An M5-brane perspective

Inspired by the recently discovered holographic duality between N=2 SCFTs and half-BPS M-theory backgrounds, we study probe M5-branes. Though our main focus is supersymmetric M5-branes whose worldvolume has an AdS_n factor, we also consider some other configurations. Of special mention is the identification of AdS_5 and AdS_3 probes preserving supersymmetry, with only the latter supporting a self-dual field strength.Comment: 27 page