bluuebunny/crossref_metadata_2025 huggingface dataset:
Women respondents report higher household food insecurity than do men in similar Canadian households
Authors: Matheson Jesse , McIntyre Lynn
Published: May 2013

Objective

We investigated factors accounting for the consistently higher levels of household food insecurity reported by women in Canada.

Design

Two cycles of the Canadian Community Health Survey for the years 2005/2006 and 2007/2008 were pooled to examine the association between household food insecurity, measured using the Household Food Security Survey Module and other metrics, and respondent sex. We stratified households as married/cohabiting (in which case, the household respondent was chosen randomly) or non-married (single/widowed/separated/divorced) and adjusted for differences in household characteristics, including the presence of children.

Setting

Canada.

Subjects

Analysis was restricted to households dependent on employment/self-employment and whose reported annual household income was below $CAN 100 000. Exclusions included respondents less than 18 years of age, any welfare receipt, and missing food insecurity, marital status, income source and amount, or household composition data.

Results

For non-married households, increased food insecurity in female-v. male-led households was accounted for by significant differences in household socio-economic characteristics. In contrast, in married/cohabiting households with or without children, higher food insecurity rates were reported when the respondent was female and neither respondent characteristics nor socio-economic factors accounted for the differences.

Conclusions

Higher rates of food insecurity in non-married households in Canada are largely attributable to women's socio-economic disadvantage. In married households, women appear to report higher levels of food insecurity than men. These findings suggest a possible bias in the measurement of population-level household food insecurity in surveys that do not account for the sex of the respondent in married/cohabiting households.
Racial/ethnic and immigrant differences in early childhood diet quality
Authors: de Hoog Marieke LA , Kleinman Ken P , Gillman Matthew W , Vrijkotte Tanja GM , van Eijsden Manon , Taveras Elsie M
Published: May 2013

Objective

To assess racial/ethnic differences in the diet in young children and the explanatory role of maternal BMI, immigrant status and perception of child's weight.

Design

Among white, black and Hispanic 3-year-olds, we used negative binomial and linear regression to examine associations of race/ethnicity with foods and nutrients assessed by a validated FFQ.

Setting

Project Viva, Boston (MA), USA.

Subjects

Children aged 3 years (n 898).

Results

Mean age was 38·3 (sd 2·8) months; 464 (52 %) were boys and 127 mothers (14 %) were immigrants. After adjustment for sociodemographic factors, black and Hispanic children (v. white) had a higher intake of sugar-sweetened beverages (rate ratio (RR) = 2·59 (95 % CI 1·95, 3·48) and RR = 1·59 (95 % CI 1·07, 2·47), respectively) and lower intakes of skimmed/1 % milk (RR = 0·42 (95 % CI 0·33, 0·53) and RR = 0·43 (95 % CI 0·31, 0·61), respectively) and trans-fat (−0·10 (95 % CI −0·18, −0·03) % of energy and −0·15 (95 % CI −0·26, −0·04) % of energy, respectively). Among Hispanics only, a lower intake of snack food (RR = 0·83 (95 % CI 0·72, 0·98)) was found and among blacks only, a higher intake of fast food (RR = 1·28 (95 % CI 1·05, 1·55)) and lower intakes of saturated fat (−0·86 (95 % CI −1·48, −0·23) % of energy), dietary fibre (0·85 (95 % CI 0·08, 1·62) g/d) and Ca (−120 (95 % CI −175, −65) mg/d) were found. Being born outside the USA was associated with more healthful nutrient intakes and less fast food.

Conclusions

Three-year-old black and Hispanic (v. white) children ate more sugar-sweetened beverages and less low-fat dairy. Total energy intake was substantially higher in Hispanic children. Snack food (Hispanic children) and fat intakes (black children) tended to be lower. Children of immigrants ate less fast food and bad fats and more fibre.
The current development of CNS drug research
Authors: Wegener Gregers , Rujescu Dan
Published: May 2013

In the past few years, several high profiled pharmaceutical companies have decided to shut down major research activities within the central nervous system (CNS) area. For example, in December 2011 Novartis announced that the company is closing its neuroscience facility in Basel, Switzerland, where Novartis is headquartered (Abbott, 2011). It follows similar moves by GlaxoSmithKline and AstraZeneca, both based in the UK, which in 2010 announced the closure of major parts of their neuroscience research divisions globally (Jack, Financial Times, 4 February 2010). Also companies primarily based in the USA, Pfizer and Merck, as well as the French company Sanofi, have pulled back on research into brain disorders. This development is still proceeding, as e.g. AstraZeneca closed their CNS/pain centres (Fiercebiotech, press release, 2 February 2012). Several of the companies have launched smaller new initiatives based on studies of genetics and biomarkers, but as mental disorders such as unipolar depression impose the largest disease burden worldwide, e.g. 6.2% disability-adjusted life year of total (WHO, 2008), and current treatments do not work particularly well for many patients, this has obviously raised a number of concerns related to how the future developments should be carried out, and whether the genetic approach may be sufficient. In June 2012, the International College of Neuropsychopharmacology (http://www.cinp.org) hosted an international workshop in order to discuss and consider the consequences and implications of the withdrawal of these research activities. This paper presents the problem background together with a summary of the viewpoints of the invited speakers and recommendations for future intervention.
Resolving views on Antarctic Neogene glacial history – the Sirius debate
Authors: Barrett P. J.
Published: May 2013

The discovery of marine Pliocene diatoms in warm-based glacial deposits (now termed the Sirius Group) high in the Transantarctic Mountains in the 1980s began a three-decade-long controversy over the stability of the East Antarctic Ice Sheet. Their presence implied that this ice sheet had collapsed as recently as three million years ago to allow their deposition in shallow interior seas, followed by transport and deposition from an expanded over-riding ice sheet. Though the glacial deposits included clasts with older diatoms, no evidence of clasts with Pliocene diatoms was published, but the hypothesis gained wide acceptance. Increasing knowledge of ice sheet behaviour and the antiquity and stability of the Transantarctic Mountains, along with new techniques for dating age and denudation rates for landscapes, has led to a more likely alternative hypothesis – that the high-level Sirius Group deposits pre-date Transantarctic Mountains uplift and their Pliocene diatoms are atmospheric contaminants. Surveys have shown that marine diatoms from the Antarctic margin and the Southern Ocean are indeed reaching the surface of the ice sheet and blowing through the mountains, with permafrost processes providing opportunities for contamination. Modelling and geological evidence is now consistent with a stable East Antarctic Ice Sheet in the interior for the last 14 Ma, with some retreat around the margins and periodic collapse of the West Antarctic ice sheet in Pliocene times.
To Be or Not to Be Unionized?
Authors: Stinglhamber Florence , Gillis Céline , Teixeira Cátia P. , Demoulin Stéphanie
Published: May 2013

This research aims at analyzing the association between two core variables of the employee-organization relationship (i.e., organizational identification and perceived organizational support) and union membership. Our study shows that perceived organizational support was negatively related to union membership but only for low identifiers. In line with prior research, highly identified employees proved less sensitive to a poor-quality exchange relationship with the organization. These findings suggest that union membership would be one possible response to a lack of support from an organization to which employees do not necessarily identify. However, future research should examine the relative weight of these variables compared to other known determinants of union membership.
Wild dog control impacts on calf wastage in extensive beef cattle enterprises
Authors: Allen Lee R.
Published: May 2013

Wild dogs (Canis lupus dingo and hybrids) are routinely controlled to protect beef cattle from predation yet beef producers are sometimes ambivalent as to whether wild dogs are a significant problem or not. This paper reports the loss of calves between birth and weaning in pregnancy-tested herds located on two beef cattle properties in south-central and far north Queensland for up to 4 consecutive years. Comparisons of lactation failures (identified when dams that previously tested pregnant were found non-lactating at weaning) were made between adjoining test herds grazed in places with or without annual (or twice annual) wild dog poison baiting programs. No correlation between wild dog relative abundance and lactation failures was apparent. Calf loss was frequently higher (three in 7 site-years, 11–32%) in baited areas than in non-baited areas (9% in 1 of 7 site-years). Predation loss of calves (in either area) only occurred in seasons of below-average rainfall, but was not related to herd nutrition. These data suggest that controlling wild dogs to protect calves on extensive beef cattle enterprises is unnecessary in most years because wild dogs do not routinely prey on calves. In those seasons when wild dog predation might occur, baiting can be counter-productive. Baiting appears to produce perturbations that change the way surviving or re-colonising wild dog populations select and handle prey and/or how they interact with livestock.
Assembling Acclimatization: Frederick McCoy, European Ideas, Australian Circumstances
Authors: Minard Peter
Published: May 2013

Between 1860 and 1870 Professor Frederick McCoy synthesized a distinct theory that guided the Acclimatisation Society of Victoria's zoological importation program. He assembled this theory via drawing upon European authorities and his own personal observations of Victorian zoology and palaeontology in order both to systemize acclimatization and to discredit Darwinism within the colony. These points will be demonstrated by investigating how McCoy formed his theory and how the Acclimatisation Society of Victoria used the theory to guide their importation program.
Fraser John Bergersen 1929 - 2011
Authors: Brockwell John , Sprent Janet I. , Day David A.
Published: May 2013

Fraser Bergersen rose from humble beginnings in New Zealand to become a leading microbiologist who specialised in the physiology and biochemistry of legume nitrogen fixation. He and his family emigrated to Australia in 1954.Virtually all of his careerwas spent in Canberra at CSIRO Plant Industry. In the 1970s, Bergersen and colleagues achieved world-wide prominence when they elucidated the role of leghaemoglobin in facilitating oxygen diffusion to the Bradyrhizobium bacteroids in soybean nodules and in the nitrogen fixation process itself. During the rest of his working life, Fraser Bergersen contributed greatly to understanding the role of oxygen, the mode of its delivery, and terminal oxidases in all forms of biological nitrogen fixation.
Graeme Reade Anthony (‘Bill’) Ellis 1921–2011
Authors: Delbourgo Robert , McCulloch Peter M.
Published: May 2013

Graeme Reade Anthony Ellis (universally known as ?Bill') was a pioneer in the area of low-frequency radio observations. By exploiting Hobart's geomagnetic latitude and the lack of background radio noise there, he was able to make major discoveries at these low frequencies (principally in the frequency range 1?10�MHz).Among the questions he pursuedwere the propagation/dispersion/reflection of radio waves in the ionosphere and the detection of radio emissions from the Sun, the galactic disk and Jupiter. He built innovative radio receivers and de-dispersers to gain information about the radio sources, for example about the Sun via aurorae and about the influence of Io on the Jovian emissions. It is thanks to Ellis' practical research investigations and clever experimental methods that radio astronomy at the University of Tasmania is today firmly established and internationally recognized.
Impaired learning resulting from Respiratory Syncytial Virus infection
Authors: Espinoza Janyra A. , Bohmwald Karen , Céspedes Pablo F. , Gómez Roberto S. , Riquelme Sebastián A. , Cortés Claudia M. , Valenzuela Javier A. , Sandoval Rodrigo A. , Pancetti Floria C. , Bueno Susan M. , Riedel Claudia A. , Kalergis Alexis M.
Published: May 2013

Respiratory syncytial virus (RSV) is the major cause of respiratory illness in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brain—such as the hippocampus, ventromedial hypothalamic nucleus, and brainstem—of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette–Guérin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV.
Heat shock protein (Hsp) 70 is an activator of the Hsp104 motor
Authors: Lee Jungsoon , Kim Ji-Hyun , Biter Amadeo B. , Sielaff Bernhard , Lee Sukyeong , Tsai Francis T. F.
Published: May 2013

Heat shock protein (Hsp) 104 is a ring-forming, protein-remodeling machine that harnesses the energy of ATP binding and hydrolysis to drive protein disaggregation. Although Hsp104 is an active ATPase, the recovery of functional protein requires the species-specific cooperation of the Hsp70 system. However, like Hsp104, Hsp70 is an active ATPase, which recognizes aggregated and aggregation-prone proteins, making it difficult to differentiate the mechanistic roles of Hsp104 and Hsp70 during protein disaggregation. Mapping the Hsp70-binding sites in yeast Hsp104 using peptide array technology and photo–cross-linking revealed a striking conservation of the primary Hsp70-binding motifs on the Hsp104 middle-domain across species, despite lack of sequence identity. Remarkably, inserting a
Strep
-Tactin binding motif at the spatially conserved Hsp70-binding site elicits the Hsp104 protein disaggregating activity that now depends on
Strep-
Tactin but no longer requires Hsp70/40. Consistent with a
Strep
-Tactin–dependent activation step, we found that full-length Hsp70 on its own could activate the Hsp104 hexamer by promoting intersubunit coordination, suggesting that Hsp70 is an activator of the Hsp104 motor.
Visualizing cellular interactions with a generalized proximity reporter
Authors: Sellmyer Mark A. , Bronsart Laura , Imoto Hiroshi , Contag Christopher H. , Wandless Thomas J. , Prescher Jennifer A.
Published: May 2013

Interactions among neighboring cells underpin many physiological processes ranging from early development to immune responses. When these interactions do not function properly, numerous pathologies, including infection and cancer, can result. Molecular imaging technologies, especially optical imaging, are uniquely suited to illuminate complex cellular interactions within the context of living tissues in the body. However, no tools yet exist that allow the detection of microscopic events, such as two cells coming into close proximity, on a global, whole-animal scale. We report here a broadly applicable, longitudinal strategy for probing interactions among cells in living subjects. This approach relies on the generation of bioluminescent light when two distinct cell populations come into close proximity, with the intensity of the optical signal correlating with relative cellular location. We demonstrate the ability of this reporter strategy to gauge cell–cell proximity in culture models in vitro and then evaluate this approach for imaging tumor–immune cell interactions using a murine breast cancer model. In these studies, our imaging strategy enabled the facile visualization of features that are otherwise difficult to observe with conventional imaging techniques, including detection of micrometastatic lesions and potential sites of tumor immunosurveillance. This proximity reporter will facilitate probing of numerous types of cell–cell interactions and will stimulate the development of similar techniques to detect rare events and pathological processes in live animals.
Ultraconserved words point to deep language ancestry across Eurasia
Authors: Pagel Mark , Atkinson Quentin D. , S. Calude Andreea , Meade Andrew
Published: May 2013

The search for ever deeper relationships among the World’s languages is bedeviled by the fact that most words evolve too rapidly to preserve evidence of their ancestry beyond 5,000 to 9,000 y. On the other hand, quantitative modeling indicates that some “ultraconserved” words exist that might be used to find evidence for deep linguistic relationships beyond that time barrier. Here we use a statistical model, which takes into account the frequency with which words are used in common everyday speech, to predict the existence of a set of such highly conserved words among seven language families of Eurasia postulated to form a linguistic superfamily that evolved from a common ancestor around 15,000 y ago. We derive a dated phylogenetic tree of this proposed superfamily with a time-depth of ∼14,450 y, implying that some frequently used words have been retained in related forms since the end of the last ice age. Words used more than once per 1,000 in everyday speech were 7- to 10-times more likely to show deep ancestry on this tree. Our results suggest a remarkable fidelity in the transmission of some words and give theoretical justification to the search for features of language that might be preserved across wide spans of time and geography.
Dynamic vaccine blocks relapse to compulsive intake of heroin
Authors: Schlosburg Joel E. , Vendruscolo Leandro F. , Bremer Paul T. , Lockner Jonathan W. , Wade Carrie L. , Nunes Ashlee A. K. , Stowe G. Neil , Edwards Scott , Janda Kim D. , Koob George F.
Published: May 2013

Heroin addiction, a chronic relapsing disorder characterized by excessive drug taking and seeking, requires constant psychotherapeutic and pharmacotherapeutic interventions to minimize the potential for further abuse. Vaccine strategies against many drugs of abuse are being developed that generate antibodies that bind drug in the bloodstream, preventing entry into the brain and nullifying psychoactivity. However, this strategy is complicated by heroin’s rapid metabolism to 6-acetylmorphine and morphine. We recently developed a “dynamic” vaccine that creates antibodies against heroin and its psychoactive metabolites by presenting multihaptenic structures to the immune system that match heroin’s metabolism. The current study presents evidence of effective and continuous sequestration of brain-permeable constituents of heroin in the bloodstream following vaccination. The result is efficient blockade of heroin activity in treated rats, preventing various features of drugs of abuse: heroin reward, drug-induced reinstatement of drug seeking, and reescalation of compulsive heroin self-administration following abstinence in dependent rats. The dynamic vaccine shows the capability to significantly devalue the reinforcing and motivating properties of heroin, even in subjects with a history of dependence. In addition, targeting a less brain-permeable downstream metabolite, morphine, is insufficient to prevent heroin-induced activity in these models, suggesting that heroin and 6-acetylmorphine are critical players in heroin’s psychoactivity. Because the heroin vaccine does not target opioid receptors or common opioid pharmacotherapeutics, it can be used in conjunction with available treatment options. Thus, our vaccine represents a promising adjunct therapy for heroin addiction, providing continuous heroin antagonism, requiring minimal medical monitoring and patient compliance.
Presynaptic maturation in auditory hair cells requires a critical period of sensory-independent spiking activity
Authors: Johnson Stuart L. , Kuhn Stephanie , Franz Christoph , Ingham Neil , Furness David N. , Knipper Marlies , Steel Karen P. , Adelman John P. , Holley Matthew C. , Marcotti Walter
Published: May 2013

The development of neural circuits relies on spontaneous electrical activity that occurs during immature stages of development. In the developing mammalian auditory system, spontaneous calcium action potentials are generated by inner hair cells (IHCs), which form the primary sensory synapse. It remains unknown whether this electrical activity is required for the functional maturation of the auditory system. We found that sensory-independent electrical activity controls synaptic maturation in IHCs. We used a mouse model in which the potassium channel SK2 is normally overexpressed, but can be modulated in vivo using doxycycline. SK2 overexpression affected the frequency and duration of spontaneous action potentials, which prevented the development of the Ca
2+
-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their morphology or general cell development. By manipulating the in vivo expression of SK2 channels, we identified the “critical period” during which spiking activity influences IHC synaptic maturation. Here we provide direct evidence that IHC development depends upon a specific temporal pattern of calcium spikes before sound-driven neuronal activity.
Calcium-dependent protein kinase/NADPH oxidase activation circuit is required for rapid defense signal propagation
Authors: Dubiella Ullrich , Seybold Heike , Durian Guido , Komander Eileen , Lassig Roman , Witte Claus-Peter , Schulze Waltraud X. , Romeis Tina
Published: May 2013

In animals and plants, pathogen recognition triggers the local activation of intracellular signaling that is prerequisite for mounting systemic defenses in the whole organism. We identified that
Arabidopsis thaliana
isoform CPK5 of the plant calcium-dependent protein kinase family becomes rapidly biochemically activated in response to pathogen-associated molecular pattern (PAMP) stimulation. CPK5 signaling resulted in enhanced salicylic acid–mediated resistance to the bacterial pathogen
Pst
DC3000, differential plant defense gene expression, and synthesis of reactive oxygen species (ROS). Using selected reaction monitoring MS, we identified the plant NADPH oxidase, respiratory burst oxidase homolog D (RBOHD), as an in vivo phosphorylation target of CPK5. Remarkably, CPK5-dependent in vivo phosphorylation of RBOHD occurs on both PAMP- and ROS stimulation. Furthermore, rapid CPK5-dependent biochemical and transcriptional activation of defense reactions at distal sites is compromised in
cpk5
and
rbohd
mutants. Our data not only identify CPK5 as a key regulator of innate immune responses in plants but also support a model of ROS-mediated cell-to-cell communication, where a self-propagating mutual activation circuit consisting of the protein kinase, CPK5, and the NADPH oxidase RBOHD facilitates rapid signal propagation as a prerequisite for defense response activation at distal sites within the plant.
Lymphatic abnormalities are associated with
RASA1
gene mutations in mouse and man
Authors: Burrows Patricia E. , Gonzalez-Garay Manuel L. , Rasmussen John C. , Aldrich Melissa B. , Guilliod Renie , Maus Erik A. , Fife Caroline E. , Kwon Sunkuk , Lapinski Philip E. , King Philip D. , Sevick-Muraca Eva M.
Published: May 2013

Mutations in gene
RASA1
have been historically associated with capillary malformation–arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. To investigate the impact of
RASA1
mutations in the lymphatic system, we performed investigational near-infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes–Weber syndrome (PKWS) patient with suspected
RASA1
mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in
RASA1
that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the
RASA1
mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders.
X-ray structure of an AdoMet radical activase reveals an anaerobic solution for formylglycine posttranslational modification
Authors: Goldman Peter J. , Grove Tyler L. , Sites Lauren A. , McLaughlin Martin I. , Booker Squire J. , Drennan Catherine L.
Published: May 2013

Arylsulfatases require a maturating enzyme to perform a co- or posttranslational modification to form a catalytically essential formylglycine (FGly) residue. In organisms that live aerobically, molecular oxygen is used enzymatically to oxidize cysteine to FGly. Under anaerobic conditions,
S
-adenosylmethionine (AdoMet) radical chemistry is used. Here we present the structures of an anaerobic sulfatase maturating enzyme (anSME), both with and without peptidyl-substrates, at 1.6–1.8 Å resolution. We find that anSMEs differ from their aerobic counterparts in using backbone-based hydrogen-bonding patterns to interact with their peptidyl-substrates, leading to decreased sequence specificity. These anSME structures from
Clostridium perfringens
are also the first of an AdoMet radical enzyme that performs dehydrogenase chemistry. Together with accompanying mutagenesis data, a mechanistic proposal is put forth for how AdoMet radical chemistry is coopted to perform a dehydrogenation reaction. In the oxidation of cysteine or serine to FGly by anSME, we identify D277 and an auxiliary [4Fe-4S] cluster as the likely acceptor of the final proton and electron, respectively. D277 and both auxiliary clusters are housed in a cysteine-rich C-terminal domain, termed SPASM domain, that contains homology to ∼1,400 other unique AdoMet radical enzymes proposed to use [4Fe-4S] clusters to ligate peptidyl-substrates for subsequent modification. In contrast to this proposal, we find that neither auxiliary cluster in anSME bind substrate, and both are fully ligated by cysteine residues. Instead, our structural data suggest that the placement of these auxiliary clusters creates a conduit for electrons to travel from the buried substrate to the protein surface.
True scale-invariant random spatial networks
Authors: Aldous David , Ganesan Karthik
Published: May 2013

Some aspects of real-world road networks seem to have an approximate scale invariance property, motivating study of mathematical models of random networks whose distributions are exactly invariant under Euclidean scaling. This requires working in the continuum plane, so making a precise definition is not trivial. We introduce an axiomatization of a class of processes we call scale-invariant random spatial networks, whose primitives are routes between each pair of points in the plane. One concrete model, based on minimum-time routes in a binary hierarchy of roads with different speed limits, has been shown to satisfy the axioms, and two other constructions (based on Poisson line processes and on dynamic proximity graphs) are expected also to do so. We initiate study of structure theory and summary statistics for general processes in the class. Many questions arise in this setting via analogies with diverse existing topics, from geodesics in first-passage percolation to transit node-based route-finding algorithms.
The phase transition of matrix recovery from Gaussian measurements matches the minimax MSE of matrix denoising
Authors: Donoho David L. , Gavish Matan , Montanari Andrea
Published: May 2013

Let

be an unknown
M
by
N
matrix. In matrix recovery, one takes

linear measurements

of

, where

and each

is an
M
by
N
matrix. A popular approach for matrix recovery is nuclear norm minimization (NNM): solving the convex optimization problem

for all

, where

denotes the nuclear norm, namely, the sum of singular values. Empirical work reveals a phase transition curve, stated in terms of the undersampling fraction

, rank fraction

, and aspect ratio

. Specifically when the measurement matrices

A
i

have independent standard Gaussian random entries, a curve

exists such that, if

, NNM typically succeeds for large
M
,
N
, whereas if

, it typically fails. An apparently quite different problem is matrix denoising in Gaussian noise, in which an unknown
M
by
N
matrix

is to be estimated based on direct noisy measurements

, where the matrix
Z
has independent and identically distributed Gaussian entries. A popular matrix denoising scheme solves the unconstrained optimization problem

. When optimally tuned, this scheme achieves the asymptotic minimax mean-squared error

, where

. We report extensive experiments showing that the phase transition

in the first problem, matrix recovery from Gaussian measurements, coincides with the minimax risk curve

in the second problem, matrix denoising in Gaussian noise:

, for any rank fraction

(at each common aspect ratio β). Our experiments considered matrices belonging to two constraint classes: real
M
by
N
matrices, of various ranks and aspect ratios, and real symmetric positive-semidefinite
N
by
N
matrices, of various ranks.
Sulfur isotopes in coal constrain the evolution of the Phanerozoic sulfur cycle
Authors: Canfield Donald E.
Published: May 2013

Sulfate is the second most abundant anion (behind chloride) in modern seawater, and its cycling is intimately coupled to the cycling of organic matter and oxygen at the Earth’s surface. For example, the reduction of sulfide by microbes oxidizes vast amounts of organic carbon and the subsequent reaction of sulfide with iron produces pyrite whose burial in sediments is an important oxygen source to the atmosphere. The concentrations of seawater sulfate and the operation of sulfur cycle have experienced dynamic changes through Earth’s history, and our understanding of this history is based mainly on interpretations of the isotope record of seawater sulfates and sedimentary pyrites. The isotope record, however, does not give a complete picture of the ancient sulfur cycle. This is because, in standard isotope mass balance models, there are more variables than constraints. Typically, in interpretations of the isotope record and in the absence of better information, one assumes that the isotopic composition of the input sulfate to the oceans has remained constant through time. It is argued here that this assumption has a constraint over the last 390 Ma from the isotopic composition of sulfur in coal. Indeed, these compositions do not deviate substantially from the modern surface-water input to the oceans. When applied to mass balance models, these results support previous interpretations of sulfur cycle operation and counter recent suggestions that sulfate has been a minor player in sulfur cycling through the Phanerozoic Eon.
IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells
Authors: Gasteiger Georg , Hemmers Saskia , Firth Matthew A. , Le Floc’h Audrey , Huse Morgan , Sun Joseph C. , Rudensky Alexander Y.
Published: May 2013

The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self–ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2–dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.
Universality limits for entire functions
Authors: Mitkovski Mishko
Published: May 2013

Various statements on the distribution of eigenvalues of random matrices are obtained by considering the limiting behavior of the reproducing kernels of a certain naturally associated sequence of orthogonal polynomials. We establish a universal limiting behavior of this type in the case when the underlying measure does not have finite moments. In this case the orthogonal polynomials are replaced by a nested family of de Branges spaces of entire functions.
Alterations to the remote control ofShhgene expression cause congenital abnormalities
Authors: Hill Robert E. , Lettice Laura A.
Published: May 2013

Multi-species conserved non-coding elements occur in the vertebrate genome and are clustered in the vicinity of developmentally regulated genes. Many are known to act ascis-regulators of transcription and may reside at long distances from the genes they regulate. However, the relationship of conserved sequence to encoded regulatory information and indeed, the mechanism by which these contribute to long-range transcriptional regulation is not well understood. The ZRS, a highly conservedcis-regulator, is a paradigm for such long-range gene regulation. The ZRS acts over approximately 1 Mb to control spatio-temporal expression ofShhin the limb bud and mutations within it result in a number of limb abnormalities, including polydactyly, tibial hypoplasia and syndactyly. We describe the activity of this developmental regulator and discuss a number of mechanisms by which regulatory mutations in this enhancer function to cause congenital abnormalities.
From remote enhancers to gene regulation: charting the genome's regulatory landscapes
Authors: Symmons Orsolya , Spitz François
Published: May 2013

Vertebrate genes are characterized by the presence ofcis-regulatory elements located at great distances from the genes they control. Alterations of these elements have been implicated in human diseases and evolution, yet little is known about how these elements interact with their surrounding sequences. A recent survey of the mouse genome with a regulatory sensor showed that the regulatory activities of these elements are not organized in a gene-centric manner, but instead are broadly distributed along chromosomes, forming large regulatory landscapes with distinct tissue-specific activities. A large genome-wide collection of expression data from this regulatory sensor revealed some basic principles of this complex genome regulatory architecture, including a substantial interplay between enhancers and other types of activities to modulate gene expression. We discuss the implications of these findings for our understanding of non-coding transcription, and of the possible consequences of structural genomic variations in disease and evolution.
Human genetic variation within neural crest enhancers: molecular and phenotypic implications
Authors: Rada-Iglesias Alvaro , Prescott Sara L. , Wysocka Joanna
Published: May 2013

Developmental gene expression programmes are coordinated by the specialized distalcis-regulatory elements called enhancers, which integrate lineage- and signalling-dependent inputs to guide morphogenesis. In previous work, we characterized the genome-wide repertoire of active enhancers in human neural crest cells (hNCC), an embryonic cell population with critical roles in craniofacial development. We showed that in hNCC, co-occupancy of a master regulator TFAP2A with nuclear receptors NR2F1 and NR2F2 correlates with the presence of permissive enhancer chromatin states. Here, we take advantage of pre-existing human genetic variation to further explore potential cooperation between TFAP2A and NR2F1/F2. We demonstrate that isolated single nucleotide polymorphisms affecting NR2F1/F2-binding sites within hNCC enhancers can alter TFAP2A occupancy and overall chromatin features at the same enhancer allele. We propose that a similar strategy can be used to elucidate other cooperative relationships between transcription factors involved in developmental transitions. Using the neural crest and its major contribution to human craniofacial phenotypes as a paradigm, we discuss how genetic variation might modulate the molecular properties and activity of enhancers, and ultimately impact human phenotypic diversity.
Expression quantitative trait loci: present and future
Authors: Nica Alexandra C. , Dermitzakis Emmanouil T.
Published: May 2013

The last few years have seen the development of large efforts for the analysis of genome function, especially in the context of genome variation. One of the most prominent directions has been the extensive set of studies on expression quantitative trait loci (eQTLs), namely, the discovery of genetic variants that explain variation in gene expression levels. Such studies have offered promise not just for the characterization of functional sequence variation but also for the understanding of basic processes of gene regulation and interpretation of genome-wide association studies. In this review, we discuss some of the key directions of eQTL research and its implications.
Effects of gene regulatory reprogramming on gene expression in human and mouse developing hearts
Authors: Hsu Chih-Hao , Ovcharenko Ivan
Published: May 2013

Lineage-specific regulatory elements underlie adaptation of species and play a role in disease susceptibility. We compared functionally conserved and lineage-specific enhancers by cross-mapping 5042 human and 6564 mouse heart enhancers. Of these, 79 per cent are lineage-specific, lacking a functional orthologue. Heart enhancers tend to cluster and, commonly, there are multiple heart enhancers in a heart locus providing a regulatory stability to the locus. We observed little cross-clustering, however, between lineage-specific and functionally conserved heart enhancers suggesting regulatory function acquisition and development in loci previously lacking heart activity. We also identified 862 human-specific heart enhancers: 417 featuring sequence conservation with mouse (class II) and 445 with neither sequence nor function conservation (class III). Ninety-eight per cent of class III enhancers were deleted from the mouse genome, and we estimated a similar-sized enhancer gain in the human lineage. Human-specific enhancers display no detectable decrease in the negative selection pressure and are strongly associated with genes partaking in the heart regulatory programmes. The loss of a heart enhancer could be compensated by activity of a redundant heart enhancer; however, we observed redundancy in only 15 per cent of class II and III enhancer loci indicating a large-scale reprogramming of the heart regulatory programme in mammals.
Chromatin organization and global regulation ofHoxgene clusters
Authors: Montavon Thomas , Duboule Denis
Published: May 2013

During development, a properly coordinated expression ofHoxgenes, within their different genomic clusters is critical for patterning the body plans of many animals with a bilateral symmetry. The fascinating correspondence between the topological organization ofHoxclusters and their transcriptional activation in space and time has served as a paradigm for understanding the relationships between genome structure and function. Here, we review some recent observations, which revealed highly dynamic changes in the structure of chromatin atHoxclusters, in parallel with their activation during embryonic development. We discuss the relevance of these findings for our understanding of large-scale gene regulation.
Deciphering
cis
-regulatory control in inflammatory cells
Authors: Ghisletti Serena , Natoli Gioacchino
Published: May 2013

In innate immune system cells, such as macrophages and dendritic cells, deployment of inducible gene expression programmes in response to microbes and danger signals requires highly precise regulatory mechanisms. The inflammatory response has to be tailored based on both the triggering stimulus and its dose, and it has to be unfolded in a kinetically complex manner that suits the different phases of the inflammatory process. Genomic characterization of regulatory elements in this context indicated that transcriptional regulators involved in macrophage specification act as pioneer transcription factors (TFs) that generate regions of open chromatin that enable the recruitment of TFs activated in response to external inputs. Therefore, competence for responses to a specific stimulus is programmed at an early stage of differentiation by factors involved in lineage commitment and maintenance of cell identity, which are responsible for the organization of a cell-type-specific
cis
-regulatory repertoire. The basic functional and organizational principles that regulate inflammatory gene expression in professional cells of the innate immune system provide general paradigms on the interplay between differentiation and environmental responses.
Dynamic binding of RBPJ is determined by Notch signaling status
Authors: Castel David , Mourikis Philippos , Bartels Stefanie J.J. , Brinkman Arie B. , Tajbakhsh Shahragim , Stunnenberg Hendrik G.
Published: May 2013

Notch signaling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighboring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and, together with the transcription factor moiety of Notch (NICD), regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole-genome binding profiles were generated for RBPJ; its coactivator, p300; NICD; and the histone H3 modifications H3 Lys 4 trimethylation (H3K4me3), H3 Lys 4 monomethylation (H3K4me1), and histone H3 Lys 27 acetylation (H3K27ac) in myogenic cells under active or inhibitory Notch signaling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300 and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signaling mediate their activities and consequently impact on cell fate decisions.
Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses
Authors: Kenzelmann Broz Daniela , Spano Mello Stephano , Bieging Kathryn T. , Jiang Dadi , Dusek Rachel L. , Brady Colleen A. , Sidow Arend , Attardi Laura D.
Published: May 2013

The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression.
The T-box transcription factor Eomesodermin is essential for AVE induction in the mouse embryo
Authors: Nowotschin Sonja , Costello Ita , Piliszek Anna , Kwon Gloria S. , Mao Chai-an , Klein William H. , Robertson Elizabeth J. , Hadjantonakis Anna-Katerina
Published: May 2013

Reciprocal inductive interactions between the embryonic and extraembryonic tissues establish the anterior–posterior (AP) axis of the early mouse embryo. The anterior visceral endoderm (AVE) signaling center emerges at the distal tip of the embryo at embryonic day 5.5 and translocates to the prospective anterior side of the embryo. The process of AVE induction and migration are poorly understood. Here we demonstrate that the T-box gene Eomesodermin (Eomes) plays an essential role in AVE recruitment, in part by directly activating the homeobox transcription factor Lhx1. Thus, Eomes function in the visceral endoderm (VE) initiates an instructive transcriptional program controlling AP identity.
Thermal deformation of cryogenically cooled silicon crystals under intense X-ray beams: measurement and finite-element predictions of the surface shape
Authors: Zhang Lin , Sánchez del Río Manuel , Monaco Giulio , Detlefs Carsten , Roth Thomas , Chumakov Aleksandr I. , Glatzel Pieter
Published: May 2013

X-ray crystal monochromators exposed to white-beam X-rays in third-generation synchrotron light sources are subject to thermal deformations that must be minimized using an adequate cooling system. A new approach was used to measure the crystal shape profile and slope of several cryogenically cooled (liquid nitrogen) silicon monochromators as a function of beam powerin situand under heat load. The method utilizes multiple angular scans across the Bragg peak (rocking curve) at various vertical positions of a narrow-gap slit downstream from the monochromator. When increasing the beam power, the surface of the liquid-nitrogen-cooled silicon crystal deforms from a concave shape at low heat load to a convex shape at high heat load, passing through an approximately flat shape at intermediate heat load. Finite-element analysis is used to calculate the crystal thermal deformations. The simulated crystal profiles and slopes are in excellent agreement with experiments. The parameters used in simulations, such as material properties, absorbed power distribution on the crystal and cooling boundary conditions, are described in detail as they are fundamental for obtaining accurate results.