bluuebunny/crossref_metadata_2025 huggingface dataset:
Is burn severity related to fire intensity? Observations from landscape scale remote sensing
Authors: Heward Heather , Smith Alistair M. S. , Roy David P. , Tinkham Wade T. , Hoffman Chad M. , Morgan Penelope , Lannom Karen O.
Published: July 2013

Biomass burning by wildland fires has significant ecological, social and economic impacts. Satellite remote sensing provides direct measurements of radiative energy released by the fire (i.e. fire intensity) and surrogate measures of ecological change due to the fire (i.e. fire or burn severity). Despite anecdotal observations causally linking fire intensity with severity, the nature of any relationship has not been examined over extended spatial scales. We compare fire intensities defined by Moderate Resolution Imaging Spectroradiometer Fire Radiative Power (MODIS FRP) products with Landsat-derived spectral burn severity indices for 16 fires across a vegetation structure continuum in the western United States. Per-pixel comparison of MODIS FRP data within individual fires with burn severity indices is not reliable because of known satellite temporal and spatial FRP undersampling. Across the fires, 69% of the variation in relative differenced normalized burn ratio was explained by the 90th percentile of MODIS FRP. Therefore, distributional MODIS FRP measures (median and 90th-percentile FRP) derived from multiple MODIS overpasses of the actively burning fire event may be used to predict potential long-term negative ecological effects for individual fires.
Short-term physiological effects of smoke on grapevine leaves
Authors: Bell T. L. , Stephens S. L. , Moritz M. A.
Published: July 2013

In recent years, bushfires and prescribed burns have caused substantial economic loss to the wine industry due to smoke taint, which makes wine unpalatable. Considerable research is being done to ameliorate smoke taint but the information available about the effect of smoke on grapevines is limited. We examined the physiological effects of short-term exposure to smoke on leaves of several varieties of grapevines. Gas exchange was measured before and after short-term exposure of leaves to smoke that was produced by combustion of two different fuels. For most varieties, short-term exposure to smoke had little effect on leaf physiology. For varieties that were affected by smoke, patterns of recovery of leaf physiology depended on fuel type. Short-term exposure to smoke had, at best, no significant effect and, at worst, only temporary effects on functioning of leaves. All varieties had recovered to pre-smoke functioning within 48h. This study will contribute to the growing body of information relevant to fire and land management agencies and the wine industry in fire-prone areas including Australia, North and South America and Europe.
The relationship of large fire occurrence with drought and fire danger indices in the western USA, 1984–2008: the role of temporal scale
Authors: Riley Karin L. , Abatzoglou John T. , Grenfell Isaac C. , Klene Anna E. , Heinsch Faith Ann
Published: July 2013

The relationship between large fire occurrence and drought has important implications for fire prediction under current and future climates. This study’s primary objective was to evaluate correlations between drought and fire-danger-rating indices representing short- and long-term drought, to determine which had the strongest relationships with large fire occurrence at the scale of the western United States during the years 1984–2008. We combined 4–8-km gridded drought and fire-danger-rating indices with information on fires greater than 404.7ha (1000acres). To account for differences in indices across climate and vegetation assemblages, indices were converted to percentile conditions for each pixel. Correlations between area burned and short-term indices Energy Release Component and monthly precipitation percentile were strong (R2=0.92 and 0.89), as were correlations between number of fires and these indices (R2=0.94 and 0.93). As the period of time tabulated by indices lengthened, correlations with fire occurrence weakened: Palmer Drought Severity Index and 24-month Standardised Precipitation Index percentile showed weak correlations with area burned (R2=0.25 and –0.01) and number of large fires (R2=0.3 and 0.01). These results indicate associations between short-term indices and moisture content of dead fuels, the primary carriers of surface fire.
Wildland firefighter entrapment avoidance: modelling evacuation triggers
Authors: Fryer Gregory K. , Dennison Philip E. , Cova Thomas J.
Published: July 2013

Wildland firefighters are often called on to make tactical decisions under stressful conditions in order to suppress a fire. These decisions can be hindered by human factors such as insufficient knowledge of surroundings and conditions, lack of experience, overextension of resources or loss of situational awareness. One potential tool for assisting fire managers in situations where human factors can hinder decision-making is the Wildland–Urban Interface Evacuation (WUIVAC) model, which models fire minimum travel times to create geographic trigger buffers for evacuation recommendations. Utilising multiple combinations of escape routes and fire environment inputs based on the 2007 Zaca fire in California, USA, we created trigger buffers for firefighter evacuations on foot, by engine and by heavy mechanised equipment (i.e. bulldozer). Our primary objective was to examine trigger buffer sensitivity to evacuation mode and expected weather and fuel conditions. Evacuation travel time was the most important factor for determining the size and extent of modelled trigger buffers. For the examined scenarios, we show that WUIVAC can provide analytically driven, physically based triggers that can assist in entrapment avoidance and ultimately contribute to firefighter safety.
The case for distributed irrigation as a development priority in sub-Saharan Africa
Authors: Burney Jennifer A. , Naylor Rosamond L. , Postel Sandra L.
Published: July 2013

Distributed irrigation systems are those in which the water access (via pump or human power), distribution (via furrow, watering can, sprinkler, drip lines, etc.), and use all occur at or near the same location. Distributed systems are typically privately owned and managed by individuals or groups, in contrast to centralized irrigation systems, which tend to be publicly operated and involve large water extractions and distribution over significant distances for use by scores of farmers. Here we draw on a growing body of evidence on smallholder farmers, distributed irrigation systems, and land and water resource availability across sub-Saharan Africa (SSA) to show how investments in distributed smallholder irrigation technologies might be used to (
i
) use the water sources of SSA more productively, (
ii
) improve nutritional outcomes and rural development throughout SSA, and (
iii
) narrow the income disparities that permit widespread hunger to persist despite aggregate economic advancement.
Experimental and computational analysis of the transition state for ribonuclease A-catalyzed RNA 2′-
O
-transphosphorylation
Authors: Gu Hong , Zhang Shuming , Wong Kin-Yiu , Radak Brian K. , Dissanayake Thakshila , Kellerman Daniel L. , Dai Qing , Miyagi Masaru , Anderson Vernon E. , York Darrin M. , Piccirilli Joseph A. , Harris Michael E.
Published: July 2013

Enzymes function by stabilizing reaction transition states; therefore, comparison of the transition states of enzymatic and nonenzymatic model reactions can provide insight into biological catalysis. Catalysis of RNA 2′-
O
-transphosphorylation by ribonuclease A is proposed to involve electrostatic stabilization and acid/base catalysis, although the structure of the rate-limiting transition state is uncertain. Here, we describe coordinated kinetic isotope effect (KIE) analyses, molecular dynamics simulations, and quantum mechanical calculations to model the transition state and mechanism of RNase A. Comparison of the
18
O KIEs on the 2′O nucleophile, 5′O leaving group, and nonbridging phosphoryl oxygens for RNase A to values observed for hydronium- or hydroxide-catalyzed reactions indicate a late anionic transition state. Molecular dynamics simulations using an anionic phosphorane transition state mimic suggest that H-bonding by protonated His12 and Lys41 stabilizes the transition state by neutralizing the negative charge on the nonbridging phosphoryl oxygens. Quantum mechanical calculations consistent with the experimental KIEs indicate that expulsion of the 5′O remains an integral feature of the rate-limiting step both on and off the enzyme. Electrostatic interactions with positively charged amino acid site chains (His12/Lys41), together with proton transfer from His119, render departure of the 5′O less advanced compared with the solution reaction and stabilize charge buildup in the transition state. The ability to obtain a chemically detailed description of 2′-
O
-transphosphorylation transition states provides an opportunity to advance our understanding of biological catalysis significantly by determining how the catalytic modes and active site environments of phosphoryl transferases influence transition state structure.
Capturing the mutational landscape of the beta-lactamase TEM-1
Authors: Jacquier Hervé , Birgy André , Le Nagard Hervé , Mechulam Yves , Schmitt Emmanuelle , Glodt Jérémy , Bercot Beatrice , Petit Emmanuelle , Poulain Julie , Barnaud Guilène , Gros Pierre-Alexis , Tenaillon Olivier
Published: July 2013

Adaptation proceeds through the selection of mutations. The distribution of mutant fitness effect and the forces shaping this distribution are therefore keys to predict the evolutionary fate of organisms and their constituents such as enzymes. Here, by producing and sequencing a comprehensive collection of 10,000 mutants, we explore the mutational landscape of one enzyme involved in the spread of antibiotic resistance, the beta-lactamase TEM-1. We measured mutation impact on the enzyme activity through the estimation of amoxicillin minimum inhibitory concentration on a subset of 990 mutants carrying a unique missense mutation, representing 64% of possible amino acid changes in that protein reachable by point mutation. We established that mutation type, solvent accessibility of residues, and the predicted effect of mutations on protein stability primarily determined alone or in combination changes in minimum inhibitory concentration of mutants. Moreover, we were able to capture the drastic modification of the mutational landscape induced by a single stabilizing point mutation (M182T) by a simple model of protein stability. This work thereby provides an integrated framework to study mutation effects and a tool to understand/define better the epistatic interactions.
HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection
Authors: Hertz Tomer , Oshansky Christine M. , Roddam Philippa L. , DeVincenzo John P. , Caniza Miguela A. , Jojic Nebojsa , Mallal Simon , Phillips Elizabeth , James Ian , Halloran M. Elizabeth , Thomas Paul G. , Corey Lawrence
Published: July 2013

Experimental and computational evidence suggests that HLAs preferentially bind conserved regions of viral proteins, a concept we term “targeting efficiency,” and that this preference may provide improved clearance of infection in several viral systems. To test this hypothesis, T-cell responses to A/H1N1 (2009) were measured from peripheral blood mononuclear cells obtained from a household cohort study performed during the 2009–2010 influenza season. We found that HLA targeting efficiency scores significantly correlated with IFN-γ enzyme-linked immunosorbent spot responses (P= 0.042, multiple regression). A further population-based analysis found that the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24, were associated with pH1N1 mortality (r= 0.37,P= 0.031) and are common in certain indigenous populations in which increased pH1N1 morbidity has been reported. HLA efficiency scores and HLA use are associated with CD8 T-cell magnitude in humans after influenza infection. The computational tools used in this study may be useful predictors of potential morbidity and identify immunologic differences of new variant influenza strains more accurately than evolutionary sequence comparisons. Population-based studies of the relative frequency of these alleles in severe vs. mild influenza cases might advance clinical practices for severe H1N1 infections among genetically susceptible populations.
Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder
Authors: Ecker Christine , Ronan Lisa , Feng Yue , Daly Eileen , Murphy Clodagh , Ginestet Cedric E. , Brammer Michael , Fletcher Paul C. , Bullmore Edward T. , Suckling John , Baron-Cohen Simon , Williams Steve , Loth Eva ,   MRC AIMS Consortium, Murphy Declan G. M. , Bailey A. J. , Baron-Cohen S. , Bolton P. F. , Bullmore E. T. , Carrington S. , Chakrabarti B. , Daly E. M. , Deoni S. C. , Ecker C. , Happe F. , Henty J. , Jezzard P. , Johnston P. , Jones D. K. , Lai M. C. , Lombardo M. V. , Madden A. , Mullins D. , Murphy C. M. , Murphy D. G. , Pasco G. , Sadek S. , Spain D. , Steward R. , Suckling J. , Wheelwright S. , Williams S. C.
Published: July 2013

Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of “cortical separation distances” to assess the global and local intrinsic “wiring costs” of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical “connectivity” in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms.
Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells
Authors: Ramakrishnaiah Vedashree , Thumann Christine , Fofana Isabel , Habersetzer Francois , Pan Qiuwei , de Ruiter Petra E. , Willemsen Rob , Demmers Jeroen A. A. , Stalin Raj Victor , Jenster Guido , Kwekkeboom Jaap , Tilanus Hugo W. , Haagmans Bart L. , Baumert Thomas F. , van der Laan Luc J. W.
Published: July 2013

Recent evidence indicates there is a role for small membrane vesicles, including exosomes, as vehicles for intercellular communication. Exosomes secreted by most cell types can mediate transfer of proteins, mRNAs, and microRNAs, but their role in the transmission of infectious agents is less established. Recent studies have shown that hepatocyte-derived exosomes containing hepatitis C virus (HCV) RNA can activate innate immune cells, but the role of exosomes in the transmission of HCV between hepatocytes remains unknown. In this study, we investigated whether exosomes transfer HCV in the presence of neutralizing antibodies. Purified exosomes isolated from HCV-infected human hepatoma Huh7.5.1 cells were shown to contain full-length viral RNA, viral protein, and particles, as determined by RT-PCR, mass spectrometry, and transmission electron microscopy. Exosomes from HCV-infected cells were capable of transmitting infection to naive human hepatoma Huh7.5.1 cells and establishing a productive infection. Even with subgenomic replicons, lacking structural viral proteins, exosome-mediated transmission of HCV RNA was observed. Treatment with patient-derived IgGs showed a variable degree of neutralization of exosome-mediated infection compared with free virus. In conclusion, this study showed that hepatic exosomes can transmit productive HCV infection in vitro and are partially resistant to antibody neutralization. This discovery sheds light on neutralizing antibodies resistant to HCV transmission by exosomes as a potential immune evasion mechanism.
Six-rowed spike4
(
Vrs4
) controls spikelet determinacy and row-type in barley
Authors: Koppolu Ravi , Anwar Nadia , Sakuma Shun , Tagiri Akemi , Lundqvist Udda , Pourkheirandish Mohammad , Rutten Twan , Seiler Christiane , Himmelbach Axel , Ariyadasa Ruvini , Youssef Helmy Mohamad , Stein Nils , Sreenivasulu Nese , Komatsuda Takao , Schnurbusch Thorsten
Published: July 2013

Inflorescence architecture of barley (
Hordeum vulgare
L.) is common among the Triticeae species, which bear one to three single-flowered spikelets at each rachis internode. Triple spikelet meristem is one of the unique features of barley spikes, in which three spikelets (one central and two lateral spikelets) are produced at each rachis internode. Fertility of the lateral spikelets at triple spikelet meristem gives row-type identity to barley spikes. Six-rowed spikes show fertile lateral spikelets and produce increased grain yield per spike, compared with two-rowed spikes with sterile lateral spikelets. Thus, far, two loci governing the row-type phenotype were isolated in barley that include
Six-rowed spike1
(
Vrs1
) and
Intermedium-C
. In the present study, we isolated
Six-rowed spike4
(
Vrs4
), a barley ortholog of the maize (
Zea mays
L.) inflorescence architecture gene
RAMOSA2
(
RA2
). Eighteen coding mutations in barley
RA2
(
HvRA2
) were specifically associated with lateral spikelet fertility and loss of spikelet determinacy. Expression analyses through mRNA in situ hybridization and microarray showed that
Vrs4
(
HvRA2
) controls the row-type pathway through
Vrs1
(
HvHox1
), a negative regulator of lateral spikelet fertility in barley. Moreover,
Vrs4
may also regulate transcripts of barley
SISTER OF RAMOSA3
(
HvSRA
), a putative trehalose-6-phosphate phosphatase involved in trehalose-6-phosphate homeostasis implicated to control spikelet determinacy. Our expression data illustrated that, although RA2 is conserved among different grass species, its down-stream target genes appear to be modified in barley and possibly other species of tribe Triticeae.
Sulfatase-activated fluorophores for rapid discrimination of mycobacterial species and strains
Authors: Beatty Kimberly E. , Williams Monique , Carlson Brian L. , Swarts Benjamin M. , Warren Robin M. , van Helden Paul D. , Bertozzi Carolyn R.
Published: July 2013

Most current diagnostic tests for tuberculosis do not reveal the species or strain of pathogen causing pulmonary infection, which can lead to inappropriate treatment regimens and the spread of disease. Here, we report an assay for mycobacterial strain assignment based on genetically conserved mycobacterial sulfatases. We developed a sulfatase-activated probe, 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)–sulfate, that detects enzyme activity in native protein gels, allowing the rapid detection of sulfatases in mycobacterial lysates. This assay revealed that mycobacterial strains have distinct sulfatase fingerprints that can be used to judge both the species and lineage. Our results demonstrate the potential of enzyme-activated probes for rapid pathogen discrimination for infectious diseases.
Stimulus-dependent variability and noise correlations in cortical MT neurons
Authors: Ponce-Alvarez Adrián , Thiele Alexander , Albright Thomas D. , Stoner Gene R. , Deco Gustavo
Published: July 2013

Population codes assume that neural systems represent sensory inputs through the firing rates of populations of differently tuned neurons. However, trial-by-trial variability and noise correlations are known to affect the information capacity of neural codes. Although recent studies have shown that stimulus presentation reduces both variability and rate correlations with respect to their spontaneous level, possibly improving the encoding accuracy, whether these second order statistics are tuned is unknown. If so, second-order statistics could themselves carry information, rather than being invariably detrimental. Here we show that rate variability and noise correlation vary systematically with stimulus direction in directionally selective middle temporal (MT) neurons, leading to characteristic tuning curves. We show that such tuning emerges in a stochastic recurrent network, for a set of connectivity parameters that overlaps with a single-state scenario and multistability. Information theoretic analysis shows that second-order statistics carry information that can improve the accuracy of the population code.
Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells
Authors: Pommier Arnaud , Audemard Alexandra , Durand Aurélie , Lengagne Renée , Delpoux Arnaud , Martin Bruno , Douguet Laetitia , Le Campion Armelle , Kato Masashi , Avril Marie-Françoise , Auffray Cédric , Lucas Bruno , Prévost-Blondel Armelle
Published: July 2013

The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4+T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4+T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.
Ca
2+
release-activated Ca
2+
channel blockade as a potential tool in antipancreatitis therapy
Authors: Gerasimenko Julia V. , Gryshchenko Oleksiy , Ferdek Pawel E. , Stapleton Eloise , Hébert Tania O. G. , Bychkova Solomiia , Peng Shuang , Begg Malcolm , Gerasimenko Oleg V. , Petersen Ole H.
Published: July 2013

Alcohol-related acute pancreatitis can be mediated by a combination of alcohol and fatty acids (fatty acid ethyl esters) and is initiated by a sustained elevation of the Ca
2+
concentration inside pancreatic acinar cells ([Ca
2+
]
i
), due to excessive release of Ca
2+
stored inside the cells followed by Ca
2+
entry from the interstitial fluid. The sustained [Ca
2+
]
i
elevation activates intracellular digestive proenzymes resulting in necrosis and inflammation. We tested the hypothesis that pharmacological blockade of store-operated or Ca
2+
release-activated Ca
2+
channels (CRAC) would prevent sustained elevation of [Ca
2+
]
i
and therefore protease activation and necrosis. In isolated mouse pancreatic acinar cells, CRAC channels were activated by blocking Ca
2+
ATPase pumps in the endoplasmic reticulum with thapsigargin in the absence of external Ca
2+
. Ca
2+
entry then occurred upon admission of Ca
2+
to the extracellular solution. The CRAC channel blocker developed by GlaxoSmithKline, GSK-7975A, inhibited store-operated Ca
2+
entry in a concentration-dependent manner within the range of 1 to 50 μM (IC
50
= 3.4 μM), but had little or no effect on the physiological Ca
2+
spiking evoked by acetylcholine or cholecystokinin. Palmitoleic acid ethyl ester (100 μM), an important mediator of alcohol-related pancreatitis, evoked a sustained elevation of [Ca
2+
]
i
, which was markedly reduced by CRAC blockade. Importantly, the palmitoleic acid ethyl ester-induced trypsin and protease activity as well as necrosis were almost abolished by blocking CRAC channels. There is currently no specific treatment of pancreatitis, but our data show that pharmacological CRAC blockade is highly effective against toxic [Ca
2+
]
i
elevation, necrosis, and trypsin/protease activity and therefore has potential to effectively treat pancreatitis.
Ultradian metabolic rhythm in the diazotrophic cyanobacterium
Cyanothece
sp. ATCC 51142
Authors: Červený Jan , Sinetova Maria A. , Valledor Luis , Sherman Louis A. , Nedbal Ladislav
Published: July 2013

The unicellular cyanobacterium
Cyanothece
sp. American Type Culture Collection (ATCC) 51142 is capable of performing oxygenic photosynthesis during the day and microoxic nitrogen fixation at night. These mutually exclusive processes are possible only by temporal separation by circadian clock or another cellular program. We report identification of a temperature-dependent ultradian metabolic rhythm that controls the alternating oxygenic and microoxic processes of
Cyanothece
sp. ATCC 51142 under continuous high irradiance and in high CO
2
concentration. During the oxygenic photosynthesis phase, nitrate deficiency limited protein synthesis and CO
2
assimilation was directed toward glycogen synthesis. The carbohydrate accumulation reduced overexcitation of the photosynthetic reactions until a respiration burst initiated a transition to microoxic N
2
fixation. In contrast to the circadian clock, this ultradian period is strongly temperature-dependent: 17 h at 27 °C, which continuously decreased to 10 h at 39 °C. The cycle was expressed by an oscillatory modulation of net O
2
evolution, CO
2
uptake, pH, fluorescence emission, glycogen content, cell division, and culture optical density. The corresponding ultradian modulation was also observed in the transcription of nitrogenase-related
nifB
and
nifH
genes and in nitrogenase activities. We propose that the control by the newly identified metabolic cycle adds another rhythmic component to the circadian clock that reflects the true metabolic state depending on the actual temperature, irradiance, and CO
2
availability.
Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation
Authors: Leppänen Veli-Matti , Tvorogov Denis , Kisko Kaisa , Prota Andrea E. , Jeltsch Michael , Anisimov Andrey , Markovic-Mueller Sandra , Stuttfeld Edward , Goldie Kenneth N. , Ballmer-Hofer Kurt , Alitalo Kari
Published: July 2013

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1–3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4–7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.
Universal collapse of stress and wrinkle-to-scar transition in spherically confined crystalline sheets
Authors: Grason Gregory M. , Davidovitch Benny
Published: July 2013

Imposing curvature on crystalline sheets, such as 2D packings of colloids or proteins, or covalently bonded graphene leads to distinct types of structural instabilities. The first type involves the proliferation of localized defects that disrupt the crystalline order without affecting the imposed shape, whereas the second type consists of elastic modes, such as wrinkles and crumples, which deform the shape and also are common in amorphous polymer sheets. Here, we propose a profound link between these types of patterns, encapsulated in a universal, compression-free stress field, which is determined solely by the macroscale confining conditions. This “stress universality” principle and a few of its immediate consequences are borne out by studying a circular crystalline patch bound to a deformable spherical substrate, in which the two distinct patterns become, respectively, radial chains of dislocations (called “scars”) and radial wrinkles. The simplicity of this set-up allows us to characterize the morphologies and evaluate the energies of both patterns, from which we construct a phase diagram that predicts a wrinkle–scar transition in confined crystalline sheets at a critical value of the substrate stiffness. The construction of a unified theoretical framework that bridges inelastic crystalline defects and elastic deformations opens unique research directions. Beyond the potential use of this concept for finding energy-optimizing packings in curved topographies, the possibility of transforming defects into shape deformations that retain the crystalline structure may be valuable for a broad range of material applications, such as manipulations of graphene’s electronic structure.
Oscillatory activity in the monkey hippocampus during visual exploration and memory formation
Authors: Jutras Michael J. , Fries Pascal , Buffalo Elizabeth A.
Published: July 2013

Primates explore the visual world through the use of saccadic eye movements. Neuronal activity in the hippocampus, a structure known to be essential for memory, is modulated by this saccadic activity, but the relationship between visual exploration through saccades and memory formation is not well understood. Here, we identify a link between theta-band (3–12 Hz) oscillatory activity in the hippocampus and saccadic activity in monkeys performing a recognition memory task. As monkeys freely explored novel images, saccades produced a theta-band phase reset, and the reliability of this phase reset was predictive of subsequent recognition. In addition, enhanced theta-band power before stimulus onset predicted stronger stimulus encoding. Together, these data suggest that hippocampal theta-band oscillations act in concert with active exploration in the primate and possibly serve to establish the optimal conditions for stimulus encoding.
Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer
Authors: Bosurgi Lidia , Bernink Jochem H. , Delgado Cuevas Victor , Gagliani Nicola , Joannas Leonel , Schmid Edward T. , Booth Carmen J. , Ghosh Sourav , Rothlin Carla V.
Published: July 2013

The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling characteristic of multiple cancer hallmarks. These contrasting oncogenic and anti-inflammatory functions of Axl and Mer posit a potential paradox in terms of anticancer therapy. Here we demonstrate that azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced inflammation-associated cancer is exacerbated in mice lacking Axl and Mer. Ablation of Axl and Mer signaling is associated with increased production of proinflammatory cytokines and failure to clear apoptotic neutrophils in the intestinal lamina propria, thereby favoring a tumor-promoting environment. Interestingly, loss of these genes in the hematopoietic compartment is not associated with increased colitis. Axl and Mer are expressed in radioresistant intestinal macrophages, and the loss of these genes is associated with an increased inflammatory signature in this compartment. Our results raise the possibility of potential adverse effects of systemic anticancer therapies with Axl and Mer inhibitors, and underscore the importance of understanding their tissue and cell type-specific functions in cancer.
Unique insights into maternal mitochondrial inheritance in mice
Authors: Luo Shi-Ming , Ge Zhao-Jia , Wang Zhong-Wei , Jiang Zong-Zhe , Wang Zhen-Bo , Ouyang Ying-Chun , Hou Yi , Schatten Heide , Sun Qing-Yuan
Published: July 2013

In animals, mtDNA is always transmitted through the female and this is termed “maternal inheritance.” Recently, autophagy was reported to be involved in maternal inheritance by elimination of paternal mitochondria and mtDNA in
Caenorhabditis elegans
; moreover, by immunofluorescence, P62 and LC3 proteins were also found to colocalize to sperm mitochondria after fertilization in mice. Thus, it has been speculated that autophagy may be an evolutionary conserved mechanism for paternal mitochondrial elimination. However, by using two transgenic mouse strains, one bearing GFP-labeled autophagosomes and the other bearing red fluorescent protein-labeled mitochondria, we demonstrated that autophagy did not participate in the postfertilization elimination of sperm mitochondria in mice. Although P62 and LC3 proteins congregated to sperm mitochondria immediately after fertilization, sperm mitochondria were not engulfed and ultimately degraded in lysosomes until P62 and LC3 proteins disengaged from sperm mitochondria. Instead, sperm mitochondria unevenly distributed in blastomeres during cleavage and persisted in several cells until the morula stages. Furthermore, by using single sperm mtDNA PCR, we observed that most motile sperm that had reached the oviduct for fertilization had eliminated their mtDNA, leaving only vacuolar mitochondria. However, if sperm with remaining mtDNA entered the zygote, mtDNA was not eliminated and could be detected in newborn mice. Based on these results, we conclude that, in mice, maternal inheritance of mtDNA is not an active process of sperm mitochondrial and mtDNA elimination achieved through autophagy in early embryos, but may be a passive process as a result of prefertilization sperm mtDNA elimination and uneven mitochondrial distribution in embryos.
Testing the diffusing boundary model for the helix–coil transition in peptides
Authors: Neumaier Sabine , Reiner Andreas , Büttner Maren , Fierz Beat , Kiefhaber Thomas
Published: July 2013

The dynamics of peptide α-helices have been studied extensively for many years, and the kinetic mechanism of the helix–coil dynamics has been discussed controversially. Recent experimental results have suggested that equilibrium helix–coil dynamics are governed by movement of the helix/coil boundary along the peptide chain, which leads to slower unfolding kinetics in the helix center compared with the helix ends and position-independent helix formation kinetics. We tested this diffusion of boundary model in helical peptides of different lengths by triplet-triplet energy transfer measurements and compared the data with simulations based on a kinetic linear Ising model. The results show that boundary diffusion in helical peptides can be described by a classical, Einstein-type, 1D diffusion process with a diffusion coefficient of 2.7⋅10
7
(amino acids)
2
/s or 6.1⋅10
−9
cm
2
/s. In helices with a length longer than about 40 aa, helix unfolding by coil nucleation in a helical region occurs frequently in addition to boundary diffusion. Boundary diffusion is slowed down by helix-stabilizing capping motifs at the helix ends in agreement with predictions from the kinetic linear Ising model. We further tested local and nonlocal effects of amino acid replacements on helix–coil dynamics. Single amino acid replacements locally affect folding and unfolding dynamics with a
ϕ

f

-value of 0.35, which shows that interactions leading to different helix propensities for different amino acids are already partially present in the transition state for helix formation. Nonlocal effects of amino acid replacements only influence helix unfolding (
ϕ

f

= 0) in agreement with a diffusing boundary mechanism.
Impaired complex IV activity in response to loss of LRPPRC function can be compensated by mitochondrial hyperfusion
Authors: Rolland Stéphane G. , Motori Elisa , Memar Nadin , Hench Jürgen , Frank Stephan , Winklhofer Konstanze F. , Conradt Barbara
Published: July 2013

Significance

Mitochondria, the powerhouses of the cell, constantly change their shape by fusing and dividing. How these two opposite processes are controlled remains unclear. In our study, we identified the
Caenorhabditis elegans
homolog of the human mitochondrial protein LRPPRC (leucine-rich pentatricopeptide repeat containing), which has been previously associated with the neurodegenerative French Canadian Leigh Syndrome. Analysis of this protein revealed an evolutionary conserved pathway that regulates mitochondrial shape. Specifically, we show that mitochondria transiently form a highly connected network to compensate for a decrease of the activity of the complex IV of the electron transport chain.
A riboswitch-regulated antisense RNA in
Listeria monocytogenes
Authors: Mellin J. R. , Tiensuu Teresa , Bécavin Christophe , Gouin Edith , Johansson Jörgen , Cossart Pascale
Published: July 2013

Riboswitches are ligand-binding elements located in 5′ untranslated regions of messenger RNAs, which regulate expression of downstream genes. In
Listeria monocytogenes
, a vitamin B
12
-binding (B
12
) riboswitch was identified, not upstream of a gene but downstream, and antisense to the adjacent gene,
pocR,
suggesting it might regulate
pocR
in a nonclassical manner. In
Salmonella enterica,
PocR is a transcription factor that is activated by 1,2-propanediol, and subsequently activates expression of the
pdu
genes. The
pdu
genes mediate propanediol catabolism and are implicated in pathogenesis. As enzymes involved in propanediol catabolism require B
12
as a cofactor, we hypothesized that the
Listeria
B
12
riboswitch might be involved in
pocR
regulation. Here we demonstrate that the B
12
riboswitch is transcribed as part of a noncoding antisense RNA, herein named AspocR. In the presence of B
12
, the riboswitch induces transcriptional termination, causing
aspocR
to be transcribed as a short transcript. In contrast, in the absence of B
12
,
aspocR
is transcribed as a long antisense RNA, which inhibits
pocR
expression. Regulation by AspocR ensures that
pocR
, and consequently the
pdu
genes, are maximally expressed only when both propanediol and B
12
are present. Strikingly, AspocR can inhibit
pocR
expression
in trans
, suggesting it acts through a direct interaction with
pocR
mRNA. Together, this study demonstrates how
pocR
and the
pdu
genes can be regulated by B
12
in bacteria and extends the classical definition of riboswitches from elements governing solely the expression of mRNAs to a wider role in controlling transcription of noncoding RNAs.
Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1
Authors: Pace Craig S. , Song Ruijiang , Ochsenbauer Christina , Andrews Chasity D. , Franco David , Yu Jian , Oren Deena A. , Seaman Michael S. , Ho David D.
Published: July 2013

In the absence of an effective HIV-1 vaccine, passive immunization using broadly neutralizing Abs or Ab-like molecules could provide an alternative to the daily administration of oral antiretroviral agents that has recently shown promise as preexposure prophylaxis. Currently, no single broadly neutralizing Ab (bNAb) or combination of bNAbs neutralizes all HIV-1 strains at practically achievable concentrations in vivo.To address this problem, we created bispecific Abs that combine the HIV-1 inhibitory activity of ibalizumab (iMab), a humanized mAb directed to domain 2 of human CD4, with that of anti-gp120 bNAbs. These bispecific bNAbs (BibNAbs) exploit iMab’s potent anti–HIV-1 activity and demonstrated clinical efficacy and safety to anchor and thereby concentrate a second broadly neutralizing agent at the site of viral entry. Two BibNabs, PG9-iMab and PG16-iMab, exhibit exceptional breadth and potency, neutralizing 100% of the 118 viruses tested at low picomolar concentrations, including viruses resistant to both parental mAbs. The enhanced potency of these BibNAbs was entirely dependent on CD4 anchoring, not on membrane anchoring per se, and required optimal Ab geometry and linker length. We propose that iMab-based BibNAbs, such as PG9-iMab and PG16-iMab, are promising candidates for passive immunization to prevent HIV-1 infection.
Context-dependent hierarchies in pigeons
Authors: Nagy Máté , Vásárhelyi Gábor , Pettit Benjamin , Roberts-Mariani Isabella , Vicsek Tamás , Biro Dora
Published: July 2013

Hierarchical organization is widespread in the societies of humans and other animals, both in social structure and in decision-making contexts. In the case of collective motion, the majority of case studies report that dominant individuals lead group movements, in agreement with the common conflation of the terms “dominance” and “leadership.” From a theoretical perspective, if social relationships influence interactions during collective motion, then social structure could also affect leadership in large, swarm-like groups, such as fish shoals and bird flocks. Here we use computer-vision–based methods and miniature GPS tracking to study, respectively, social dominance and in-flight leader–follower relations in pigeons. In both types of behavior we find hierarchically structured networks of directed interactions. However, instead of being conflated, dominance and leadership hierarchies are completely independent of each other. Although dominance is an important aspect of variation among pigeons, correlated with aggression and access to food, our results imply that the stable leadership hierarchies in the air must be based on a different set of individual competences. In addition to confirming the existence of independent and context-specific hierarchies in pigeons, we succeed in setting out a robust, scalable method for the automated analysis of dominance relationships, and thus of social structure, applicable to many species. Our results, as well as our methods, will help to incorporate the broader context of animal social organization into the study of collective behavior.
In vivo synaptic recovery following optogenetic hyperstimulation
Authors: Kittelmann Maike , Liewald Jana F. , Hegermann Jan , Schultheis Christian , Brauner Martin , Steuer Costa Wagner , Wabnig Sebastian , Eimer Stefan , Gottschalk Alexander
Published: July 2013

Significance

Chemical synapses are key contact points in the nervous system, where signals are transmitted between neurons. These signals, small chemical molecules, are released from membranous synaptic vesicles by fusion with the neuronal membrane. Synaptic vesicle membrane and proteins need to be recycled to support ongoing transmission. Upon seizure, massive amounts of synaptic vesicles fuse, while neurons become exhausted and need to recover. We used optical stimulation of neurons in live
Caenorhabditis elegans
nematodes to induce extreme neuronal activity and followed processes underlying the recovery progression at behavioral, genetic, physiological, and ultrastructural levels in an intact animal.
Neuropathic and inflammatory pain are modulated by tuberoinfundibular peptide of 39 residues
Authors: Dimitrov Eugene L. , Kuo Jonathan , Kohno Kenji , Usdin Ted B.
Published: July 2013

Nociceptive information is modulated by a large number of endogenous signaling agents that change over the course of recovery from injury. This plasticity makes understanding regulatory mechanisms involved in descending inhibition of pain scientifically and clinically important. Neurons that synthesize the neuropeptide TIP39 project to many areas that modulate nociceptive information. These areas are enriched in its receptor, the parathyroid hormone 2 receptor (PTH2R). We previously found that TIP39 affects several acute nociceptive responses, leading us to now investigate its potential role in chronic pain. Following nerve injury, both PTH2R and TIP39 knockout mice developed less tactile and thermal hypersensitivity than controls and returned to baseline sensory thresholds faster. Effects of hindpaw inflammatory injury were similarly decreased in knockout mice. Blockade of α-2 adrenergic receptors increased the tactile and thermal sensitivity of apparently recovered knockout mice, returning it to levels of neuropathic controls. Mice with locus coeruleus (LC) area injection of lentivirus encoding a secreted PTH2R antagonist had a rapid, α-2 reversible, apparent recovery from neuropathic injury similar to the knockout mice. Ablation of LC area glutamatergic neurons led to local PTH2R-ir loss, and barley lectin was transferred from local glutamatergic neurons to GABA interneurons that surround the LC. These results suggest that TIP39 signaling modulates sensory thresholds via effects on glutamatergic transmission to brainstem GABAergic interneurons that innervate noradrenergic neurons. TIP39’s normal role may be to inhibit release of hypoalgesic amounts of norepinephrine during chronic pain. The neuropeptide may help maintain central sensitization, which could serve to enhance guarding behavior.
Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria
Authors: An Hyun-Jung , Cho Geunyoung , Lee Jie-Oh , Paik Sang-Gi , Kim Young Sang , Lee Hayyoung
Published: July 2013

The activity and morphology of mitochondria are maintained by dynamic fusion and fission processes regulated by a group of proteins residing in, or attached to, their inner and outer membranes. Hypoxia-induced gene domain protein-1a (Higd-1a)/HIMP1-a/HIG1, a mitochondrial inner membrane protein, plays a role in cell survival under hypoxic conditions. In the present study, we showed that Higd-1a depletion resulted in mitochondrial fission, depletion of mtDNA, disorganization of cristae, and growth retardation. We demonstrated that Higd-1a functions by specifically binding to Optic atrophy 1 (Opa1), a key element in fusion of the inner membrane. In the absence of Higd-1a, Opa1 was cleaved, resulting in the loss of its long isoforms and accumulation of small soluble forms. The small forms of Opa1 do not interact with Higd-1a, suggesting that a part of Opa1 in or proximal to the membrane is required for that interaction. Opa1 cleavage, mitochondrial fission, and cell death induced by dissipation of the mitochondrial membrane potential were significantly inhibited by ectopic expression of Higd-1a. Furthermore, growth inhibition due to Higd-1a depletion could be overcome by overexpression of a noncleavable form of Opa1. Collectively, our observations demonstrate that Higd-1a inhibits Opa1 cleavage and is required for mitochondrial fusion by virtue of its interaction with Opa1.