bluuebunny/crossref_metadata_2025 huggingface dataset:
Cacao use and the San Lorenzo Olmec
Authors: Powis Terry G. , Cyphers Ann , Gaikwad Nilesh W. , Grivetti Louis , Cheong Kong
Published: May 2011

Mesoamerican peoples had a long history of cacao use—spanning more than 34 centuries—as confirmed by previous identification of cacao residues on archaeological pottery from Paso de la Amada on the Pacific Coast and the Olmec site of El Manatí on the Gulf Coast. Until now, comparable evidence from San Lorenzo, the premier Olmec capital, was lacking. The present study of theobromine residues confirms the continuous presence and use of cacao products at San Lorenzo between 1800 and 1000 BCE, and documents assorted vessels forms used in its preparation and consumption. One elite context reveals cacao use as part of a mortuary ritual for sacrificial victims, an event that occurred during the height of San Lorenzo's power.
Anuran radiations and the evolution of tadpole morphospace
Authors: Roelants Kim , Haas Alexander , Bossuyt Franky
Published: May 2011

Anurans (frogs and toads) are unique among land vertebrates in possessing a free-living larval stage that, parallel to adult frogs, diversified into an impressive range of ecomorphs. The tempo and mode at which tadpole morphology evolved through anuran history as well as its relationship to lineage diversification remain elusive. We used a molecular phylogenetic framework to examine patterns of morphological evolution in tadpoles in light of observed episodes of accelerated lineage diversification. Our reconstructions show that the expansion of tadpole morphospace during the basal anuran radiation in the Triassic/Early Jurassic was unparalleled by the basal neobatrachian radiation in the Late Jurassic/Early Cretaceous or any subsequent radiation in the Late Cretaceous/Early Tertiary. Comparative analyses of radiation episodes indicate that the slowdown of morphospace expansion was caused not only by a drop in evolutionary rate after the basal anuran radiation but also by an overall increase in homoplasy in the characters that did evolve during later radiations. The overlapping sets of evolving characters among more recent radiations may have enhanced tadpole diversity by creating unique combinations of homoplastic traits, but the lack of innovative character changes prevented the exploration of fundamental regions in morphospace. These complex patterns transcend the four traditionally recognized tadpole morphotypes and apply to most tissue types and body parts.
Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to
mda
-7/IL-24–mediated toxicity
Authors: Dash Rupesh , Azab Belal , Quinn Bridget A. , Shen Xuening , Wang Xiang-Yang , Das Swadesh K. , Rahmani Mohamed , Wei Jun , Hedvat Michael , Dent Paul , Dmitriev Igor P. , Curiel David T. , Grant Steven , Wu Bainan , Stebbins John L. , Pellecchia Maurizio , Reed John C. , Sarkar Devanand , Fisher Paul B.
Published: May 2011

Limited options are available for treating patients with advanced prostate cancer (PC). Melanoma differentiation associated gene-7/interleukin-24 (
mda
-7/IL-24), an IL-10 family cytokine, exhibits pleiotropic anticancer activities without adversely affecting normal cells. We previously demonstrated that suppression of the prosurvival Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1), is required for
mda
-7/IL-24–mediated apoptosis of prostate carcinomas. Here we demonstrate that pharmacological inhibition of Mcl-1 expression with the unique Apogossypol derivative BI-97C1, also called Sabutoclax, is sufficient to sensitize prostate tumors to
mda
-7/IL-24–induced apoptosis, whereas ABT-737, which lacks efficacy in inhibiting Mcl-1, does not sensitize
mda
-7/IL-24–mediated cytotoxicity. A combination regimen of tropism-modified adenovirus delivered
mda
-7/IL-24 (Ad.5/3-
mda
-7) and BI-97C1 enhances cytotoxicity in human PC cells, including those resistant to
mda
-7/IL-24 or BI-97C1 alone. The combination regimen causes autophagy that facilitates NOXA- and Bim-induced and Bak/Bax-mediated mitochondrial apoptosis. Treatment with Ad.5/3-
mda
-7 and BI-97C1 significantly inhibits the growth of human PC xenografts in nude mice and spontaneously induced PC in Hi-myc transgenic mice. Tumor growth inhibition correlated with increased TUNEL staining and decreased Ki-67 expression in both PC xenografts and prostates of Hi-myc mice. These findings demonstrate that pharmacological inhibition of Mcl-1 with the Apogossypol derivative, BI-97C1, sensitizes human PCs to
mda
-7/IL-24–mediated cytotoxicity, thus potentially augmenting the therapeutic benefit of this combinatorial approach toward PC.
Optogenetic-guided cortical plasticity after nerve injury
Authors: Li Nan , Downey John E. , Bar-Shir Amnon , Gilad Assaf A. , Walczak Piotr , Kim Heechul , Joel Suresh E. , Pekar James J. , Thakor Nitish V. , Pelled Galit
Published: May 2011

Peripheral nerve injury causes sensory dysfunctions that are thought to be attributable to changes in neuronal activity occurring in somatosensory cortices both contralateral and ipsilateral to the injury. Recent studies suggest that distorted functional response observed in deprived primary somatosensory cortex (S1) may be the result of an increase in inhibitory interneuron activity and is mediated by the transcallosal pathway. The goal of this study was to develop a strategy to manipulate and control the transcallosal activity to facilitate appropriate plasticity by guiding the cortical reorganization in a rat model of sensory deprivation. Since transcallosal fibers originate mainly from excitatory pyramidal neurons somata situated in laminae III and V, the excitatory neurons in rat S1 were engineered to express halorhodopsin, a light-sensitive chloride pump that triggers neuronal hyperpolarization. Results from electrophysiology, optical imaging, and functional MRI measurements are concordant with that within the deprived S1, activity in response to intact forepaw electrical stimulation was significantly increased by concurrent illumination of halorhodopsin over the healthy S1. Optogenetic manipulations effectively decreased the adverse inhibition of deprived cortex and revealed the major contribution of the transcallosal projections, showing interhemispheric neuroplasticity and thus, setting a foundation to develop improved rehabilitation strategies to restore cortical functions.
F-box protein MAX2 has dual roles in karrikin and strigolactone signaling in
Arabidopsis thaliana
Authors: Nelson David C. , Scaffidi Adrian , Dun Elizabeth A. , Waters Mark T. , Flematti Gavin R. , Dixon Kingsley W. , Beveridge Christine A. , Ghisalberti Emilio L. , Smith Steven M.
Published: May 2011

Smoke is an important abiotic cue for plant regeneration in postfire landscapes. Karrikins are a class of compounds discovered in smoke that promote seed germination and influence early development of many plants by an unknown mechanism. A genetic screen for karrikin-insensitive mutants in
Arabidopsis thaliana
revealed that karrikin signaling requires the F-box protein MAX2, which also mediates responses to the structurally-related strigolactone family of phytohormones. Karrikins and the synthetic strigolactone GR24 trigger similar effects on seed germination, seedling photomorphogenesis, and expression of a small set of genes during these developmental stages. Karrikins also repress
MAX4
and
IAA1
transcripts, which show negative feedback regulation by strigolactone. We demonstrate that all of these common responses are abolished in
max2
mutants. Unlike strigolactones, however, karrikins do not inhibit shoot branching in
Arabidopsis
or pea, indicating that plants can distinguish between these signals. These results suggest that a
MAX2
-dependent signal transduction mechanism was adapted to mediate responses to two chemical cues with distinct roles in plant ecology and development.
Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition
Authors: Krawczyk Przemek M. , Eppink Berina , Essers Jeroen , Stap Jan , Rodermond Hans , Odijk Hanny , Zelensky Alex , van Bree Chris , Stalpers Lukas J. , Buist Marrije R. , Soullié Thomas , Rens Joost , Verhagen Hence J. M. , O'Connor Mark J. , Franken Nicolaas A. P. , ten Hagen Timo L. M. , Kanaar Roland , Aten Jacob A.
Published: May 2011

Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41–42.5 °C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized on-demand induction of HR deficiency, an approach that we term induced synthetic lethality.
Genomic insights into the physiology and ecology of the marine filamentous cyanobacterium
Lyngbya majuscula
Authors: Jones Adam C. , Monroe Emily A. , Podell Sheila , Hess Wolfgang R. , Klages Sven , Esquenazi Eduardo , Niessen Sherry , Hoover Heather , Rothmann Michael , Lasken Roger S. , Yates John R. , Reinhardt Richard , Kube Michael , Burkart Michael D. , Allen Eric E. , Dorrestein Pieter C. , Gerwick William H. , Gerwick Lena
Published: May 2011

Filamentous cyanobacteria of the genus
Lyngbya
are important contributors to coral reef ecosystems, occasionally forming dominant cover and impacting the health of many other co-occurring organisms. Moreover, they are extraordinarily rich sources of bioactive secondary metabolites, with 35% of all reported cyanobacterial natural products deriving from this single pantropical genus. However, the true natural product potential and life strategies of
Lyngbya
strains are poorly understood because of phylogenetic ambiguity, lack of genomic information, and their close associations with heterotrophic bacteria and other cyanobacteria. To gauge the natural product potential of
Lyngbya
and gain insights into potential microbial interactions, we sequenced the genome of
Lyngbya majuscula
3L, a Caribbean strain that produces the tubulin polymerization inhibitor curacin A and the molluscicide barbamide, using a combination of Sanger and 454 sequencing approaches. Whereas ∼293,000 nucleotides of the draft genome are putatively dedicated to secondary metabolism, this is far too few to encode a large suite of
Lyngbya
metabolites, suggesting
Lyngbya
metabolites are strain specific and may be useful in species delineation. Our analysis revealed a complex gene regulatory network, including a large number of sigma factors and other regulatory proteins, indicating an enhanced ability for environmental adaptation or microbial associations. Although
Lyngbya
species are reported to fix nitrogen, nitrogenase genes were not found in the genome or by PCR of genomic DNA. Subsequent growth experiments confirmed that
L. majuscula
3L is unable to fix atmospheric nitrogen. These unanticipated life history characteristics challenge current views of the genus
Lyngbya
.
Synchrotron-aided reconstruction of the conodont feeding apparatus and implications for the mouth of the first vertebrates
Authors: Goudemand Nicolas , Orchard Michael J. , Urdy Séverine , Bucher Hugo , Tafforeau Paul
Published: May 2011

The origin of jaws remains largely an enigma that is best addressed by studying fossil and living jawless vertebrates. Conodonts were eel-shaped jawless animals, whose vertebrate affinity is still disputed. The geometrical analysis of exceptional three-dimensionally preserved clusters of oro-pharyngeal elements of the Early Triassic
Novispathodus
, imaged using propagation phase-contrast X-ray synchrotron microtomography, suggests the presence of a pulley-shaped lingual cartilage similar to that of extant cyclostomes within the feeding apparatus of euconodonts (“true” conodonts). This would lend strong support to their interpretation as vertebrates and demonstrates that the presence of such cartilage is a plesiomorphic condition of crown vertebrates.
Lipid cubic phase as a membrane mimetic for integral membrane protein enzymes
Authors: Li Dianfan , Caffrey Martin
Published: May 2011

The lipidic cubic mesophase has been used to crystallize important membrane proteins for high-resolution structure determination. To date, however, no integral membrane enzymes have yielded to this method, the
in meso
. For a crystal structure to be meaningful the target protein must be functional. Using the
in meso
method with a membrane enzyme requires that the protein is active in the mesophase that grows crystals. Because the cubic phase is sticky and viscous and is bicontinuous topologically, quantitatively assessing enzyme activity
in meso
is a challenge. Here, we describe a procedure for characterizing the catalytic properties of the integral membrane enzyme, diacylglycerol kinase, reconstituted into the bilayer of the lipidic cubic phase. The kinase activity of this elusive crystallographic target was monitored spectrophotometrically using a coupled assay in a high-throughput, 96-well plate format.
In meso
, the enzyme exhibits classic Michaelis–Menten kinetics and works with a range of lipid substrates. The fact that the enzyme and its lipid substrate and product remain confined to the porous mesophase while its water-soluble substrate and product are free to partition into the aqueous bathing solution suggests a general and convenient approach for characterizing membrane enzymes that function with lipids in a membrane-like environment. The distinctive rheology of the cubic phase means that a procedural step to physically separate substrate from product is not needed. Because of its open, bicontinuous nature, the cubic phase offers the added benefit that the protein is accessible for assay from both sides of the membrane.
Quantitative descriptions of generalized arousal, an elementary function of the vertebrate brain
Authors: Quinkert Amy Wells , Vimal Vivek , Weil Zachary M. , Reeke George N. , Schiff Nicholas D. , Banavar Jayanth R. , Pfaff Donald W.
Published: May 2011

We review a concept of the most primitive, fundamental function of the vertebrate CNS, generalized arousal (GA). Three independent lines of evidence indicate the existence of GA: statistical, genetic, and mechanistic. Here we ask, is this concept amenable to quantitative analysis? Answering in the affirmative, four quantitative approaches have proven useful: (i) factor analysis, (ii) information theory, (iii) deterministic chaos, and (iv) application of a Gaussian equation. It strikes us that, to date, not just one but at least four different quantitative approaches seem necessary for describing different aspects of scientific work on GA.
Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease
Authors: Arboleda-Velasquez Joseph F. , Manent Jan , Lee Jeong Hyun , Tikka Saara , Ospina Carolina , Vanderburg Charles R. , Frosch Matthew P. , Rodríguez-Falcón Manuel , Villen Judit , Gygi Steven , Lopera Francisco , Kalimo Hannu , Moskowitz Michael A. , Ayata Cenk , Louvi Angeliki , Artavanis-Tsakonas Spyros
Published: May 2011

The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with mutations in the Notch 3 receptor. CADASIL pathology is characterized by vascular smooth muscle cell degeneration and accumulation of diagnostic granular osmiophilic material (GOM) in vessels. The functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease and GOM accumulation remain enigmatic. To gain insight into how Notch 3 function is linked to CADASIL pathophysiology, we studied two phenotypically distinct mutations, C455R and R1031C, respectively associated with early and late onset of stroke, by using hemodynamic analyses in transgenic mouse models, receptor activity assays in cell culture, and proteomic examination of postmortem human tissue. We demonstrate that the C455R and R1031C mutations define different hypomorphic activity states of Notch 3, a property linked to ischemic stroke susceptibility in mouse models we generated. Importantly, these mice develop osmiophilic deposits and other age-dependent phenotypes that parallel remarkably the human condition. Proteomic analysis of human brain vessels, carrying the same CADASIL mutations, identified clusterin and collagen 18 α1/endostatin as GOM components. Our findings link loss of Notch signaling with ischemic cerebral small-vessel disease, a prevalent human condition. We determine that CADASIL pathophysiology is associated with hypomorphic Notch 3 function in vascular smooth muscle cells and implicate the accumulation of clusterin and collagen 18 α1/endostatin in brain vessel pathology.
Measuring the evolutionary rate of protein–protein interaction
Authors: Qian Wenfeng , He Xionglei , Chan Edwin , Xu Huailiang , Zhang Jianzhi
Published: May 2011

Despite our extensive knowledge about the rate of protein sequence evolution for thousands of genes in hundreds of species, the corresponding rate of protein function evolution is virtually unknown, especially at the genomic scale. This lack of knowledge is primarily because of the huge diversity in protein function and the consequent difficulty in gauging and comparing rates of protein function evolution. Nevertheless, most proteins function through interacting with other proteins, and protein–protein interaction (PPI) can be tested by standard assays. Thus, the rate of protein function evolution may be measured by the rate of PPI evolution. Here, we experimentally examine 87 potential interactions betweenKluyveromyces waltiiproteins, whose one to one orthologs in the related budding yeastSaccharomyces cerevisiaehave been reported to interact. Combining our results with available data from other eukaryotes, we estimate that the evolutionary rate of protein interaction is (2.6 ± 1.6) × 10−10per PPI per year, which is three orders of magnitude lower than the rate of protein sequence evolution measured by the number of amino acid substitutions per protein per year. The extremely slow evolution of protein molecular function may account for the remarkable conservation of life at molecular and cellular levels and allow for studying the mechanistic basis of human disease in much simpler organisms.
Concerted electron-proton transfer in the optical excitation of hydrogen-bonded dyes
Authors: Westlake Brittany C. , Brennaman M. Kyle , Concepcion Javier J. , Paul Jared J. , Bettis Stephanie E. , Hampton Shaun D. , Miller Stephen A. , Lebedeva Natalia V. , Forbes Malcolm D. E. , Moran Andrew M. , Meyer Thomas J. , Papanikolas John M.
Published: May 2011

The simultaneous, concerted transfer of electrons and protons—electron-proton transfer (EPT)—is an important mechanism utilized in chemistry and biology to avoid high energy intermediates. There are many examples of thermally activated EPT in ground-state reactions and in excited states following photoexcitation and thermal relaxation. Here we report application of ultrafast excitation with absorption and Raman monitoring to detect a photochemically driven EPT process (photo-EPT). In this process, both electrons and protons are transferred during the absorption of a photon. Photo-EPT is induced by intramolecular charge-transfer (ICT) excitation of hydrogen-bonded-base adducts with either a coumarin dye or 4-nitro-4′-biphenylphenol. Femtosecond transient absorption spectral measurements following ICT excitation reveal the appearance of two spectroscopically distinct states having different dynamical signatures. One of these states corresponds to a conventional ICT excited state in which the transferring H
+
is initially associated with the proton donor. Proton transfer to the base (B) then occurs on the picosecond time scale. The other state is an ICT-EPT photoproduct. Upon excitation it forms initially in the nuclear configuration of the ground state by application of the Franck–Condon principle. However, due to the change in electronic configuration induced by the transition, excitation is accompanied by proton transfer with the protonated base formed with a highly elongated
+
H─B bond. Coherent Raman spectroscopy confirms the presence of a vibrational mode corresponding to the protonated base in the optically prepared state.
N
-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice
Authors: Sompol Pradoldej , Liu Xia , Baba Kenkichi , Paul Ketema N. , Tosini Gianluca , Iuvone P. Michael , Ye Keqiang
Published: May 2011

N
-acetylserotonin (NAS), the immediate precursor of melatonin, the pineal gland indole, is regulated in a circadian rhythm. NAS swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. Here we show that NAS regulates an early event of neurogenesis by increasing neuronal progenitor cell (NPC) proliferation. Subchronic and chronic NAS administration induces NPC proliferation in adult mice. Chronic NAS treatment triggers TrkB receptor activation and its downstream signaling in NPCs. Blockade of TrkB abolishes NAS-elicited neurogenesis in TrkBF616A knockin mice, suggesting that TrkB activation is essential for the effect of NAS-induced NPC proliferation. Moreover, NAS induces NPC proliferation in both active and sleeping phases of the mice. Strikingly, NAS significantly enhances NPC proliferation in sleep-deprived mice. Thus, our finding demonstrates a unique function of NAS in promoting robust NPC proliferation, which may contribute to hippocampal plasticity during sleeping period.
Active transport, substrate specificity, and methylation of Hg(II) in anaerobic bacteria
Authors: Schaefer Jeffra K. , Rocks Sara S. , Zheng Wang , Liang Liyuan , Gu Baohua , Morel François M. M.
Published: May 2011

The formation of methylmercury (MeHg), which is biomagnified in aquatic food chains and poses a risk to human health, is effected by some iron- and sulfate-reducing bacteria (FeRB and SRB) in anaerobic environments. However, very little is known regarding the mechanism of uptake of inorganic Hg by these organisms, in part because of the inherent difficulty in measuring the intracellular Hg concentration. By using the FeRB
Geobacter sulfurreducens
and the SRB
Desulfovibrio desulfuricans
ND132 as model organisms, we demonstrate that Hg(II) uptake occurs by active transport. We also establish that Hg(II) uptake by
G. sulfurreducens
is highly dependent on the characteristics of the thiols that bind Hg(II) in the external medium, with some thiols promoting uptake and methylation and others inhibiting both. The Hg(II) uptake system of
D. desulfuricans
has a higher affinity than that of
G. sulfurreducens
and promotes Hg methylation in the presence of stronger complexing thiols. We observed a tight coupling between Hg methylation and MeHg export from the cell, suggesting that these two processes may serve to avoid the build up and toxicity of cellular Hg. Our results bring up the question of whether cellular Hg uptake is specific for Hg(II) or accidental, occurring via some essential metal importer. Our data also point at Hg(II) complexation by thiols as an important factor controlling Hg methylation in anaerobic environments.
Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress
Authors: Shaw Alice T. , Winslow Monte M. , Magendantz Margaret , Ouyang Chensi , Dowdle James , Subramanian Aravind , Lewis Timothy A. , Maglathin Rebecca L. , Tolliday Nicola , Jacks Tyler
Published: May 2011

Activating
K-RAS
mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic

K-ras
G12D

allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras–expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras–driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies.
Mitochondrial DNA polymerase editing mutation,

Polg
D257A

, reduces the diabetic phenotype of Akita male mice by suppressing appetite
Authors: Fox Raymond , Kim Hyung-Suk , Reddick Robert L. , Kujoth Gregory C. , Prolla Tomas A. , Tsutsumi Shuichi , Wada Youichiro , Smithies Oliver , Maeda Nobuyo
Published: May 2011

Diabetes and the development of its complications have been associated with mitochondrial DNA (mtDNA) dysfunction, but causal relationships remain undetermined. With the objective of testing whether increased mtDNA mutations exacerbate the diabetic phenotype, we have compared mice heterozygous for the Akita diabetogenic mutation (Akita) with mice homozygous for the D257A mutation in mitochondrial DNA polymerase gamma (Polg) or with mice having both mutations (Polg-Akita). The Polg-D257A protein is defective in proofreading and increases mtDNA mutations. At 3 mo of age, the Polg-Akita and Akita male mice were equally hyperglycemic. Unexpectedly, as the Polg-Akita males aged to 9 mo, their diabetic symptoms decreased. Thus, their hyperglycemia, hyperphagia and urine output declined significantly. The decrease in their food intake was accompanied by increased plasma leptin and decreased plasma ghrelin, while hypothalamic expression of the orexic gene, neuropeptide Y, was lower and expression of the anorexic gene, proopiomelanocortin, was higher. Testis function progressively worsened with age in the double mutants, and plasma testosterone levels in 9-mo-old Polg-Akita males were significantly reduced compared with Akita males. The hyperglycemia and hyperphagia returned in aged Polg-Akita males after testosterone administration. Hyperglycemia-associated distal tubular damage in the kidney also returned, and Polg-D257A-associated proximal tubular damage was enhanced. The mild diabetes of female Akita mice was not affected by the Polg-D257A mutation. We conclude that reduced diabetic symptoms of aging Polg-Akita males results from appetite suppression triggered by decreased testosterone associated with damage to the Leydig cells of the testis.
Titin isn't a sleeping giant
Authors: Short Ben
Published: May 2011

Photobleaching reveals that the backbone of muscle myofibrils is surprisingly mobile.
Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology
Authors: Chen Chiung-Ya , Lin Chia-Wen , Chang Chiung-Ying , Jiang Si-Tse , Hsueh Yi-Ping
Published: May 2011

Dendritic arborization is a critical neuronal differentiation process. Here, we demonstrate that syndecan-2 (Sdc2), a synaptic heparan sulfate proteoglycan that triggers dendritic filopodia and spine formation, regulates dendritic arborization in cultured hippocampal neurons. This process is controlled by sterile α and TIR motif–containing 1 protein (Sarm1), a negative regulator of Toll-like receptor 3 (TLR3) in innate immunity signaling. We show that Sarm1 interacts with and receives signal from Sdc2 and controls dendritic arborization through the MKK4–JNK pathway. In Sarm1 knockdown mice, dendritic arbors of neurons were less complex than those of wild-type littermates. In addition to acting downstream of Sdc2, Sarm1 is expressed earlier than Sdc2, which suggests that it has multiple roles in neuronal morphogenesis. Specifically, it is required for proper initiation and elongation of dendrites, axonal outgrowth, and neuronal polarization. These functions likely involve Sarm1-mediated regulation of microtubule stability, as Sarm1 influenced tubulin acetylation. This study thus reveals the molecular mechanism underlying the action of Sarm1 in neuronal morphogenesis.
NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway
Authors: Habbig Sandra , Bartram Malte P. , Müller Roman U. , Schwarz Ricarda , Andriopoulos Nikolaos , Chen Shuhua , Sägmüller Josef G. , Hoehne Martin , Burst Volker , Liebau Max C. , Reinhardt H. Christian , Benzing Thomas , Schermer Bernhard
Published: May 2011

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.
Tuberous sclerosis complex and Myc coordinate the growth and division ofDrosophilaintestinal stem cells
Authors: Amcheslavsky Alla , Ito Naoto , Jiang Jin , Ip Y. Tony
Published: May 2011

Intestinal stem cells (ISCs) in the adult Drosophila melanogaster midgut can respond to damage and support repair. We demonstrate in this paper that the tuberous sclerosis complex (TSC) plays a critical role in balancing ISC growth and division. Previous studies have shown that imaginal disc cells that are mutant for TSC have increased rates of growth and division. However, we report in this paper that loss of TSC in the adult Drosophila midgut results in the formation of much larger ISCs that have halted cell division. These mutant ISCs expressed proper stem cell markers, did not differentiate, and had defects in multiple steps of the cell cycle. Slowing the growth by feeding rapamycin or reducing Myc was sufficient to rescue the division defect. The TSC mutant guts had a thinner epithelial structure than wild-type tissues, and the mutant flies were more susceptible to tissue damage. Therefore, we have uncovered a context-dependent phenotype of TSC mutants in adult ISCs, such that the excessive growth leads to inhibition of division.
miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice
Authors: Boldin Mark P. , Taganov Konstantin D. , Rao Dinesh S. , Yang Lili , Zhao Jimmy L. , Kalwani Manorama , Garcia-Flores Yvette , Luong Mui , Devrekanli Asli , Xu Jessica , Sun Guizhen , Tay Jia , Linsley Peter S. , Baltimore David
Published: May 2011

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.
Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection
Authors: Brigl Manfred , Tatituri Raju V.V. , Watts Gerald F.M. , Bhowruth Veemal , Leadbetter Elizabeth A. , Barton Nathaniel , Cohen Nadia R. , Hsu Fong-Fu , Besra Gurdyal S. , Brenner Michael B.
Published: May 2011

Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor–driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12–induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.
Gram-Negative Multidrug-Resistant Organism Colonization in a US Military Healthcare Facility in Iraq
Authors: Ake Julie , Scott Paul , Wortmann Glenn , Huang Xiao-Zhe , Barber Melissa , Wang Zhining , Nikolich Mikeljon , Van Echo David , Weintrob Amy , Lesho Emil
Published: May 2011

Objective.

To investigate potential sources of gram-negative multidrug-resistant organisms (MDROs) in a deployed US military healthcare facility.

Design.

Active surveillance.

Methods.

Swab sampling of patients, hospital personnel, and environmental surfaces was performed before the opening of a new medical treatment facility in Iraq and then serially for the next 6 months. Multidrug resistant isolates were genotypically characterized using pulsed-field gel electrophoresis (PFGE). Univariate and multivariate analysis were performed to evaluate associations between patient characteristics and MDRO carriage.

Setting.

Deployed US military medical facility.

Results.

A total of 1,348 samples were obtained, yielding 654 isolates, 42 of which were MDROs. One hundred fifty-eight patients were sampled; swabs from 18 patients yielded 29 MDR isolates. Host nation patients comprised 89% of patients with MDROs and 37% of patients without MDROs (P < .001 ). Host nation patient status was also significantly associated with MDRO carriage in multivariate logistic regression analysis (adjusted odds ratio, 2.9; confidence interval, 1.3-6.3; P = .009). Bacteria with PFGE patterns matching those recovered from host nation patients were later isolated from environmental surfaces including recovery room patient monitors and the trauma bay floor.

Conclusions.

At this facility, MDRO isolation was predominantly obtained from newly admitted host nation patients,,which may reflect baseline colonization with MDROs in the community. Patient MDRO carriage was linked to subsequent environmental contamination. These findings support intensive infection control efforts in forward deployed facilities.
Thermoregulation and Risk of Surgical Site Infection
Authors: Beltramini Amanda M. , Salata Robert A. , Ray Amy J.
Published: May 2011

Surgical site infections (SSIs) occur in approximately 2%–5% of patients undergoing surgery in the acute care setting in the United States. These infections result in increased length of stay, higher risk of death, and increased cost of care compared with that in uninfected surgical patients. Given the inclusion of maintenance of perioperative normothermia for all major surgeries as a means of lowering the risk of infection in the Surgical Care Improvement Project 2009, we prepared a summary of the literature to determine the strength and quantity of the evidence underlying the performance measure. Although the data are generally supportive of perioperative normothermia as a means of reducing the risk of SSIs, a more rigorous approach using standard SSI definitions as well as standardized temperature measurements (and timing thereof) will further delineate the role played by temperature regulation in SSI development.
Fabrication and study of laser-damage-resistant transparent conductive W-doped In2O3 films
Authors: Wang Haifeng , Zhang Dayong , Luo Yongquan , Zhao Xiangjie , Luo Fei , Huang Lixian , Li Yanglong , Wang Weiping
Published: May 2011

We report that In1.97W0.03O3 (IWO) transparent conductive oxide films grown on quartz glass substrates by laser ablation show good polycrystalline properties, with a preferential orientation of (2 2 2), and excellent optical transmittance in the visible range, with a direct allowed band gap of 4.2 eV. A laser-induced damage study is carried out at 1064 nm with a 15 ns laser pulse in one-on-one mode. It is revealed that IWO films not only possess good electronic conductivity with a low resistivity of 7.85 × 10−4 Ω cm, but also have a laser-induced damage threshold of more than 2.2 J cm−2 which is 2.4 times more than that of a In1.8Sn0.2O3 film deposited by laser ablation with approximately the same resistivity. Weak laser absorption due to low carrier density and low free-electron excitation in the near-infrared region are the primary reasons for the high laser damage resistance of the IWO films.
Determination of the temperature of electrons heated by microwaves from the spectral line intensities emitted by the neon afterglow plasma
Authors: Malinovský L' , Lukáč P , Morva I , Zábudlá Z
Published: May 2011

The electron temperature dependence of the dissociative recombination coefficient of
ions with electrons was investigated in the afterglow of a pulsed high frequency discharge using both microwave cavity and optical emission spectrometry methods. The present experimental results show the close correlation between the relative intensities of the emitted lines, the electron temperature and the incident microwave power. It is proposed to calibrate the electron temperature as a function of absorbed microwave power by measuring the spectral line intensities from Ne(3p) to Ne(3s) transitions. It is confirmed that the electron temperature dependence of the dissociative recombination coefficient of molecular
ions follows the power law
.
Large subgroups of a finite group of even order
Authors: Amberg Bernhard , Kazarin Lev
Published: May 2011

It is shown that if

G
G

is a group of even order with trivial center such that

|

G

|

>
2

|

C

G

(
t
)

|

3

|G|>2|C_{G}(t)|^{3}

for some involution

t
∈
G

t\in G

, then there exists a proper subgroup

H
H

of

G
G

such that

|

G

|

>

|

H

|

2

|G|> |H|^{2}

. If

|

G

|

>

|

C

G

(
t
)

|

3

|G|>|C_{G}(t)|^{3}

and

k
(
G
)

k(G)

is the class number of

G
G

, then

|

G

|

≤
k
(
G

)

3

|G|\leq k(G)^{3}

.
Model building and intelligent acquisition with application to protein subcellular location classification
Authors: Jackson C. , Glory−Afshar E. , Murphy R. F. , Kovačević J.
Published: May 2011

Motivation: We present a framework and algorithms to intelligently acquire movies of protein subcellular location patterns by learning their models as they are being acquired, and simultaneously determining how many cells to acquire as well as how many frames to acquire per cell. This is motivated by the desire to minimize acquisition time and photobleaching, given the need to build such models for all proteins, in all cell types, under all conditions. Our key innovation is to build models during acquisition rather than as a post-processing step, thus allowing us to intelligently and automatically adapt the acquisition process given the model acquired.

Results: We validate our framework on protein subcellular location classification, and show that the combination of model building and intelligent acquisition results in time and storage savings without loss of classification accuracy, or alternatively, higher classification accuracy for the same total acquisition time.

Availability and implementation: The data and software used for this study will be made available upon publication at http://murphylab.web.cmu.edu/software and http://www.andrew.cmu.edu/user/jelenak/Software.

Contact:  jelenak@cmu.edu
The advantages of an audit over a census approach to the review of video imagery in fishery monitoring
Authors: Stanley Richard D. , McElderry Howard , Mawani Tameezan , Koolman John
Published: May 2011

Stanley, R. D., McElderry, H., Mawani, T., and Koolman, J. 2011. The advantages of an audit over a census approach to the review of video imagery in fishery monitoring. – ICES Journal of Marine Science, 68: 1621–1627. Technology-based fishery monitoring, or electronic monitoring (EM), has emerged as an alternative to human observers and is being applied in a variety of fisheries. The method records sensor and image data from fishing operations, so can be used to provide 100% monitoring of catches and fishing activity. Alternatively, EM can be used to audit catch data self-reported by harvesters. If the random audit indicates that these data are sufficiently accurate, they can provide useful catch estimates with less reviewing time and, hence, cost. The audit approach was adopted in the groundfish hook-and-line fishery in British Columbia, Canada, in 2006, and experience has shown that it can meet operational requirements for accuracy and timeliness. It is also more robust to the impact of equipment malfunction and can provide an independent estimate of total catch. Moreover, because catch estimates are derived from self-reported data rather than “black-box” records, the estimation process is more transparent and intuitive and, hence, more trusted by harvesters. Although cost reduction is always a primary concern, the audit approach offers significant additional benefits that should be considered in the design and implementation of EM programmes.
Specification Issues in Assessing the Moderating Role of Issue Importance: A Comment on Grynaviski and Corrigan (2006)
Authors: Malhotra Neil , Tahk Alexander
Published: May 2011

The empirical study of spatial issue voting has experienced a resurgence in recent years due to advances in data collection and research design. Grynaviski and Corrigan make several important contributions to this literature. In this note, we comment on one of Grynaviski and Corrigan's recommendations—to not include a main effect for issue importance when estimating models assessing the interactive relationship between importance and policy proximity. According to the authors, including the main importance term is incorrect because it is not necessary in representing a scale-invariant functional form under some assumptions and is insufficient under others. In deriving their reduced-form expression, the authors produce a model that is unintuitive and inappropriate for most data. Moreover, the restrictions Grynaviski and Corrigan impose on their model can produce perverse empirical predictions. We show that a model including main effect terms for importance is indeed scale invariant and that inclusion of the main importance term is necessary for scale invariance with respect to partial utility functions.
Viscosity and Solubility of β‐Glucan Extracted Under In Vitro Conditions from Barley β‐Glucan‐Fortified Bread and Evaluation of Loaf Characteristics
Authors: Moriartey Stephanie , Temelli Feral , Vasanthan Thava , Gänzle Michael
Published: May 2011

Fortifying bread with β‐glucan has been shown to reduce bread quality and the associated health benefits of barley β‐glucan. Fortification of bread using β‐glucan concentrates that are less soluble during bread preparation steps has not been investigated. The effects of β‐glucan concentration and gluten addition on the physicochemical properties of bread and β‐glucan solubility and viscosity were investigated using a less soluble β‐glucan concentrate, as were the effects of baking temperature and prior β‐glucan solubilization. Fortification of bread with β‐glucan decreased loaf volume and height (P ≤ 0.05) and increased firmness (P ≤ 0.05). Gluten addition to bread at the highest β‐glucan level increased height and volume (P ≤ 0.05) to values exceeding those for the control and decreased firmness (P ≤ 0.05). β‐Glucan addition increased (P ≤ 0.05) extract viscosity, as did gluten addition to the bread with the highest β‐glucan level. Baking at low temperature decreased (P ≤ 0.05) β‐glucan viscosity and solubility, as did solubilizing it prior to dough formulation. Utilization of β‐glucan that is less soluble during bread preparation may hold the key to effectively fortifying bread with β‐glucan without compromising its health benefits, although more research is required.
The Cucurbit Pathogenic Bacterium Acidovorax citrulli Requires a Polar Flagellum for Full Virulence Before and After Host-Tissue Penetration
Authors: Bahar Ofir , Levi Noam , Burdman Saul
Published: May 2011

Acidovorax citrulli causes seedling blight and bacterial fruit blotch of cucurbits. Previous reports demonstrated the contribution of type IV pili (T4P) to A. citrulli virulence and to systemic infection of melon seedlings. Microfluidic flow-chamber assays demonstrated the involvement of T4P in surface adhesion and biofilm formation, whereas polar flagella did not appear to contribute to either of these features. On the other hand, a transposon mutant impaired in the biosynthesis of polar flagella was identified in screens for reduced virulence of an A. citrulli mutant library. Further characterization of polar flagellum mutants confirmed that A. citrulli requires a polar flagellum for full virulence on melon plants. Foliage and stem inoculation experiments revealed that polar flagella contribute to A. citrulli virulence and growth in planta at both pre- and post-host-tissue penetration. Interestingly, light microscope observations revealed that almost all A. citrulli wild-type cells extracted from the xylem sap of stem-inoculated melon seedlings remained motile, supporting the importance of this organelle in virulence and colonization of the host vascular system. We also report a negative effect of polar flagellum impairment on T4P-mediated twitching motility of A. citrulli and discuss a possible co-regulation of these two motility machineries in this bacterium.