bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide assessment of worldwide chicken SNP genetic diversity indicates significant absence of rare alleles in commercial breeds
Authors: Muir William M. , Wong Gane Ka-Shu , Zhang Yong , Wang Jun , Groenen Martien A. M. , Crooijmans Richard P. M. A. , Megens Hendrik-Jan , Zhang Huanmin , Okimoto Ron , Vereijken Addie , Jungerius Annemieke , Albers Gerard A. A. , Lawley Cindy Taylor , Delany Mary E. , MacEachern Sean , Cheng Hans H.
Published: November 2008

Breed utilization, genetic improvement, and industry consolidation are predicted to have major impacts on the genetic composition of commercial chickens. Consequently, the question arises as to whether sufficient genetic diversity remains within industry stocks to address future needs. With the chicken genome sequence and more than 2.8 million single-nucleotide polymorphisms (SNPs), it is now possible to address biodiversity using a previously unattainable metric: missing alleles. To achieve this assessment, 2551 informative SNPs were genotyped on 2580 individuals, including 1440 commercial birds. The proportion of alleles lacking in commercial populations was assessed by (1) estimating the global SNP allele frequency distribution from a hypothetical ancestral population as a reference, then determining the portion of the distribution lost, and then (2) determining the relationship between allele loss and the inbreeding coefficient. The results indicate that 50% or more of the genetic diversity in ancestral breeds is absent in commercial pure lines. The missing genetic diversity resulted from the limited number of incorporated breeds. As such, hypothetically combining stocks within a company could recover only preexisting within-breed variability, but not more rare ancestral alleles. We establish that SNP weights act as sentinels of biodiversity and provide an objective assessment of the strains that are most valuable for preserving genetic diversity. This is the first experimental analysis investigating the extant genetic diversity of virtually an entire agricultural commodity. The methods presented are the first to characterize biodiversity in terms of allelic diversity and to objectively link rate of allele loss with the inbreeding coefficient.
Infectious myonecrosis virus has a totivirus-like, 120-subunit capsid, but with fiber complexes at the fivefold axes
Authors: Tang Jinghua , Ochoa Wendy F. , Sinkovits Robert S. , Poulos Bonnie T. , Ghabrial Said A. , Lightner Donald V. , Baker Timothy S. , Nibert Max L.
Published: November 2008

Infectious myonecrosis virus (IMNV) is an emerging pathogen of penaeid shrimp in global aquaculture. Tentatively assigned to family
Totiviridae
, it has a nonsegmented dsRNA genome of 7,560 bp and an isometric capsid of the 901-aa major capsid protein. We used electron cryomicroscopy and 3D image reconstruction to examine the IMNV virion at 8.0-Å resolution. Results reveal a totivirus-like, 120-subunit T = 1 capsid, 450 Å in diameter, but with fiber complexes protruding a further 80 Å at the fivefold axes. These protrusions likely mediate roles in the extracellular transmission and pathogenesis of IMNV, capabilities not shared by most other totiviruses. The IMNV structure is also notable in that the genome is centrally organized in five or six concentric shells. Within each of these shells, the densities alternate between a dodecahedral frame that connects the threefold axes vs. concentration around the fivefold axes, implying certain regularities in the RNA packing scheme.
Antigen-mediated T cell expansion regulated by parallel pathways of death
Authors: Ch'en Irene L. , Beisner Daniel R. , Degterev Alexei , Lynch Candace , Yuan Junying , Hoffmann Alexander , Hedrick Stephen M.
Published: November 2008

T cells enigmatically require caspase-8, an inducer of apoptosis, for antigen-driven expansion and effective antiviral responses, and yet the pathways responsible for this effect have been elusive. A defect in caspase-8 expression does not affect progression through the cell cycle but causes an abnormally high rate of cell death that is distinct from apoptosis and does not involve a loss of NFκB activation. Instead, antigen or mitogen activated
Casp8
-deficient T cells exhibit an alternative type of cell death similar to programmed necrosis that depends on receptor interacting protein (Ripk1). The selective genetic ablation of caspase-8, NFκB, and Ripk1, reveals two forms of cell death that can regulate virus-specific T cell expansion.
Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax
Authors: Fletcher Jamie I. , Meusburger Sarina , Hawkins Christine J. , Riglar David T. , Lee Erinna F. , Fairlie W. Douglas , Huang David C. S. , Adams Jerry M.
Published: November 2008

A central issue in the control of apoptosis is whether its essential mediators Bax and Bak must be restrained by Bcl-2-like prosurvival relatives to prevent their damaging mitochondria and unleashing apoptosis. The issue is particularly vexed for Bax, which is largely a cytosolic monomer in unstressed cells. To determine whether Bax regulation requires its binding by prosurvival relatives, we replaced a conserved aspartate in its BH3 interaction domain with arginine. Bax D68R functioned and behaved like wild-type Bax in localization and activation but had greatly impaired binding to the prosurvival family members. Nevertheless, Bcl-x
L
remained able to block apoptosis induced by Bax D68R. Whereas cells with sufficient Bcl-x
L
tolerated expression of Bax D68R, it provoked apoptosis when Bcl-x
L
was absent, downregulated, or inactivated. Moreover, Bax D68R rendered membrane bound by a C-terminal anchor mutation overwhelmed endogenous Bcl-x
L
and killed cells. These unexpected results suggest that engagement of Bax by its prosurvival relatives is a major barrier to its full activation. We propose that the Bcl-2-like proteins must capture the small proportion of Bax molecules with an exposed BH3 domain, probably on the mitochondrial membrane, to prevent Bax-imposed cell death, but that Bcl-x
L
also controls Bax by other mechanisms.
Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors
Authors: Barth Rolf F. , Yang Weilian , Wu Gong , Swindall Michele , Byun Youngjoo , Narayanasamy Sureshbabu , Tjarks Werner , Tordoff Kevin , Moeschberger Melvin L. , Eriksson Staffan , Binns Peter J. , Riley Kent J.
Published: November 2008

The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-{2-(2,3-dihydroxyprop-1-yl)-
o
-carboran-1-yl}pentan-1-yl] thymidine, designated N5–2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma model. Target validation was established using the thymidine kinase (TK) 1(+) wild-type, murine L929 cell line and its TK1(−) mutant counterpart, which were implanted s.c. (s.c.) into nude mice. Two intratumoral (i.t.) injections of
10
B-enriched N5–2OH were administered to tumor-bearing mice at 2-hour intervals, after which BNCT was carried out at the Massachusetts Institute of Technology (MIT) Research Reactor. Thirty days after BNCT, mice bearing TK1(+) L929 tumors had a 15× reduction in tumor volume compared with TK1(−) controls. Based on these favorable results, BNCT studies were then initiated in rats bearing intracerebral (i.c.) RG2 gliomas, after i.c. administration of N5–2OH by Alzet osmotic pumps, either alone or in combination with i.v. (i.v.) boronophenylalanine (BPA), a drug that has been used clinically. The mean survival times (MSTs) of RG2 glioma bearing rats were 45.6 ± 7.2 days, 35.0 ± 3.3days, and 52.9 ± 8.9 days, respectively, for animals that received N5–2OH, BPA, or both. The differences between the survival plots of rats that received N5–2OH and BPA alone were highly significant (
P
= 0.0003). These data provide
proof-of-principle
that a 3CTA can function as a boron delivery agent for NCT. Further studies are planned to design and synthesize 3CTAs with enhanced chemical and biological properties, and increased therapeutic efficacy.
Stimulation of Ebola virus production from persistent infection through activation of the Ras/MAPK pathway
Authors: Strong James E. , Wong Gary , Jones Shane E. , Grolla Allen , Theriault Steven , Kobinger Gary P. , Feldmann Heinz
Published: November 2008

Human infections with Ebola virus (EBOV) result in a deadly viral disease known as Ebola hemorrhagic fever. Up to 90% of infected patients die, and there is no available treatment or vaccine. The sporadic human outbreaks are believed to result when EBOV “jumps” from an infected animal to a person and is subsequently transmitted between persons by direct contact with infected blood or body fluids. This study was undertaken to investigate the mechanism by which EBOV can persistently infect and then escape from model cell and animal reservoir systems. We report a model system in which infection of mouse and bat cell lines with EBOV leads to persistence, which can be broken with low levels of lipopolysaccharide or phorbol-12-myristate-13-acetate (PMA). This reactivation depends on the Ras/MAPK pathway through inhibition of RNA-dependent protein kinase and eukaryotic initiation factor 2α phosphorylation and occurs at the level of protein synthesis. EBOV also can be evoked from mice 7 days after infection by PMA treatment, indicating that a similar mechanism occurs
in vivo
. Our findings suggest that EBOV may persist in nature through subclinical infection of a reservoir species, such as bats, and that appropriate physiological stimulation may result in increased replication and transmission to new hosts. Identification of a presumptive mechanism responsible for EBOV emergence from its reservoir underscores the “hit-and-run” nature of the initiation of human and/or nonhuman primate EBOV outbreaks and may provide insight into possible countermeasures to interfere with transmission.
Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes
Authors: Jakubzick Claudia , Bogunovic Milena , Bonito Anthony J. , Kuan Emma L. , Merad Miriam , Randolph Gwendalyn J.
Published: November 2008

Observations that dendritic cells (DCs) constitutively enter afferent lymphatic vessels in many organs and that DCs in some tissues, such as the lung, turnover rapidly in the steady state have led to the concept that a major fraction of lymph node DCs are derived from migratory DCs that enter the lymph node through upstream afferent lymphatic vessels. We used the lysozyme M–Cre reporter mouse strain to assess the relationship of lymph node and nonlymphoid organ DCs. Our findings challenge the idea that a substantial proportion of lymph node DCs derive from the upstream tissue during homeostasis. Instead, our analysis suggests that nonlymphoid organ DCs comprise a major population of DCs within lymph nodes only after introduction of an inflammatory stimulus.
Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1
Authors: Li Xiaoyu , Gounari Fotini , Protopopov Alexei , Khazaie Khashayarsha , von Boehmer Harald
Published: November 2008

Mutations resulting in overexpression of intracellular Notch1 (ICN1) are frequently observed in human T cell acute lymphoblastic leukemia (T-ALL). We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Early consequences are the generation of polyclonal nontumorigenic CD4+8+ T cell receptor (TCR)-αβ+ cells that do not qualify as tumor precursors despite the observation that they overexpress Notch 1 and c-Myc and degrade the tumor suppressor E2A by posttranslational modification. The first tumorigenic cells are detected among more immature CD4−8+TCR-αβ− cells that give rise to monoclonal tumors with a single, unique TCR-β chain and diverse TCR-α chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR-α rearrangement. In T-ALL, E2A deficiency is accompanied by further transcriptional up-regulation of c-Myc and concomitant dysregulation of the c-Myc-p53 axis at the transcriptional level. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found. As judged by array-based comparative genomic hybridization (array CGH) and spectral karyotype (SKY) analysis, none of the tumors arise because of genomic instability.
Activation of a dendritic cell–T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells
Authors: Perreau Matthieu , Pantaleo Giuseppe , Kremer Eric J.
Published: November 2008

The STEP HIV vaccine trial, which evaluated a replication-defective adenovirus type 5 (Ad5) vector vaccine, was recently stopped. The reasons for this included lack of efficacy of the vaccine and a twofold increase in the incidence of HIV acquisition among vaccinated recipients with increased Ad5-neutralizing antibody titers compared with placebo recipients. To model the events that might be occurring in vivo, the effect on dendritic cells (DCs) of Ad5 vector alone or treated with neutralizing antiserum (Ad5 immune complexes [IC]) was compared. Ad5 IC induced more notable DC maturation, as indicated by increased CD86 expression, decreased endocytosis, and production of tumor necrosis factor and type I interferons. We found that DC stimulation by Ad5 IC was mediated by the Fcγ receptor IIa and Toll-like receptor 9 interactions. DCs treated with Ad5 IC also induced significantly higher stimulation of Ad5-specific CD8 T cells equipped with cytolytic machinery. In contrast to Ad5 vectors alone, Ad5 IC caused significantly enhanced HIV infection in DC–T cell cocultures. The present results indicate that Ad5 IC activates a DC–T cell axis that, together with the possible persistence of the Ad5 vaccine in seropositive individuals, may set up a permissive environment for HIV-1 infection, which could account for the increased acquisition of HIV-1 infection among Ad5 seropositive vaccine recipients.
Mortality Attributable to Hospital-Acquired Infections Among Surgical Patients
Authors: Geffers Christine , Sohr Dorit , Gastmeier Petra
Published: November 2008

We performed a multicenter prospective matched cohort study to evaluate the mortality attributable to hospital-acquired infections among 12,791 patients admitted to surgical departments. We were able to match 731 patients with 1 or more hospital-acquired infections (ie, case patients) with 731 patients without a hospital-acquired infection (ie, control patients) at a 1 : 1 ratio. Of the 731 case patients, 42 (5.7%) died; of the 731 control patients, 23 (3.1%) died—a significant difference of 2.6%.
Ecological Study of the Effectiveness of Isolation Precautions in the Management of Hospitalized Patients Colonized or Infected WithAcinetobacter baumannii
Authors: Gbaguidi-Haore Houssein , Legast Sophie , Thouverez Michelle , Bertrand Xavier , Talon Daniel
Published: November 2008

Objective.

To assess the impact of isolation precautions on the incidence of patients colonized or infected withAcinetobacter baumannii(case patients) in a university hospital during the period from 1999 to 2006.

Design.

Ecological study.

Setting.

The Besançon University Hospital in France, a 1,200-bed acute care hospital with approximately 50,000 admissions per year.

Methods.

Using Poisson regression analysis, we evaluated a total of 350,000 patient-days to determine the annual incidence of case patients. This annual incidence was used as the outcome variable, and infection control practices, antibiotic use, and other aggregated data regarding patients' age, sex, McCabe score, and immune status were used as covariates.

Results.

The implementation of isolation precautions was independently and negatively associated with the incidence of patients colonized or infected withA. baumannii(relative risk, 0.50 [95% confidence interval, 0.40–0.64];P< .001).

Conclusions.

Our study suggests that the implementation of isolation precautions, in addition to standard precautions, effectively prevents the spread ofA. baumanniiin a hospital setting.
ITER startup studies in the DIII-D tokamak
Authors: Jackson G.L. , Casper T.A. , Luce T.C. , Humphreys D.A. , Ferron J.R. , Hyatt A.W. , Lazarus E.A. , Moyer R.A. , Petrie T.W. , Rudakov D.L. , West W.P.
Published: November 2008

A plasma initiation and current ramp up scenario envisioned for ITER has been simulated in DIII-D experiments. These discharges were limited on the low field side (LFS) during the initial current ramp up, as specified for the ITER baseline startup scenario. Initial experiments produced internal inductance (ℓi), higher than the design value for the ITER shaping coils, often leading to vertical instabilities. A modified startup with larger volume was developed to reduce ℓi in the current ramp up. This large-bore scenario, also limiting on the LFS, produced a lower ℓi and avoided the vertical instabilities. Feedback control of ℓi, using the ohmic field coil power supply as the actuator, was successfully demonstrated. Such control may be useful in avoiding vertical instabilities and in providing access to sawtooth-free steady state and hybrid scenarios in ITER. Experiments at reduced inductive voltage and with electron cyclotron assist for breakdown and burnthrough have also been carried out. The Corsica equilibrium and transport code has modelled these data to provide validation of transport models used to simulate this phase of ITER discharges in order to yield more accurate extrapolation to ITER scenarios.
A new simple formula for fusion cross-sections of light nuclei
Authors: Li Xing Z. , Wei Qing M. , Liu Bin
Published: November 2008

The recent ENDF/B VII.0 data are compared with the fitting formula (NRL handbook—Plasma Formulary). The differences between experimental data and the fitting formula for three major fusion cross-sections reveal the need for a replacement to the old 5-parameter fitting formula. The new formula in this paper has only 3 parameters, but its fit with the experimental data is greatly improved because the energy dependence of the incident-channel (deuteron) width is taken explicitly into account through a penetrability function of the Mott form.
Toroidally resolved radiation dynamics during a gas jet mitigated disruption on Alcator C-Mod
Authors: Reinke M.L. , Whyte D.G. , Granetz R. , Hutchinson I.H.
Published: November 2008

Measurements of the radiation dynamics during an Alcator C-Mod disruption induced by a high pressure He/Ar gas jet are presented. Data are analysed from four 22-channel Absolute eXtreme UltraViolet diode arrays viewing on horizontal planes from different toroidal and vertical locations, both towards and away from the gas jet. Prior to the loss of the core plasma stored energy, strong emission is seen from a shell at the plasma edge that expands toroidally and poloidally away from the the gas jet at 650 m s−1, consistent with neutral expansion rates. Both the energy loss from this region and from the bulk plasma are shown to be of comparable magnitudes and important in dissipating the electron thermal energy outside the q = 2 surface. During the thermal quench, line-integrated brightnesses exceed 100 MW m−2. But while the brightness ratio of equivalent toroidally/vertically spaced views varies from 0.4 to 4.0, energy loss integrated over the disruption is shown to be symmetric to within 25%. Radiative energy loss local to the gas jet is shown to preheat nearby surfaces making them more susceptible to melting when the bulk of the thermal energy is lost.
Sustainable Traditional Medicine: Taking the Inspirations from Ancient Veterinary Science
Authors: Rastogi Sanjeev , Kaphle Krishna
Published: November 2008

Rapid reduction in natural resources as a consequence to the expanded urbanization, global warming and reduced natural habitat posed a considerable threat to the sustainability of traditional medicine. Being completely dependent upon natural resources like herbs, minerals and animal products, traditional medicine would possibly rank first in order of extinction of heritage if an alternative way is not considered well in time. In reference to the use of animal products, Ayurveda presents some unique examples where animals are used without causing harm to them and so without posing a threat to their existence. In the current context, when natural resources are facing a threat to their existence, a revisit to these ideas may give us a new insight to refine our look at natural resources used in traditional medicine.
Iridescence from photonic crystals and its suppression in butterfly scales
Authors: Poladian Leon , Wickham Shelley , Lee Kwan , Large Maryanne C.J
Published: November 2008

Regular three-dimensional periodic structures have been observed in the scales of over half a dozen butterfly species. We compare several of these structures: we calculate their photonic bandgap properties; measure the angular variation of the reflection spectra; and relate the observed iridescence (or its suppression) to the structures. We compare the mechanisms for iridescence suppression in different species and conclude with some speculations about form, function, development and evolution.
Characterization of the bovine pseudoautosomal boundary: Documenting the evolutionary history of mammalian sex chromosomes
Authors: Van Laere Anne-Sophie , Coppieters Wouter , Georges Michel
Published: November 2008

Here, we report the sequence characterization of the bovine pseudoautosomal boundary (PAB) and its neighborhood. We demonstrate that it maps to the 5′ end of the GPR143 gene, which has concomitantly lost upstream noncoding exons on the Y chromosome. We show that the bovine PAB was created ∼20.7 million years ago by illegitimate intrachromatid recombination between inverted, ruminant-specific Bov-tA repeats. Accordingly, we demonstrate that cattle share their PAB with all other examined ruminants including sheep, but not with cetaceans or more distantly related mammals. We provide evidence that, since its creation, the ancestral ruminant PAB has been displaced by attrition, which occurs at variable rates in different species, and that it is capable of retreat by attrition erasure. We have estimated the ratio of male to female mutation rates in the Bovidae family as ∼1.7, and we provide evidence that the mutation rate is higher in the recombining pseudoautosomal region than in the adjacent, nonrecombining gonosome-specific sequences.
Multigenome DNA sequence conservation identifies Hox cis-regulatory elements
Authors: Kuntz Steven G. , Schwarz Erich M. , DeModena John A. , De Buysscher Tristan , Trout Diane , Shizuya Hiroaki , Sternberg Paul W. , Wold Barbara J.
Published: November 2008

To learn how well ungapped sequence comparisons of multiple species can predict cis-regulatory elements in Caenorhabditis elegans, we made such predictions across the large, complex ceh-13/lin-39 locus and tested them transgenically. We also examined how prediction quality varied with different genomes and parameters in our comparisons. Specifically, we sequenced ∼0.5% of the C. brenneri and C. sp. 3 PS1010 genomes, and compared five Caenorhabditis genomes (C. elegans, C. briggsae, C. brenneri, C. remanei, and C. sp. 3 PS1010) to find regulatory elements in 22.8 kb of noncoding sequence from the ceh-13/lin-39Hox subcluster. We developed the MUSSA program to find ungapped DNA sequences with N-way transitive conservation, applied it to the ceh-13/lin-39 locus, and transgenically assayed 21 regions with both high and low degrees of conservation. This identified 10 functional regulatory elements whose activities matched known ceh-13/lin-39 expression, with 100% specificity and a 77% recovery rate. One element was so well conserved that a similar mouse Hox cluster sequence recapitulated the native nematode expression pattern when tested in worms. Our findings suggest that ungapped sequence comparisons can predict regulatory elements genome-wide.
Progesterone regulation of synaptic transmission and plasticity in rodent hippocampus
Authors: Foy Michael R. , Akopian Garnik , Thompson Richard F.
Published: November 2008

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the highest concentration of P4 tested (10−6 M) decreased the baseline synaptic transmission and magnitude of LTP, but did not affect LTD. Intracellular studies suggest the P4 effect to be mediated, at least in part, by GABAA activity. These results establish a general effect of P4 on synaptic transmission, multiple forms of synaptic plasticity, and a possible mechanism of P4 action in hippocampus.
Ontogenetic change in the auditory conditioned stimulus pathway for eyeblink conditioning
Authors: Freeman John H. , Campolattaro Matthew M.
Published: November 2008

Two experiments examined the neural mechanisms underlying the ontogenetic emergence of auditory eyeblink conditioning. Previous studies found that the medial auditory thalamus is necessary for eyeblink conditioning with an auditory conditioned stimulus (CS) in adult rats. In experiment 1, stimulation of the medial auditory thalamus was used as a CS in rat pups trained on postnatal days (P) 17–18, 24–25, or 31–32. All three age groups showed significant acquisition relative to unpaired controls. However, there was an age-related increase in the rate of conditioning. Experiment 2 examined the effect of inactivating the medial auditory thalamus with muscimol on auditory eyeblink conditioning in rats trained on P17–18, 24–25, or 31–32. Rat pups trained on P24–25 and P31–32, but not P17–18, showed a significant reduction in conditioned responses following muscimol infusions. The findings suggest that the thalamic contribution to auditory eyeblink conditioning continues to develop through the first postnatal month.
PKMζ inactivation induces spatial familiarity
Authors: Moncada Diego , Viola Haydée
Published: November 2008

Spatial familiarization consists of a decrease in the exploratory activity over time after exposure to a place. Here, we show that a 30-min exposure to an open field led to a pronounced decrease in the exploratory behavior of rats, generating context familiarity. This behavioral output is associated with a selective decrease in hippocampal PKMζ levels. A short 5-min exposure did not induce spatial familiarity or a decrease in PKMζ, while inactivation of hippocampal PKMζ by the specific inhibitor ZIP was sufficient to induce spatial familiarity, suggesting that the decrease in PKMζ is involved in setting a given context as a familiar place.
Consolidation of sensorimotor learning during sleep
Authors: Brawn Timothy P. , Fenn Kimberly M. , Nusbaum Howard C. , Margoliash Daniel
Published: November 2008

Consolidation of nondeclarative memory is widely believed to benefit from sleep. However, evidence is mainly limited to tasks involving rote learning of the same stimulus or behavior, and recent findings have questioned the extent of sleep-dependent consolidation. We demonstrate consolidation during sleep for a multimodal sensorimotor skill that was trained and tested in different visual-spatial virtual environments. Participants performed a task requiring the production of novel motor responses in coordination with continuously changing audio-visual stimuli. Performance improved with training, decreased following waking retention, but recovered and stabilized following sleep. These results extend the domain of sleep-dependent consolidation to more complex, adaptive behaviors.
Serotonin mediates a learned increase in attraction to high concentrations of benzaldehyde in aged C. elegans
Authors: Tsui David , van der Kooy Derek
Published: November 2008

We utilized olfactory-mediated chemotaxis in Caenorhabditis elegans to examine the effect of aging on information processing and animal behavior. Wild-type (N2) young adults (day 4) initially approach and eventually avoid a point source of benzaldehyde. Aged adult animals (day 7) showed a stronger initial approach and a delayed avoidance to benzaldehyde compared with young adults. This delayed avoidance is due to an increased attraction rather than a decreased avoidance to benzaldehyde because (1) aged odr-3 mutants that are defective in odor attraction showed no delayed benzaldehyde avoidance, and (2) the delay in avoidance was also observed with another attractant diacetyl, but not the repellent octanol. Interestingly, the stronger expression of attractive behavior was only observed at benzaldehyde concentrations of 1% or higher. When worms were grown on nonbacterial growth media instead of Escherichia coli, thus removing the contingency between odors released from the food and the food itself, the increase in attraction to benzaldehyde disappeared. The increased attraction recovered after reinitiating the odor–food contingency by returning animals to E. coli food or supplementing axenic media with benzaldehyde. Moreover, serotonin-deficient mutants showed a deficit in the age-enhanced attraction. These results suggest that the increased attraction to benzaldehyde in aged worms is (1) serotonin mediated, (2) specific to high concentration of odorants, and (3) dependent on a learned association of odor metabolites with the presence of food. We propose that associative learning may selectively modify pathways at or downstream from a low-affinity olfactory receptor.
Gustatory plasticity inC. elegansinvolves integration of negative cues and NaCl taste mediated by serotonin, dopamine, and glutamate
Authors: Hukema Renate K. , Rademakers Suzanne , Jansen Gert
Published: November 2008

While naïveCaenorhabditis elegansindividuals are attracted to 0.1–200 mM NaCl, they become strongly repelled by these NaCl concentrations after prolonged exposure to 100 mM NaCl. We call this behavior gustatory plasticity. Here, we show thatC. elegansdisplays avoidance of low NaCl concentrations only when pre-exposure to NaCl is combined with a negative stimulus, e.g., a repellent, or in the absence of food. By testing serotonin and/or dopamine signaling mutants and rescue by exogenously supplying these neurotransmitters, we found that serotonin and dopamine play a role during the plasticity response, while serotonin is also required during development. In addition, we also show that glutamate plays an important role in the response to NaCl, both in chemoattraction to NaCl and in gustatory plasticity. Thus,C. eleganscan associate NaCl with negative stimuli using dopaminergic, serotonergic, and glutamatergic neurotransmission. Finally, we show that prolonged starvation enhances gustatory plasticity and can induce avoidance of NaCl in most gustatory plasticity mutants tested. Only mutation of the glutamate-gated Cl−channel geneavr-15affected starvation-enhanced gustatory plasticity. These results suggest that starvation induces avoidance of NaCl largely independent of the normal gustatory plasticity mechanism.
Over‐expression of putative transcriptional coactivator KELP interferes withTomato mosaic viruscell‐to‐cell movement
Authors: SASAKI NOBUMITSU , OGATA TAKUYA , DEGUCHI MASAKAZU , NAGAI SHOKO , TAMAI ATSUSHI , MESHI TETSUO , KAWAKAMI SHIGEKI , WATANABE YUICHIRO , MATSUSHITA YASUHIKO , NYUNOYA HIROSHI
Published: November 2008

Tomato mosaic virus(ToMV) encodes a movement protein (MP) that is necessary for virus cell‐to‐cell movement. We have demonstrated previously that KELP, a putative transcriptional coactivator ofArabidopsis thaliana, and its orthologue fromBrassica campestriscan bind to ToMV MPin vitro. In this study, we examined the effects of the transient over‐expression of KELP on ToMV infection and the intracellular localization of MP inNicotiana benthamiana, an experimental host of the virus. In co‐bombardment experiments, the over‐expression of KELP inhibited virus cell‐to‐cell movement. The N‐terminal half of KELP (KELPdC), which had been shown to bind to MP, was sufficient for inhibition. Furthermore, the over‐expression of KELP and KELPdC, both of which were co‐localized with ToMV MP, led to a reduction in the plasmodesmal association of MP. In the absence of MP expression, KELP was localized in the nucleus and the cytoplasm by the localization signal in its N‐terminal half. It was also shown that ToMV amplified normally in protoplasts prepared from leaf tissue that expressed KELP transiently. These results indicate that over‐expressed KELP interacts with MPin vivoand exerts an inhibitory effect on MP function for virus cell‐to‐cell movement, but not on virus amplification in individual cells.
Large‐scale blood group genotyping – clinical implications
Authors: Avent Neil D.
Published: November 2008

The molecular background of blood group antigen expression of the major clinically significant blood group antigens has been largely accomplished. Despite this large body of work, blood group phenotype prediction by genotyping has a marginal supporting role in the routine blood bank. It has however had a major impact in the prenatal determination of fetal blood group status in the management of haemolytic disease of the fetus and newborn. In the past few years several high throughput systems have been in development that have the potential capacity to perform genotyping on a mass scale. Such systems have been designed for use on donor‐ and patient‐derived DNA and provide much more comprehensive information regarding an individuals blood group than is possible by using serological methods alone. DNA‐based typing methodology is easier to standardize than serology and has the potential to replace it as a front line diagnostic in blood banks. This review overviews the current situation in this area and attempts to predict how blood group genotyping will evolve in the future.
Consolidation with alemtuzumab improves progression‐free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission – long‐term follow‐up of a randomized phase III trial of the German CLL Study Group (GCLLSG)
Authors: Schweighofer Carmen D. , Ritgen Matthias , Eichhorst Barbara F. , Busch Raymonde , Abenhardt Wolfgang , Kneba Michael , Hallek Michael , Wendtner Clemens‐Martin
Published: November 2008

Alemtuzumab has shown considerable activity in untreated and relapsed chronic lymphocytic leukaemia. We report our long‐term experience in 21 patients within a randomized phase III trial investigating the role of alemtuzumab for consolidation therapy after first‐line fludarabine ± cyclophosphamide, which was stopped prematurely due to severe infections. However, after a median follow‐up of 48 months, progression‐free survival was significantly prolonged for patients receiving alemtuzumab consolidation compared to those with no further treatment (P = 0·004). Minimal residual disease (MRD) levels were persistently reduced after consolidation. Therefore, despite toxicity, MRD reduction by alemtuzumab consolidation translates into a significantly improved long‐term clinical outcome.
Whole blood coagulation in children with thrombocytopenia and the response to platelet replacement, recombinant factor VIIa, and a potent factor VIIa analogue
Authors: Larsen Ole H. , Clausen Niels , Persson Egon , Ezban Mirella , Ingerslev Jørgen , Sørensen Benny
Published: November 2008

The present study evaluated dynamic coagulation profiles, platelet aggregation, and thrombin generation in whole blood (WB) from eight children with thrombocytopenia during chemotherapy, and the haemostatic potential of platelets (+60 × 109/l), recombinant factor VIIa (rFVIIa – NovoSeven®), and a potent rFVIIa analogue (NN1731) both at 1 and 4 μg/ml. Dynamic WB coagulation profiles were recorded by thrombelastometry employing activation with tissue factor (TF – Innovin®) at low concentrations. The baseline WB coagulation patterns were characterised by a prolonged clotting time (CT) and a pronounced reduction in clot propagation (MaxVel). WB platelet aggregation signal was five times lower in the study group compared with measurements in modelled thrombocytopenic WB from healthy volunteers. In vitro addition of fresh platelets reversed the coagulopathy. Addition of rFVIIa induced no significant changes in the thrombelastographic profile, whereas spiking with NN1731 shortened the CT significantly. The changes in WB thrombin generation reflected the changes in the MaxVel. In modeled thrombocytopenic WB from healthy individuals, both rFVIIa and NN1731 exhibited a pronounced haemostatic effect with NN1731 showing greater potency than rFVIIa. Compromised platelet function in the study group was assumingly responsible for the weakened haemostatic potential of rFVIIa as well as that of NN1731.
Phase II study of subcutaneous alemtuzumab without dose escalation in patients with advanced‐stage, relapsed chronic lymphocytic leukaemia
Authors: Karlsson Claes , Lundin Jeanette , Kimby Eva , Kennedy Ben , Moreton Paul , Hillmen Peter , Österborg Anders
Published: November 2008

This phase II study (n = 20) aimed to evaluate type, severity and duration of side‐effects and efficacy following subcutaneous (SC) alemtuzumab, without dose‐escalation, in advanced‐stage relapsed chronic lymphocytic leukaemia (CLL) patients. Alemtuzumab 30 and 3 mg was administered SC simultaneously day 1, followed by 30 mg three times per week. Injection‐site‐reactions were recorded every 6–24 h until resolved using National Cancer Institute criteria and a new skin toxicity subscale. The first doses of 30 mg and 3 mg produced injection‐site‐reactions (all but one were grade 1/2) in 13/20 and 9/20 patients, respectively. The second dose (on day 3) resulted in skin‐reactions in 10/20 patients and the third, fourth, fifth and sixth injections produced reactions in 6/20, 1/20, 2/20 and 0/20 patients, respectively. Mild “flu‐like” symptoms occurred during week 1 in 10/20 patients. All side‐effects had subsided by the sixth dose. 15/20 patients (75%) responded (12 partial responses, three complete responses) with a median time‐to‐treatment‐failure of 20 months. Symptomatic cytomegalovirus‐reactivation occurred in 6/20 patients. Two deaths occurred: one bacterial pneumonia and one adenovirus‐infection. The present study showed how to assess cutaneous‐toxicity in detail and that 30 mg alemtuzumab SC administered upfront was well tolerated. Optimized alemtuzumab therapy in properly selected patients may result in high efficacy even in advanced CLL. Our results need to be confirmed in extended studies.
Sleep problems and the need for parental night‐time attention in children with physical disabilities
Authors: Hemmingsson H. , Stenhammar A. M. , Paulsson K.
Published: November 2008

Background  The aim of the study was to investigate the frequency and predictors of sleep problems and the need for parental night‐time attention in children with physical disabilities.

Methods  A questionnaire on sleep problems and need for parental night‐time attention was completed by 505 parents of children with physical disabilities aged 1–16 years (mean 9 years 3 months) with moderate to severe motor disabilities. General characteristics of the children were analysed by frequencies and cross‐tabulations. Logistic regression analysis was used to identify factors associated with sleep problems and the need for parental night‐time attention.

Results  The results showed a high prevalence of sleep problems, which in general were chronic. Currently 48% of the children had sleep problems, of which 23% estimated the problems to be serious. About one‐third (37%) needed parental night‐time attention every night, and 10% needed help five times or more. No significant differences were found between younger children and school‐aged children regarding sleep problems and the need for parental night‐time attention. Having pain [odds ratio (OR) = 3.4] was associated with sleep problems, as was having problems eating and drinking (OR = 3) and the diagnosis of cerebral palsy (OR = 2.5) (P < 0.05). Children with muscular dystrophy (OR = 68.5), cerebral palsy (OR = 26.7) and ‘other diagnosis’ (OR = 18.5) were more likely to need support at night than were children with spina bifida, P < 0.001. Pain (OR = 7.6) was also associated with need for support at night, P < 0.001.

Conclusions  The prevalence of sleep problems and need for parental night‐time attention is high among children with physical disabilities. This in turn affects the whole family, and paediatric caregivers must keep this in mind. Besides certain diagnoses, the results suggest that children who have pain should be prioritized.
An investigation of the impact of the location and timing of antigen-specific T cell division on airways inflammation
Authors: Hutchison S , Choo-Kang B S W , Gibson V B , Bundick R V , Leishman A J , Brewer J M , McInnes I B , Garside P
Published: November 2008

It is widely accepted that allergic asthma is orchestrated by T helper type 2 lymphocytes specific for inhaled allergen. However, it remains unclear where and when T cell activation and division occurs after allergen challenge, and whether these factors have a significant impact on airways inflammation. We therefore employed a CD4-T cell receptor transgenic adoptive transfer model in conjunction with laser scanning cytometry to characterize the location and timing of T cell division in asthma in vivo. Thus, for the first time we have directly assessed the division of antigen-specific T cells in situ. We found that accumulation of divided antigen-specific T cells in the lungs appeared to occur in two waves. The first very early wave was apparent before dividing T cells could be detected in the lymph node (LN) and coincided with neutrophil influx. The second wave of divided T cells accumulating in lung followed the appearance of these cells in LN and coincided with peak eosinophilia. Furthermore, accumulation of antigen-specific T cells in the draining LN and lung tissue, together with accompanying pathology, was reduced by intervention with the sphingosine 1-phosphate receptor agonist FTY720 2 days after challenge. These findings provide greater insight into the timing and location of antigen-specific T cell division in airways inflammation, indicate that distinct phases and locations of antigen presentation may be associated with different aspects of pathology and that therapeutics targeted against leukocyte migration may be useful in these conditions.
Lagged effects of experimental warming and doubled precipitation on annual and seasonal aboveground biomass production in a tallgrass prairie
Authors: SHERRY REBECCA A. , WENG ENSHENG , ARNONE III JOHN A. , JOHNSON DALE W. , SCHIMEL DAVE S. , VERBURG PAUL S. , WALLACE LINDA L. , LUO YIQI
Published: November 2008

Global climate change is expected to result in a greater frequency of extreme weather, which can cause lag effects on aboveground net primary production (ANPP). However, our understanding of lag effects is limited. To explore lag effects following extreme weather, we applied four treatments (control, doubled precipitation, 4 °C warming, and warming plus doubled precipitation) for 1 year in a randomized block design and monitored changes in ecosystem processes for 3 years in an old‐field tallgrass prairie in central Oklahoma. Biomass was estimated twice in the pretreatment year, and three times during the treatment and posttreatment years. Total plant biomass was increased by warming in spring of the treatment year and by doubled precipitation in summer. However, double precipitation suppressed fall production. During the following spring, biomass production was significantly suppressed in the formerly warmed plots 2 months after treatments ceased. Nine months after the end of treatments, fall production remained suppressed in double precipitation and warming plus double precipitation treatments. Also, the formerly warmed plots still had a significantly greater proportion of C4 plants, while the warmed plus double precipitation plots retained a high proportion of C3 plants. The lag effects of warming on biomass did not match the temporal patterns of soil nitrogen availability determined by plant root simulator probes, but coincided with warming‐induced decreases in available soil moisture in the deepest layers of soil which recovered to the pretreatment pattern approximately 10 months after the treatments ceased. Analyzing the data with an ecosystem model showed that the lagged temporal patterns of effects of warming and precipitation on biomass can be fully explained by warming‐induced differences in soil moisture. Thus, both the experimental results and modeling analysis indicate that water availability regulates lag effects of warming on biomass production.
Warming and drying suppress microbial activity and carbon cycling in boreal forest soils
Authors: ALLISON STEVEN D. , TRESEDER KATHLEEN K.
Published: November 2008

Climate warming is expected to have particularly strong effects on tundra and boreal ecosystems, yet relatively few studies have examined soil responses to temperature change in these systems. We used closed‐top greenhouses to examine the response of soil respiration, nutrient availability, microbial abundance, and active fungal communities to soil warming in an Alaskan boreal forest dominated by mature black spruce. This treatment raised soil temperature by 0.5 °C and also resulted in a 22% decline in soil water content. We hypothesized that microbial abundance and activity would increase with the greenhouse treatment. Instead, we found that bacterial and fungal abundance declined by over 50%, and there was a trend toward lower activity of the chitin‐degrading enzymeN‐acetyl‐glucosaminidase. Soil respiration also declined by up to 50%, but only late in the growing season. These changes were accompanied by significant shifts in the community structure of active fungi, with decreased relative abundance of a dominant Thelephoroid fungus and increased relative abundance of Ascomycetes and Zygomycetes in response to warming. In line with our hypothesis, we found that warming marginally increased soil ammonium and nitrate availability as well as the overall diversity of active fungi. Our results indicate that rising temperatures in northern‐latitude ecosystems may not always cause a positive feedback to the soil carbon cycle, particularly in boreal forests with drier soils. Models of carbon cycle‐climate feedbacks could increase their predictive power by incorporating heterogeneity in soil properties and microbial communities across the boreal zone.
On linking multiyear biometric measurements of tree growth with eddy covariance‐based net ecosystem production
Authors: OHTSUKA TOSHIYUKI , SAIGUSA NOBUKO , KOIZUMI HIROSHI
Published: November 2008

Annual measurements of the diameter growth and litter fall of trees began in 1998 using a 1.0 ha permanent plot beneath a flux tower at the Takayama flux site, central Japan. This opened up an opportunity for studies that compare the interannual variability in tree growth with eddy covariance‐based net ecosystem production (NEP). A possible link between multiyear biometric‐based net primary production (NPP) and eddy covariance‐based NEP was investigated to determine the contribution of autotrophic production and heterotrophic respiration (HR) to the interannual variability of NEP in deciduous forest ecosystems. We also defined the NEP* as the measurable organic matter stored in an ecosystem during the interval in which soil respiration (SR) measurements were taken. The difference of biometric‐based NEP* from eddy covariance‐based NEP within a given year varied between 55% and 105%. Woody tissue NPP (stems and coarse roots) varied markedly from 0.88 to 1.96 Mg C ha−1 yr−1 during the 8‐year study period (1999–2006). Annual woody tissue NPP was positively correlated with eddy covariance‐based NEP (r2=0.52, P<0.05). However, neither foliage NPP (r2=0.03) nor HR (r2=0.06) were correlated with eddy covariance‐based NEP. Therefore, it was hypothesized that interannual variability in the ecosystem carbon exchange was directly responsible for much of the interannual variation in autotrophic production, especially carbon accumulation in the woody components of the ecosystem. Moreover, similar interannual variations of biometric‐based NEP* and eddy covariance‐based NEP with small variations in SR and foliage NPP suggest a constant net accumulation of carbon in nonliving pools at the Takayama site.