bluuebunny/crossref_metadata_2025 huggingface dataset:
IKKα and alternative NF-κB regulate PGC-1β to promote oxidative muscle metabolism
Authors: Bakkar Nadine , Ladner Katherine , Canan Benjamin D. , Liyanarachchi Sandya , Bal Naresh C. , Pant Meghna , Periasamy Muthu , Li Qiutang , Janssen Paul M.L. , Guttridge Denis C.
Published: February 2012

Although the physiological basis of canonical or classical IκB kinase β (IKKβ)–nuclear factor κB (NF-κB) signaling pathway is well established, how alternative NF-κB signaling functions beyond its role in lymphoid development remains unclear. In particular, alternative NF-κB signaling has been linked with cellular metabolism, but this relationship is poorly understood. In this study, we show that mice deleted for the alternative NF-κB components IKKα or RelB have reduced mitochondrial content and function. Conversely, expressing alternative, but not classical, NF-κB pathway components in skeletal muscle stimulates mitochondrial biogenesis and specifies slow twitch fibers, suggesting that oxidative metabolism in muscle is selectively controlled by the alternative pathway. The alternative NF-κB pathway mediates this specificity by direct transcriptional activation of the mitochondrial regulator PPAR-γ coactivator 1β (PGC-1β) but not PGC-1α. Regulation of PGC-1β by IKKα/RelB also is mammalian target of rapamycin (mTOR) dependent, highlighting a cross talk between mTOR and NF-κB in muscle metabolism. Together, these data provide insight on PGC-1β regulation during skeletal myogenesis and reveal a unique function of alternative NF-κB signaling in promoting an oxidative metabolic phenotype.
Arf6 promotes autophagosome formation via effects on phosphatidylinositol 4,5-bisphosphate and phospholipase D
Authors: Moreau Kevin , Ravikumar Brinda , Puri Claudia , Rubinsztein David C.
Published: February 2012

Macroautophagy (in this paper referred to as autophagy) and the ubiquitin–proteasome system are the two major catabolic systems in cells. Autophagy involves sequestration of cytosolic contents in double membrane–bounded vesicles called autophagosomes. The membrane source for autophagosomes has received much attention, and diverse sources, such as the plasma membrane, Golgi, endoplasmic reticulum, and mitochondria, have been implicated. These may not be mutually exclusive, but the exact sources and mechanism involved in the formation of autophagosomes are still unclear. In this paper, we identify a positive role for the small G protein Arf6 in autophagosome formation. The effect of Arf6 on autophagy is mediated by its role in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2) and in inducing phospholipase D (PLD) activity. PIP2 and PLD may themselves promote autophagosome biogenesis by influencing endocytic uptake of plasma membrane into autophagosome precursors. However, Arf6 may also influence autophagy by indirect effects, such as either by regulating membrane flow from other compartments or by modulating PLD activity independently of the mammalian target of rapamycin.
Does the Branly effect occur in spark plasma sintering?
Authors: Guyot P , Rat V , Coudert J F , Jay F , Maître A , Pradeilles N
Published: February 2012

Spark plasma sintering (SPS) is a non-conventional method of powder consolidation. We show that the Branly effect can occur in SPS of copper powder in the early stages of the process due to inductive effects generated by the applied pulsed current. It leads to the formation of melting zones between contact areas of copper grains which can enhance material densification.
Tailoring the blue–violet photoluminescence from Sn-implanted SiO2 using a two-step annealing process
Authors: Kremer F , Luce F P , Fabrim Z E , Sanchez D F , Lang R , Zawislak F C , Fichtner P F P
Published: February 2012

The blue–violet photoluminescence (PL) response of ion beam synthesized Sn nanoparticles (NPs) in silica is studied in samples submitted to a two-step thermal annealing process. This process consists of a low temperature and long time ageing treatment (523 K, 100 h) followed by a high temperature and short time one (T > 773 K, 0.5 h). The comparison between aged and non-aged control samples by means of transmission electron microscopy observations and Rutherford backscattering spectrometry measurements demonstrates that the ageing treatment causes the formation of a more thermally stable and dense array of rather small Sn NPs. This phenomenon is correlated with the enhancement in the blue–violet PL intensity caused by the formation of luminescent defects at the NP/matrix interface region, persisting even at annealing temperatures as high as 1373 K.
Elliptic elements in a Weyl group: a homogeneity property
Authors: Lusztig G.
Published: February 2012

LetGGbe a reductive group over an algebraically closed field whose characteristic is not a bad prime forGG. Letwwbe an elliptic element of the Weyl group which has minimum length in its conjugacy class. We show that there exists a unique unipotent classXXinGGsuch that the following holds: ifVVis the variety of pairs(g,B)(g,B)whereg∈Xg\in XandBBis a Borel subgroup such thatB,gBg−1B,gBg^{-1}are in relative positionww, thenVVis a homogeneousGG-space.
Survey of Fungal, Nematode and Virus Diseases of Soybean in Alabama
Authors: Sikora Edward J. , Murphy John F. , Lawrence Kathy S. , Mullen Jacqueline M.
Published: February 2012

Observations on incidence of foliar diseases, plant viruses, and plant-parasitic nematodes were collected from soybean fields in Alabama from 2008-2010. Cercospora leaf blight (Cercospora kikuchii), downy mildew (Peronospora manshurica), and target spot (Corynespora cassiicola) were the most common foliar diseases observed in the study. Cercospora leaf blight was found in 45% (2008), 77% (2009), and 70% (2010) of the fields surveyed. Downy mildew was observed in 72% (2008), 38% (2009), and 29% (2010) and target spot was detected in 45% (2008 and 2009) and 29% (2010) of the fields in the study. Soybean rust (Phakopsora pachyrhizi) was found in 43% of the fields surveyed in 2009 but was only found in one field in 2008 and was not detected in 2010. Bean pod mottle virus was detected at relatively high levels in all three years, whereas Soybean mosaic virus occurrence was less consistent and of lower incidence. Tomato spotted wilt virus was detected for the first time on soybean in Alabama. Reniform (Rotylenchulus reniformis), soybean cyst (Heterodera glycines), root-knot (Meloidogyne spp.), and lesion nematodes (Pratylenchus spp.) were the most common plant-parasitic nematodes collected with reniform nematodes found in over 30% of the fields surveyed. Soybean cyst nematode races 2, 4, 5, 6, and 14 were identified among the field population collected. The survey has increased disease awareness among growers and has aided in directing research efforts in the state.

Accepted for publication 18 November 2011. Published 27 December 2011.
Myrothecium roridum Leaf Spot and Stem Canker on Watermelon in the Southern Great Plains: Possible Factors for Its Outbreak
Authors: Bruton Benny D. , Fish Wayne W.
Published: February 2012

In 2010, a foliar and stem-lesion disease was observed for the first time in Oklahoma causing moderate to severe defoliation. Using microscopic examination, the physical features of the fungus were consistent with Myrothecium roridum. There was a wide range of susceptibility among watermelon cultivars in the field indicating a moderately high level of resistance to Myrothecium leaf spot in some cultivars. In greenhouse inoculation experiments, cantaloupe, honeydew, cucumber, squash, and watermelon were all susceptible to the fungus with cantaloupe and honeydew being the most susceptible and watermelon the most resistant. Furthermore, greenhouse inoculations supported the field observations as differential resistance was exhibited among the watermelon cultivars as well as the cucurbit types. Although cantaloupe was most susceptible to the foliar phase of this disease, watermelon was most susceptible to the fruit-rot phase. Natural infection of watermelon fruit has never been reported.

Accepted for publication 15 December 2011. Published 30 January 2012.
Ab initio
modelling of protein–biomaterial interactions: influence of amino acid polar side chains on adsorption at hydroxyapatite surfaces
Authors: Rimola Albert , Corno Marta , Garza Jorge , Ugliengo Piero
Published: February 2012

The adsorption from the gas phase of five different amino acids (AAs), namely Gly, Ser, Lys, Gln and Glu, on three surface models of hexagonal hydroxyapatite (HA) has been studied at B3LYP level with Gaussian type basis set within a periodic approach. The AA adsorption was simulated on the (001) and (010) stoichiometric surfaces, the latter both in its pristine and water-reacted form. Low/high AA coverage has been studied by doubling the HA unit cell size. The AAs have been docked to the HA surfaces following the electrostatic complementarity between the electrostatic potentials of AA and the bare HA. Gly adsorbs as a zwitterion at the (001) surface, whereas at the (010) ones, the proton of the COOH group is transferred to the surface resulting in an HA
+
/Gly
−
ion pair. For the other AAs, the common COOH−CH−NH
2
moiety behaves like in Gly, while the specific side-chain functionalities adsorb at the HA surfaces by maximizing electrostatic and H-bond interactions. The interactions between the side chains and the HA surface impart a higher stability compared with the Gly case, with Glu being the strongest adsorbate owing to its high Ca affinity and H-bond donor propensity. For AAs of large size, the adsorption is more favourable in conditions of low coverage as repulsion between adjacent AAs is avoided. For all considered AAs, the strongest interaction is always established on the (010) faces rather than on the (001) one, therefore suggesting an easier growth along the
c
-direction of HA crystals from AA solutions.
High-resolution three-dimensional probes of biomaterials and their interfaces
Authors: Grandfield Kathryn , Palmquist Anders , Engqvist Håkan
Published: February 2012

Interfacial relationships between biomaterials and tissues strongly influence the success of implant materials and their long-term functionality. Owing to the inhomogeneity of biological tissues at an interface, in particular bone tissue, two-dimensional images often lack detail on the interfacial morphological complexity. Furthermore, the increasing use of nanotechnology in the design and production of biomaterials demands characterization techniques on a similar length scale. Electron tomography (ET) can meet these challenges by enabling high-resolution three-dimensional imaging of biomaterial interfaces. In this article, we review the fundamentals of ET and highlight its recent applications in probing the three-dimensional structure of bioceramics and their interfaces, with particular focus on the hydroxyapatite–bone interface, titanium dioxide–bone interface and a mesoporous titania coating for controlled drug release.
Local structures of mesoporous bioactive glasses and their surface alterations
in vitro
: inferences from solid-state nuclear magnetic resonance
Authors: Gunawidjaja Philips N. , Mathew Renny , Lo Andy Y. H. , Izquierdo-Barba Isabel , García Ana , Arcos Daniel , Vallet-Regí María , Edén Mattias
Published: February 2012

We review the benefits of using
29
Si and
1
H magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy for probing the local structures of both bulk and surface portions of mesoporous bioactive glasses (MBGs) of the CaO–SiO
2
−(P
2
O
5
) system. These mesoporous materials exhibit an ordered pore arrangement, and are promising candidates for improved bone and tooth implants. We discuss experimental MAS NMR results from three MBGs displaying different Ca, Si and P contents: the
29
Si NMR spectra were recorded either directly by employing radio-frequency pulses to
29
Si, or by magnetization transfers from neighbouring protons using cross polarization, thereby providing quantitative information about the silicate speciation present in the pore wall and at the MBG surface, respectively. The surface modifications were monitored for the three MBGs during their immersion in a simulated body fluid (SBF) for intervals between 30 min and one week. The results were formulated as a reaction sequence describing the interconversions between the distinct silicate species. We generally observed a depletion of Ca
2+
ions at the MBG surface, and a minor condensation of the silicate-surface network over one week of SBF soaking.
Molecular modelling of protein adsorption on the surface of titanium dioxide polymorphs
Authors: Raffaini Giuseppina , Ganazzoli Fabio
Published: February 2012

This paper reports a molecular modelling study of the adsorption of protein subdomains with unlike secondary structures on different surfaces of ceramic titanium dioxide (TiO2), forming a passivating film on titanium biomaterials that provides the interface between the bulk metal and the physiological environment, affecting its biocompatibility and performance. Using molecular dynamics methods, we study the effect of the nanoscale structure of the common TiO2polymorphs (rutile, anatase and brookite) on the adsorption of an albumin subdomain and on two connected fibronectin modules, respectively containing α-helices and β-sheets. We find that the larger protein subdomain shows a stronger adsorption, as expected because of its size, but also that the three surfaces behave differently. In particular, brookite shows the weakest adsorption, whereas anatase leads to the strongest intrinsic adsorption, in particular for the fibronectin modules. Moreover, the simulations indicate a significant conformational change of the adsorbed protein subdomains with extensive surface nanopatterning. These results show that classical molecular dynamics methods can provide useful information about the influence of nanostructure and topology on protein physisorption at a fixed surface chemistry.
Titanium-containing bioactive phosphate glasses
Authors: Kiani A. , Lakhkar N. J. , Salih V. , Smith M. E. , Hanna J. V. , Newport R. J. , Pickup D. M. , Knowles J. C.
Published: February 2012

The use of biomaterials has revolutionized the biomedical field and has received substantial attention in the last two decades. Among the various types of biomaterials, phosphate glasses have generated great interest on account of their remarkable bioactivity and favourable physical properties for various biomedical applications relating to both hard and soft tissue regeneration. This review paper focuses mainly on the development of titanium-containing phosphate-based glasses and presents an overview of the structural and physical properties. The effect of titanium incorporation on the glassy network is to introduce favourable properties. The biocompatibility of these glasses is described along with recent developments in processing methodologies, and the potential of Ti-containing phosphate-based glasses as a bone substitute material is explored.
Characterizing the hierarchical structures of bioactive sol–gel silicate glass and hybrid scaffolds for bone regeneration
Authors: Martin R. A. , Yue S. , Hanna J. V. , Lee P. D. , Newport R. J. , Smith M. E. , Jones J. R.
Published: February 2012

Bone is the second most widely transplanted tissue after blood. Synthetic alternatives are needed that can reduce the need for transplants and regenerate bone by acting as active temporary templates for bone growth. Bioactive glasses are one of the most promising bone replacement/regeneration materials because they bond to existing bone, are degradable and stimulate new bone growth by the action of their dissolution products on cells. Sol–gel-derived bioactive glasses can be foamed to produce interconnected macropores suitable for tissue ingrowth, particularly cell migration and vascularization and cell penetration. The scaffolds fulfil many of the criteria of an ideal synthetic bone graft, but are not suitable for all bone defect sites because they are brittle. One strategy for improving toughness of the scaffolds without losing their other beneficial properties is to synthesize inorganic/organic hybrids. These hybrids have polymers introduced into the sol–gel process so that the organic and inorganic components interact at the molecular level, providing control over mechanical properties and degradation rates. However, a full understanding of how each feature or property of the glass and hybrid scaffolds affects cellular response is needed to optimize the materials and ensure long-term success and clinical products. This review focuses on the techniques that have been developed for characterizing the hierarchical structures of sol–gel glasses and hybrids, from atomic-scale amorphous networks, through the covalent bonding between components in hybrids and nanoporosity, to quantifying open macroporous networks of the scaffolds. Methods for non-destructive
in situ
monitoring of degradation and bioactivity mechanisms of the materials are also included.
Structure and biological activity of glasses and ceramics
Authors: Cormack A. N. , Tilocca A.
Published: February 2012

Biomaterials for repairing and regenerating parts of the human body play a key role in contemporary medicine, and have an increasing impact in modern society. Given the importance of orthopaedic medicine (bone is the second most replaced organ after blood), bioactive glasses and ceramics represent a key reference to guide technological advances in this field. Their established role in current biomedical applications has already led many research groups worldwide to look into their structural properties, with a view to identifying the molecular basis of their biological activity. As the efforts directed towards this crucial and exciting direction continue to increase, it is now timely to review the situation, in order to guide future investigations on structure–bioactivity relationships. In this introductory article, the field is reviewed, to provide an appropriate context for the contributions to this Theme Issue.
Overexpression of ADP‐ribosylation factor 1 in human gastric carcinoma and its clinicopathological significance
Authors: Tsai Ming‐Ming , Lin Paul Y. , Cheng Wan‐Li , Tsai Chung‐Ying , Chi Hsiang‐Cheng , Chen Cheng‐Yi , Tseng Yi‐Hsin , Cheng Yi‐Fen , Chen Chi‐De , Liang Ying , Liao Chia‐Jung , Wu Sheng‐Ming , Lin Yang‐Hsiang , Chung I‐Hsiao , Wang Chia‐Siu , Lin Kwang‐Huei
Published: February 2012

Gastric cancer is the sixth leading cause of cancer‐related death in Taiwan, and the identification of related factors is essential to increase patient survival. ADP‐ribosylation factor 1 (ARF1) was initially identified using 2‐D electrophoresis combined with MALDI–time‐of‐flight mass spectrometry. ADP‐ribosylation factor 1 belongs to the Ras superfamily or GTP‐binding protein family and has been shown to enhance cell proliferation. In the current study, we evaluated the potential of ARF1 as a biomarker for gastric cancer detection. ADP‐ribosylation factor 1 mRNA was upregulated in tumor tissues (compared with adjacent non‐tumor tissues, n = 55) in approximately 67.2% of gastric cancer patients. Expression of ARF1 protein was additionally observed using Western blot and immunohistochemistry (IHC) analyses. The clinicopathological correlations of ARF1 were further evaluated. Elevated ARF1 expression was strongly correlated with lymph node metastasis (P = 0.008), serosal invasion (P = 0.046), lymphatic invasion (P = 0.035), and pathological staging (P = 0.010). Moreover, the 5‐year survival rate for the lower ARF1 expression group (n = 50; IHC score < 90) was higher than that of the higher expression group (n = 60; IHC score ≥ 90) (P = 0.0228, log–rank test). To establish the specific function of ARF1 in human gastric cancer, isogenic ARF1‐overexpressing cell lines were prepared. Our results showed that ARF1‐overexpressing clones display enhanced cell proliferation, migration, and invasion. Furthermore, ARF1‐overexpression might contribute to poor prognosis of patients. These findings collectively support the utility of ARF1 as a novel prognostic marker for gastric cancer and its role in cell invasion. Cancer Sci 2012; 103: 1136–1144)
Orally active lysophosphatidic acid receptor antagonist attenuates pancreatic cancer invasion and metastasis in vivo
Authors: Komachi Mayumi , Sato Koichi , Tobo Masayuki , Mogi Chihiro , Yamada Takayuki , Ohta Hideo , Tomura Hideaki , Kimura Takao , Im Dong‐Soon , Yanagida Keisuke , Ishii Satoshi , Takeyoshi Izumi , Okajima Fumikazu
Published: February 2012

Pancreatic cancer is highly metastatic and has a poor prognosis. However, there is no established treatment for pancreatic cancer. Lysophosphatidic acid (LPA) has been shown to be present in effluents of cancers and involved in migration and proliferation in a variety of cancer cells, including pancreatic cancer cells, in vitro. In the current study, we examined whether an orally active LPA antagonist is effective for pancreatic cancer tumorigenesis and metastasis in vivo. Oral administration of Ki16198, which is effective for LPA1 and LPA3, into YAPC‐PD pancreatic cancer cell‐inoculated nude mice significantly inhibited tumor weight and remarkably attenuated invasion and metastasis to lung, liver, and brain, in association with inhibition of matrix metalloproteinase (MMP) accumulation in ascites in vivo. Ki16198 inhibited LPA‐induced migration and invasion in several pancreatic cancer cells in vitro, which was associated with the inhibition of LPA‐induced MMP production. In conclusion, Ki16198 is a promising orally active LPA antagonist for inhibiting the invasion and metastasis of pancreatic cancer cells. The inhibitory effects of the antagonist on invasion and metastasis in vivo may be partially explained by the inhibition of motility activity and MMP production in cancer cells. (Cancer Sci 2012; 103: 1099–1104)
Decrease in the oral bioavailability of dabigatran etexilate after co‐medication with rifampicin
Authors: Härtter Sebastian , Koenen‐Bergmann Michael , Sharma Ashish , Nehmiz Gerhard , Lemke Ute , Timmer Wolfgang , Reilly Paul A.
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Dabigatran etexilate is an oral prodrug that is rapidly converted to dabigatran, a direct and reversible thrombin inhibitor.

• Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system, and dabigatran does not affect the metabolism of other drugs that utilize this system, leading to a low potential for drug–drug interactions.

• Dabigatran etexilate, but not dabigatran, is a P‐glycoprotein (P‐gp) substrate, and the bioavailability of dabigatran may be altered by P‐gp inhibitors or inducers.

WHAT THIS STUDY ADDS

• Administration of rifampicin (a strong P‐gp inducer) for 7 days before a single dose of dabigatran etexilate resulted in a significant reduction in the bioavailability of dabigatran compared with administration of dabigatran etexilate alone.

• Within 7 days following the cessation of rifampicin administration, the bioavailability of dabigatran returned almost to baseline values.

• Rifampicin is not recommended for use with dabigatran etexilate because of the potential for reduced systemic exposure to dabigatran.

AIMS This study examined the effects of the CYP3A/P‐glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.

METHODS This was an open‐label, fixed‐sequence, four‐period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2–8, and single doses of dabigatran etexilate on days 9, 16 and 23.

RESULTS Twenty‐four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration–time curve (AUC0–∞) and maximal plasma concentration (Cmax) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half‐life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC0–∞ and 34.5% (90% confidence interval 26.9, 44.1%) for Cmax, indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC0–∞ and Cmax of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good.

CONCLUSIONS Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.
Interventions to reduce medication errors in adult intensive care: a systematic review
Authors: Manias Elizabeth , Williams Allison , Liew Danny
Published: February 2012

Critically ill patients need life saving treatments and are often exposed to medications requiring careful titration. The aim of this paper was to review systematically the research literature on the efficacy of interventions in reducing medication errors in intensive care. A search was conducted of PubMed, CINAHL EMBASE, Journals@Ovid, International Pharmaceutical Abstract Series via Ovid, ScienceDirect, Scopus, Web of Science, PsycInfo and The Cochrane Collaboration from inception to October 2011. Research studies involving delivery of an intervention in intensive care for adult patients with the aim of reducing medication errors were examined. Eight types of interventions were identified: computerized physician order entry (CPOE), changes in work schedules (CWS), intravenous systems (IS), modes of education (ME), medication reconciliation (MR), pharmacist involvement (PI), protocols and guidelines (PG) and support systems for clinical decision making (SSCD). Sixteen out of the 24 studies showed reduced medication error rates. Four intervention types demonstrated reduced medication errors post‐intervention: CWS, ME, MR and PG. It is not possible to promote any interventions as positive models for reducing medication errors. Insufficient research was undertaken with any particular type of intervention, and there were concerns regarding the level of evidence and quality of research. Most studies involved single arm, before and after designs without a comparative control group. Future researchers should address gaps identified in single faceted interventions and gather data on multi‐faceted interventions using high quality research designs. The findings demonstrate implications for policy makers and clinicians in adopting resource intensive processes and technologies, which offer little evidence to support their efficacy.
How I manage aplastic anaemia in children
Authors: Samarasinghe Sujith , Webb David K. H.
Published: February 2012

Aplastic anaemia (AA) is a rare heterogeneous condition in children. 15–20% of cases are constitutional and correct diagnosis of these inherited causes of AA is important for appropriate management. For idiopathic severe aplastic anaemia, a matched sibling donor (MSD) haematopoietic stem cell transplant (HSCT) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. IST with horse anti‐thymocyte globulin (ATG) is superior to rabbit ATG and has good long‐term results. In contrast, IST with rabbit ATG has an overall response of only 30–40%. Due to improvements in outcome over the last two decades in matched unrelated donor (MUD) HSCT, results are now similar to that of MSD HSCT. The decision to proceed with IST with ATG or MUD HSCT will depend on the likelihood of finding a MUD and the differing risks and benefits that each therapy provides.
The effect of gestation and fetal mismatching on the development of autoimmune diabetes in non-obese diabetic mice
Authors: Adler K , Krause S , Fuchs Y F , Foertsch K , Ziegler A-G , Bonifacio E
Published: February 2012

The impact of gestation and fetal–maternal interactions on pre-existent autoimmune beta cell destruction is widely unknown. The aim of this study was to investigate the influence of gestation per se and fetal mismatching on the onset of autoimmune diabetes in female non-obese diabetic (NOD) mice. We examined cumulative diabetes frequencies of NOD dams mated to syngeneic NOD, haploidentical CByB6F1/J and fully mismatched C57BL/6J male mice. Pregnancy from NOD males neither increased nor accelerated the diabetes onset of NOD dams (71% by age 28 weeks) compared to unmated female NOD mice (81% by age 28 weeks; P = 0·38). In contrast, delayed diabetes onset was observed when NOD dams were mated at 10 weeks of age with major histocompatibility complex (MHC) haploidentical CByB6F1/J male mice (38% at age 28 weeks; P = 0·01). Mating with fully MHC mismatched C57BL/6J male mice (72% diabetes by age 28 weeks; P = 0·22) or mating with the haploidentical males at the later time-point of age 13 weeks (64% versus 91% in unmated litter-matched controls; P = 0·13) did not delay diabetes significantly in NOD females. Because infusion of haploidentical male mouse splenocytes was found previously to prevent diabetes in NOD mice we looked for, but found no evidence of, persistent chimeric lymphocytes from haploidentical paternal origin within the dams' splenocytes. Gestation per se appears to have no aggravating or ameliorating effects on pre-existent autoimmune beta cell destruction, but pregnancy from MHC partially mismatched males delays diabetes onset in female NOD mice.
Cordycepin as a sensitizer to tumour necrosis factor (TNF)-α-induced apoptosis through eukaryotic translation initiation factor 2α (eIF2α)- and mammalian target of rapamycin complex 1 (mTORC1)-mediated inhibition of nuclear factor (NF)-κB
Authors: Kadomatsu M , Nakajima S , Kato H , Gu L , Chi Y , Yao J , Kitamura M
Published: February 2012

Cordycepin (3′-deoxyadenosine) is one of the major bioactive substances produced by Cordyceps militaris, a traditional medicinal mushroom. Cordycepin possesses several biological activities, including both pro-apoptotic and anti-apoptotic properties. In the present report, we investigated an effect of cordycepin on the survival of cells exposed to tumour necrosis factor (TNF)-α. We found that subtoxic doses of cordycepin increased susceptibility of cells to TNF-α-induced apoptosis. It was associated with suppression of nuclear factor-κB (NF-κB), a major prosurvival component involved in TNF-α signalling. The adenosine transporter and A3 adenosine receptor, but not A1 and A2 adenosine receptors, mediated both anti-NF-κB and pro-apoptotic effects. We found that cordycepin had the potential to phosphorylate eukaryotic translation initiation factor 2α (eIF2α) and that activation of eIF2α mimicked the suppressive effect of cordycepin on the NF-κB pathway. Furthermore, activation of eIF2α sensitized cells to TNF-α-induced apoptosis. To identify molecular events downstream of eIF2α, the role of mammalian target of rapamycin complex 1 (mTORC1) was examined. Selective activation of 3eIF2α, as well as treatment with cordycepin, caused phosphorylation of mTORC1. Rapamycin, an inhibitor of mTORC1, significantly reversed the suppressive effects of eIF2α on NF-κB. These results suggest that cordycepin sensitizes cells to TNF-α-induced apoptosis, at least in part, via induction of the eIF2α–mTORC1 pathway and consequent suppression of NF-κB.
Sex cells in changing environments: can organisms adjust the physiological function of gametes to different temperatures?
Authors: Adriaenssens Bart , van Damme Raoul , Seebacher Frank , Wilson Robbie S.
Published: February 2012

Over the past decade, hundreds of studies have examined the abilities of whole organisms to modify their physiology and behaviour in response to environmental temperature changes; despite this, virtually nothing is known about the ability of sex cells to adjust to different temperature conditions. In fact, a recent meta‐analysis based on studies of 309 species and 112 physiological and ecological traits found no studies examining the influence of temperature on gamete function. Because sex cells play a critical role in the adaptation and persistence of species, this represents a severe oversight in physiological studies of thermal adaptation. Our study examines whether sex cells can respond phenotypically to variation in the thermal environment that is experienced by the whole‐organism. Specifically, we studied the thermal dependence of sperm swimming and the critical thermal limits of sperm cells in males of the poeciliid fish, Gambusia holbrooki. This species is well known for its ability to modify physiological function and maintains burst and sustained swimming performance and mating ability across a wide range of thermal conditions. In contrast, we found that sperm cells from male G. holbrooki did not adjust their physiological function as predicted by adaptive models. After acclimation of adult males to cool or warm temperatures, we found that the critical thermal limits of sperm function remained unchanged, as did the effect of temperature on sperm swimming performance. However, warm‐acclimated fish had sperm with higher swimming speeds across all temperatures. The absence of phenotypic changes in the critical thermal limits of sperm or thermal dependence of sperm swimming performance is surprising given that whole‐organism traits in G. holbrooki generally show improved performance after exposure to novel environments. As such an inability to thermally adjust gamete function may be widespread among other organisms, we urge biologists to investigate the generality of this result.
Climate effects on size‐at‐age: growth in warming waters compensates for earlier maturity in an exploited marine fish
Authors: Neuheimer Anna B. , Grønkjær Peter
Published: February 2012

Over the past 3 decades, North Sea Atlantic cod (Gadus morhua) have exhibited variable length‐at‐age along with declines in spawning stock biomass and timing of maturity. Multiple factors affecting growth and development in fish acted on this economically important stock over the same period including warming waters and an intensive fishery. Here, we employ North Sea cod as a model population, exploring how a physiologically relevant temperature metric (the growing degree‐day, GDD; °C day) can be used to compare year‐classes on a physiologically relevant time‐scale, disentangling influences of climate (thermal history) on observed length‐at‐age trends. We conclude that the trends in North Sea cod length‐at‐age observed during the last three decades can be explained by a combination of temperature‐dependent growth increases and a trend toward earlier maturation, the latter likely induced by the intensive fishing pressure, and possibly evidence of fisheries‐induced evolution.
The value of immunohistochemistry for CD14, CD123, CD33, myeloperoxidase and CD68R in the diagnosis of acute and chronic myelomonocytic leukaemias
Authors: Rollins‐Raval Marian A , Roth Christine G
Published: February 2012

Rollins‐Raval M A & Roth C G  (2012) Histopathology 60, 933–942

The value of immunohistochemistry for CD14, CD123, CD33, myeloperoxidase and CD68R in the diagnosis of acute and chronic myelomonocytic leukaemias

Aims:  In the absence of adequate aspirate films and touch imprints, distinction of chronic myelomonocytic leukaemia (CMML) from acute myeloid leukaemia with monocytic differentiation (Mo‐AML) may be difficult solely on the basis of bone marrow biopsy morphological features. The aim of this study was to evaluate the diagnostic utility of a novel immunohistochemical panel for the diagnosis of acute and chronic myelomonocytic leukaemias in bone marrow biopsies.

Methods and results:  Immunohistochemical labelling for CD14, CD123, CD33, myeloperoxidase (MPO) and CD68R was assessed in 49 myeloid neoplasms with monocytic differentiation (24 CMMLs and 25 Mo‐AMLs) and compared with that of 15 non‐monocytic acute myeloid leukaemias (NM‐AMLs) and 17 non‐neoplastic controls. More than 20% CD14 immunohistochemistry (IHC)+ cells were seen only in Mo‐AMLs and CMMLs, although Mo‐AMLs showed wide variability and overlapped with other categories. More than 20% CD68R IHC+ cells had the highest sensitivity and specificity for Mo‐AML. Discrepant MPO–/CD33+ expression was specific for Mo‐AML but insensitive. A subset of blasts in Mo‐AMLs and NM‐AMLs were weakly CD123+.

Conclusions:  A significantly increased number of CD14+ cells raises the possibility of a myelomonocytic neoplasm but does not distinguish between CMML and Mo‐AML. Significantly increased numbers of CD68R IHC+ cells and a discrepant MPO–/CD33+ staining pattern are specific for Mo‐AML but are best utilized in a comprehensive panel.
Poorly differentiated oncocytic thyroid carcinoma – diagnostic implications and outcome
Authors: Dettmer Matthias , Schmitt Anja , Steinert Hans , Moch Holger , Komminoth Paul , Perren Aurel
Published: February 2012

Dettmer M, Schmitt A, Steinert H, Moch H, Komminoth P & Perren A  (2012) Histopathology 60, 1045–1051

Poorly differentiated oncocytic thyroid carcinoma – diagnostic implications and outcome

Aims:  Poorly differentiated thyroid carcinomas (PDTC) are an ongoing diagnostic challenge. Although the Turin consensus criteria for PDTC excluded consideration of oncocytic tumours, the World Health Organization (WHO) classification does recognise an oncocytic variant of conventional PDTC. The aims of this study were to establish whether the Turin criteria can be applied to oncocytic PDTC, and to determine if there are prognostic differences between conventional and oncocytic PDTC.

Methods and results:  We applied the Turin criteria to 129 thyroid carcinomas. We identified 18 oncocytic PDTC and 16 conventional PDTC. Kaplan–Meier analysis revealed a significantly worse outcome for oncocytic PDTC with regard to overall and tumour‐specific survival but no difference for relapse‐free survival, all of which were confirmed by multivariate analysis. There was no association of survival with gender, age or tumour stage.

Conclusions:  The Turin criteria can be applied to oncocytic PDTC and patients with this variant have a decreased survival using conventional radioiodine treatment compared to conventional PDTC and might therefore be candidates for novel treatment modalities.
Nanoparticle tracking analysis monitors microvesicle and exosome secretion from immune cells
Authors: Soo Chin Y. , Song Yaqiong , Zheng Ying , Campbell Elaine C. , Riches Andrew C. , Gunn‐Moore Frank , Powis Simon J.
Published: February 2012

Nanoparticle tracking analysis permits the determination of both the size distribution and relative concentration of microvesicles, including exosomes, in the supernatants of cultured cells and biological fluids. We have studied the release of microvesicles from the human lymphoblastoid T‐cell lines Jurkat and CEM. Unstimulated, both cell lines release microvesicles in the size range 70–90 nm, which can be depleted from the supernatant by ultracentrifugation at 100 000 g, and by anti‐CD45 magnetic beads, and which by immunoblotting also contain the exosome‐associated proteins Alix and Tsg101. Incubation with known potentiators of exosome release, the ionophores monensin and A23187, resulted in a significant increase in microvesicle release that was both time and concentration dependent. Mass spectrometric analysis of proteins isolated from ultracentrifuged supernatants of A23187‐treated cells revealed the presence of exosome‐associated proteins including heat‐shock protein 90, tubulin, elongation factor α1, actin and glyceraldehyde 3‐phosphate dehydrogenase. Additionally, treatment of peripheral blood monocyte‐derived dendritic cells with bacterial lipopolysaccharide displayed an increase in secreted microvesicles. Consequently, nanoparticle tracking analysis can be effectively applied to monitor microvesicle release from cells of the immune system.
T‐cell receptor retrogenic mice: a rapid, flexible alternative to T‐cell receptor transgenic mice
Authors: Bettini Matthew L. , Bettini Maria , Vignali Dario A. A.
Published: February 2012

The T‐cell receptor (TCR) is unique in its complexity. It determines not only positive (life) and negative (death) selection in the thymus, but also mediates proliferation, anergy, differentiation, cytotoxicity and cytokine production in the periphery. Through its association with six CD3 signalling chains (εγ, δε and ζζ), the TCR is capable of recognizing an extensive variety of antigenic peptides, from both pathogens and self‐antigens, and translating these interactions into multiple signalling pathways that mediate diverse T‐cell developmental and functional responses. The analysis of TCR biology has been revolutionized by the development of TCR transgenic mice, which express a single clonotypic T‐cell population, with diverse specificities and genetic backgrounds. However, they are time consuming to generate and characterize, limiting the analysis of large numbers of TCR over a short period of time in multiple genetic backgrounds. The recent development of TCR retrogenic technology resolves these limitations and could in time have a similarly important impact on our understanding of T‐cell development and function. In this review, we will discuss the advantages and limitations of retrogenic technology compared with the generation and use of TCR transgenic mice for studying all aspects of T‐cell biology.
Differential regulation of monocyte cytokine release by αV and β2 integrins that bind CD23
Authors: Edkins Adrienne L. , Borland Gillian , Acharya Mridu , Cogdell Richard J. , Ozanne Bradford W. , Cushley William
Published: February 2012

The human soluble CD23 (sCD23) protein displays highly pleiotropic cytokine‐like activity. Monocytic cells express the sCD23‐binding integrins αVβ3, αVβ5, αMβ2 and αXβ2, but it is unclear which of these four integrins most acutely regulates sCD23‐driven cytokine release. The hypothesis that ligation of different sCD23‐binding integrins promoted release of distinct subsets of cytokines was tested. Lipopolysaccharide (LPS) and sCD23 promoted release of distinct groups of cytokines from the THP‐1 model cell line. The sCD23‐driven cytokine release signature was characterized by elevated amounts of RANTES (CCL5) and a striking increase in interleukin‐8 (IL‐8; CXCL8) secretion, but little release of macrophage inflammatory protein 1β (MIP‐1β; CCL4). Antibodies to αVβ3 or αXβ2 both promoted IL‐8 release, consistent with the sCD23‐driven pattern, but both also evoked strong MIP‐1β secretion; simultaneous ligation of these two integrins further increased cytokine secretion but did not alter the pattern of cytokine output. In both model cell lines and primary tissue, integrin‐mediated cytokine release was more pronounced in immature monocyte cells than in mature cells. The capacity of anti‐integrin monoclonal antibodies to elicit a cytokine release response is epitope‐dependent and also reflects the differentiation state of the cell. Although a pattern of cytokine release identical to that provoked by sCD23 could not be elicited with any individual anti‐integrin monoclonal antibody, αXβ2 and αVβ3 appear to regulate IL‐8 release, a hallmark feature of sCD23‐driven cytokine secretion, more acutely than αMβ2 or αVβ5.
Adrenomedullin, a neuropeptide with immunoregulatory properties induces semi‐mature tolerogenic dendritic cells
Authors: Rullé Sandrine , Kioon Marie‐Dominique Ah , Asensio Carine , Mussard Julie , Ea Hang‐Korng , Boissier Marie‐Christophe , Lioté Frédéric , Falgarone Géraldine
Published: February 2012

Dendritic cells (DC) play a pivotal role in tolerance. Adrenomedullin (AM), a neuropeptide with anti‐apoptotic and anti‐inflammatory effects, may decrease T helper type 1 effector cells and induce regulatory T (Treg) cells. The aim of this study was to evaluate AM effects on murine dendritic cell (DC) maturation and functions. Bone marrow‐derived DC were produced and stimulated with CpG motifs, lipopolysaccharide or AM for 24 hr. Then, DC maturation and expression of AM and AM receptors were evaluated. Compared with lipopolysaccharide‐stimulated or CpG‐stimulated DC, AM‐stimulated DC had lower levels of co‐stimulatory molecule expression and pro‐inflammatory cytokine release. The AM induced high levels of interferon‐γ but not of interleukin‐10. Importantly, AM inhibited lipopolysaccharide‐induced maturation of DC. However, allogeneic T‐cell stimulation and endocytic capacity of AM‐stimulated DC were comparable to those of semi‐mature and mature DC. Moreover, DC expressed AM and its receptors at a basal level, and AM receptor expression increased with DC maturation. The AM stimulation induced indoleamine 2,3‐dioxygenase (IDO) expression, promoting Treg cell expansion. For the first time, we describe the DC maturation phenotype by a neuropeptide (AM). We have demonstrated that AM and its receptors are expressed in DC and that exogenous AM can modify the DC phenotype and functions and can induce a semi‐mature DC phenotype with IDO expression. These results indicate close interactions among immune system regulation mechanisms and calcitonin‐like peptides.
A dynamic Brownian bridge movement model to estimate utilization distributions for heterogeneous animal movement
Authors: Kranstauber Bart , Kays Roland , LaPoint Scott D. , Wikelski Martin , Safi Kamran
Published: February 2012

1. The recently developed Brownian bridge movement model (BBMM) has advantages over traditional methods because it quantifies the utilization distribution of an animal based on its movement path rather than individual points and accounts for temporal autocorrelation and high data volumes. However, the BBMM assumes unrealistic homogeneous movement behaviour across all data.

2. Accurate quantification of the utilization distribution is important for identifying the way animals use the landscape.

3. We improve the BBMM by allowing for changes in behaviour, using likelihood statistics to determine change points along the animal's movement path.

4. This novel extension, outperforms the current BBMM as indicated by simulations and examples of a territorial mammal and a migratory bird. The unique ability of our model to work with tracks that are not sampled regularly is especially important for GPS tags that have frequent failed fixes or dynamic sampling schedules. Moreover, our model extension provides a useful one‐dimensional measure of behavioural change along animal tracks.

5. This new method provides a more accurate utilization distribution that better describes the space use of realistic, behaviourally heterogeneous tracks.