bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of novel cellular targets for therapeutic intervention against Ebola virus infection by siRNA screening
Authors: Kolokoltsov Andrey A. , Saeed Mohammad F. , Freiberg Alexander N. , Holbrook Michael R. , Davey Robert A.
Published: June 2009

While much progress has been made in developing drugs against a few prominent viruses such as HIV, few examples exist for emerging infectious agents. In some cases, broad spectrum anti‐viral drugs, such as ribavirin, are effective, but for some groups of viruses, these show little efficacy in animal models. Traditional methods focus on screening small molecule libraries to identify drugs that target virus factors, with the intention that side‐effects to the host can be minimized. However, this greatly limits potential drug targets and virus genes can rapidly mutate to avoid drug action. Recent advances in siRNA gene‐targeting technologies have provided a powerful tool to specifically target and suppress the expression of cell genes. Since viruses are completely dependent upon host cell proteins for propagation, siRNA screening promises to reveal novel cell proteins and signaling pathways that may be viable targets for drug therapy regimens. Here we used an siRNA screening approach to identify gene products that play critical roles in Ebola virus infection. By gene cluster analysis, proteins in phosphatidylinositol‐3‐kinase and calcium/calmodulin kinase related networks were identified as important for Zaire Ebola virus infection and prioritized for further evaluation. The key roles of each were confirmed by testing available drugs specific for members of each pathway. Interestingly, both sets of proteins are also important in cancer and subject to intense investigation. Thus, development of new drugs against these cancer targets may also prove useful in combating Ebola virus. Drug Dev Res 70:255–265, 2009. © 2009 Wiley‐Liss, Inc.
U.S. Army Botulinum Neurotoxin (BoNT) Medical Therapeutics Research Program: past accomplishments and future directions
Authors: Larsen Joseph C.
Published: June 2009

The United States Army (USA) under the auspices of the Medical Research and Material Command (USAMRMC) and the Defense Threat Reduction Agency (DTRA) sponsored several major efforts to develop an effective medical countermeasure against botulinum neurotoxin (BoNT). This review focuses on the U.S. Army's research and development efforts for a BoNT therapeutic over the period from 1975–2007. Two antitoxin preparations: Human botulism immunoglobulin (BIG) and Botulism Immune Globulin F(ab')2 Heptavalent Equine (BIGHE) were administered to humans and shown to possess acceptable efficacy and safety levels. BIGHE was deployed in Operation Desert Storm/Desert Shield. BoNT/A monoclonal antibodies were developed and are currently undergoing clinical evaluation with funding from the National Institute of Allergy and Infectious Disease (NIAID). The development of small molecules for the treatment of BoNT has also been supported. Efforts have focused on molecules to inhibit nearly every aspect of BoNT pathogenesis. This would include toxin binding, translocation, catalytic activity, and recovery following intoxication. Several compounds capable of inhibiting toxin activity or mitigating the severity of paralysis have been identified. To date, none of the compounds possess the appropriate properties (safety, efficacy, solubility) to be considered for clinical studies. Drug Dev Res 70:266–278, 2009. Published 2009 Wiley‐Liss, Inc.
Manufacturing a rapid biologic response
Authors: Latham Peter W.
Published: June 2009

There are two major components in making new biologic medical countermeasures available for bio‐defense and pandemic response: (1) the detection/discovery of effective countermeasures, and (2) their subsequent Process Development (PD) and manufacture. PD and manufacturing, however, are often the most costly and time‐consuming parts of the process, potentially taking years and costing hundreds of millions to billions of dollars. To address these long timelines, governments have historically stockpiled countermeasures for known biothreats. Unfortunately, this kind of stockpiling is very expensive, and does not provide protection against novel threats. Fortunately, there currently exist many new technologies that, when combined strategically, have the potential to significantly reduce the time and cost associated with the PD and manufacturing of biologic countermeasures. Drug Dev Res 70:288–295, 2009. © 2009 Wiley‐Liss, Inc.
Using a systems biology approach to dissect parasite–host interactions
Authors: Vaidyanathan Rajeev , Kodukula Krishna
Published: June 2009

The reductionist approach to biology has allowed us to understand the cell at a component level. But in recent years, with the deluge of genome‐derived and empirically obtained data, we must interpret biological complexity holistically. Thus, systems biology research allows us to connect the seemingly independent elements in biological networks. Protozoan parasites in the genus Leishmania cause clinically distinct diseases in humans with visceral, cutaneous, and mucocutaneous pathologies. In this article, we take the example of Leishmania parasites and their interactions with the vertebrate host as a model to generate a global view of molecular and biochemical processes in both spatial and temporal compartments, based on genomic, transcriptomic, proteomic, and metabolomic data. Furthermore, we propose extending this approach to other pathogen‐host relationships, thus enabling us to identify novel therapeutic targets, vaccine candidates, and to develop immune monitoring and diagnosis. Drug Dev Res 70:296–302, 2009 © 2009 Wiley‐Liss, Inc.
Accelerating botulism therapeutic product development in the Department of Defense
Authors: Stahl Andrea M. , Adler Michael , Millard Charles B. , Gilfillan Lynne
Published: June 2009

Coordinated small‐molecule drug discovery research efforts for the treatment of botulism by the public sector, especially the U.S. Department of Defense (DoD) and Department of Health and Human Services (DHHS), began in the 1990s and represent a significant resource investment. Organization of an effective botulism therapeutic drug program, however, presents formidable technical and logistical challenges. Seven distinct BoNT serotypes are known, each representing a different target. Moreover, BoNT exerts its action inside peripheral cholinergic neurons, and some serotypes may persist functionally within nerve cells for weeks or months. Clinical botulism occurs infrequently, and the effectiveness of prolonged mechanical ventilation to treat poisoning further limits experimental drug testing. The efficacy of experimental compounds must be extrapolated from disparate cell‐ or tissue‐based or rodent models. Numerous compounds with moderate efficacy in experimental laboratory assays have been reported, but may not possess the necessary safety, efficacy, and pharmacokinetic profile to support therapeutic development. To mitigate these challenges, we propose product development tools to assist in management of the BoNT portfolio and to clearly define the desired therapeutic product. Establishing a target product profile (TPP) is proposed to guide public sector managers toward critical aspects of the desired therapeutic product. Additional product development tools to assist in shaping research portfolios and to inform decisions regarding lead candidates to pursue are also discussed. Product development tools that facilitate the characterization of the ideal therapeutic product, and assist in the maintenance of a robust portfolio, will ameliorate the inherent financial risk in drug development for treating BoNT intoxication. Drug Dev Res 70:303–326, 2009. Published 2009 Wiley‐Liss, Inc.
Tools for planning and coordinating development of medical countermeasures in the public sector
Authors: Manger Ian , Pearson Jay , Winegar Richard , Gilfillan Lynne
Published: June 2009

In spite of significant increases in biodefense spending in the 7 years since the 2001 anthrax attacks, the United States may not yet be fully prepared to respond effectively to many potential biothreats. The principal reasons appear to be that: (1) the problem is extremely complex, and the metrics for success are often unclear; (2) although the US Congress has allocated substantial resources for this effort, these funds are insufficient for the task as initially conceived, i.e., “one drug for each bug;” and (3) there is insufficient coordination among the many agencies working to achieve the goal of protecting the nation from biothreats. In the last few years, much of the biodefense community has come to recognize that an approach that focuses on developing and stockpiling a medical countermeasure (MCM) for each possible biothreat agent is unachievable for reasons of cost, time, and the sheer diversity of emerging threats. Promising alternative models are emerging, including broad spectrum and technology platform approaches, but the requisite cross‐agency planning and coordination, although improving, is still problematic. We have developed a set of software tools and methods for using them that could support the desired coordination and that could also provide for more rapid, comprehensive, and shared identification of key enabling technologies for accomplishing the development of effective medical countermeasures in time to counter or prevent a biothreat. The tools and methods could also make possible a collaborative public‐private partnership for the development of MCM, which many believe is critical to success. Drug Dev Res 70:327–334, 2009 © 2009 Wiley‐Liss, Inc.
Temperament does not affect the overall establishment of mutual preference between the mother and her young in sheep measured in a choice test
Authors: Bickell S.L. , Nowak R. , Poindron P. , Sèbe F. , Chadwick A. , Ferguson D. , Blache D.
Published: June 2009

Temperament influences maternal behavior and lamb survival in Merino sheep selected for calm or nervous temperament. The impact of this selection on mother‐young recognition and early expression of temperament in lambs is unknown. We tested the ability of multiparous ewes selected for calm (n = 16) or nervous (n = 18) temperament to recognize their own lambs 6 hr after parturition, the ability of the lambs to display a preference for their own mother at 18 hr, and the temperament of the lambs at 1 and 16 weeks of age. Ewes and lambs from both genotypes showed a similar preference for their familiar kin. In contrast, differences in temperament were detectable at 1 and 16 weeks of age. Nervous lambs showed higher vocal and locomotor activity than calm lambs. Thus, temperament did not affect the early process of ewe‐lamb bonding but might affect the quality of the mother‐young relationship under more challenging situations. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 429–438, 2009.
Ror‐family receptor tyrosine kinases in noncanonical Wnt signaling: Their implications in developmental morphogenesis and human diseases
Authors: Minami Yasuhiro , Oishi Isao , Endo Mitsuharu , Nishita Michiru
Published: June 2009

The Ror‐family receptor tyrosine kinases (RTKs) play crucial roles in the development of various organs and tissues. In mammals, Ror2, a member of the Ror‐family RTKs, has been shown to act as a receptor or coreceptor for Wnt5a to mediate noncanonical Wnt signaling. Ror2‐ and Wnt5a‐deficient mice exhibit similar abnormalities during developmental morphogenesis, reflecting their defects in convergent extension movements and planar cell polarity, characteristic features mediated by noncanonical Wnt signaling. Furthermore, mutations within the human Ror2 gene are responsible for the genetic skeletal disorders dominant brachydactyly type B and recessive Robinow syndrome. Accumulating evidence demonstrate that Ror2 mediates noncanonical Wnt5a signaling by inhibiting the β‐catenin‐TCF pathway and activating the Wnt/JNK pathway that results in polarized cell migration. In this article, we review recent progress in understanding the roles of noncanonical Wnt5a/Ror2 signaling in developmental morphogenesis and in human diseases, including heritable skeletal disorders and tumor invasion. Developmental Dynamics 239:1–15, 2010. © 2009 Wiley‐Liss, Inc.
Role of Wnt signaling in the biology of the periodontium
Authors: Rooker Scott M. , Liu Bo , Helms Jill A.
Published: June 2009

Continuously erupting teeth have associated with them a continuously regenerating periodontal ligament, but the factors that control this amazing regenerative potential are unknown. We used genetic strategies to show that the periodontal ligament arises from the cranial neural crest. Despite their histological similarity, the periodontal ligament of continuously erupting incisor teeth differs dramatically from the periodontal ligament of molar teeth. The most notable difference was in the distribution of Wnt responsive cells in the incisor periodontal ligament, which coincided with regions of periodontal ligament cell proliferation. We discuss these findings in the context of dental tissue regeneration. Developmental Dynamics 239:140–147, 2010. © 2009 Wiley‐Liss, Inc.
Insulation resistance under DC stress and electrification characteristics of GIS epoxy insulator
Authors: Kaneko Shuhei , Okabe Shigemitsu , Kobayashi Takayuki , Nojima Kenichi , Takei Masafumi , Miyamoto Taketoshi
Published: June 2009

Gas‐insulated switchgear (GIS) has widely been used for AC power distribution because of its high reliability and compactness. Recently, DC GIS has been developed with various investigations for dielectric breakdown characteristics of DC gas insulation. GIS insulation is composed of SF6 gas and solid spacers, and it has been recognized that the dielectric performance of DC GIS is mainly influenced by solid spacers. Under DC stress, the electric field is directed one way, the effect of electrification for charges to be accumulated in the spacer must be taken into account and also the effect exists in AC GIS because the switching operations may leave the remnant DC charge on the AC GIS spacer. This paper first describes the effective resistivity (the bulk or the surface) of the solid spacer under the DC stress from the experimental investigation, and the critical factor on the solid spacer that causes reduced dielectric performance of the GIS insulation is studied. Second, the present paper deals with the electrification on the GIS with various levels of surface roughness of the epoxy insulator and metallic electrode. Finally, the DC insulation characteristics of GIS insulator are investigated based on the experimental results. © 2009 Wiley Periodicals, Inc. Electr Eng Jpn, 168(4): 6–13, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20788
Development of a novel commutation method that sharply reduces commutation failure of matrix converters
Authors: Kato Koji , Itoh Jun‐Ichi
Published: June 2009

This paper proposes the safest novel commutation method for a matrix converter. There are two conventional commutation methods which depend on the polarity of the input line voltage (it is called “voltage commutation”) and depend on the polarity of the output current (it is called “current commutation”). However, problem of the voltage commutation is that commutation failure occurs around zero of the input line voltage. It is difficult to detect its polarity due to depending on offset and delay of the sensor. Similarly, the current commutation failure occurs around zero of the load current. A cause of these detection errors are a detection delay and an offset of a sensor. The proposed commutation method combines the input voltage commutation and the load current commutation. Therefore, the proposed commutation method can decrease the commutation failure without high accuracy sensor. In addition, a voltage error compensation based on the proposed commutation method is proposed in this paper. The proposed method can simply compensate for the commutation error of the output voltage and the input current at the same time.

The effects of the proposed method are confirmed by experimental results with a 750 W induction motor and a R‐L load. Those results confirm that the proposed commutation can decrease commutation failure. Moreover, the total harmonics distortion of the input current and the output current are 2.6 point and 0.9 point lower than that of the condition without the compensation at 100% output power. © 2009 Wiley Periodicals, Inc. Electr Eng Jpn, 168(4): 49–57, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20826
A novel control strategy for matrix converters in the overmodulation range
Authors: Tamai Yasuhiro , Sato Ikuya , Odaka Akihiro , Mine Hironori , Itoh Jun‐Ichi
Published: June 2009

This paper proposes a control strategy for matrix converters to reduce the torque ripple in the overmodulation range. In the overmodulation range, motor drive performance of matrix converters is deteriorated because of the output voltage saturation. In particular, the torque ripple which has lower frequency components than the input voltage frequency is remarkable. This paper presents a theoretical analysis of the causes of the torque ripple and the effect of the proposed control strategy. Experimental examinations including performance comparison with a trapezoidal wave modulation are carried out using a 400‐V, 22‐kW experimental system. The experimental results verify the validity of the theoretical analysis and confirm the effectiveness of the proposed control strategy for reducing the torque ripple. Furthermore, the harmonic distortion of the output current is also reduced compared with the trapezoidal wave modulation. © 2009 Wiley Periodicals, Inc. Electr Eng Jpn, 168(4): 40–48, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20829
Experience‐based teaching materials of logic circuits for beginners
Authors: Miyagoshi Takashi , Okino Koji , Tajima Masato
Published: June 2009

At an open campus, it is necessary to prepare intuitive experience‐based teaching materials for high school students without technical knowledge. In this teaching material, which is based on an algorithm derived from the MA method (i.e., the method of Ref. 1), the students can sequentially experience the following functions using X‐Windows under UNIX: multilevel NAND circuit generation, simplification of the initially constructed circuit, proper rearrangement of circuit elements, verification of the resulting circuit, time chart display, etc. © 2009 Wiley Periodicals, Inc. Electr Eng Jpn, 168(4): 1–5, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20860
Recurrent chromosomal rearrangements implicate oncogenes contributing to T‐cell lymphomagenesis in Lck‐MyrAkt2 transgenic mice
Authors: Timakhov Roman A. , Tan Yinfei , Rao Mamta , Liu Zemin , Altomare Deborah A. , Pei Jianming , Wiest David L. , Favorova Olga O. , Knepper Janice E. , Testa Joseph R.
Published: June 2009

The oncogene v‐akt was isolated from a retrovirus that induced naturally occurring thymic lymphomas in AKR mice. We hypothesized that constitutive activation of Akt2 could serve as a first hit for the clonal expansion of malignant T‐cells by promoting cell survival and genomic instability, leading to chromosome alterations. Furthermore, genes that cooperate with Akt2 to promote malignant transformation may reside at translocation/inversion junctions found in spontaneous thymic lymphomas from transgenic mice expressing constitutively active Akt2 specifically in T cells. Cytogenetic analysis revealed that thymic tumors from multiple founder lines exhibited either of two recurrent chromosomal rearrangements, inv(6)(A2B1) or t(14;15)(C2;D1). Fluorescence in situ hybridization, array CGH, and PCR analysis were used to delineate the inv(6) and t(14;15) breakpoints. Both rearrangements involved T‐cell receptor loci. The inv(6) results in robust upregulation of the homeobox/transcription factor gene Dlx5 because of its relocation near the Tcrb enhancer. The t(14;15) places the Tcra enhancer in the vicinity of the Myc proto‐oncogene, resulting in upregulated Myc expression. These findings suggest that activation of the Akt pathway can act as the initial hit to promote cell survival and genomic instability, whereas the acquisition of T‐cell‐specific overexpression of Dlx5 or Myc leads to lymphomagenesis. © 2009 Wiley‐Liss, Inc.
Clinical and cytogenetic features of a population‐based consecutive series of 285 pediatric T‐cell acute lymphoblastic leukemias: Rare T‐cell receptor gene rearrangements are associated with poor outcome
Authors: Karrman Kristina , Forestier Erik , Heyman Mats , Andersen Mette K. , Autio Kirsi , Blennow Elisabeth , Borgström Georg , Ehrencrona Hans , Golovleva Irina , Heim Sverre , Heinonen Kristiina , Hovland Randi , Johannsson Johann H. , Kerndrup Gitte , Nordgren Ann , Palmqvist Lars , Johansson Bertil
Published: June 2009

Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population‐based consecutive series of 285 pediatric T‐cell acute lymphoblastic leukemias (T‐ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T‐ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T‐cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 × 109/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5‐year event‐free survival (EFS) and overall survival for all patients were 0.61 (±0.03) and 0.67 (±0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of ≥200 × 109/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T‐ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results. © 2009 Wiley‐Liss, Inc.
Rearrangements of the MLL gene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding
Authors: Le Hongan , Singh Sheetal , Shih Shyh‐Jen , Du Nga , Schnyder Sabine , Loredo Grace A. , Bien Christine , Michaelis Laura , Toor Amir , Diaz Manuel O. , Vaughan Andrew T.
Published: June 2009

The location of MLL translocation breakpoints within therapy‐related acute myeloid leukemia linked to drugs targeting Topoisomerase II and infant acute leukemia (IAL) are biased toward the intron 11–exon 12 region of MLL, although lacking a comprehensive explanation. To address this, blood samples were taken from breast cancer and lymphoma patients receiving Topoisomerase II inhibitor therapy. Inverse PCR analysis was used to interrogate the exon 12 region of MLL for rearrangements. Eleven of 19 observed translocations showed breakpoint junctions restricted to a single 5 bp location within exon 12. A similarly restricted distribution (11/20 breakpoint junctions) was observed in TK6 cells exposed to either estrogen (linked to IAL) or anti‐CD95 antibody. The translocation hotspot was at the 5′ edge of a 10‐bp tract matched with a perfect palindrome, 101 bp distant. A high stringency Topoisomerase II consensus sequence binding site was noted at the geometric midpoint of the palindromes. Ligation‐mediated PCR to screen TK6 cells exposed to anti‐CD95 antibody showed 14/37 (38%) of DNA breaks adjacent to the 5′ palindrome and 10/37 (27%) at the 3′ partner. We propose a model whereby Topoisomerase II facilitates the organization of nuclease‐sensitive secondary structures, stabilized by palindrome association, which are prone to rearrangement. © 2009 Wiley‐Liss, Inc.
WNT/β‐catenin pathway activation in Wilms tumors: A unifying mechanism with multiple entries?
Authors: Corbin Marie , de Reyniès Aurélien , Rickman David S. , Berrebi Dominique , Boccon‐Gibod Liliane , Cohen‐Gogo Sarah , Fabre Monique , Jaubert Francis , Faussillon Marine , Yilmaz Funda , Sarnacki Sabine , Landman‐Parker Judith , Patte Catherine , Schleiermacher Gudrun , Antignac Corinne , Jeanpierre Cécile
Published: June 2009

Based on characterization of both genomic and expression status of WT1 and CTNNB1 (β‐catenin) in a series of 60 Wilms tumor samples, combined with genome‐wide expression profiling of these tumors, normal mature and fetal kidney controls, we show that WT1/β‐catenin expression was a better classifier than WT1/CTNNB1 mutations. We present molecular data supporting that the WNT pathway is involved in both tumor classes, with and without WT1/β‐catenin alterations. In the tumor class with WT1/β‐catenin alterations, we identified overexpression of 14 previously unreported WNT target genes, including TWIST1. We show that the TWIST1 protein was specifically expressed in these tumors, where staining was restricted to the stromal, nuclear β‐catenin positive, component. By comparing the state of the WNT pathway in tumors without WT1/β‐catenin alterations and fetal kidneys we provide evidence that suggests that these tumors have a heightened level of pathway activation. We characterized mutations of the WNT pathway regulator gene WTX in 16% of this tumor class. Moreover, genome‐transcriptome correlation analysis allowed us to identify three other WNT pathway regulator genes that could participate in the activation of the WNT pathway: BCL9 (1p36.2), CTNNBIP1 (1p36.2), and CBY1 (22q13.1). These genes thus represent new potential important actors in WT tumorigenesis. © 2009 Wiley‐Liss, Inc.
DNA hypermethylation accompanied by transcriptional repression in follicular lymphoma
Authors: Bennett Lynda B. , Schnabel Jennifer L. , Kelchen Jean M. , Taylor Kristen H. , Guo Juyuan , Arthur Gerald L. , Papageorgio Christos N. , Shi Huidong , Caldwell Charles W.
Published: June 2009

High‐throughput microarray technologies were used to study DNA methylation accompanied by transcriptional changes in follicular lymphoma (FL). Using Methylated CpG Island Amplification with Microarrays to study CpG Island DNA methylation in FL, we discovered widespread hypermethylation of homeobox genes and previously identified targets of polycomb repressive complex 2 (PRC2) in cell lines and primary tumors, but not in benign follicular hyperplasia (BFH). DNA methylation for HOXA11, HOXD10, HOXB7, HOXC12, PAX6, LHX9, SFMBT2, EN2, and PAX7 was independently validated in the RL cell line and HOXA11, HOXD10, PAX6, and EN2 in primary tumors. Combined Bisulfite Restriction Analysis (COBRA) also established DNA methylation for the previously identified PRC2 targets DCC, DES, GAD2, AQP5, GPR61, GRIA4, GJD2, and AMPH in FL but not in BFH. Gene expression analyses revealed 411 genes that were hypermethylated and transcriptionally repressed in RL, 74% of which were reactivated by the demethylating agent 5‐aza‐2′‐deoxycytidine (5‐azaD) plus or minus the histone deacetylase inhibitor trichostatin A (TSA). Forty genes were also downregulated in primary FL. Our results suggest that extensive hypermethylation in promoters of polycomb target genes is a characteristic of FL and that loss of expression of certain SUZ12 target genes could be functionally relevant for lymphomagenesis. © 2009 Wiley‐Liss, Inc.
Frontolimbic responses to emotional face memory: The neural correlates of first impressions
Authors: Satterthwaite Theodore D. , Wolf Daniel H. , Gur Ruben C. , Ruparel Kosha , Valdez Jeffrey N. , Gur Raquel E. , Loughead James
Published: June 2009

First impressions, especially of emotional faces, may critically impact later evaluation of social interactions. Activity in limbic regions, including the amygdala and ventral striatum, has previously been shown to correlate with identification of emotional content in faces; however, little work has been done describing how these signals may influence emotional face memory. We report an event‐related functional magnetic resonance imaging study in 21 healthy adults where subjects attempted to recognize a neutral face that was previously viewed with a threatening (angry or fearful) or nonthreatening (happy or sad) affect. In a hypothesis‐driven region of interest analysis, we found that neutral faces previously presented with a threatening affect recruited the left amygdala. In contrast, faces previously presented with a nonthreatening affect activated the left ventral striatum. A whole‐brain analysis revealed increased response in the right orbitofrontal cortex to faces previously seen with threatening affect. These effects of prior emotion were independent of task performance, with differences being seen in the amygdala and ventral striatum even if only incorrect trials were considered. The results indicate that a network of frontolimbic regions may provide emotional bias signals during facial recognition. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.
Neuroanatomical markers of speaking Chinese
Authors: Crinion Jenny T. , Green David W. , Chung Rita , Ali Nliufa , Grogan Alice , Price Gavin R. , Mechelli Andrea , Price Cathy J.
Published: June 2009

The aim of this study was to identify regional structural differences in the brains of native speakers of a tonal language (Chinese) compared to nontonal (European) language speakers. Our expectation was that there would be differences in regions implicated in pitch perception and production. We therefore compared structural brain images in three groups of participants: 31 who were native Chinese speakers; 7 who were native English speakers who had learnt Chinese in adulthood; and 21 European multilinguals who did not speak Chinese. The results identified two brain regions in the vicinity of the right anterior temporal lobe and the left insula where speakers of Chinese had significantly greater gray and white matter density compared with those who did not speak Chinese. Importantly, the effects were found in both native Chinese speakers and European subjects who learnt Chinese as a non‐native language, illustrating that they were language related and not ethnicity effects. On the basis of prior studies, we suggest that the locations of these gray and white matter changes in speakers of a tonal language are consistent with a role in linking the pitch of words to their meaning. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.
Priming words with pictures: Neural correlates of semantic associations in a cross‐modal priming task using fMRI
Authors: Kircher Tilo , Sass Katharina , Sachs Olga , Krach Sören
Published: June 2009

In our everyday life we process information from different modalities simultaneously with great ease. With the current study we had the following goals: to detect the neural correlates of (1) automatic semantic processing of associates and (2) to investigate the influence of different visual modalities on semantic processing. Stimuli were presented with a short SOA (350 ms) as subjects performed a lexical decision task. To minimize the variance and increase homogeneity within our sample, only male subjects were measured. Three experimental conditions were compared while brain activation was measured with a 3 T fMRI scanner: related word‐pairs (e.g., frame–picture), unrelated word‐pairs (e.g., frame–car) as well as word‐nonword pairs (e.g., frame–fubber). They were presented uni‐ (word ‐word) and cross‐modally (picture–word). Behavioral data revealed a priming effect for cross‐modal and unimodal word‐pairs. On a neural level, the unimodal condition revealed response suppression in bilateral fronto‐parietal regions. Cross‐modal priming led to response suppression within the right inferior frontal gyrus. Common areas of deactivation for both modalities were found in bilateral fronto‐tempo‐parietal regions. These results suggest that the processing of semantic associations presented in different modalities lead to modality‐specific activation caused by early access routes. However, common activation for both modalities refers to a common neural network for semantic processing suggesting amodal processing. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.
Superior temporal lobe dysfunction and frontotemporal dysconnectivity in subjects at risk of psychosis and in first‐episode psychosis
Authors: Crossley Nicolas A. , Mechelli Andrea , Fusar‐Poli Paolo , Broome Matthew R. , Matthiasson Pall , Johns Louise C. , Bramon Elvira , Valmaggia Lucia , Williams Steven C.R. , McGuire Philip K.
Published: June 2009

Background: Superior temporal lobe dysfunction is a robust finding in functional neuroimaging studies of schizophrenia and is thought to be related to a disruption of fronto‐temporal functional connectivity. However, the stage of the disorder at which these functional alterations occur is unclear. We addressed this issue by using functional MRI (fMRI) to study subjects in the prodromal and first episode phases of schizophrenia. Methods: Subjects with an at risk mental state (ARMS) for psychosis, a first psychotic episode (FEP), and controls were studied using fMRI while performing a working memory task. Activation in the superior temporal gyrus (STG) was assessed using statistical parametric mapping, and its relationship to frontal activation was examined using dynamic causal modeling. Results: The STG was differentially engaged across the three groups. There was deactivation of this region during the task in controls, whereas subjects with FEP showed activation and the response in subjects with ARMS was intermediately relative to the two other groups. There were corresponding differences in the effective connectivity between the STG and the middle frontal gyrus across the three groups, with a negative coupling between these areas in controls, a positive coupling in the FEP group, and an intermediate value in the ARMS group. Conclusions: A failure to deactivate the superior temporal lobe during tasks that engage prefrontal cortex is evident at the onset of schizophrenia and may reflect a disruption of fronto‐temporal connectivity. Qualitatively similar alterations are evident in people with prodromal symptoms of the disorder. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.
Inhibition of Transforming Growth Factor β Receptor I Kinase Blocks Hepatocellular Carcinoma Growth Through Neo-angiogenesis Regulation†
Authors: Mazzocca Antonio , Fransvea Emilia , Lavezzari Gabriela , Antonaci Salvatore , Giannelli Gianluigi
Published: June 2009

Curative therapies for patients with hepatocellular carcinoma (HCC) are mainly invasive, and with the exception of sorafenib, no medical treatments are available for advanced or metastatic stages of HCC. We investigated the antitumoral effect of blocking the transforming growth factor β (TGF-β) signaling pathway in HCC with LY2109761, a kinase inhibitor of TGF-β receptor I kinase. The antitumor activity of LY2109761 was associated with inhibition of molecular pathways involved in neo-angiogenesis and tumor growth of HCC. This anti-angiogenic effect is more effective than that of bevacizumab, which specifically targets vascular endothelial growth factor (VEGF). We found that the paracrine cross-talk between HCC and endothelial cells is blocked by LY210976, inhibiting blood vessel formation. This effect was mediated by SMAD2/3 and affected the secretion of VEGF. Finally, LY2109761 does not show significant effects on phsyiological angiogenetic development.

Conclusion:

These data support the rationale for targeting TGF-β signaling in patients with HCC. (Hepatology 2009.)
Advances in Pediatric Nonalcoholic Fatty Liver Disease†
Authors: Loomba Rohit , Sirlin Claude B. , Schwimmer Jeffrey B. , Lavine Joel E.
Published: June 2009

Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in children and adolescents in the United States. A two- to three-fold rise in the rates of obesity and overweight in children over the last two decades is probably responsible for the NAFLD epidemic. Emerging data suggest that children with nonalcoholic steatohepatitis (NASH) progress to cirrhosis, which may ultimately increase liver-related mortality. More worrisome is the recognition that cardiovascular risk and morbidity in children and adolescents are associated with fatty liver. Pediatric fatty liver disease often displays a histologic pattern distinct from that found in adults. Liver biopsy remains the gold standard for diagnosis of NASH. Noninvasive biomarkers are needed to identify individuals with progressive liver injury. Targeted therapies to improve liver histology and metabolic abnormalities associated with fatty liver are needed. Currently, randomized-controlled trials are underway in the pediatric population to define pharmacologic therapy for NAFLD.

Conclusion:

Public health awareness and intervention are needed to promote healthy diet, exercise, and lifestyle modifications to prevent and reduce the burden of disease in the community. (Hepatology 2009.)
Hepatic Targeting and Biodistribution of Human Fetal Liver Stem/Progenitor Cells and Adult Hepatocytes in Mice†
Authors: Cheng Kang , Benten Daniel , Bhargava Kuldeep , Inada Mari , Joseph Brigid , Palestro Christopher , Gupta Sanjeev
Published: June 2009

Tracking stem/progenitor cells through noninvasive imaging is a helpful means of assessing the targeting of transplanted cells to specific organs. We performed in vitro and in vivo studies wherein adult human hepatocytes and human fetal liver stem/progenitor cells were labeled with indium-111 (111In)-oxine and technetium-99m (99mTc)-Ultratag or 99mTc-Ceretec. The labeling efficiency and viability of cells was analyzed in vitro, and organ biodistribution of cells was analyzed in vivo after transplantation in xenotolerant nonobese diabetic/severe combined immunodeficiency mice through intrasplenic or intraportal routes. We found that adult hepatocytes and fetal liver stem/progenitor cells incorporated 111In but not 99mTc labels. After radiolabeling, cell viability was unchanged. Transplanted adult hepatocytes or fetal liver stem/progenitor cells were targeted to the liver more effectively by the intraportal rather than the intrasplenic route. Transplanted cells were retained in the liver after intraportal injection and in the liver and spleen after intrasplenic injection, without translocations into pulmonary or systemic circulations. Compared with fetal liver stem/progenitor cells, fewer adult hepatocytes were retained in the spleen after intrasplenic transplantation. The distribution of transplanted cells in organs was substantiated by genetic assays, including polymerase chain reaction amplification of DNA sequences from a primate-specific Charcot-Marie-Tooth element, and in situ hybridization for primate alphoid satellite sequences ubiquitous in all centromeres.

Conclusion:

111In labeling of human fetal liver stem/progenitor cells and adult hepatocytes was effective for noninvasive localization of transplanted cells. This should facilitate continued development of cell therapies through further animal and clinical studies. (Hepatology 2009.)
Targeting Liver Fibrosis
Authors: Popov Yury , Schuppan Detlef
Published: June 2009

We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many

in vitro

and

in vivo

models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents. (Hepatology 2009.)
Mcl-1 and Bcl-xL Cooperatively Maintain Integrity of Hepatocytes in Developing and Adult Murine Liver†
Authors: Hikita Hayato , Takehara Tetsuo , Shimizu Satoshi , Kodama Takahiro , Li Wei , Miyagi Takuya , Hosui Atsushi , Ishida Hisashi , Ohkawa Kazuyoshi , Kanto Tatsuya , Hiramatsu Naoki , Yin Xiao-Ming , Hennighausen Lothar , Tatsumi Tomohide , Hayashi Norio
Published: June 2009

Anti-apoptotic members of the Bcl-2 family, including Bcl-2, Bcl-xL, Mcl-1, Bcl-w and Bfl-1, inhibit the mitochondrial pathway of apoptosis. Bcl-xL and Mcl-1 are constitutively expressed in the liver. Although previous research established Bcl-xL as a critical apoptosis antagonist in differentiated hepatocytes, the significance of Mcl-1 in the liver, especially in conjunction with Bcl-xL, has not been clear. To examine this question, we generated hepatocyte-specific Mcl-1–deficient mice by crossing

mcl-1

flox

/

flox

mice and

AlbCre

mice and further crossed them with

bcl-x

flox

/

flox

mice, giving Mcl-1/Bcl-xL–deficient mice. The

mcl-1

flox

/

flox

AlbCre

mice showed spontaneous apoptosis of hepatocytes after birth, as evidenced by elevated levels of serum alanine aminotransferase (ALT) and caspase-3/7 activity and an increased number of terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL)-positive cells in the liver; these phenotypes were very close to those previously found in hepatocyte-specific Bcl-xL–deficient mice. Although

mcl-1

flox

/+

AlbCre

mice did not display apoptosis, their susceptibility to Fas-mediated liver injury significantly increased. Further crossing of Mcl-1 mice with Bcl-xL mice showed that

bcl-x

flox

/+

mcl-1

flox

/+

AlbCre

mice also showed spontaneous hepatocyte apoptosis similar to Bcl-xL–deficient or Mcl-1–deficient mice. In contrast,

bcl-x

flox

/

flox

mcl-1

flox

/+

AlbCre

,

bcl-x

flox

/+

mcl-1

flox

/

flox

AlbCre,

and

bcl-x

flox

/

flox

mcl-1

flox

/

flox

AlbCre

mice displayed a decreased number of hepatocytes and a reduced volume of the liver on day 18.5 of embryogenesis and rapidly died within 1 day after birth, developing hepatic failure evidenced by increased levels of blood ammonia and bilirubin.

Conclusion:

Mcl-1 is critical for blocking apoptosis in adult liver and, in the absence of Bcl-xL, is essential for normal liver development. Mcl-1 and Bcl-xL are two major anti-apoptotic Bcl-2 family proteins expressed in the liver and cooperatively control hepatic integrity during liver development and in adult liver homeostasis in a gene dose-dependent manner. (Hepatology 2009.)
Aerobic Exercise Training Reduces Hepatic and Visceral Lipids in Obese Individuals Without Weight Loss†
Authors: Johnson Nathan A. , Sachinwalla Toos , Walton David W. , Smith Kate , Armstrong Ashley , Thompson Martin W. , George Jacob
Published: June 2009

Weight loss remains the most common therapy advocated for reducing hepatic lipid in obesity and nonalcoholic fatty liver disease. Yet, reduction of body weight by lifestyle intervention is often modest, and thus, therapies which effectively modulate the burden of fatty liver but are not contingent upon weight loss are of the highest practical significance. However, the effect of aerobic exercise on liver fat independent of weight loss has not been clarified. We assessed the effect of aerobic exercise training on hepatic, blood, abdominal and muscle lipids in 19 sedentary obese men and women using magnetic resonance imaging and proton magnetic resonance spectroscopy (1H-MRS). Four weeks of aerobic cycling exercise, in accordance with current physical activity guidelines, significantly reduced visceral adipose tissue volume by 12% (

P

< 0.01) and hepatic triglyceride concentration by 21% (

P

< 0.05). This was associated with a significant (14%) reduction in plasma free fatty acids (

P

< 0.05). Exercise training did not alter body weight, vastus lateralis intramyocellular triglyceride concentration, abdominal subcutaneous adipose tissue volume, 1H-MRS–measured hepatic lipid saturation, or HOMA-IR (homeostasis model assessment of insulin resistance;

P

> 0.05).

Conclusion:

These data provide the first direct experimental evidence demonstrating that regular aerobic exercise reduces hepatic lipids in obesity even in the absence of body weight reduction. Physical activity should be strongly promoted for the management of fatty liver, the benefits of which are not exclusively contingent upon weight loss. (Hepatology 2009.)
Changes in spatial memory and BDNF expression to concurrent dietary restriction and voluntary exercise
Authors: Khabour Omar F. , Alzoubi Karem H. , Alomari Mahmoud A. , Alzubi Mohammad A.
Published: June 2009

Substantial data suggest that cognitive function can be influenced by many lifestyle activities associated with changes in energy metabolism such as exercise and diet. In the current study, we investigated the combined effects of voluntary exercise (access to running wheels) and dietary restriction (every other day fasting, EODF) on spatial memory formation and on the levels of brain‐derived neurotrophic factor (BDNF) in the hippocampus of Wistar male rats. Spatial learning and memory formation was assessed using the radial arm water maze (RAWM) paradigm, while BDNF protein was measured using ELISA test. Voluntary exercise and/or EODF were instituted for 6 weeks. Voluntary exercise alone significantly enhanced short‐term, intermediate‐term, and long‐term memory formation, and increased BDNF protein levels in the hippocampus. EODF enhanced mean running wheel activity by approximately twofold. However, EODF did not modulate the effects of exercise on memory formation and expression of BDNF. In addition, EODF alone had no effect on memory and BDNF protein in the hippocampus. In conclusion, results of this study indicate that exercise enhanced while EODF had neutral effect on both spatial memory formation and hippocampus BDNF levels. © 2009 Wiley‐Liss, Inc.