bluuebunny/crossref_metadata_2025 huggingface dataset:
Serial Transcriptome Analysis and Cross-Species Integration Identifies Centromere-Associated Protein E as a Novel Neuroblastoma Target
Authors: Balamuth Naomi J. , Wood Andrew , Wang Qun , Jagannathan Jayanti , Mayes Patrick , Zhang Zhe , Chen Zhongxue , Rappaport Eric , Courtright Joshua , Pawel Bruce , Weber Barbara , Wooster Richard , Sekyere Eric O. , Marshall Glenn M. , Maris John M.
Published: March 2010

Cancer genomic studies that rely on analysis of biopsies from primary tumors may not fully identify the molecular events associated with tumor progression. We hypothesized that characterizing the transcriptome during tumor progression in the TH-MYCN transgenic model would identify oncogenic drivers that would be targetable therapeutically. We quantified expression of 32,381 murine genes in nine hyperplastic ganglia harvested at three time points and four tumor cohorts of progressively larger size in mice homozygous for the TH-MYCN transgene. We found 93 genes that showed a linearly increasing or decreasing pattern of expression from the preneoplastic ganglia to end stage tumors. Cross-species integration identified 24 genes that were highly expressed in human MYCN-amplified neuroblastomas. The genes prioritized were not exclusively driven by increasing Myc transactivation or proliferative rate. We prioritized three targets [centromere-associated protein E (Cenpe), Gpr49, and inosine monophosphate dehydrogenase type II] with previously determined roles in cancer. Using siRNA knockdown in human neuroblastoma cell lines, we further prioritized CENPE due to inhibition of cellular proliferation. Targeting CENPE with the small molecular inhibitor GSK923295 showed inhibition of in vitro proliferation of 19 neuroblastoma cell lines (median IC50, 41 nmol/L; range, 27–266 nmol/L) and delayed tumor growth in three xenograft models (P values ranged from P < 0.0001 to P = 0.018). We provide preclinical validation that serial transcriptome analysis of a transgenic mouse model followed by cross-species integration is a useful method to identify therapeutic targets and identify CENPE as a novel therapeutic candidate in neuroblastoma. Cancer Res; 70(7); 2749–58
Glutamine Synthetase Immunostaining Correlates with Pathologic Features of Hepatocellular Carcinoma and Better Survival after Radiofrequency Thermal Ablation
Authors: Dal Bello Barbara , Rosa Laura , Campanini Nicoletta , Tinelli Carmine , Torello Viera Francesca , D'Ambrosio Gioacchino , Rossi Sandro , Silini Enrico M.
Published: March 2010

Purpose: Activation of the wnt pathway identifies a subgroup of hepatocellular carcinomas (HCC) with specific epidemiologic and genetic profiles. Wnt activation is predicted by mutation and/or nuclear translocation of β-catenin and by glutamine synthetase (GS) immunoreactivity. We investigated whether GS staining associates with specific pathologic features of HCC and with survival after radiofrequency thermal ablation.

Experimental Design: Monoistitutional retrospective-prospective study in a tertiary hospital setting. Two hundred and seven cirrhotics (mean age, 70 years; 63% males, 82.1% hepatitis C virus positive) with early HCC were consecutively treated with radiofrequency thermal ablation (RFTA). Mean tumor size was 2.7 cm; 20.3% of patients had multiple nodules; and median follow-up was 36 months with 54.6% overall mortality. Tumor samples were mainly obtained by biopsy (92,5%) and examined by H&E and immunostaining for β-catenin and GS. Main outcome measures were overall and tumor-specific mortality by Kaplan-Meier analysis and Cox proportional hazard models corrected for competing risks.

Results: Ninety-one patients (43.9%) had GS-positive HCCs by immunostaining. These tumors had larger size (P = 0.012) and characteristic histology (low grade, pseudoacini, hydropic changes, bile staining, lack of steatosis, and fibrosis). Other clinical or treatment variables were similar between groups. Variables correlating with tumor-specific and overall mortality by univariate analysis were tumor recurrence, advanced disease, posttreatment α-fetoprotein levels, and GS staining. Yearly, overall mortality rate was lower in GS-positive patients (12.4 versus 20% yearly; P = 0.006). By multivariate analysis, GS immunostaining correlated with reduced specific (hazard ratio, 0.58; 95% confidence interval, 0.34-0.97) and overall mortality (hazard ratio, 0.62; 95% confidence interval, 0.40-0.96).

Conclusions: Standard histology and GS status identify a HCC subset with distinct clinical and pathologic features. Clin Cancer Res; 16(7); 2157–66. ©2010 AACR.
Viral Response to Chemotherapy in Endemic Burkitt Lymphoma
Authors: Tang Weihua , Harmon Paula , Gulley Margaret L. , Mwansambo Charles , Kazembe Peter N. , Martinson Francis , Wokocha Clifford , Kenney Shannon C. , Hoffman Irving , Sigel Carlie , Maygarden Susan , Hoffman Mariah , Shores Carol
Published: March 2010

Purpose: Some EBV-directed therapies are predicted to be effective only when lytic viral replication occurs. We studied whether cyclophosphamide chemotherapy induces EBV to switch from latent to lytic phases of infection in a series of EBV-associated Burkitt lymphomas.

Experimental Design: Children with first presentation of an expanding, solid maxillary or mandibular mass consistent with Burkitt lymphoma underwent fine-needle aspiration just prior to the initiation of cyclophosphamide therapy and again 1 to 5 days later. Aspirated cells were examined for latent and lytic EBV infection using in situ hybridization to EBV-encoded RNA (EBER), immunohistochemical analysis of the lytic EBV proteins BZLF1 and BMRF1, reverse transcription PCR targeting BZLF1 transcripts, and EBV viral load measurement by quantitative PCR.

Results: Among 21 lymphomas expressing EBER prior to chemotherapy, 9 of 10 still expressed EBER on day 1 after therapy whereas only 2 of 11 (18%) specimens still expressed EBER at days 3 to 5, implying that chemotherapy was fairly effective at eliminating latently infected cells. Neither of the lytic products, BZLF1 or BMRF1, were significantly upregulated at the posttherapy time points examined. However, EBV genomic copy number increased in 5 of 10 samples 1 day after treatment began, suggesting that viral replication occurs within the first 24 hours.

Conclusion: Cyclophosphamide may induce the lytic phase of EBV infection and is fairly effective in diminishing EBER-expressing tumor cells within 5 days. These findings provide the rationale for a trial testing synergistic tumor cell killing using cyclophosphamide with a drug like ganciclovir targeting lytically infected cells. Clin Cancer Res; 16(7); 2055–64. ©2010 AACR.
Sulforaphane Inhibits Constitutive and Interleukin-6–Induced Activation of Signal Transducer and Activator of Transcription 3 in Prostate Cancer Cells
Authors: Hahm Eun-Ryeong , Singh Shivendra V.
Published: March 2010

d,l-Sulforaphane (SFN), a synthetic analogue of broccoli-derived l-isomer, inhibits viability of human prostate cancer cells and prevents development of prostate cancer and distant site metastasis in a transgenic mouse model. However, the mechanism underlying the anticancer effect of SFN is not fully understood. We now show that SFN inhibits constitutive and interleukin-6 (IL-6)–inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer. Growth-suppressive concentrations of SFN (20 and 40 μmol/L) decreased constitutive (DU145 cells) and IL-6–induced (DU145 and LNCaP cells) phosphorylation of STAT3 (Tyr705) as well as its upstream regulator Janus-activated kinase 2 (Tyr1007/1008). Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL-6–induced transcriptional activity of STAT3 as judged by luciferase reporter assay and (b) nuclear translocation of phospho-STAT3 as revealed by immunofluorescence microscopy. Levels of many STAT3-regulated gene products, including Bcl-2, cyclin D1, and survivin, were also reduced in SFN-treated cells. The IL-6–mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis as evidenced by cytoplasmic histone-associated DNA fragmentation and cleavage of poly(ADP-ribose) polymerase and procaspase-3. Furthermore, knockdown of STAT3 protein using small interfering RNA resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation in DU145 cells. Suppression of STAT3 activation was also observed in cells treated with naturally occurring analogues of SFN. In conclusion, the present study indicates that inhibition of STAT3 partially contributes to the proapoptotic effect of SFN. Cancer Prev Res; 3(4); 484–94. ©2010 AACR.
Viviparity and Temperature-Dependent Sex Determination
Authors: Robert K.A. , Thompson M.B.
Published: March 2010

Although temperature-dependent sex determination (TSD) has been a ‘hot topic’ for well over 30 years, the discovery of TSD in viviparous taxa is recent. Viviparity and TSD was regarded unlikely on theoretical grounds as viviparity allows for high stable developmental temperatures through maternal basking. However, pregnant squamates of many species choose different body temperatures from non-pregnant females and males, and we now know that differential temperature selection by viviparous species with TSD allows for the production of sons or daughters. Three species of squamate reptiles (all are skinks) are now know to exhibit TSD. The physiological mechanism by which viviparous reptiles control the sex of their offspring is not understood, but exposure to different operational sex ratios in the adult population is a factor in some species. The functional role of sex steroid hormones in egg yolk and how the hormones are manipulated in utero is still an area requiring detailed investigation. Fast maturing squamate reptiles provide an excellent, but as yet underutilized, model system for studying the adaptive significance of TSD, and the occurrence of TSD in viviparous species requires substantially more work on a phylogenetically diverse range of species.
Potential Contributions of Heat Shock Proteins to Temperature-Dependent Sex Determination in the American Alligator
Authors: Kohno S. , Katsu Y. , Urushitani H. , Ohta Y. , Iguchi T. , Guillette, Jr. L.J.
Published: March 2010

Sex determination in the American alligator depends on the incubation temperature experienced during a thermo-sensitive period (TSP), although sex determination can be ‘reversed’ by embryonic exposure to an estrogenic compound. Thus, temperature and estrogenic signals play essential roles during temperature-dependent sex determination (TSD). The genetic basis for TSD is poorly understood, although previous studies observed that many of the genes associated with genetic sex determination (GSD) are expressed in species with TSD. Heat shock proteins (HSPs), good candidates because of their temperature-sensitive expression, have not been examined in regard to TSD but HSPs have the ability to modify steroid receptor function. A number of HSP cDNAs (HSP27, DNAJ, HSP40, HSP47, HSP60, HSP70A, HSP70B, HSP70C, HSP75, HSP90α, HSP90β, and HSP108) as well as cold-inducible RNA binding protein (CIRBP) and HSP-binding protein (HSPBP) were cloned, and expression of their mRNA in the gonadal-adrenal-mesonephros complex (GAM) was investigated. Embryonic and neonatal GAMs exhibited mRNA for all of the HSPs examined during and after the TSP. One-month-old GAMs were separated into 3 portions (gonad, adrenal gland, and mesonephros), and sexual dimorphism in the mRNA expression of gonadal HSP27 (male > female), gonadal HSP70A (male < female), and adrenal HSP90α (male > female) was observed. These findings provide new insights on TSD and suggest that further studies examining the role of HSPs during gonadal development are needed.
Multivariate Expression Analysis of the Gene Network Underlying Sexual Development in Turtle Embryos with Temperature-Dependent and Genotypic Sex Determination
Authors: Valenzuela N.
Published: March 2010

Sexual development has long been the target of study and despite great advances in our understanding of the composition and regulation of the gene network underlying gonadogenesis, our knowledge remains incomplete. Of particular interest is the relative role that the environment and the genome play in directing gonadal formation, especially the effect of environmental temperature in directing this process in vertebrates. Comparative analyses in closely related taxa with contrasting sex-determining mechanisms should help fill this gap. Here I present a multivariate study of the regulation of the gene network underlying sexual development in turtles with temperature-dependent (TSD; Chrysemys picta) and genotypic sex determination (GSD; Apalone mutica). I combine novel data on SOX9 and DMRT1 from these species with contrasting sex-determining mechanisms for the first time with previously reported data on DAX1, SF-1 (NR5A1), WT1, and aromatase (CYP19A1) from these same taxa. Comparative expression analyses of SOX9 and DMRT1 from these and other species indicate additional elements whose expression has diverged among TSD taxa, further supporting the notion that significant evolutionary changes have accrued in the regulation of the TSD gene network in reptiles. A non-parametric MANOVA revealed that temperature had a significant effect in multivariate gene expression in C. picta that varied during embryonic development, whereas the covariation of gene expression in A. mutica was insensitive to temperature. A phenotypic trajectory analysis (PTA) of gene expression comparing both species directly indicated that the relative covariation in gene expression varied between temperatures in C. picta. Furthermore, the 25°C trajectory of C. picta differed from that of A. mutica in the magnitude of gene expression change. Additional analyses revealed a stronger covariation in gene expression and a more interconnected regulatory network in A. mutica, consistent with the hypothesis that sexual development is a more canalized process in A. mutica, as would be expected if GSD evolved in this lineage through directional selection from its TSD ancestor.
A Review of Sex Determining Mechanisms in Geckos (Gekkota: Squamata)
Authors: Gamble T.
Published: March 2010

Geckos are a species-rich clade of reptiles possessing diverse sex determining mechanisms. Some species possess genetic sex determination, with both male and female heterogamety, while other species have temperature-dependent sex determination. I compiled information from the literature on the taxonomic distribution of these sex determining mechanisms in geckos. Using phylogenetic data from the literature, I reconstructed the minimum number of transitions among these sex determining mechanisms with parsimony-based ancestral state reconstruction. While only a small number of gecko species have been characterized, numerous changes among sex determining mechanisms were inferred. This diversity, coupled with the high frequency of transitions, makes geckos excellent candidates as a model clade for the study of vertebrate sex determination and evolution.
Diabetes in Primary Care: Prospective Associations between Depression, Nonadherence and Glycemic Control
Authors: Dirmaier Jörg , Watzke Birgit , Koch Uwe , Schulz Holger , Lehnert Hendrik , Pieper Lars , Wittchen Hans-Ulrich
Published: March 2010

Background: Findings are inconsistent regarding the degree to which depression may exert a negative impact on glycemic control in patients with type 2 diabetes. We therefore aimed to examine the longitudinal relationship between depression, behavioral factors, and glycemic control. Methods: In a prospective component of a nationally representative sample, 866 patients with type 2 diabetes aged ≧18 years completed a standardized assessment including a laboratory screening, questionnaires, and diagnostic measures. Subsequent to baseline (t₀), patients were tracked over a period of 12 months (t1). Depression was assessed according to DSM-IV and ICD-10 criteria. Glycemic control was determined by levels of glycosylated hemoglobin (HbA1c); a level of ≧7% was judged as unsatisfactory. Regression analyses were performed to analyze the prospective relationship between depression, medication adherence, diabetes-related health behavior, and HbA1c. Results: Patients with depression at t₀ revealed increased rates of medication nonadherence (adjusted OR: 2.67; CI: 1.38–5.15) at t1. Depression (adjusted regression coefficient: β = 0.96; p = 0.001) and subthreshold depression (β = 1.01; p < 0.001) at t₀ also predicted increased problems with diabetes-related health behavior at t1. Adjusted ORs for poor glycemic control (HbA1c ≧7%) at t1 were also increased for patients with baseline depression (2.01; CI: 1.10–3.69). However, problems with medication adherence as well as problems with diabetes-related health behavior at t₀ did not predict poor glycemic control at t1. Conclusions: In a prospective representative study of patients with type 2 diabetes, baseline depression predicted problems with medication adherence, problems with health-related behaviors, and unsatisfactory glycemic control at follow-up.
Indications for Catheter-Directed Thrombolysis in the Management of Acute Proximal Deep Venous Thrombosis
Authors: Patterson Benjamin O. , Hinchliffe Robert , Loftus Ian M. , Thompson Matt M. , Holt Peter J.E.
Published: March 2010

Deep vein thromboses (DVTs) cause significant morbidity and mortality in the general population. Oral anticoagulation therapy may reduce thrombus propagation but does not cause clot lysis and therefore does not prevent postthrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) can be used to treat DVTs as an adjunct to medical therapy, but there is no consensus defining exact indications. Current evidence suggests that CDT can reduce clot burden and DVT recurrence and consequently prevents the formation of PTS compared with systemic anticoagulation. Appropriate indications include younger individuals with acute proximal thromboses, a long life expectancy, and relatively few comorbidities. Limb-threatening thromboses may also be treated with CDT, although the subsequent mortality remains high. A number of randomized controlled trials are currently under way comparing the longer-term outcomes of CDT compared with anticoagulation alone. Initial reports suggest that venous patency and valvular function are better maintained after CDT. The effectiveness of combined pharmacomechanical thrombectomy and the role of vena cava filters need to be investigated further before strong recommendations can be made. The reported short-term outcomes following catheter-based intervention for DVT are encouraging in selected patients. Further evidence is required to establish long-term benefits and cost-effectiveness.
PI3K(p110α) Protects Against Myocardial Infarction-Induced Heart Failure
Authors: Lin Ruby C.Y. , Weeks Kate L. , Gao Xiao-Ming , Williams Rohan B.H. , Bernardo Bianca C. , Kiriazis Helen , Matthews Vance B. , Woodcock Elizabeth A. , Bouwman Russell D. , Mollica Janelle P. , Speirs Helen J. , Dawes Ian W. , Daly Roger J. , Shioi Tetsuo , Izumo Seigo , Febbraio Mark A. , Du Xiao-Jun , McMullen Julie R.
Published: March 2010

Objective—

Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110α)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110α) provides protection in a setting of MI is unknown, and PI3K(p110α) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110α) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110α).

Methods and Results—

Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110α) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110α) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction.

Conclusion—

Activation of PI3K(p110α) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110α) represent new drug targets for heart failure.
Impact of Longitudinal Myocardial Deformation on the Prognosis of Chronic Heart Failure Patients
Authors: Nahum Julien , Bensaid Alexandre , Dussault Caroline , Macron Laurent , Clémence Darrort , Bouhemad Belaid , Monin Jean-Luc , Rande Jean-Luc Dubois , Gueret Pascal , Lim Pascal
Published: March 2010

Background—

Longitudinal myocardial deformation indexes appear superior to left ventricular ejection fraction (LVEF) in assessing myocardial contractility. However, few studies have addressed the prognostic value of longitudinal motion markers (velocity, strain, and strain rate) in predicting outcome in heart failure patients.

Methods and Results—

The study included 125 consecutive symptomatic heart failure patients (63�16 years, 77% male, LVEF=31�10%). All patients underwent a complete echocardiographic and clinical examination, and brain natriuretic peptide level was assessed in 93 patients. Longitudinal myocardial velocity by tissue Doppler imaging, global-ε, and strain rate by speckle tracking were computed from apical views (4-, 3-, and 2-chambers views) and compared with the occurrence of major adverse cardiac events. On the whole, peak longitudinal velocity, global-ε, and strain rate averaged 5�2 cm/s (range, 1 to 9), −8�3% (range, −3 to −18), and −0.33�0.16 s
−1
(range, −0.83 to −0.05), respectively. During the follow-up period (266�177 days), major adverse cardiac events occurred in 47 (38%) patients (15 deaths, 29 recurrent heart failure, and 4 heart transplantations). By univariable analysis using Cox model global-ε, strain rate, and LVEF were associated with the occurrence of major adverse cardiac events, whereas only global-ε remained independently predictive of outcome by multivariate analysis.

Conclusions—

In the heart failure population, longitudinal global strain by speckle tracking is superior to LVEF and other longitudinal markers in identifying patients with poor outcome.
The Deception Dividend: FDR's Undeclared War
Authors: Schuessler John M.
Published: March 2010

When do leaders resort to deception to sell wars to their publics? Dan Reiter and Allan Stam have advanced a “selection effects” explanation for why democracies win the wars they initiate: leaders, because they must secure public consent first, “select” into those wars they expect to win handily. In some cases, however, the “selection effect” breaks down. In these cases, leaders, for realist reasons, are drawn toward wars where an easy victory is anything but assured. Leaders resort to deception in such cases to preempt what is sure to be a contentious debate over whether the use of force is justified by shifting blame for hostilities onto the adversary. The events surrounding the United States' entry into World War II is useful in assessing the plausibility of this argument. President Franklin Roosevelt welcomed U.S. entry into the war by the fall of 1941 and attempted to manufacture events accordingly. An important implication from this finding is that deception may sometimes be in the national interest.
Sex and the Shaheed: Insights from the Life Sciences on Islamic Suicide Terrorism
Authors: Thayer Bradley A. , Hudson Valerie M.
Published: March 2010

Theoretical insights from evolutionary psychology and biology can help academics and policymakers better understand both deep and proximate causes of Islamic suicide terrorism. The life sciences can contribute explanations that probe the influence of the following forces on the phenomenon of Islamic suicide terrorism: high levels of gender differentiation, the prevalence of polygyny, and the obstruction of marriage markets delaying marriage for young adult men in the modern Middle East. The influence of these forces has been left virtually unexplored in the social sciences, despite their presumptive application in this case. Life science explanations should be integrated with more conventional social science explanations, which include international anarchy, U.S. hegemony and presence in the Middle East, and culturally molded discourse sanctioning suicide terrorism in the Islamic context. Such a consilient approach, melding the explanatory power of the social and life sciences, offers greater insight into the causal context of Islamic fundamentalist suicide terrorism, the motivation of suicide terrorists, and effective approaches to subvert this form of terrorism.
Status Seekers: Chinese and Russian Responses to U.S. Primacy
Authors: Larson Deborah Welch , Shevchenko Alexei
Published: March 2010

The United States needs support from other states to carry out global governance, particularly from rising powers such as China and Russia. Securing cooperation from China and Russia poses special problems, however, because neither state is part of the liberal Western community, ruling out appeals to common values and norms. Nevertheless, an alternative approach that is rooted in appreciation of China's and Russia's heightened status concerns may be viable. Since the end of the Cold War, Chinese and Russian foreign policy has been shaped by the goal of restoring both countries' great power status, which received major blows after China's Tiananmen Square repression and the Soviet Union's breakup and loss of empire. This desire for status can be explained by social identity theory, which argues that social groups strive for a distinctive, positive identity. Social identity theory provides a typology of strategies that states may use to enhance their relative status and suggests appropriate responses to status concerns of rising powers. Redirecting scholarly attention to status considerations and incentives could contribute to a diplomatic strategy for engaging rising powers.
Breaking the Ring of Encirclement: The Sino-Soviet Rift and Chinese Policy toward Vietnam, 1964–1968
Authors: Khoo Nicholas
Published: March 2010

The recent literature on China's relations with North Vietnam has given insufficient attention to the impact of the Sino-Soviet conflict. This article underscores the centrality of the Soviet factor in Beijing's relations with Hanoi and the importance of triangular relations during the 1964–1968 period. The article points to the Sino-Soviet conflict as the main cause of the fissures in the Sino-North Vietnamese alliance that emerged more fully after the Vietnam War.
Autonomous Evolution of Topographic Regularities in Artificial Neural Networks
Authors: Gauci Jason , Stanley Kenneth O.
Published: March 2010

Looking to nature as inspiration, for at least the past 25 years, researchers in the field of neuroevolution (NE) have developed evolutionary algorithms designed specifically to evolve artificial neural networks (ANNs). Yet the ANNs evolved through NE algorithms lack the distinctive characteristics of biological brains, perhaps explaining why NE is not yet a mainstream subject of neural computation. Motivated by this gap, this letter shows that when geometry is introduced to evolved ANNs through the hypercube-based neuroevolution of augmenting topologies algorithm, they begin to acquire characteristics that indeed are reminiscent of biological brains. That is, if the neurons in evolved ANNs are situated at locations in space (i.e., if they are given coordinates), then, as experiments in evolving checkers-playing ANNs in this letter show, topographic maps with symmetries and regularities can evolve spontaneously. The ability to evolve such maps is shown in this letter to provide an important advantage in generalization. In fact, the evolved maps are sufficiently informative that their analysis yields the novel insight that the geometry of the connectivity patterns of more general players is significantly smoother and more contiguous than less general ones. Thus, the results reveal a correlation between generality and smoothness in connectivity patterns. They also hint at the intriguing possibility that as NE matures as a field, its algorithms can evolve ANNs of increasing relevance to those who study neural computation in general.
Memory Dynamics in Attractor Networks with Saliency Weights
Authors: Tang Huajin , Li Haizhou , Yan Rui
Published: March 2010

Memory is a fundamental part of computational systems like the human brain. Theoretical models identify memories as attractors of neural network activity patterns based on the theory that attractor (recurrent) neural networks are able to capture some crucial characteristics of memory, such as encoding, storage, retrieval, and long-term and working memory. In such networks, long-term storage of the memory patterns is enabled by synaptic strengths that are adjusted according to some activity-dependent plasticity mechanisms (of which the most widely recognized is the Hebbian rule) such that the attractors of the network dynamics represent the stored memories. Most of previous studies on associative memory are focused on Hopfield-like binary networks, and the learned patterns are often assumed to be uncorrelated in a way that minimal interactions between memories are facilitated. In this letter, we restrict our attention to a more biological plausible attractor network model and study the neuronal representations of correlated patterns. We have examined the role of saliency weights in memory dynamics. Our results demonstrate that the retrieval process of the memorized patterns is characterized by the saliency distribution, which affects the landscape of the attractors. We have established the conditions that the network state converges to unique memory and multiple memories. The analytical result also holds for other cases for variable coding levels and nonbinary levels, indicating a general property emerging from correlated memories. Our results confirmed the advantage of computing with graded-response neurons over binary neurons (i.e., reducing of spurious states). It was also found that the nonuniform saliency distribution can contribute to disappearance of spurious states when they exit.
First-Spike Latency in the Presence of Spontaneous Activity
Authors: Pawlas Zbyněk , Klebanov Lev B. , Beneš Viktor , Prokešová Michaela , Popelář Jiří , Lánský Petr
Published: March 2010

A new statistical method for the estimation of the response latency is proposed. When spontaneous discharge is present, the first spike after the stimulus application may be caused by either the stimulus itself, or it may appear due to the prevailing spontaneous activity. Therefore, an appropriate method to deduce the response latency from the time to the first spike after the stimulus is needed. We develop a nonparametric estimator of the response latency based on repeated stimulations. A simulation study is provided to show how the estimator behaves with an increasing number of observations and for different rates of spontaneous and evoked spikes. Our nonparametric approach requires very few assumptions. For comparison, we also consider a parametric model. The proposed probabilistic model can be used for both single and parallel neuronal spike trains. In the case of simultaneously recorded spike trains in several neurons, the estimators of joint distribution and correlations of response latencies are also introduced. Real data from inferior colliculus auditory neurons obtained from a multielectrode probe are studied to demonstrate the statistical estimators of response latencies and their correlations in space.
Withdrawal and Criminal Liability under the Criminal Laws of Jordan and Australia: A Comparative Study
Authors: Abu-Zeitoun Mamoun , Al-Qudah Mouaid
Published: March 2010

This article is a comparative study of withdrawal as a defence to the criminal liability of an offender in Jordan (a civil law jurisdiction) and Australia (a common law jurisdiction). The analysis in this paper reveals that, in both jurisdictions, criminal laws have long accepted withdrawal as a conduit through which the offender’s liability can be modified or completely quashed. However, there has been no serious attempt, at least in Jordan, to provide anything approaching a complete explanation of the conditions under which the defence may be available and to explore its limits and boundaries. Neither has any serious effort been made to offer an account of the defence’s conceptual nature and governing rationale. The present paper seeks to identify and explore the defence’s conceptual basis and rationale, its current state of law and the appropriate direction in which the defence might be developed. To achieve this purpose, the paper is divided into three sections. In Section 1, it explores the conceptual nature of withdrawal. Section 2 addresses the rationale of the defence in light of the underlying principles of criminal liability in both jurisdictions. In Section 3 a comparative analysis of the defence’s qualifying requirements is undertaken in relation to both primary and accessorial criminal liability. Comparative analysis shows that withdrawal can be used as a defence to all forms of criminal complicity with differing degrees of variations in relation to both its qualifying requirements and the extent to which it may affect the liability of an offender. In cases involving incitement, however, the inciter cannot rely on the defence to avoid criminal liability although his or her punishment can be reduced pursuant to his or her voluntary withdrawal under the JPC.
Liability Exemption for Failure to Perform under both the Vienna Convention for International Sale of Goods 1980 and Islamic Jurisprudence
Authors: Mahasneh Nisreen S.
Published: March 2010

This paper discusses the concept of liability exemption and its conditions under the Vienna Convention for International Sale of Goods 1980 as compared with Islamic Juris-prudence. Also discussed are other related issues, such as liability exemption involving a third party, partial impediment and temporary impediment. It appears that the Convention deals with the legal consequences of liability exemption in a way distinct from all other systems, including the Islamic Jurisprudence, in the sense that it keeps the contract in force and only prevents damages. However, the conditions for an impediment under the Convention closely resemble those in Islamic Jurisprudence.
Federal Iraqi Law Applicable to Construction Contracts
Authors: Al-Saadoon Omar
Published: March 2010

The background and ethos of the Iraqi Federal Civil Code and its applicability to agreements relating to construction projects are explored. The article provides a lucid description of the structure of the Code setting out the essential issues that relate to a construction contract. Mr. Al-Saadoon goes on to explore a whole range of legal issues that generally arise in construction agreements, including general contract law as well as an analysis of issues of particular relevance to the construction industry, such as defects, delay, payment and liquidated damages, to name but a few. The article establishes awareness that the provisions of the Code are not wholly dissimilar to the provisions found in commercial, and in particular, construction contracts used internationally. The Code has formed the template for other Civil Codes in Middle Eastern jurisdictions such as the United Arab Emirates.
Estimating Slope and Level Change in N = 1 Designs
Authors: Solanas Antonio , Manolov Rumen , Onghena Patrick
Published: March 2010

The current study proposes a new procedure for separately estimating slope change and level change between two adjacent phases in single-case designs. The procedure eliminates baseline trend from the whole data series before assessing treatment effectiveness. The steps necessary to obtain the estimates are presented in detail, explained, and illustrated. A simulation study is carried out to explore the bias and precision of the estimators and compare them to an analytical procedure matching the data simulation model. The experimental conditions include 2 data generation models, several degrees of serial dependence, trend, and level and/or slope change. The results suggest that the level and slope change estimates provided by the procedure are unbiased for all levels of serial dependence tested and trend is effectively controlled for. The efficiency of the slope change estimator is acceptable, whereas the variance of the level change estimator may be problematic for highly negatively autocorrelated data series.
Sanctification of Marriage and General Religiousness as Buffers of the Effects of Marital Inequity
Authors: DeMaris Alfred , Mahoney Annette , Pargament Kenneth I.
Published: March 2010

Theory suggests that relationship inequity will be associated with less marital and personal distress among the more religious, and that this interaction effect will be stronger for women than men. Data are from 178 married couples experiencing the third trimester of pregnancy of their first biological child. Five outcome variables were assessed for each spouse: marital satisfaction, love, marital conflict, depression, and anxiety. Consistent with equity theory, perceived relative advantage was related in a nonmonotonic fashion to all outcomes, with increasing advantage predicting better outcomes up to the equity point, but worse outcomes afterwards. Sanctification of marriage appeared to be a more important moderator of inequity effects than general religiousness. In particular, relative advantage had weaker effects among higher sanctifiers. The influence of relative advantage was also conditioned by gender. Wives’ psychological well-being appeared to be more adversely affected than men’s because of considering oneself overbenefited in the relationship. Moreover, the interaction between sanctification and relative advantage was somewhat stronger for wives.
Comparing Whole-Word and Morphograph Instruction During Computer-Assisted Peer Tutoring on Students’ Acquisition and Generalization of Vocabulary
Authors: Wood Charles L. , Mustian April L. , Cooke Nancy L.
Published: March 2010

Students with disabilities often have large vocabulary deficits that continue to increase over time if effective interventions that supplement daily academic instruction are not put in place. The current study used a simultaneous treatments design to analyze the comparative effects of whole-word vocabulary instruction and morphograph instruction on students’ vocabulary acquisition and generalization through the use of a computer-assisted peer-tutoring program. Seven of eight middle school participants with mild disabilities involved in this study acquired higher percentages of vocabulary in the morphograph condition compared to the whole-word condition. All eight students were better able to generalize to unknown vocabulary in the morphograph condition. This study’s findings indicate a functional relationship between morphograph instruction and the acquisition and generalization of vocabulary.
Differentiation: A sociological approach to international relations theory
Authors: Buzan Barry , Albert Mathias
Published: March 2010

This article sets out an analytical framework of differentiation derived from sociology and anthropology and argues that it can and should be applied to international relations (IR) theory. Differentiation is about how to distinguish and analyse the components that make up any social whole: are all the components essentially the same, or are they distinguishable by status or function? We argue that this approach provides a framing for IR theory that is more general and integrative than narrower theories derived from economics or political science. We show why this set of ideas has so far not been given much consideration within IR, and how and why the one encounter between IR and sociology that might have changed this — Waltz’s transposition of anarchy and functional differentiation from Durkheim — failed to do so. We set out in some detail how differentiation theory bears on the subject matter of IR arguing that this set of ideas offers new ways of looking not only at the understanding of structure in IR, but also at structural change and world history. We argue that differentiation holds out to IR a major possibility for theoretical development. What is handed on from anthropology and sociology is mainly designed for smaller and simpler subject matters than that of IR. In adapting differentiation theory to its more complex, layered subject matter, IR can develop it into something new and more powerful for social theory as a whole.
Cystine 186–cystine 209 disulfide bond is not essential for the procoagulant activity of tissue factor or for its de-encryption
Authors: Kothari Hema , Nayak Ramesh C. , Rao L. Vijaya Mohan , Pendurthi Usha R.
Published: March 2010

Tissue factor (TF) on cell surfaces resides mostly in a cryptic state. It is not entirely clear how cryptic TF differs from procoagulantly active TF and how deencryption occurs. Here, we critically evaluated the importance of cystine 186–cystine 209 (Cys186-Cys209) bond formation for TF procoagulant activity and its de-encryption. Chinese hamster ovary cells transfected with TFC186S, TFC209S, or TFC186S/C209S expressed little procoagulant activity at the cell surface. TF monoclonal antibody and activated factor VII (FVIIa) binding studies showed that little TF protein was present at the cell surface in cells expressing mutant TF. Similar data were obtained in human umbilical vein endothelial cells (HUVECs) transduced to express TFC186S, TFC209S, or TFC186S/C209S. Analysis of TF activity in HUVECs expressing similar levels of wild-type TF and TFC186S/C209S showed that TF mutant in the presence of saturating concentrations of FVIIa exhibited similar coagulant activity as that of wild-type TF. More importantly, treatment of HUVECs expressing TFC186S/C209S with HgCl2 or ionomycin increased the cell-surface TF activity to the same extent as that of the wild-type TF. Our data provide clear evidence that TF lacking the Cys186-Cys209 bond is coagulantly active once it is complexed with FVIIa, and TF de-encryption does not require Cys186-Cys209 disulfide bond formation.
IL-4 enhances IFN-λ1 (IL-29) production by plasmacytoid DCs via monocyte secretion of IL-1Ra
Authors: Megjugorac Nicholas J. , Gallagher Grant E. , Gallagher Grant
Published: March 2010

The type-III interferon (IFN) family is composed of 3 molecules in humans: IFN-λ1 (interleukin-29 [IL-29]), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B), each of which signals through the same receptor complex. Plasmacytoid dendritic cells (pDCs) are major IFN-λ producers among peripheral lymphocytes. Recently, it has been shown that IFN-λ1 exerts a powerful inhibitory effect over the T-helper 2 (Th2) response by antagonizing the effect of IL-4 on CD4+ T cells and inhibiting the production of Th2-associated cytokines. Here, we asked whether Th2 cytokines exert reciprocal control over IFN-λ production. IL-4 treatment during stimulation of human peripheral lymphocytes significantly elevated IFN-λ1 transcription and secretion. However, pDCs were not directly responsive to IL-4. Using depletion and reconstitution experiments, we showed that IL-4–responsive monocytes are an intermediary cell, responding to IL-4 by elevating their secretion of IL-1 receptor antagonist (IL-Ra); this IL-1Ra acts on pDCs to elevate their IFN-λ1 output. Thus, our experiments revealed a novel mechanism for regulation of both IFN-λ1 production and pDC function, and suggests an expanded immunomodulatory role for Th2-associated cytokines.
Surface IgM of CLL cells displays unusual glycans indicative of engagement of antigen in vivo
Authors: Krysov Sergey , Potter Kathleen N. , Mockridge C. Ian , Coelho Vania , Wheatley Isla , Packham Graham , Stevenson Freda K.
Published: March 2010

Surface IgM (sIgM) has a key influence on the clinical behavior of chronic lymphocytic leukemia (CLL). We now report that it exists in 2 forms with different N-glycosylation patterns in the μ-constant region. One glycoform is similar to normal B cells in bearing mature complex glycans common to most cell-surface glycoproteins. The other is an immature mannosylated form more characteristic of μ chains in the endoplasmic reticulum. Unmutated CLL (U-CLL) expresses a higher proportion of mannosylated surface μ chains than mutated CLL. Normal B cells express only the mature glycoform but can express the immature form after persistent engagement of sIgM, suggesting that glycan modification is a consequence of antigen exposure. CLL cells express variable proportions of the mannosylated form and can revert to the mature form after incubation in vitro. Both glycoforms are able to signal after sIgM engagement in vitro, leading to enhanced tyrosine phosphorylation. These findings support the concept that CLL cells are continuously exposed to antigen in vivo, driving the N-glycosylation pattern of expressed sIgM toward a mannosylated form, especially in U-CLL. Strikingly, this is reminiscent of follicular lymphoma, where mannosylated Ig is expressed constitutively via N-glycosylation sites in the variable region, suggesting a functional asset for this glycoform.
Mast cell proteases: multifaceted regulators of inflammatory disease
Authors: Pejler Gunnar , Rönnberg Elin , Waern Ida , Wernersson Sara
Published: March 2010

Mast cells (MCs) are currently receiving increased attention among the scientific community, largely because of the recent identification of crucial functions for MCs in a variety of disorders. However, it is in many cases not clear exactly how MCs contribute in the respective settings. MCs express extraordinarily high levels of a number of proteases of chymase, tryptase, and carboxypeptidase A type, and these are stored in high amounts as active enzymes in the MC secretory granules. Hence, MC degranulation leads to the massive release of fully active MC proteases, which probably have a major impact on any condition in which MC degranulation occurs. Indeed, the recent generation and evaluation of mouse strains lacking individual MC proteases have indicated crucial contributions of these to a number of different disorders. MC proteases may thus account for many of the effects ascribed to MCs and are currently emerging as promising candidates for treatment of MC-driven disease. In this review, we discuss these findings.