Miracle-dz/UniFAR-FTUs huggingface dataset:
Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors

Toll‐like receptors (TLRs) recognize a set of conserved molecular structures, so called pathogen‐associated molecular patterns, which allow them to sense and initiate innate and adaptive immune responses. In this study, we examined the expression of TLRs in both human and murine glioma. We then analyzed the change in TLR expression after treatment with synthetic phosphorothioate oligodeoxynucleotides (ODNs) containing unmethylated CpG dinucleotides (CpG ODNs), strong activators of both innate and adaptive immunity. In addition, we investigated the in vivo effect of CpG injection into C57BL/6 mice implanted with syngeneic GL261 glioma. Our results indicate that TLR9 is overexpressed in human and murine glioma cell lines and CpG stimulation prolongs the survival of mice with experimental brain tumors. CpGs induce TLR9 down‐regulation, followed by apoptosis of GL261 cells in vitro as well as in vivo. Furthermore, the effects of CpG stimulation appear to enhance the antigen presenting capacity of microglia, shift the immune response toward CD8+ T cells, and decrease the number of CD4+CD25+ regulatory T cells. Taken together, our data support the role of CpG in glioma immunotherapy and provide a rationale for further clinical development of CpG therapy in patients with malignant glioma. © 2006 Wiley‐Liss, Inc.
Molecular dynamics simulations of retinoblastoma protein

Tumor suppressor proteins play a crucial role in cell cycle regulation. Retinoblastoma protein (pRB) is one among them which regulates G1-S transition by binding with transcription factors. The activity of pRB is deregulated by cyclin dependent kinases-mediated hyper-phosphorylation and also due to cancer-derived mutations. In addition, it is also deactivated by binding of viral onco-proteins such as large T antigen, E1A, and E7. These viral proteins initially recognize pRB through their conserved LxCxE motif and facilitate dissociation of preexisting pRB–E2F complex. Based on these features, molecular dynamics (MD) simulation is performed for four different states of pRB for which the crystal structure is available. The unliganded/apo form and complex forms with E2F and E7 peptides reveal the molecular mechanism behind the activation and inactivation of pRB. In addition, the ternary complex of pRB with both E7 and E2F (for which no crystal structure is available) is modeled and simulated to understand the influence of binding of one ligand on the other. The variations in the three major factors such as conformational changes, inter- and intra-molecular interactions, and binding free energies between the apo and complex forms confirm the possibility for designing a small molecule inhibitor to inhibit pRB–E7 interactions without altering the prebound E2F. The present study deals with the molecular modeling and MD simulations of pRB in free and ligand-bound forms and confirms that pRB could be a valid target for the anticancer drug design when the cancer is induced by the viral onco-proteins and forms a clear base for designing E7 antagonists.
SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.

BACKGROUND & AIMS Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. METHODS Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography-based model building and statistical studies were performed. RESULTS Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. CONCLUSIONS SPINK1 mutations are common in the population (approximately 2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.
Investigating parental monitoring, school and family influences on adolescent alcohol use

This study aims to: â? ¢ test different causal hypotheses explaining the longitudinal relationship between parental monitoring and alcohol use trajectories â? ¢ test the role of peer- and school-level factors in influencing individual drinking trajectories and monitoring â? ¢ investigate how patterns of monitoring dimensions (e.g. parental control and child disclosure) and their association with alcohol use change when considering other factors To achieve these aims, this study was divided into a number of sections; path analysis investigating how parental monitoring and alcohol use are related; multilevel modelling, investigating how alcohol use, and parental monitoring varies between different schools, and finally; structural equation models to assess the direct and indirect associations between monitoring and other important family characteristics. Key findings â? ¢ Children whose parents exert greater control over their free time activities tend to drink less frequently. Early control has a lasting influence on alcohol use â? ¢ Higher rates of drinking in early adolescence leads to reduced levels of parent-controlled boundaries and limits at home â? ¢ Being in a school with a higher proportion of frequent drinkers is a risk factor for frequent drinking â? ¢ Girls who attend single-sex post-primary schools tend to drink more than pupils attending co-educational schools or male-only schools
Development of CpG-Oligodeoxynucleotides for Effective Activation of Rabbit TLR9 Mediated Immune Responses

CpG-oligodeoxynucleotides (CpG-ODN) are potent immune stimuli being developed for use as adjuvants in different species. Toll-like receptor 9 (TLR9) is the cellular receptor for CpG-ODN in mammalian cells. The CpG-ODN with 18–24 deoxynucleotides that are in current use for human and mouse cells, however, have low activity with rabbit TLR9. Using a cell-based activation assay, we developed a type of CpG-ODN containing a GACGTT or AACGTT motif in 12 phosphorothioate-modified deoxynucleotides with potent stimulatory activity for rabbit TLR9. The developed CpG-ODN have higher activities than other developed CpG-ODN in eliciting antigen-nonspecific immune responses in rabbit splenocytes. When mixed with an NJ85 peptide derived from rabbit hemorrhagic disease virus, they had potent activities to boost an antigen-specific T cell activation and antibody production in rabbits. Compared to Freund’s adjuvant, the developed CpG-ODN are capable of boosting a potent and less toxic antibody response. The results of this study suggest that both the choice of CpG-motif and its length are important factors for CpG-ODN to effectively activate rabbit TLR9 mediated immune responses.
Strategic disclosure of evidence to detect deception: towards a new research agenda

Research has shown that both lay people and presumed lie experts are medicore at assessing veracity. However, research on deception detection in legal contexts has largely failed to take into account how interrogation styles affect deception detection. This paper focuses on the strategic use of evidence during interroga-tions. It is proposed that evidence has the potential of being a powerful tool in the process of assessing veracity. More specifically, it is argued that disclosing the evidence in a late rather than early stage of the interrogation is beneficial for de-ception detection. Results from two recently conducted experiments support these predictions; these results are presented and discussed.
Wavelet analysis of oscillations in the peripheral blood circulation measured by laser Doppler technique

The wavelet transform technique, a time-frequency method with logarithmic frequency resolution, was used to analyze oscillations in human peripheral blood flow measured by laser Doppler flowmetry. The oscillations extended over a wide frequency state and their periods varied in time. Within the frequency range studied, 0.0095-1.6 Hz, five characteristic oscillations were revealed, arising from both local and central regulatory mechanisms. After the insertion of endothelium-dependent and endothelium-independent vasodilators the spectra of blood how markedly differed in the frequency interval 0.0095-0.02 Hz. In this way it was demonstrated that endothelial activity is a rhythmic process that contributes to oscillations in blood flow with a characteristic frequency of around 0.01 Hz. The study illustrates the potential of laser Doppler flowmetry combined with dynamical systems analysis for studies of both the micro- and macroscopic mechanisms of blood flow regulation in vivo.
Grammar Variational Autoencoder

Deep generative models have been wildly successful at learning coherent latent representations for continuous data such as video and audio. However, generative modeling of discrete data such as arithmetic expressions and molecular structures still poses significant challenges. Crucially, state-of-the-art methods often produce outputs that are not valid. We make the key observation that frequently, discrete data can be represented as a parse tree from a context-free grammar. We propose a variational autoencoder which encodes and decodes directly to and from these parse trees, ensuring the generated outputs are always valid. Surprisingly, we show that not only does our model more often generate valid outputs, it also learns a more coherent latent space in which nearby points decode to similar discrete outputs. We demonstrate the effectiveness of our learned models by showing their improved performance in Bayesian optimization for symbolic regression and molecular synthesis.
Omapatrilat Versus Lisinopril: Efficacy and Neurohormonal Profile in Salt-Sensitive Hypertensive Patients

Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (P =0.008), ambulatory systolic blood pressure (P =0.004), and ambulatory mean arterial pressure (P =0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (P <0.001) increased urinary excretion of atrial natriuretic peptide over 0- to 24-hour (3.8-fold) and 12- to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (P <0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.
Validation of reference genes in human chordoma

Background: Chordoma are rare slow-growing tumors of the axial skeleton, which are thought to arise from remnants of the notochord. Little is known about the underlying mechanisms that drive this tumor. However, the assessment of gene expression levels by quantitative real-time polymerase chain reaction (qRT-PCR) is hampered due to a lack of validated reference genes. Using an unstable reference gene in qRT-PCR may lead to irreproducible results. Methods: The expression of 12 candidate reference genes (ACTB, B2M, T, EF1a, GAPDH, HPRT, KRT8, KRT19, PGK1, RS27a, TBP, and YWHAZ) was analyzed by qRT-PCR in flash frozen chordoma samples from 18 patients. GeNorm and NormFinder algorithms were used to rank the stability of the genes. Results: From most to least stably expressed, the top six genes found by geNorm were PGK1, YWHAZ, ACTB, HPRT, EF1A, and TBP. When analyzed by NormFinder, the top six genes were ACTB, YWHAZ, PGK1, B2M, TBP, and HPRT. GAPDH alone, which is often used as a reference gene in chordoma gene expression studies, is not stable enough for reliable results. Conclusion: In gene expression studies of human chordomas, PGK1, ACTB, and YWHAZ are more stably expressed, and therefore, are preferred reference genes over the most often used reference gene so far, GAPDH.
Should Congress Look Like America? Explaining Preferences About Descriptive Representation

Descriptive representation is believed to provide both an important symbolic value for underrepresented groups such as women and minorities as well as policy benefits. Little is known, however, about how the public views diversity in representation. This paper examines attitudes about the gender and racial balance in the U.S. Congress. We propose and test several hypotheses. One hypothesis assumes that group self interest will motivate attitudes about representation. This leads one to expect that women and minorities will be more likely to believe that Congress should reflect diversity. Another theory assumes that racial and gender stereotypes will shape attitudes about the role of minorities and women in politics . A third explanation assumes that ideology will structure support. We test these hypotheses using original data measuring attitudes about the gender and ethnic representation of the U.S. Congress. These data were collected during the 2008 election through the Cooperative Campaign Analysis Project (CCAP). The analysis has implications for our understanding of public attitudes about government and institutions as well as understanding how concerns about minority representation structure support for electoral reform.
Mutational profile of primary breast diffuse large B-cell lymphoma

Primary breast lymphoma is a rare form of extra-nodal lymphoid neoplasm. The most common histological type is the diffuse large B-cell lymphoma, which represents 60–80% of all the cases. Our study analyzes the mutational profile of the primary lymphoma of the breast through targeted massive sequencing with a panel of 38 genes in a group of 17 patients with primary breast diffuse large B-cell lymphoma. Seventy-point-five percent of the patients presented with stage IE and 29.5% with stage IIE. 44% of the cases correspond to lymphomas with germinal center phenotype and 33.3% to activated B-cell. The genes with a higher mutational frequency include PIM1 (in 50% of the analyzed samples), MYD88 (39%), CD79B, PRDM1 and CARD11 (17%), KMT2D, TNFIAP3 and CREBBP (11%). The profile of mutant genes involves mostly the NFκB signaling pathway. The high frequency of mutations in PIM1 compared with other lymphomas may have implications in the clinical presentation and evolution of this type of lymphoma.
The complete mitochondrial genome sequence of Jinshaia abbreviata (Cypriniformes, Balitoridae)

Abstract Jinshaia abbreviata, belonging to the family Balitoridae in Cypriniformes, is endemic to the Upper Yangtze River with most population distributed in the Jinsha River. In this study, the complete mitochondrial genome of J. abbreviata was sequenced with its structure analyzed. The mitochondrial genome of J. abbreviata is similar to those of the typical vertebrates, 16,567 bp in length, including 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one non-coding control region (D-loop). The D-loop of J. abbreviata was characterized by one termination-associated sequence with two pair of motifs and six conserved sequence blocks (CSB-F, CSB-E, CSB-D, and CSB I-III). The mitogenome sequence of J. abbreviata could contribute to estimate the phylogenetic relationship of the Balitoridae. And further investigations with more Jinshaia species and individuals included need to be performed to better understand the speciation process and evolutionary history of the genus Jinshaia.
Evidence on the Molecular Basis of the Ac/ac Adaptive Cyanogenesis Polymorphism in White Clover (Trifolium repens L.)

White clover is polymorphic for cyanogenesis, with both cyanogenic and acyanogenic plants occurring in nature. This chemical defense polymorphism is one of the longest-studied and best-documented examples of an adaptive polymorphism in plants. It is controlled by two independently segregating genes: Ac/ac controls the presence/absence of cyanogenic glucosides; and Li/li controls the presence/absence of their hydrolyzing enzyme, linamarase. Whereas Li is well characterized at the molecular level, Ac has remained unidentified. Here we report evidence that Ac corresponds to a gene encoding a cytochrome P450 of the CYP79D protein subfamily (CYP79D15), and we describe the apparent molecular basis of the Ac/ac polymorphism. CYP79D orthologs catalyze the first step in cyanogenic glucoside biosynthesis in other cyanogenic plant species. In white clover, Southern hybridizations indicate that CYP79D15 occurs as a single-copy gene in cyanogenic plants but is absent from the genomes of ac plants. Gene-expression analyses by RT–PCR corroborate this finding. This apparent molecular basis of the Ac/ac polymorphism parallels our previous findings for the Li/li polymorphism, which also arises through the presence/absence of a single-copy gene. The nature of these polymorphisms may reflect white clover's evolutionary origin as an allotetraploid derived from cyanogenic and acyanogenic diploid progenitors.
hysiology ctin marker lines in grapevine reveal a gatekeeper function of uard cells in

Resistance to abiotic and biotic stress is a central topic for sustainable agriculture, especially in grapevine, one of the field crops with the highest economic output per acreage. As early cellular factors for plant defense, actin microfilaments (AF) are of high relevance. We therefore generated a transgenic actin marker line for grapevine by expressing a fusion protein between green fluorescent protein and the second actinbinding domain of Arabidopsis (Arabidopsis thaliana) fimbrin, AtFIM1. Based on this first cytoskeletalmarker line in grapevine, the response of AFs to phytopathogenic microorganisms could be followed
Overweight and obese children do not consult their general practitioner more often than normal weight children for musculoskeletal complaints during a 2-year follow-up

Background Childhood obesity is associated with self-reported musculoskeletal complaints, injuries and fractures. In the current study, we investigated the association between weight status of children and the frequency and type of musculoskeletal consultations at the general practitioner (GP) during a 2-year follow-up. Methods Data from a prospective longitudinal cohort study including children aged 2–18 years presenting in general practices in the Netherlands were used. Height and weight were measured at baseline, at 6-month, 1-year and 2-year follow-ups. Electronic medical files were used to collect information on the frequency and type of consultations at the GP during the 2-year follow-up period. Associations between weight status and frequency and type of GP consultations were calculated. Results Of the 617 included children, 111 (18%) were overweight or obese and 506 (82%) were non-overweight. Overweight children were significantly older (mean age in years (SD): 9.8 (3.6)vs7.8 (4.0), p=0.004). Overweight children consulted the GP in general significantly more frequent during the 2-year follow-up than non-overweight children (mean (SD): 7.3 (5.7)vs6.7 (5.4), OR 1.09, 95% CI 1.01 to 1.18). No significant difference was seen in the number of overweight and non-overweight children consulting their GP for musculoskeletal complaints (OR 1.20 (0.86 to 1.68)). Additionally, no significant difference between overweight and non-overweight children was seen for the number of consultations for further specified musculoskeletal disorders. Conclusion No association was seen between childhood weight status and the frequency and type of musculoskeletal consultations at the GP during a 2-year follow-up.
Evaluative comments in narratives of Cantonese speaking children

This study investigated the use of evaluative devices in narratives of Cantonese speaking children. The evaluative devices include: a) frames of mind, b) negative qualifiers, c) hedges, d) character's speech, and e) causal connectors. A 24-pictured story-book was used to elicit narrative. Four groups of Cantonesespeaking subjects were recruited: five-, seven-, nine-year-old children and University undergraduate students. A quantitative comparison revealed that (i) there is significant increase in the use of frames of mind, negative qualifiers and causal connectors across age. (ii) Pattern of evaluative devices used by fiveyear-old children is similar to that of the seven-year-old children. While adults and nine-year-old children form unique pattern in the use of different evaluative devices. These findings are discussed with cognitive, linguistic and pragmatic achievements.
Sibshops: Workshops for Siblings of Children With Special Needs

Foreword Preface Acknowledgments What are Sibshops? Becoming a Sibshop Siblings' Unique Concerns Information Needs of Siblings Unique Opportunities Minimizing siblings' concerns and maximizing their opportunities What sibling would like parents and service providers to know Getting Started Putting It All Together Introductory Activities Sibshop Discussion and Peer Support Activities Sibshop Recreational and Food Activities Information Activities, Guest Speakers, and Special Events Adapting Sibshops for Younger Brothers and Sisters Adapting the Sibshop Model for Teenage Brothers and Sisters Workshops for Parents and Service Providers on Sibling Issues Programs for Adult Siblings of People with Disabilities Appendices A-K References Index.