Miracle-dz/UniFAR-FTUs huggingface dataset:
GSK3β regulates ameloblast differentiation via Wnt and TGF‐β pathways

Wnt and TGF‐β signaling pathways participate in regulating a variety of cell fates during organogenesis, including tooth development. Despite well‐documented, the specific mechanisms, especially how these two pathways act coordinately in regulating enamel development, remain unknown. In this study, we identified Glycogen Synthase Kinase 3 beta (GSK3β), a negative regulator of Wnt signal pathway, participated in ameloblast differentiation via Wnt and TGF‐β pathways during enamel development. In vitro rat mandible culture treated with specific GSK3β inhibitor SB415286 displayed enamel defects, accompanied by disrupted ameloblasts polarization, while odontoblasts and dentin appeared to be unaffected. Moreover, after GSK3β knockdown by lentivirus‐mediated RNA silencing, HAT‐7 cells displayed abnormal cell polarity and cell adhesion, and failed to synthesize appreciable amounts of ameloblast‐specific proteins. More importantly, inactivation of GSK3β caused upregulated Wnt and downregulated TGF‐β pathway, while reactivation of TGF‐β signaling or suppression of Wnt signaling partially rescued the differentiation defects of ameloblasts caused by the GSK3β knock‐down. Taken together, these results suggested that GSK3β was essential for ameloblasts differentiation, which might be indirectly mediated through Wnt and TGF‐β signaling pathways.
Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries

Objectives Cardiovascular disease (CVD) risk calculators developed for the general population do not accurately predict CVD events in patients with RA. We sought to externally validate risk calculators recommended for use in patients with RA including the EULAR 1.5 multiplier, the Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) and QRISK2. Methods Seven RA cohorts from UK, Norway, Netherlands, USA, South Africa, Canada and Mexico were combined. Data on baseline CVD risk factors, RA characteristics and CVD outcomes (including myocardial infarction, ischaemic stroke and cardiovascular death) were collected using standardized definitions. Performance of QRISK2, EULAR multiplier and ERS-RA was compared with other risk calculators [American College of Cardiology/American Heart Association (ACC/AHA), Framingham Adult Treatment Panel III Framingham risk score-Adult Treatment Panel (FRS-ATP) and Reynolds Risk Score] using c-statistics and net reclassification index. Results Among 1796 RA patients without prior CVD [mean ( s . d .) age: 54.0 (14.0) years, 74% female], 100 developed CVD events during a mean follow-up of 6.9 years (12430 person-years). Estimated CVD risk by ERS-RA [mean ( s . d .) 8.8% (9.8%)] was comparable to FRS-ATP [mean ( s . d .) 9.1% (8.3%)] and Reynolds [mean ( s . d .) 9.2% (12.2%)], but lower than ACC/AHA [mean ( s . d .) 9.8% (12.1%)]. QRISK2 substantially overestimated risk [mean ( s . d .) 15.5% (13.9%)]. Discrimination was not improved for ERS-RA (c-statistic = 0.69), QRISK2 or EULAR multiplier applied to ACC/AHA compared with ACC/AHA (c-statistic = 0.72 for all) or for FRS-ATP (c-statistic = 0.75). The net reclassification index for ERS-RA was low (-0.8% vs ACC/AHA and 2.3% vs FRS-ATP). Conclusion The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population.
Linkage Analysis in Familial Non-Lynch Syndrome Colorectal Cancer Families from Sweden

Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies.
Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations

Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. In addition to autism, the EC system is also involved in several other psychiatric disorders (i.e., anxiety, major depression, bipolar disorder and schizophrenia). This system is a key regulator of metabolic and cellular pathways involved in autism, such as food intake, energy metabolism and immune system control. Early studies in autism animal models have demonstrated alterations in the brain’s EC system. Autism is also characterized by immune system dysregulation. This alteration includes differential monocyte and macrophage responses, and abnormal cytokine and T cell levels. EC system dysfunction in a monocyte and macrophagic cellular model of autism has been demonstrated by showing that the mRNA and protein for CB2 receptor and EC enzymes were significantly dysregulated, further indicating the involvement of the EC system in autism-associated immunological disruptions. Taken together, these new findings offer a novel perspective in autism research and indicate that the EC system could represent a novel target option for autism pharmacotherapy.
Children’s Prototypic Facial Expressions During Emotion-Eliciting Conversations With Their Mothers

Despite theoretical claims that emotions are primarily communicated through prototypic facial expressions, empirical evidence is surprisingly scarce. This study aimed to (a) test whether children produced more components of a prototypic emotional facial expression during situations judged or self-reported to involve the corresponding emotion than situations involving other emotions (termed “intersituational specificity”), (b) test whether children produced more components of the prototypic expression corresponding to a situation’s judged or self-reported emotion than components of other emotional expressions (termed “intrasituational specificity”), and (c) examine coherence between children’s self-reported emotional experience and observers’ judgments of children’s emotions. One hundred and 20 children (ages 7–9) were video-recorded during a discussion with their mothers. Emotion ratings were obtained for children in 441 episodes. Children’s nonverbal behaviors were judged by observers and coded by FACS-trained researchers. Children’s self-reported emotion corresponded significantly to observers’ judgments of joy, anger, fear, and sadness but not surprise. Multilevel modeling results revealed that children produced joy facial expressions more in joy episodes than nonjoy episodes (supporting intersituational specificity for joy) and more joy and surprise expressions than other emotional expressions in joy and surprise episodes (supporting intrasituational specificity for joy and surprise). However, children produced anger, fear, and sadness expressions more in noncorresponding episodes and produced these expressions less than other expressions in corresponding episodes. Findings suggest that communication of negative emotion during social interactions—as indexed by agreement between self-report and observer judgments—may rely less on prototypic facial expressions than is often theoretically assumed.
Cysteine kinetics and oxidation at different intakes of methionine and cystine in young adults.

BACKGROUND We previously studied methionine kinetics and oxidation with the tracer L-[1-(13)C, methyl-(2)H(3)]methionine. OBJECTIVES We sought to explore methionine-cysteine interrelations in adults by using L-[1-(13)C]cysteine under different dietary conditions. DESIGN In experiment 1, 12 adults consumed a protein-free diet for 6 d. On day 7, methionine (n = 6) or cysteine (n = 6) oxidation rates were measured during an 8-h continuous infusion of L-[1-(13)C, methyl-(2)H(3)]methionine or L-[1-(13)C]cysteine, respectively. In experiment 2, 6 young men consumed 3 diets for 6 d each before a tracer study on day 7 with L-[1-(13)C]cysteine. The amounts (in mg*kg(-)(1)*d(-)(1)) of methionine and cysteine, respectively, were: high-methionine (HM) diet, 13 and 0; low-methionine (LM) diet, 6.5 and 0; and methionine-plus-cystine (MC) diet, 6.5 and 5.6. Cysteine flux and oxidation rates were determined and sulfur amino acid (SAA, methionine plus cysteine) balances were estimated. RESULTS In experiment 1, rates of methionine and cysteine oxidation were similar to losses predicted from obligatory nitrogen losses. In experiment 2, SAA balance was less negative when subjects consumed the HM diet than the LM and MC diets (interaction, P = 0.034), largely because of a difference in fed-state balance (HM compared with LM, P < 0.01; HM compared with MC, P < 0.05). There was no evidence of a sparing effect of dietary cystine on the methionine requirement. CONCLUSION These studies support use of [1-(13)C]cysteine for studying whole-body SAA oxidation and conclusions that maintenance of SAA balance is best achieved by supplying methionine at approximately the FAO/WHO/UNU recommendations for total SAA intake (13 mg*kg(-)(1)*d(-)(1)).
Waist circumference: a simple, inexpensive, and reliable tool that should be included as part of physical examinations in the doctor's office.

Increasing evidence shows that abdominal adiposity has a direct influence on health and that visceral fat correlates with health risks to a greater extent than does adipose tissue in other regions of the body. Janssen et al (1) reported that increased visceral fat, as measured by magnetic resonance imaging in 341 whites, had a stronger correlation with waist circumference (WC) than with body mass index (BMI; in kg/m 2 ). Using the third National Health and Nutrition Examination Survey data in 9019 whites, Zhu et al (2) recently reported that WC is more closely linked to cardiovascular disease risk factors than is BMI.The compelling statistical results presented in the article by Kahn and Valdez (3) in this issue of the Journal are based on data obtained from the same group of study participants reported on by Zhu et al. These results provide the first irrefut-able evidence that WC is a reliable risk indicator for the syndrome of lipid overaccumulation, as documented by elevated fasting triacylglycerol concentrations and by accelerated mortality after middle age in a large population with wide age and BMI ranges. Measurement of fasting serum triacylglycerol concentrations is a reliable laboratory procedure to determine the amount of accumulated lipid in the metabolic pool of the body. The results presented by Kahn and Valdez serve to validate the potential usefulness of WC in physical examinations for clinical purposes; therefore, their results should en-courage physicians to include WC measurement in the health evaluation procedures that they use in their routine clinical practices. This inclusion was suggested recently in a report by Ross and Katzmarzyk that was based on their observations of 7573 participants in the Canadian Population Survey. Ross and Katzmarzyk reported that cardiorespiratory fitness is inversely associated with WC and is independent of BMI. Therefore, they emphasized that the measurement of WC would be a reliable, easy, and inexpensive indicator by which to identify persons at risk of lipid accumulation (4).
Association between speech–language, general cognitive functioning and behaviour problems in individuals with Williams syndrome

BACKGROUND Williams syndrome (WS) phenotype is described as unique and intriguing. The aim of this study was to investigate the associations between speech-language abilities, general cognitive functioning and behavioural problems in individuals with WS, considering age effects and speech-language characteristics of WS sub-groups. METHODS The study's participants were 26 individuals with WS and their parents. General cognitive functioning was assessed with the Wechsler Intelligence Scale. Peabody Picture Vocabulary Test, Token Test and the Cookie Theft Picture test were used as speech-language measures. Five speech-language characteristics were evaluated from a 30-min conversation (clichés, echolalia, perseverative speech, exaggerated prosody and monotone intonation). The Child Behaviour Checklist (CBCL 6-18) was used to assess behavioural problems. RESULTS Higher single-word receptive vocabulary and narrative vocabulary were negatively associated with CBCL T-scores for Social Problems, Aggressive Behaviour and Total Problems. Speech rate was negatively associated with the CBCL Withdrawn/Depressed T-score. Monotone intonation was associated with shy behaviour, as well as exaggerated prosody with talkative behaviour. WS with perseverative speech and exaggerated prosody presented higher scores on Thought Problems. Echolalia was significantly associated with lower Verbal IQ. No significant association was found between IQ and behaviour problems. Age-associated effects were observed only for the Aggressive Behaviour scale. CONCLUSIONS Associations reported in the present study may represent an insightful background for future predictive studies of speech-language, cognition and behaviour problems in WS.
Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease

Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain‐of‐function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is overexpression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease.
Vitamin A supplementation selectively improves the linear growth of indonesian preschool children: results from a randomized controlled trial.

BACKGROUND Vitamin A deficiency is associated with stunting and wasting in preschool children, but vitamin A supplementation trials have not shown a consistent effect on growth. OBJECTIVE We examined the effect of vitamin A supplementation on height and weight increments among Indonesian preschool children. DESIGN Data were obtained from a randomized, double-masked, placebo-controlled trial of rural Javanese children aged 6-48 mo. Children received 206000 IU vitamin A (103000 IU if aged <12 mo) or placebo every 4 mo. RESULTS High-dose vitamin A supplementation modestly improved the linear growth of the children by 0.16 cm/4 mo. The effect was modified by age, initial vitamin A status, and breast-feeding status. Vitamin A supplementation improved height by 0.10 cm/4 mo in children aged <24 mo and by 0.22 cm/4 mo in children aged >/=24 mo. The vitamin A-supplemented children with an initial serum retinol concentration <0.35 micromol/L gained 0.39 cm/4 mo more in height and 152 g/4 mo more in weight than did the placebo group. No growth response to vitamin A was found among children with an initial serum retinol concentration >/=0.35 micromol/L. In non-breast-fed children, vitamin A supplementation improved height by 0.21 cm/4 mo regardless of age. In breast-fed children, vitamin A supplementation improved linear growth by approximately 0.21 cm/4 mo among children aged >/=24 mo, but had no significant effect on the growth of children aged <24 mo. CONCLUSION High-dose vitamin A supplementation improves the linear growth of children with very low serum retinol and the effect is modified by age and breast-feeding.
Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

ABSTRACT Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumor-inhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications.
Early adversity and learning: implications for typical and atypical behavioral development

BACKGROUND Children who experience early adversity often develop emotion regulatory problems, but little is known about the mechanisms that mediate this relation. We tested whether general associative learning processes contribute to associations between adversity, in the form of child maltreatment, and negative behavioral outcomes. METHODS Eighty-one participants between 12 and 17 years of age were recruited for this study and completed a probabilistic learning Task. Forty-one of these participants had been exposed to physical abuse, a form of early adversity. Forty additional participants without any known history of maltreatment served as a comparison group. All participants (and their parents) also completed portions of the Youth Life Stress Interview to understand adolescent's behavior. We calculated measures of associative learning, and also constructed mathematical models of learning. RESULTS We found that adolescents exposed to high levels of adversity early in their lives had lower levels of associative learning than comparison adolescents. In addition, we found that impaired associative learning partially explained the higher levels of behavioral problems among youth who suffered early adversity. Using mathematical models, we also found that two components of learning were specifically affected in children exposed to adversity: choice variability and biases in their beliefs about the likelihood of rewards in the environment. CONCLUSIONS Participants who had been exposed to early adversity were less able than their peers to correctly learn which stimuli were likely to result in reward, even after repeated feedback. These individuals also used information about known rewards in their environments less often. In addition, individuals exposed to adversity made decisions early in the learning process as if rewards were less consistent and occurred more at random. These data suggest one mechanism through which early life experience shapes behavioral development.
Improved performance of perovskite light-emitting diodes using a PEDOT:PSS and MoO3 composite layer

We demonstrate the enhanced performance of perovskite light-emitting diodes (PeLEDs) using a solution-processable MoO3 and PEDOT:PSS (PEDOT:MoO3) composite layer as the hole transport layer (HTL). The PEDOT:MoO3 composite layer presents improved hole injection through a reduction in the contact barrier between the HTL and the CH3NH3PbBr3 layer and enhanced crystallinity of the perovskite film. The optimized PeLEDs with the PEDOT:MoO3 composite film showed enhanced external quantum efficiency (EQE) and maximum luminous efficiency, compared to a PeLED using a pristine PEDOT:PSS layer.
Ribosomopathy-like properties of murine and human cancers

Ribosomopathies comprise a heterogeneous group of hematologic and developmental disorders, often characterized by bone marrow failure, skeletal and other developmental abnormalities and cancer predisposition. They are associated with mutations and/or haplo-insufficiencies of ribosomal proteins (RPs) and inefficient ribosomal RNA (rRNA) processing. The resulting ribosomal stress induces the canonical p19ARF/Mdm2/p53 tumor suppressor pathway leading to proliferative arrest and/or apoptosis. It has been proposed that this pathway is then inactivated during subsequent neoplastic evolution. We show here that two murine models of hepatoblastoma (HB) and hepatocellular carcinoma (HCC) unexpectedly possess features that mimic the ribosomopathies. These include loss of the normal stoichiometry of RP transcripts and proteins and the accumulation of unprocessed rRNA precursors. Silencing of p19ARF, cytoplasmic sequestration of p53, binding to and inactivation of Mdm2 by free RPs, and up-regulation of the pro-survival protein Bcl-2 may further cooperate to drive tumor growth and survival. Consistent with this notion, re-instatement of constitutive p19ARF expression in the HB model completely suppressed tumorigenesis. In >2000 cases of human HCC, colorectal, breast, and prostate cancer, RP transcript deregulation was a frequent finding. In HCC and breast cancer, the severity of this dysregulation was associated with inferior survival. In HCC, the presence of RP gene mutations, some of which were identical to those previously reported in ribosomopathies, were similarly negatively correlated with long-term survival. Taken together, our results indicate that many if not all cancers possess ribosomopathy-like features that may affect their biological behaviors.