Miracle-dz/UniFAR-FTUs huggingface dataset:
Runx2 Protein Stabilizes Hypoxia-inducible Factor-1α through Competition with von Hippel-Lindau Protein (pVHL) and Stimulates Angiogenesis in Growth Plate Hypertrophic Chondrocytes*

Background: Runt-related transcription factor 2 (Runx2) is a key factor in bone development. Hypoxia-inducible factor-1α (HIF-1α) is the primary regulator of blood vessel formation. Results: Runx2 bound and activated HIF-1α by competing with von Hippel-Lindau protein (pVHL), protecting HIF-1α from degradation. Conclusion: Runx2 stabilizes HIF-1α during endochondral bone formation. Significance: Runx2/HIF-1α stimulate the invasion of blood vessels in hypertrophic zones. The regulation of hypoxia-inducible factor-1α (HIF-1α) during endochondral bone formation is not fully understood. Here, we investigated the cross-talk between HIF-1α and Runt-related transcription factor 2 (Runx2) in the growth plate. Runx2 caused the accumulation of HIF-1α protein in ATDC5 chondrocytes and HEK293 cells under normoxic conditions. Runx2 also increased the nuclear translocation of HIF-1α when coexpressed in HEK293 cells and interacted with HIF-1α at the oxygen-dependent degradation domain (ODDD). In addition, Runx2 competed with von Hippel-Lindau tumor suppressor protein by directly binding to ODDD-HIF-1α and significantly inhibited the ubiquitination of HIF-1α, even though Runx2 did not change the hydroxylation status of HIF-1α. Furthermore, overexpression of Runx2 resulted in the significant enhancement of vascular endothelial growth factor (VEGF) promoter reporter activity and protein secretion. Runx2 significantly increased angiogenic activity in human umbilical vein endothelial cells in vitro. In wild-type mice, HIF-1α and Runx2 were colocalized in hypertrophic chondrocytes in which the cluster of differentiation 31 (CD31) protein was expressed at embryonic day 15.5 (E15.5). In contrast, the expression of HIF-1α was markedly reduced in areas of CD31 expression in Runx2−/− mice. These results suggest that Runx2 stabilizes HIF-1α by binding to ODDD to block the interaction between von Hippel-Lindau protein and HIF-1α. In conclusion, Runx2, HIF-1α, and VEGF may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation.
Intra-uterine Mortality and Maternal Nutritional Status in Rural Bangladesh

This paper is an investigation of the relationship of a maternal nutritional status with intra-uterine mortality in a population of chronically malnourished rural Bangladeshi women. First, life-table techniques are used to compare the level of intra-uterine mortality in this population with levels reported in other studies. Then the relationships of maternal nutritional status, age, parity, foetal loss and season of conception with intra-uterine mortality are examined in a multivariate analysis. The results indicate foetal mortality in rural Bangladesh to be markedly higher than in other populations where living conditions and health care are superior. Maternal nutritional status, maternal age and season of conception all appear to be related significantly to foetal mortality.
Involvement of interstitial telomeric sequences in two new cases of mosaicism for autosomal structural rearrangements

Mosaicism for an autosomal structural rearrangement that does not involve ring or marker chromosomes is rare. The mechanisms responsible for genome instability have not always been explained. Several studies have shown that interstitial telomeric sequences (ITSs), involved in some mosaic constitutional anomalies, are potent sources of genomic instability. Here we describe two cases of mosaicism for uncommon constitutional autosomal rearrangements, involving ITSs, identified by karyotyping and characterized by FISH and SNP‐array analysis. The first patient, a boy with global developmental delay, had a rare type of pure distal 1q inverted duplication (1q32‐qter), attached to the end of the short arm of the same chromosome 1, in approximately 35% of his cells. The second patient, a phenotypically normal man, was diagnosed as having mosaic for a balanced non‐reciprocal translocation of the distal segment of 7q (7q33qter), onto the terminal region of the short arm of a whole chromosome 12, in approximately 80% of his cells. The remaining 20% of the cells showed an unbalanced state of the translocation, with only the der(7) chromosome. He was ascertained through his malformed fetus carrying a non‐mosaic partial monosomy 7q, identified at prenatal diagnosis. We show that pan‐telomeric and subtelomeric sequences were observed at the interstitial junction point of the inv dup(1q) and of the der(12)t(7;12), respectively. The present cases and review of the literature suggest that the presence of ITSs at internal sites of the chromosomes may explain mechanisms of the patients's mosaic structural rearrangements. © 2014 Wiley Periodicals, Inc.
Mosaicism for trisomy 21: A review

The clinical and cytogenetic findings associated with mosaicism for trisomy 21/Down syndrome are the focus of this review. The primary topics discussed in this overview of the extant literature include the history of this condition and its diagnosis, the incidence of mosaicism, the meiotic and/or mitotic chromosomal malsegregation events resulting in mosaicism, the observation of mosaicism in the parents of children with the non‐mosaic form of Down syndrome, and the variation in phenotypic outcome for both constitutional and acquired traits present in people with mosaicism for trisomy 21/Down syndrome, including cognition, fertility, and overall phenotypic findings. Additional topics reviewed include the social conditions of people with mosaicism, as well as age‐related and epigenetic alterations observed in people with mosaicism for trisomy 21/Down syndrome. © 2014 Wiley Periodicals, Inc.
The Back Pain Revolution

The problem diagnostic triage pain and disability back pain through history the epidemiology of back pain risk factors the clinical course of low back pain the physical basis of simple backache physical impairment illness behaviour psychological distress beliefs about back pain social influences a new clinical model rest or stay active? treatment - the scientific evidence clinical guidelines information for patients approaches to chronic pain and disability UK health care for backs US health care for backs future health care for back pain.
Cornelia de Lange syndrome caused by heterozygous deletions of chromosome 8q24: Comments on the article by Pereza et al. [2012]

In the March issue of the Journal in 2012, we reported on a girl with Langer‐Giedion syndrome (LGS) phenotype and a 7.5 Mb interstitial deletion at 8q23.3q24. 13, encompassing the EXT1, but not the TRPS1 gene. Recent discoveries have shown that heterozygous intragenic mutations or contiguous gene deletions including the RAD21 gene, which is located downstream of the TRPS1 gene, are the cause of Cornelia de Lange syndrome‐4. Considering that the interstitial deletion in our patient included the RAD21 and 30 other RefSeq genes, we would like to suggest a revision of the diagnosis reported in our previous paper and compare our patient to other reported patients with Cornelia de Lange syndrome‐4 caused by heterozygous deletions of chromosome 8q24. © 2015 Wiley Periodicals, Inc.
Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene*

Background: β-Galactoside α2,6-sialyltransferase 1 (ST6Gal-1) action is essential for the anti-inflammatory activity in intravenous immunoglobulin (IVIG) therapy. Results: Fc sialylation changes in accordance to the severity of inflammation. Inactivation of the P1 promoter abrogated IgG Fc sialylation. Conclusion: Fc sialylation depends on ST6Gal-1 in the circulation. Defective Fc sialylation is a mechanism for the generally proinflammatory tendencies of the P1-ablated mutant mouse (Siat1ΔP1). Significance: Anti-inflammatory bioactivity of IVIG requires sialylated Fc. The anti-inflammatory properties associated with intravenous immunoglobulin therapy require the sialic acid modification of the N-glycan of the Fc domain of IgG. Sialylation of the Fc fragment is mediated by β-galactoside α2,6-sialyltransferase 1 (ST6Gal-1), acting on the Gal(β4)GlcNAc terminal structure of the biantennary N-glycans on the Fc domain. However, little is known regarding the in vivo regulation of Fc sialylation and its role in the progression of inflammatory processes. Here, we report that decreased Fc sialylation of circulatory IgG accompanies the acute phase response elicited by turpentine exposure or upon acute exposure to either nontypeable Haemophilus influenzae or ovalbumin. However, Fc sialylation was increased 3-fold from the base line upon transition to chronic inflammation by repeated exposure to challenge. The P1 promoter of the ST6Gal-1 gene is critical for Fc sialylation, but P1 does not drive ST6Gal-1 expression in B cells. The Siat1ΔP1 mouse, with a dysfunctional P1 promoter, was unable to produce sialylated Fc in the systemic circulation, despite the presence of Gal(β4)GlcNAc termini on the Fc glycans. The major contribution of P1 action is to synthesize ST6Gal-1 enzymes that are deposited into the systemic circulation. The data strongly indicate that this pool of extracellular ST6Gal-1 in the blood impacts the sialylation of IgG Fc and that defective Fc sialylation is likely a major contributing mechanism for the proinflammatory tendencies previously noted in Siat1ΔP1 animals.
Factors Affecting Heart Rate Recovery After Symptom-limited Exercise Stress Testing

Background . Heart rate recovery (HRR) has been recognized as an independent predictor of mortality. Objective . To identify factors that may affect HRR in patient with unknown coronary artery disease (CAD). Methods . This cross sectional study was performed in National Cardiac Center Harapan Kita. We reviewed the chart of patients with unknown CAD who underwent symptom-limited exercise stress testing for medical check up between January – December 2006. Factors that may influence HRR were recorded including current medications, peak exercise heart rate (HR), HR after 3-minute recovery, and the ischemic response to exercise. HRR was defined as the change in HR from peak exercise to 3-minute recovery. We further categorized patients to normal or abnormal HRR by using mean HRR as cut off value. All factors related to HRR and normal/abnormal categories were analyzed. Results . There were 188 patients aged 48 + 11 years. HRR significantly influenced by male sex (p=0.003), hypertension (p=0.028), â-blocker (p=0.03), calcium channel blocker (p=0.008), aspirin (p 57x). On further analysis, there was significant association between age (p=0.003), male sex (p=0.02), hypertension (p=0.02), use of â-blocker (p=0.026) and aspirin (p<0.005). Conclusion . In patients with unknown CAD who underwent symptomlimited exercise stress testing, HRR was influenced by age, male sex, hypertension, the presence of provoked ischemia, use of â-blocker, calcium channel blocker, and aspirin.
Desensitization Mechanism in Prokaryotic Ligand-gated Ion Channel

Background: GLIC, a prokaryotic homologue of pentameric ligand-gated ion channel (LGIC), is activated by protons, and crystal structures suggest a putative open conformation. Results: GLIC function characterized in proteoliposomes reveals rapid activation and slow desensitization. Desensitization is modulated by voltage, blockers, and membrane cholesterol. Conclusion: GLIC desensitization shows many hallmark features of the mechanism in LGIC. Significance: Understanding GLIC desensitization is an important step toward structure-function characterization of LGIC. Crystal structures of Gloeobacter violaceus ligand-gated ion channel (GLIC), a proton-gated prokaryotic homologue of pentameric ligand-gated ion channel (LGIC) from G. violaceus, have provided high-resolution models of the channel architecture and its role in selective ion conduction and drug binding. However, it is still unclear which functional states of the LGIC gating scheme these crystal structures represent. Much of this uncertainty arises from a lack of thorough understanding of the functional properties of these prokaryotic channels. To elucidate the molecular events that constitute gating, we have carried out an extensive characterization of GLIC function and dynamics in reconstituted proteoliposomes by patch clamp measurements and EPR spectroscopy. We find that GLIC channels show rapid activation upon jumps to acidic pH followed by a time-dependent loss of conductance because of desensitization. GLIC desensitization is strongly coupled to activation and is modulated by voltage, permeant ions, pore-blocking drugs, and membrane cholesterol. Many of these properties are parallel to functions observed in members of eukaryotic LGIC. Conformational changes in loop C, measured by site-directed spin labeling and EPR spectroscopy, reveal immobilization during desensitization analogous to changes in LGIC and acetylcholine binding protein. Together, our studies suggest conservation of mechanistic aspects of desensitization among LGICs of prokaryotic and eukaryotic origin.
Yeast Adaptor Protein, Nbp2p, Is Conserved Regulator of Fungal Ptc1p Phosphatases and Is Involved in Multiple Signaling Pathways*

Background: Nbp2p is a yeast SH3 domain-containing adaptor protein. Results: We identified a highly conserved motif in Nbp2p required for binding the Ptc1p phosphatase. The Nbp2p-Ptc1 complex down-regulates the cell wall integrity MAPK pathway and other pathways. Conclusion: A conserved role of Nbp2p is to recruit Ptc1p through SH3 domain-mediated interactions. Significance: Knowledge of adaptor protein functions is extended. Nbp2p is an Src homology 3 (SH3) domain-containing yeast protein that is involved in a variety of cellular processes. This small adaptor protein binds to a number of different proteins through its SH3 domain, and a region N-terminal to the SH3 domain binds to the protein phosphatase, Ptc1p. Despite its involvement in a large number of physical and genetic interactions, the only well characterized function of Nbp2p is to recruit Ptc1p to the high osmolarity glycerol pathway, which results in down-regulation of this pathway. In this study, we have discovered that Nbp2p orthologues exist in all Ascomycete and Basidiomycete fungal genomes and that all possess an SH3 domain and a conserved novel Ptc1p binding motif. The ubiquitous occurrence of these two features, which we have shown are both critical for Nbp2p function in Saccharomyces cerevisiae, implies that a conserved role of Nbp2p in all of these fungal species is the targeting of Ptc1p to proteins recognized by the SH3 domain. We also show that in a manner analogous to its role in the high osmolarity glycerol pathway, Nbp2p functions in the down-regulation of the cell wall integrity pathway through SH3 domain-mediated interaction with Bck1p, a component kinase of this pathway. Based on functional studies on the Schizosaccharomyces pombe and Neurospora crassa Nbp2p orthologues and the high conservation of the Nbp2p binding site in Bck1p orthologues, this function of Nbp2p appears to be conserved across Ascomycetes. Our results also clearly imply a function for the Nbp2p-Ptc1p complex other cellular processes.
Etiology and pathogenesis of robin sequence in a large Dutch cohort

Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non‐isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995–2013 in three academic hospitals were evaluated. Four clinical geneticists re‐evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re‐evaluated. Subsequent results were re‐discussed and a final conclusion was drawn. We included 191 RS patients. After re‐evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty‐two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non‐isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non‐isolated RS patients compared to other studies. Re‐evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re‐evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated. © 2015 Wiley Periodicals, Inc.
Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report

We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor‐induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23‐producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor‐β and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease‐causing genes for McCune‐Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose‐positron emission tomography, and thus could not completely exclude occult FGF23‐producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast‐macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction. © 2015 Wiley Periodicals, Inc.
Estimate of antioxidant capacity and lipid peroxidation in plasma of healthy subjects

Serum contains various antioxidant molecules that may provide important protection against free radical attack. The aim of this work was to assess the total antioxidant capacity of plasma and a marker of lipid per oxidation [(thiobarbituric acid-reactive substances (TBARS)] in plasma of healthy smoking and non-smoking young and elderly subjects. In addition, we investigated plasma concentrations of α-tocopherol, β-carotene, and ascorbic acid. In in vitro experiments, the effects of exogenous compounds (ascorbic acid, uric acid, Trolox) on total ferric-reducing activity of plasma (FRAP) were also tested. We demonstrated that total antioxidant capacity of plasma obtained from healthy non-smoking young subjects was significantly higher than plasma antioxidant capacity of smoking elderly subjects. The concentration of TBARS in young non-smoking volunteers was lower than that in young smokers. The concentration of TBARS in elderly non-smoking volunteers was lower than in elderly smokers. Plasma concentrations of alpha-tocopherol, beta-carotene and ascorbic acid were significantly lower in elderly smoker than in elderly non-smokers of the same age. No difference in the plasma levels of alpha-tocopherol, beta-carotene and ascorbic acid were found in 22-year-old smoking and non-smoking subjects. In vitro addition of ascorbic acid, uric acid, or Trolox to plasma samples significantly increased their total antioxidant capacity. Decrease of FRAP values and increase of TBARS concentrations is a significant physiologic condition of the aging process. Supplementation of antioxidants could be useful for the enhancement of antioxidant screen in plasma.
Pellino 2 Is critical for Toll-like Receptor/Interleukin-1 Receptor (TLR/IL-1R)-mediated Post-transcriptional Control*

Background: Pellino proteins are involved in polyubiquitination and degradation of IRAK1, a key molecule in TLR/IL-1R-mediated signaling. Results: Pellino 2 knockdown reduced TAK1-dependent NFκB activation and inflammatory gene mRNA stabilization. Conclusion: Pellino 2 plays a critical role for TLR/IL-1R-mediated post-transcriptional control. Significance: Pellino 2 is the critical signaling molecule controlling TAK1- and MEKK3-dependent pathways and also plays a critical role for TLR/IL-1R-mediated post-transcriptional control. Interleukin 1 receptor-associated kinase 1(IRAK1), a key molecule in TLR/IL-1R-mediated signaling, is phosphorylated, ubiquitinated, and degraded upon ligand stimulation. We and others have recently identified Pellino proteins as novel RING E3 ubiquitin ligases involved in IRAK1 polyubiquitination and degradation. However, it remains unclear how each Pellino member distinctly regulates TLR/IL-1R signaling by modulating IRAK1 ubiquitination. In this study we examined the role of Pellino 2 in IL-1- and LPS-mediated signaling and gene expression by knocking down Pellino 2 in human 293-IL-1R cells and primary bone marrow macrophages. Pellino 2 (but not Pellino 1) knockdown abolished IL-1- and LPS-induced Lys-63-linked IRAK1 ubiquitination with reduced Lys-48-linked IRAK1 ubiquitination. Furthermore, Pellino 2 is required for TAK1-dependent NFκB activation. However, because of the retained TAK1-independent NFκB activation, the levels of IL-1- and LPS-induced NFκB activation were not substantially affected in Pellino 2 knockdown 293-IL-1R cells and primary macrophages, respectively. On the other hand, Pellino 2 knockdown reduced the IL-1- and LPS-induced inflammatory gene expression at late time points, which was accompanied by increased decay rates of the mRNAs of the inflammatory genes. Importantly, IL-1- and LPS-mediated JNK and ERK activation were substantially attenuated in Pellino 2 knock-down cells, implicating MAPK activation in TLR/IL-1R-induced mRNA stabilization. Taken together, this study demonstrated that Pellino 2 plays a critical role for TLR/IL-1R-mediated post-transcriptional control.