Miracle-dz/UniFAR-FTUs huggingface dataset:
ADAMTS10 Protein Interacts with Fibrillin-1 and Promotes Its Deposition in Extracellular Matrix of Cultured Fibroblasts*

Autosomal recessive and autosomal dominant forms of Weill-Marchesani syndrome, an inherited connective tissue disorder, are caused by mutations in ADAMTS10 (encoding a secreted metalloprotease) and FBN1 (encoding fibrillin-1, which forms tissue microfibrils), respectively, yet they are clinically indistinguishable. This genetic connection prompted investigation of a potential functional relationship between ADAMTS10 and fibrillin-1. Specifically, fibrillin-1 was investigated as a potential ADAMTS10 binding partner and substrate, and the role of ADAMTS10 in influencing microfibril biogenesis was addressed. Using ligand affinity blotting and surface plasmon resonance, recombinant ADAMTS10 was found to bind to fibrillin-1 with a high degree of specificity and with high affinity. Two sites of ADAMTS10 binding to fibrillin-1 were identified, one toward the N terminus and another in the C-terminal half of fibrillin-1. Confocal microscopy and immunoelectron microscopy localized ADAMTS10 to fibrillin-1-containing microfibrils in human tissues. Furin-activated ADAMTS10 could cleave fibrillin-1, but innate resistance of ADAMTS10 zymogen to propeptide excision by furin was observed, suggesting that, unless activated, ADAMTS10 is an inefficient fibrillinase. To investigate the role of ADAMTS10 in microfibril biogenesis, fetal bovine nuchal ligament cells were cultured in the presence or absence of ADAMTS10. Exogenously added ADAMTS10 led to accelerated fibrillin-1 microfibril biogenesis. Conversely, fibroblasts obtained from a Weill-Marchesani syndrome patient with ADAMTS10 mutations deposited fibrillin-1 microfibrils sparsely compared with unaffected control cells. Taken together, these findings suggest that ADAMTS10 participates in microfibril biogenesis rather than in fibrillin-1 turnover.
Effectiveness of calcium hydroxide-based intracanal medicaments against Enterococcus faecalis.

AIM To evaluate the antimicrobial efficacy of calcium hydroxide-based intracanal medicaments against Enterococcus faecalis. METHODOLOGY One hundred and six single-rooted human teeth were inoculated with E. faecalis (ATCC 29212) and incubated in an microaerophilic environment for 21 days. Teeth were divided according to the medicaments and period: G1 - Calen (7 days); G2 - Calen (14 days); G3 - Calen/camphorated paramonochlorophenol (CMCP) (7 days); G4 - Calen/CMCP (14 days); G5 - Calen/0.4% chlorhexidine (CHX) (7 days); G6 - Calen/0.4% CHX (14 days); G7 - Calen/1% CHX (7 days); G8 - Calen/1% CHX (14 days); G9 - chemo-mechanical preparation with no medication and G10 - no chemo-mechanical preparation and no medication. Microbial samples were harvested immediately after removal of the intracanal dressing and 7 days later. Data were subjected to anova (P < 0.05). RESULTS All medicaments were associated with a reduction in E. faecalis after removal of the dressing (post-medication harvest). However, all specimens were associated with an increase in CFU mL(-1) values after 7 days (final harvest). Calen/CMCP and Calen/CHX had the lowest CFU mL(-1) values (P < 0.05). CONCLUSION In this laboratory study using extracted teeth all calcium hydroxide-based medicaments were able to significantly reduce the CFU mL(-1) values of E. faecalis in the root canal system.
Effectiveness of ProTaper, D-RaCe, and Mtwo retreatment files with and without supplementary instruments in the removal of root canal filling material.

AIM To assess the efficacy of different retreatment rotary files in removing gutta-percha and endodontic sealer from canals. METHODOLOGY Ninety straight single-rooted premolars were prepared up to a size 30 and filled with gutta-percha and sealer and then randomly assigned to six retreatment groups (n = 15). Groups I, III, and V were retreated using rotary systems ProTaper Universal Retreatment (PTUR), D-RaCe, and Mtwo Retreatment, respectively. Groups II, IV, and VI were retreated using the additional instruments F4, size 40, . 04 taper RaCe, and size 40, . 04 taper Mtwo, respectively. The roots were split vertically, and images of the halves were obtained using a high-resolution scanner and evaluated with AutoCAD software to calculate the percentage of residual material. Data were analyzed with Kruskal-Wallis and Student-Newman-Keuls tests using a 5% significance cutoff (P < 0.05). RESULTS There were no statistically significant differences (P > 0.05) between groups when additional instruments were used. The percentage of residual material was lowest in the PTUR group and was statistically significant only when compared to the D-RaCe system (P = 0.0038). CONCLUSIONS All root canals had residual filling material after retreatment even when additional instruments were used.
The F-BAR Protein Rapostlin Regulates Dendritic Spine Formation in Hippocampal Neurons*

Pombe Cdc15 homology proteins, characterized by Fer/CIP4 homology Bin-Amphiphysin-Rvs/extended Fer/CIP4 homology (F-BAR/EFC) domains with membrane invaginating property, play critical roles in a variety of membrane reorganization processes. Among them, Rapostlin/formin-binding protein 17 (FBP17) has attracted increasing attention as a critical coordinator of endocytosis. Here we found that Rapostlin was expressed in the developing rat brain, including the hippocampus, in late developmental stages when accelerated dendritic spine formation and maturation occur. In primary cultured rat hippocampal neurons, knockdown of Rapostlin by shRNA or overexpression of Rapostlin-QQ, an F-BAR domain mutant of Rapostlin that has no ability to induce membrane invagination, led to a significant decrease in spine density. Expression of shRNA-resistant wild-type Rapostlin effectively restored spine density in Rapostlin knockdown neurons, whereas expression of Rapostlin deletion mutants lacking the protein kinase C-related kinase homology region 1 (HR1) or Src homology 3 (SH3) domain did not. In addition, knockdown of Rapostlin or overexpression of Rapostlin-QQ reduced the uptake of transferrin in hippocampal neurons. Knockdown of Rnd2, which binds to the HR1 domain of Rapostlin, also reduced spine density and the transferrin uptake. These results suggest that Rapostlin and Rnd2 cooperatively regulate spine density. Indeed, Rnd2 enhanced the Rapostlin-induced tubular membrane invagination. We conclude that the F-BAR protein Rapostlin, whose activity is regulated by Rnd2, plays a key role in spine formation through the regulation of membrane dynamics.
Krüppel-like Factor 4 (KLF4) Activates the Transcription of the Gene for the Platelet Isoform of Phosphofructokinase (PFKP) in Breast Cancer

Krüppel-like factor 4 (KLF4) is a transcription factor that plays an important role in cell differentiation, proliferation, and survival, especially in the context of cancers. This study revealed that KLF4 activates glycolytic metabolism in breast cancer cells by up-regulating the platelet isoform of phosphofructokinase (PFKP). KLF4 activated the transcription of the PFKP gene by directly binding to the PFKP promoter. Whereas glucose uptake and lactate production were inhibited by the knockdown of KLF4, they were activated by the overexpression of KLF4. Unlike PFKP, the expressions of the other isoforms of phosphofructokinase and glycolytic genes were unaffected by KLF4. The human breast cancer tissues showed a close correlation between KLF4 and PFKP expression. This study also showed that PFKP plays a critical role in cell proliferation in breast cancer cells. In conclusion, it is suggested that KLF4 plays a role in maintenance of high glycolytic metabolism by transcriptional activation of the PFKP gene in breast cancer cells.
3D micro-CT analysis of the interface voids associated with Thermafil root fillings used with AH Plus or a flowable MTA sealer.

AIM To investigate nondestructively the percentage of 3D voids and marginal gaps in a pre-defined interface volume of interest (VOI) within root fillings produced by Thermafil Obturators with either a hydrophobic epoxy-resin-based sealer (AH Plus) or a hydrophilic flowable calcium-silicate sealer [mineral trioxide aggregate (MTA) Flow]. METHODOLOGY Sixteen single root canals from extracted premolar teeth were prepared with ProTaper rotary instruments, randomly allocated into two groups (n = 8) and filled with size 30 Thermafil Obturators in association with AH Plus or MTA Flow sealers. The filled roots were stored at 37 °C in 5 mL of Hank's balanced salt solution (HBSS) used to represent body fluids and scanned after 7 days and 6 months using a high-resolution micro-CT. From each root, images of 3000 sections were analysed in 3D and binarized using a high-resolution micro-CT (4-μ resolution). The 3D distribution of voids (porosity and marginal gaps) at the gutta-percha-sealer-dentine interface was detected through a threshold grey level and expressed as percentage of the 40-μ-thick pre-defined interface VOI (20 μ of interface dentine and 20 μ of gutta-percha/sealer). A method of analysis based on the root canal segmentation was used, and coronal, middle and apical thirds considered separately. The percentage of 3D void volume was compared statistically using one-way anova (significance for P < 0.05). Environmental Scanning Electron Microscope with Energy Dispersive X-ray (ESEM-EDX) analysis was performed on the surface of both sealers after soaking in HBSS. RESULTS Micro-CT detected gaps at the dentine-sealer interface in both groups. Void volumes wider than 10.21 μm(3) with 1.35 μm diameter were detected. Cul-de-sac-type voids (blind pores) and through-and-through voids (continuous pores) were discriminated. The apical thirds had a significantly lower 3D void volume (P < 0.05) than the middle and coronal thirds. The 3D void volume reduced significantly (P < 0.05) over time. ESEM-EDX analysis revealed that MTA Flow sealer created a dense apatite layer after 7 days of immersion in HBSS, whilst only sparse calcium phosphate deposits were detected on AH Plus even after 28 days. CONCLUSIONS Micro-CT proved to be a powerful nondestructive 3D analysis tool for visualizing the porous internal microstructure of dental/endodontic materials at the interface with dentine. The proportion of voids was least in the apical third of root canals. Voids reduced over time in the presence of simulated body fluid.
Exploring the incidence of lung cancer in small areas across Scotland

VI LIST OFT ABLES . VIII LIST OF FI GURES . X ACKN'OWLEDGEMENTS . XID 1. IN'TRODUCTION . •. 1 1.1 BACKGROUND . •. •••••. ••. •. •. •. ••. •. •. •. •••. •. •. •. ••. •. •. •. •. •. •••. ••. •. ••. •. •. •. •. •. •••. ••• 1 1.2 GEOGRAPHIES OF HEALTH . ••. •. •. •. •. ••••. •. •. •. •. •. ••. •. •. •. ••••. •••. ••. •. •• 4 1.3 AIMS OF THESIS . 15 1.4 DATA CONSiDERATIONS . 17 1.5 STRUCTURE OF THESIS ••. •. •. •. •. •. •. •. •. •. •. •. •. ••••. •. ••. •. ••. • 20 1.6 CONCLUSiON . •. •. ••. •. ••. •. •. ••••. •••••. •••• 22 2. BACKGROUND TO LUNG CANCER . 24 2.
THE IDENTIFICATION AND MEASUREMENT OF THE PSYCHONEUROSES IN MEDICAL PRACTICE: THE MINNESOTA MULTIPHASIC PERSONALITY INVENTORY

Many a medical man has wished for an easily applicable measuring device which would identify and characterize the psychoneurotic patient with a minimum use of the time consuming interview technic that is conventional in the psychiatric approach. One may not desire to deal with the psychoneuroses in one's practice, but the physician or surgeon is indeed insensitive to the problem or very young in the profession who has not been plagued by his inability appropriately to assess the role of the neurotic element in some of his patients. Without wishing to belabor the topic of the neuroses unnecessarily, because much has been published on it, we should like to remind the reader of a few general points that are pertinent to this report. Competent internists have estimated variously that from 30 to 70 per cent of the ambulatory patients who appear for medical attention come primarily because of one or
Genetic polymorphisms in the thioredoxin 2 (TXN2) gene and risk for spina bifida

TXN2 encodes human thioredoxin 2, a small redox protein important in cellular antioxidant defenses, as well as in the regulation of apoptosis. Txn2 knockout mice fail to complete neural tube closure by E10.5 and die in utero. We hypothesized that genetic variation in human TXN2 gene may alter the function of the encoded protein in a manner associated with an increased risk for neural tube defects (NTDs). A DNA re‐sequencing effort of the human TXN2 gene was taken. After a variation in the promoter was identified, the transcriptional activity of different alleles was investigated. The possible association between these variations and the risk of spina bifida was further evaluated in a subset of samples obtained from a large population‐based case‐control study in California in two different ethnicity groups, non‐Hispanic white and Hispanic white. We identified a novel promoter insertion polymorphism located 9 base pairs upstream of the transcription start site of exon 1(‐9 insertion). The GA, G and GGGA insertions were associated with a marked decrease of transcriptional activity when overexpressed in both U2‐OS (an osteosarcoma cell line) and 293 cells (derived from human embryonic kidney). Further analysis revealed that the GA insertion was associated with increased spina bifida risk for Hispanic whites. Our study revealed a novel Ins/Del polymorphism in the human TXN2 gene proximal promoter region that altered the transcriptional activity and is associated with spina bifida risk. This polymorphism may be a genetic modifier of spina bifida risk in this California population. © 2009 Wiley‐Liss, Inc.
Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype–phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy

Mutations in the gene encoding fibrillin 1 (FBN1) cause Marfan syndrome (MFS), and related connective tissue disorders. The disease spectrum is wide and while many genotype–phenotype correlations have been reported, few have been consistent. In this study FBN1 was analyzed in 113 patients with MFS or Marfan‐like features. Fifty‐three mutations were identified in 52 individuals, 41 of which were novel. The mutations comprised 26 missense, 11 splice site, 7 frameshift, 6 nonsense, 1 in‐frame deletion, and 2 whole exon deletions. In common with previous studies, genotype–phenotype analysis showed that a FBN1 mutation was more likely to be identified in patients fulfilling Ghent criteria (P = 0.005) and in those who had ectopia lentis (EL) (P < 0.0001). Other previously reported genotype–phenotype correlations were also considered and a new inverse association between a mutation in exons 59–65, and EL emerged (P = 0.002). © 2009 Wiley‐Liss, Inc.
Genetic counseling for teratogenic risk due to exposure to medications: 89 pregnancies conceived during oral contraceptive use

Congenital malformations are relatively frequent (2% of the general population) but only a small proportion of them can be ascribed to medication exposure during pregnancy. Nevertheless for the purposes of accurate prenatal diagnosis monitoring and research is it important to offer teratology counseling to patients exposed to drugs. There are approximately 20 medications currently on the market that have been universally acknowledged as teratogenic. At the current state of the art exposure of early embryos to oral contraceptives is not considered teratogenic. Oral contraceptive use may be continuous (estrogen and progesterone or progesterone alone) or emergency (levonorgestrel is the only drug authorized in Italy). Like all drugs oral contraceptives have a therapeutic failure rate which means that a number of women on oral contraceptives conceive each year and request genetic counseling about teratogenic effects. During the period 1998-2006 at our genetics clinic we received 89 requests for counseling regarding teratogenic risk due to oral contraceptives. Our study of these patients confirms an absence of teratogenic risk for pregnancies occurring during oral contraceptive use. Teratology counseling was useful to reassure the mothers about the low risk (in the case of oral contraceptive use alone) since only 12 women chose to terminate pregnancy.
Molecular (SNP) analyses of overlapping hemizygous deletions of 10q25.3 to 10qter in four patients: Evidence for HMX2 and HMX3 as candidate genes in hearing and vestibular function

We report on the analyses of four unrelated patients with de novo, overlapping, hemizygous deletions of the long arm of chromosome 10. These include two small terminal deletions (10q26.2 to 10qter), a larger terminal deletion (10q26.12 to 10qter), and an interstitial deletion (10q25.3q26.13). Single nucleotide polymorphism (SNP) studies (Illumina 550 K) established that these deletions resulted in the hemizygous loss of ∼6.1, ∼6.1, ∼12.5, and ∼7.0 Mb respectively. Additionally, these data establish that Patients 1, 2, and 3 share common, distal, hemizygous deleted regions of 6.09 Mb containing 37 RefSeq genes. Patients 3 and 4 share a 2.52 Mb deleted region corresponding to the proximal deleted region of Patient 3 and the distal deleted region of Patient 4. This common, hemizygous region contains 20 RefSeq genes including two H6 family homeobox genes (HMX2 and HMX3). Based on previous reports that Hmx2/Hmx3 knockout mice have vestibular anomalies, we propose that hemizygous deletions of HMX2 and HMX3 are responsible for the inner ear malformations observed from CT images, vestibular dysfunction, and congenital sensorineural hearing loss found in Patients 3 and 4. © 2009 Wiley‐Liss, Inc.
TRIM32 Protein Sensitizes Cells to Tumor Necrosis Factor (TNFα)-induced Apoptosis via Its RING Domain-dependent E3 Ligase Activity against X-linked Inhibitor of Apoptosis (XIAP)*

TRIM32, which belongs to the tripartite motif (TRIM) protein family, has the RING finger, B-box, and coiled-coil domain structures common to this protein family, along with an additional NHL domain at the C terminus. TRIM32 reportedly functions as an E3 ligase for actin, a protein inhibitor of activated STAT y (PIASy), dysbindin, and c-Myc, and it has been associated with diseases such as muscular dystrophy and epithelial carcinogenesis. Here, we identify a new substrate of TRIM32 and propose a mechanism through which TRIM32 might regulate apoptosis. Our overexpression and knockdown experiments demonstrate that TRIM32 sensitizes cells to TNFα-induced apoptosis. The RING domain is necessary for this pro-apoptotic function of TRM32 as well as being responsible for its E3 ligase activity. TRIM32 colocalizes and directly interacts with X-linked inhibitor of apoptosis (XIAP), a well known cancer therapeutic target, through its coiled-coil and NHL domains. TRIM32 overexpression enhances XIAP ubiquitination and subsequent proteasome-mediated degradation, whereas TRIM32 knockdown has the opposite effect, indicating that XIAP is a substrate of TRIM32. In vitro reconstitution assay reveals that XIAP is directly ubiquitinated by TRIM32. Our novel results collectively suggest that TRIM32 sensitizes TNFα-induced apoptosis by antagonizing XIAP, an anti-apoptotic downstream effector of TNFα signaling. This function may be associated with TRIM32-mediated tumor suppressive mechanism.
Connexin mutations in Brazilian patients with skin disorders with or without hearing loss

The connexins are a family of proteins whose major function is as part of the gap junctions of cell‐to‐cell channels. They are expressed in several tissues including brain, skin, and cochlea. Mutations in connexin genes play a major role in non‐syndromic sensorineural deafness, but have been also described in individuals with variable dermatological features. In recent years, many genes responsible for hereditary skin diseases have been discovered. These genes may encode different proteins that participate in the terminal differentiation of the epidermis. Therefore alteration or absence of these proteins causes a keratinization disorder. It has been demonstrated that distinct germline mutations within six connexin (Cx) genes GJB2 (Cx26), GJB6 (Cx30), GJB3 (Cx31), GJA1 (Cx43), GJB4 (Cx30.3), and GJB5 (Cx31.1), may cause sensorineural hearing loss and various skin disease phenotypes. The crucial functional importance of each of these connexins in the mentioned ectodermic tissues is reflected by the finding that genetic defects in their genes produce a wide spectrum of genetic disorders comprising sensorineural hearing loss, disorders of cornification of the skin, hair, and nails, and keratitis. Here, we report on different mutations in the connexin genes in individuals with or without hearing loss and different skin disorders illustrating the clinical and genetic heterogeneity of the condition. © 2009 Wiley‐Liss, Inc.
The American Disease: Origins of Narcotic Control

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Adiponectin Ameliorates Doxorubicin-induced Cardiotoxicity through Akt Protein-dependent Mechanism*

Accumulating evidence shows that obesity is associated with doxorubicin cardiac toxicity in the heart, but the molecular mechanisms that contribute to this pathological response are not understood. Adiponectin is an adipose-derived, cardioprotective factor that is down-regulated in obesity. Here, we investigated the effect of adiponectin on doxorubicin (DOX)-induced cardiotoxicity and assessed the mechanisms of this effect. A single dose of DOX was intraperitoneally injected into the abdomen of adiponectin knock-out (APN-KO) and wild-type (WT) mice. APN-KO mice had increased mortality and exacerbated contractile dysfunction of left ventricle compared with WT mice. APN-KO mice also showed increased apoptotic activity and diminished Akt signaling in the failing myocardium. Systemic delivery of adenoviral vector expressing adiponectin improved left ventricle dysfunction and myocardial apoptosis following DOX injection in WT and APN-KO mice but not in Akt1 heterozygous KO mice. In cultured rat neonatal cardiomyocytes, adiponectin stimulated Akt phosphorylation and inhibited DOX-stimulated apoptosis. Treatment with sphingosine kinase-1 inhibitor or sphingosine 1-phosphate receptor antagonist diminished adiponectin-induced Akt phosphorylation and reversed the inhibitory effects of adiponectin on myocyte apoptosis. Pretreatment with anti-calreticulin antibody reduced the binding of adiponectin to cardiac myocytes and blocked the adiponectin-stimulated increase in Akt activation and survival in cardiomyocytes. Interference of the LRP1/calreticulin co-receptor system by siRNA or blocking antibodies diminished the stimulatory actions of adiponectin on Akt activation and myocyte survival. These data show that adiponectin protects against DOX-induced cardiotoxicity by its ability to promote Akt signaling.
Hemostasis and Thrombosis: Basic Principles and Clinical Practice

Since publication of the First Edition in 1982, Hemostasis and Thrombosis has established itself as the pre-eminent book in the field of coagulation disorders. No other book is as inclusive in scope, with coverage of the field from the standpoint of both basic scientists and clinicians. This comprehensive resource details the essentials of bleeding and thrombotic disorders and the management of patients with these and related problems, and delivers the most up-to-date information on normal biochemistry and function of platelets or endothelial cells, as well as in-depth discussions of the pharmacology of anticoagulant, fibrinolytic, and hemostatic drugs.