Miracle-dz/UniFAR-FTUs huggingface dataset:
TARDBP gene mutations in south Italian patients with amyotrophic lateral sclerosis

TAR-DNA-binding protein 43 (TDP-43) has recently been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS) and SOD1 negative familial cases with amyotrophic lateral sclerosis (FALS). TDP-43 is evolutionarily conserved, consisting of two RNA recognition motifs and a glycine-rich C-terminal domain. It is involved in the regulation of expression and splicing, and in other cellular processes such as microRNA biogenesis, apoptosis and cell division.1 2 Starting in early 2008, dominant mutations in TARDBP gene have been reported by several groups as a primary cause of ALS. To date, a total of 30 mutations of TARDBP have been reported not only in SOD1 -negative FALS cases (∼3%) but also in SALS cases (∼1.5%). All but one of the mutations identified (D169G) reside in exon 6 of the TARDBP gene, which encodes for the C-terminal glycine-rich domain of TDP-43. All of these mutations are dominantly inherited missense changes with the exception of a truncating mutation (Y374X) at the extreme C terminus of the protein.3 In this study, in order to investigate the presence and frequency of TARDBP mutations in a cohort of 310 south Italian patients affected by ALS, we performed a mutational screening of the exon 4 and exon 6 of the gene in SOD1 -negative FALS and SALS patients. …
Identification and characterization of new elements involved in checkpoint and feedback controls in fission yeast.

To investigate the mechanisms that ensure the dependency relationships between cell cycle events and to investigate the checkpoints that prevent progression through the cell cycle after DNA damage, we have isolated mutants defective in the checkpoint and feedback control pathways. We report the isolation and characterization of 11 new loci that define distinct classes of mutants defective in one or more of the checkpoint and feedback control pathways. Two mutants, rad26.T12 and rad27.T15, were selected for molecular analysis. The null allele of the rad26 gene (rad26.d) shares the phenotype reported for the "checkpoint rad" mutants rad1, rad3, rad9, rad17, and hus1, which are defective in the radiation checkpoint and in the feedback controls that ensure the order of cell cycle events. The null allele of the rad27 gene (rad27.d) defines a new class of Schizosaccharomyces pombe mutant. The rad27 complementing gene codes for a putative protein kinase that is required for cell cycle arrest after DNA damage but not for the feedback control that links mitosis to the completion of prior DNA synthesis (the same gene has recently been described by Walworth et al. (1993) as chk1). These properties are similar to those of the rad9 gene of Saccharomyces cerevisiae. A comparative analysis of the radiation responses in rad26.d, rad26.T12, and rad27.d cells has revealed the existence of two separable responses to DNA damage controlled by the "checkpoint rad" genes. The first, G2 arrest, is defective in rad27.d and rad26.d but is unaffected in rad26.T12 cells. The second response is not associated with G2 arrest after DNA damage and is defective in rad26.d and rad26.T12 but not rad27.d cells. A study of the radiation sensitivity of these mutants through the cell cycle suggests that this second response is associated with S phase and that the checkpoint rad mutants, in addition to an inability to arrest mitosis after radiation, are defective in an S phase radiation checkpoint.
Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands

Background: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. Methods: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling “clinical” criteria. In patients with unfulfilled “clinical” criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the “clinical” international criteria. Results: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled “clinical criteria” when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. Conclusions: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
An Exploratory Study of a Novel Peritoneal Combination Dialysate (1.36% Glucose/7.5% Icodextrin), Demonstrating Improved Ultrafiltration Compared to Either Component Studied Alone

Objective Concerns regarding the impact of ultrafiltration failure on peritoneal dialysis and the effect of hypertonic glucose on the peritoneal membrane have lead to a search for alternative dialysates. Computer simulations based on the three-pore theory suggest that a combination of 1.36% glucose and 7.5% icodextrin (glucose polymer) offers an improved ultrafiltration profile. The aim of the present study was to investigate the ultrafiltration profile of this combination fluid. Design Prospective open study comparing 1.36% glucose, 3.86% glucose, 7.5% icodextrin, and the combination fluid (1.36% glucose/7.5% icodextrin). Setting Sheffield Kidney Institute, Northern General Hospital, Sheffield, UK. Patients 11 patients currently using peritoneal dialysis not previously exposed to icodextrin. Main Outcome Measure Intraperitoneal volume was measured using a radioisotope dilution method. Results The combination fluid showed a biphasic ultrafiltration profile, with a steep initial increase in intraperitoneal volume, then a maintained plateau phase for the duration of the study dwell (7 hours). The final volume was greater than that with the 1.36% glucose dwell and the 7.5% icodextrin dwell. The fluid was well tolerated by the patients. Conclusions These findings are in keeping with computer simulations using the three-pore model. The combination fluid offers an improved ultrafiltration profile, with a final volume similar to 3.86% glucose, while avoiding exposing the peritoneal membrane to high glucose concentrations. It may have a role as a long dwell to optimize ultrafiltration and possibly prolong peritoneal dialysis technique survival.
Eurogin Roadmap: Comparative epidemiology of HPV infection and associated cancers of the head and neck and cervix

The EUROGIN 2012 roadmap is focused on the comparative epidemiology of human papillomavirus (HPV) associated head and neck squamous cell cancers (HNSCC) and cervical cancers. Discussed are the similarities and differences between the two cancers with regard to global disease burden, HPV prevalence and type distribution, disease cofactors, molecular pathogenesis, treatment approaches, prognostic factors and primary and secondary prevention. The global incidence of HNSCC and cervical cancer is similar; however, a minority of HNSCC in comparison to virtually all cervical cancers is caused by HPV. HPV infection prevalence is considerably lower in the oral than genital regions for reasons that are as yet unclear. Infection at both sites is strongly associated with sexual behavior, but this association does not appear to explain the male predominance of oral HPV infection. Studies of the molecular pathogenesis of HPV‐associated HNSCC (predominantly oropharyngeal cancers) are hampered by the lack of a readily detectable intermediate clinical endpoint analogous to cervix intraepithelial neoplasia. Nevertheless, similarities in chromosomal aberrations, gene expression, methylation and microRNA profiles between HPV‐positive HNSCC and cervical cancer argue for shared carcinogenic pathways. Treatment approaches to oropharyngeal and cervical cancers are remarkably similar, with the development of HPV‐targeted therapies as the ultimate treatment goal. Key research challenges include understanding oral HPV transmission and male predominance, clarifying the role of cofactors, and developing new screening and treatment methods for HPV‐associated HNSCC.
Improving the accuracy of SF6 leakage detection for high voltage switchgear

Even though average leakage rates of SF6 in high voltage equipment are very low, there is no guarantee for a 100% leakage-free system, especially when considering the generally long lifespan of high-voltage equipment. Taking in view the rather strict maximum allowed leakage rate of SF6 per year, regulated by international standards, these facilities should be equipped with suitable monitoring devices. However, accurate detection of low rates of gas leakage is not an easy task. This paper sheds light on the challenges of leakage detection by thorough analysis of physical aspects. Furthermore, it proposes two methods for high-fidelity leakage monitoring and detection with special emphasis on their suitability for use in substations. Application of these methods in the laboratory environment revealed an accuracy of detection levels of 0.3% per year. This is a substantial improvement from the present monitoring systems that show fluctuation levels of the indicator to be as high as up to several percent, which is clearly above the acceptable level.
Echocardiography. Clinical application in mitral stenosis.

An echocardiogram is the graphic registration of ultrasound waves reflected from the heart. The waveform recording from the anterior leaflet of the mitral valve is specific for this structure. The mitral valve echocardiogram in patients with solitary mitral stenosis correlates well with the findings obtained through cardiac catheterization and with observations made during open-heart surgery. The motion of the anterior leaflet expressed as a diastolic slope in millimeters per second has been shown to decrease as the mitral valve area lessens. The echocardiogram, obtained without risk or serious technical difficulty, can be used in determining the severity of mitral stenosis. This bedside procedure may also be used to study the evolution of mitral stenosis from the onset of rheumatic activity and to appraise the motion of the leaflet after mitral valvotomy.
Collagen alpha1(I) gene (COL1A1) is repressed by RFX family.

Collagen type I is composed of three polypeptide chains transcribed from two separate genes (COL1A1 and COL1A2) with different promoters requiring coordinate regulation. Our recent publications, centering on COL1A2 regulation, demonstrate that methylation in the first exon of COL1A2 at a regulatory factor for X box (RFX) site (at -1 to +20) occurs in human cancer cells and correlates with increased RFX1 binding and decreased collagen transcription (Sengupta, P. K., Erhlich, M., and Smith, B. D. (1999) J. Biol. Chem. 274, 36649-36655; Sengupta, S. , Smith, E. M. , Kim, K. , Murnane, M. J., and Smith, B. D. (2003) Cancer Res. 63, 1789-1797). In normal cells, RFX5 complex along with major histocompatibility class II transactivator (CIITA) is induced by interferon-gamma to occupy this site and repress collagen transcription (Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2004) J. Biol. Chem. 279, 41319-41332). In this paper, we demonstrate that COL1A1 has an RFX consensus binding site surrounding the transcription start site (-11 to +10) that contains three methylation sites rather than one in the COL1A2 gene RFX binding site. RFX1 interacts weakly with the unmethylated COL1A1 site, and binds with higher affinity to the methylated site. RFX1 represses the unmethylated COL1A1 less efficiently than COL1A2. COL1A1 promoter activity is sensitive to DNA methylation and the COL1A1 gene is methylated in human cancer cells with coordinately decreased collagen expression. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (aza-dC) increases collagen gene expression with time in human cancer cells. On the other hand, RFX5 interacts with both collagen type I genes with a similar binding affinity and represses both promoters equally in transient transfections. Two dominant negative forms of RFX5 activate both collagen genes coordinately. Finally, CIITA RNA interference experiments indicate that CIITA induction is required for interferon gamma-mediated repression of both collagen type I genes.
The sensitivity of acute lymphoblastic leukemia cells carrying the t(12;21) translocation to campath-1H-mediated cell lysis.

BACKGROUND AND OBJECTIVES Campath-1H is used in conditioning regimens and more recently as an anti-leukemic therapy in acute lymphoblastic leukemias (ALL). We therefore investigated CD52 expression and campath-1H-mediated lysis of ALL cells in vitro. DESIGN AND METHODS Complement-mediated cytotoxicity assays were performed on freshly isolated neoplastic cells and cell lines using human serum. Antibody-dependent cellular cytotoxicity (ADCC) was performed by calcein-AM release assays. RESULTS CD52 was expressed in four out of eight ALL cell lines studied. Among 61 freshly isolated ALL samples CD52 was expressed at varying levels in 87% of cases. Whereas ADCC was equivalent in different CD52+ lines, complement-dependent cytotoxicity (CDC) was variable. The REH cell line bearing the t(12;21) translocation showed 47-60% lysis when treated with 10 microg/mL campath-1H compared to 0-6% for the other cell lines expressing equivalent amounts of CD52. Furthermore all nine ALL samples with t(12;21) showed very high CDC (mean 97%) compared to the other 24 CD52+cases (mean 24%)(p<0.0001). In t(12;21) samples, efficient CDC was obtained with as little as 1 microg/mL campath-1H. CDC correlated in part with CD52 levels, suggesting that CD52 expression and other yet undefined factors contribute to the particular sensitivity of t(12;21) cells. The resistance of non t(12;21) ALL cases could be overcome to a limited extent by increasing the concentration of campath-1H, blocking the CD55 and CD59 complement inhibitors, and more effectively by combining campath-1H with fludarabine. INTERPRETATION AND CONCLUSIONS We conclude that most ALL samples express CD52 to a variable level and that campath-1H has cytotoxic activity against CD52+ALL, alone or in combination with cytotoxic drugs.
Oxygen therapy in acute medical care

The potential dangers of hyperoxia need to be recognised Oxygen is cheap, widely available, and used in a range of settings and conditions to relieve or prevent tissue hypoxia. Since its discovery by Scheele and Priestley in the 1770s, it has remained one of the most effective therapeutic agents available. However, as a result of poor prescribing and monitoring, inappropriate doses are often given.1 Oxygen is most commonly delivered by devices with variable performance such as face masks and nasal cannulae. These can produce unexpectedly high concentrations of inspired oxygen, particularly when ventilation is depressed.2 In addition, masks that incorporate a reservoir bag are often used in emergencies, following the widespread adoption of advanced trauma life support style (or ATLS) guidelines. These appliances can produce systemic hyperoxia that is generally assumed to be harmless. However, emerging evidence suggests that for some patients with acute medical conditions, hyperoxia may be harmful. Oxygen therapy is often …
Novel Kind of Semislow Light Photonic Crystal Waveguides With Large Delay-Bandwidth Product

A novel type of semislow light photonic crystal waveguide obtained by shifting the boundaries of a W1 waveguide in the direction of light propagation is presented. The structure produces unusual "U-type" group index -frequency curves, which results in a nearly constant group index ng over large bandwidth. A versatile control of ng (11 <; ng 210) with large normalized delay-bandwidth products ranging from 0.1363 to 0.3141 is obtained at the wavelength of 1550 nm using a unique geometrical parameter. Additionally, depending on the chosen waveguide geometry, ultralow group velocity dispersion (GVD) values in large slow light bandwidth can be achieved, with controllable positive or negative GVD.
Amplification of low-frequency antiviral CD8 T cell responses using autologous dendritic cells

Objective To utilize the potent antigen-presenting capacity of mature dendritic cells (MDC) in order to develop a rapid, sensitive method for quantifying antigen-specific CD8 T cells present at low frequency in peripheral blood. Design Peripheral blood mononuclear cells (PBMC) were obtained from seven HIV-1-positive individuals with low to moderate CD8 T cell responses, including five on highly active antiretroviral therapy (HAART). IFN-γ ELISPOT assays were performed using either monocytes or MDC to present antigens expressed by recombinant vaccinia viruses (r-VV). Methods Peripheral blood-derived monocytes were cultured for 5–6 days in the presence of IL-4 and granulocyte macrophage colony-stimulating factor, then matured in monocyte-conditioned medium. MDC were infected with r-VV and co-cultured in an ELISPOT assay with autologous monocyte-depleted PBMC. Results Relative to autologous monocytes, MDC amplified detection of antigen-specific CD8 T cells by 2–30-fold in response to antigens from HIV-1, Epstein–Barr virus and cytomegalovirus. Furthermore, antigenic specificities were revealed that had not been detected using standard ELISPOT of PBMC. Conclusion This assay will prove useful for the detection of memory T cells present at low frequency, and may be of interest for identifying subdominant cytotoxic T lymphocyte epitopes. This method may have broad applications for the detection of antiviral CD8 T cell responses in patient populations in whom such responses have been difficult to detect, including HIV-1-seropositive individuals with advanced disease or undergoing HAART.
The Krüppel-like factor 9 ( KLF 9 ) network in HEC-1-A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF 9 expression

Background: Krüppel-like factor 9 (KLF9) is a transcriptional regulator of uterine endometrial cell proliferation, adhesion and differentiation; processes essential for pregnancy success and which are subverted during tumorigenesis. The network of endometrial genes controlled by KLF9 is largely unknown. Over-expression of KLF9 in the human endometrial cancer cell line HEC-1-A alters cell morphology, proliferative indices, and differentiation, when compared to KLF9 under-expressing HEC-1A cells. This cell line provides a unique model for identifying KLF9 downstream gene targets and signaling pathways. Methods: HEC-1-A sub-lines differing in relative levels of KLF9 were subjected to microarray analysis to identify differentially-regulated RNAs. Results: KLF9 under-expression induced twenty four genes. The KLF9-suppressed mRNAs encode protein participants in: aldehyde metabolism (AKR7A2, ALDH1A1); regulation of the actin cytoskeleton and cell motility (e.g., ANK3, ITGB8); cellular detoxification (SULT1A1, ABCC4); cellular signaling (e.g., ACBD3, FZD5, RAB25, CALB1); and transcriptional regulation (PAX2, STAT1). Sixty mRNAs were more abundant in KLF9 over-expressing sub-lines. The KLF9-induced mRNAs encode proteins which participate in: regulation and function of the actin cytoskeleton (COTL1, FSCN1, FXYD5, MYO10); cell adhesion, extracellular matrix and basement membrane formation (e.g., AMIGO2, COL4A1, COL4A2, LAMC2, NID2); transport (CLIC4); cellular signaling (e.g., BCAR3, MAPKAPK3); transcriptional regulation [e.g., KLF4, NR3C1 (glucocorticoid receptor), RXRα], growth factor/cytokine actions (SLPI, BDNF); and membrane-associated proteins and receptors (e.g., CXCR4, PTCH1). In addition, the abundance of mRNAs that encode hypothetical proteins (KLF9-inhibited: C12orf29 and C1orf186; KLF9-induced: C10orf38 and C9orf167) were altered by KLF9 expression. Human endometrial tumors of high tumor grade had decreased KLF9 mRNA abundance. Conclusion: KLF9 influences the expression of uterine epithelial genes through mechanisms likely involving its transcriptional activator and repressor functions and which may underlie altered tumor biology with aberrant KLF9 expression. Published: 10 September 2008 Reproductive Biology and Endocrinology 2008, 6:41 doi:10.1186/1477-7827-6-41 Received: 23 June 2008 Accepted: 10 September 2008 This article is available from: http://www.rbej. com/content/6/1/41 © 2008 Simmen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Threshold-Type Dose Response for Induction of Neoplastic Transformation by 1 GeV/nucleon Iron Ions

Abstract Elmore, E. , Lao, X-Y. , Kapadia, R. and Redpath, J. L. Threshold-Type Dose Response for Induction of Neoplastic Transformation by 1 GeV/nucleon Iron Ions. Radiat. Res. 171, 764ndash;770 (2009). Neoplastic transformation of HeLa × skin fibroblast human hybrid cells by doses of 1 GeV/nucleon iron ions in the range 1 cGy to 1 Gy to exposed cultures has been examined. The data indicate a threshold-type dose–response curve with no increase in transformation frequency until doses above 20 cGy. At doses <10 cGy, not all exposed cells receive a direct traversal of an iron-ion track core, but all exposed cells receive up to several mGy of low-LET radiation associated with the δ-ray penumbra. It is proposed that the threshold-type response seen is a consequence of an adaptive response associated with the δ-ray exposure. For comparison purposes, the dose response for 137Cs γ rays over the same dose range was examined using the same experimental procedure. As we have shown previously, the dose response for 137Cs γ radiation was J-shaped. The iron ions were 1.5 to 1.7 times more biologically effective than the γ radiation over the dose range examined.