Miracle-dz/UniFAR-FTUs huggingface dataset:
Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide.

BACKGROUND Glioma stem cells (GSCs) from human glioblastomas (GBMs) are resistant to radiation and chemotherapy and may drive recurrence. Treatment efficacy may depend on GSCs, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype. METHODS To model genetic alterations in human GBM core signaling pathways, we induced Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Neurosphere culture, differentiation, and orthotopic transplantation assays were used to assess whether these mutations induced de-differentiation into GSCs. Genome-wide chromatin landscape alterations and expression profiles were examined by formaldehyde-assisted isolation of regulatory elements (FAIRE) seq and RNA-seq. Radiation and temozolomide efficacy were examined in vitro and in an allograft model in vivo. Effects of radiation on transcriptome subtype were examined by microarray expression profiling. RESULTS Cultured triple mutant astrocytes gained unlimited self-renewal and multilineage differentiation capacity. These cells harbored significantly altered chromatin landscapes that were associated with downregulation of astrocyte- and upregulation of stem cell-associated genes, particularly the Hoxa locus of embryonic transcription factors. Triple-mutant astrocytes formed serially transplantable glioblastoma allografts that were sensitive to radiation but expressed MGMT and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of GBM allografts from proneural to mesenchymal. CONCLUSION A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into GSCs with altered chromatin landscapes and transcriptomes. This non-germline genetically engineered mouse model mimics human proneural GBM on histopathological, molecular, and treatment response levels. It may be useful for dissecting the mechanisms of treatment resistance and developing more effective therapies.
Reoperation Versus Clinical Recurrence Rate After Ventral Hernia Repair

Objective:To compare the clinical recurrence rate with reoperation rate for recurrence after ventral hernia repair. Background:Reoperation is often used as an outcome measure after ventral hernia repair, but it is unknown whether reoperation rate reflects the overall clinical risk for recurrence. Methods:The study cohort was recruited from the Danish Ventral Hernia Database and the Danish National Patient Registry during January 1, 2007, to December 31, 2007. Inclusion criteria were primary umbilical/epigastric (umb/epi) or incisional hernia repair from a regional area of 2 million inhabitants. A prospective clinical follow-up was conducted in January 2011 using a validated questionnaire on reoperation and possible recurrence. Suspicion of recurrence was the criterion for clinical examination. A telephone interview and/or patients' hospital files confirmed reoperation. Results:A total of 945 patients were eligible, and 902 patients responded to the questionnaire (response rate 95%) with a median postoperative follow-up of 41 months (range 0–48 months). The analysis comprised 646 patients with umb/epi and 256 patients with incisional hernia repair. Clinical examination was required in 241 patients. After umb/epi and incisional hernia repair, the cumulative risks of reoperation and overall recurrence (reoperation + clinical) were 4% and 15% (fourfold underestimation), and 8% and 37% (fivefold underestimation) (P < 0.001), respectively. Conclusions:Reoperation rate for recurrence 41 months after primary umbilical/epigastric or incisional hernia repair underestimated overall risk of recurrence by four- to fivefolds. This study was registered in www.clinicaltrials. gov (NCT01325246).
Leiomodins: larger members of the tropomodulin (Tmod) gene family.

The 64-kDa autoantigen D1 or 1D, first identified as a potential autoantigen in Graves' disease, is similar to the tropomodulin (Tmod) family of actin filament pointed end-capping proteins. A novel gene with significant similarity to the 64-kDa human autoantigen D1 has been cloned from both humans and mice, and the genomic sequences of both genes have been identified. These genes form a subfamily closely related to the Tmods and are here named the Leiomodins (Lmods). Both Lmod genes display a conserved intron-exon structure, as do three Tmod genes, but the intron-exon structure of the Lmods and the Tmods is divergent. mRNA expression analysis indicates that the gene formerly known as the 64-kDa autoantigen D1 is most highly expressed in a variety of human tissues that contain smooth muscle, earning it the name smooth muscle Leiomodin (SM-Lmod; HGMW-approved symbol LMOD1). Transcripts encoding the novel Lmod gene are present exclusively in fetal and adult heart and adult skeletal muscle, and it is here named cardiac Leiomodin (C-Lmod; HGMW-approved symbol LMOD2). Human C-Lmod is located near the hypertrophic cardiomyopathy locus CMH6 on human chromosome 7q3, potentially implicating it in this disease. Our data demonstrate that the Lmods are evolutionarily related and display tissue-specific patterns of expression distinct from, but overlapping with, the expression of Tmod isoforms.
Timing constraints and symbolic execution for a hybrid synchronous language

Recent work in the Inria/ENS team Parkas, in collaboration with Esterel Technologies, the developers of Scade, has resulted in a compiler for a language called Zélus that combines discrete Lustre-like programs [7] with continuous dynamics modelled as Ordinary Differential Equations (ODEs) with resets. Such hybrid systems modellers are used not only in the highlevel design and simulation of complex embedded systems, but also as development platforms in which the same source is used for formal verification, testing, simulation, and the generation of target executables. The quintessential example is the Simulink/Stateflow1 suite which is widely used in Industry. Zélus is distinguished by a novel type system [3], a completely integrated treatment of both discrete and continuous automata [4], and a semantic theory based on non-standard analysis [5]. A compiler [6] and example programs are available at http://zelus.di. ens.fr. An ODE with reset is written in Zélus as an equation:
Structure prediction of stem bromelain from pineapples (Ananas comosus) using procaricain enzyme as a modelling template

Bromelain is a general name for a family of sulfhydryl that can be found in the proteolytic enzyme group from pineapples (Ananas Comosus). In this study focuses on the prediction of three dimensional structure (3D) of bromelain using homology modelling by MODELLER. The amino acid sequence of bromelain was obtained from the NCBI database and the analysis was done using various bioinformatics tools. 1PCI was used as the target templates for bromelain structure prediction. The 1PCI was found to be the most suitable template for the prediction of the bromelain structure.
Characterization of the pelL gene encoding a novel pectate lyase of Erwinia chrysanthemi 3937

Erwinia chrysanthemi 3937 secretes five major isoenzymes of pectate lyases encoded by the pelA, pelB, pelC, pelD and pelE genes. Recently, a new set of pectate lyases was identified in E. chrysanthemi mutants deleted of those pel genes. We cloned the pelL gene, encoding one of these secondary pectate lyases of E. chrysanthemi 3937, from a genomic bank of a strain deleted of the five major pel genes. The nucleotide sequence of the region containing the pelL gene was determined. The pelL reading frame is 1275 bases long, corresponding to a protein of 425 amino acids including a typical amino‐terminal signal sequence of 25 amino acids. Comparison of the amino acid sequences of PelL and the exo‐pectate lyase PelX of E. chrysanthemi EC16 revealed a low homology, limited to 220 residues of the central part of the proteins. No homology was detected with other bacterial pectinolytic enzymes. Regulation of pelL transcription was analysed using gene fusion. As shown for the other pel genes, the transcription of pelL is dependent on various environmental conditions. It is induced by pectic catabolic products and affected by growth phase, temperature, iron starvation, osmolarity, anaerobiosis, nitrogen starvation and catabolite repression. Regulation of pelL expression appeared to be independent of the KdgR repressor, which controls all the steps of pectin catabolism. In contrast, the pecS gene, which is involved in regulation of the synthesis of the major pectate lyases and of cellulase, also appeared to be involved in pelL expression. The PelL protein is able to macerate plant tissue. This enzyme has a basic isoelectric point, presents an endo‐cleaving activity on polygalacturonate or partially methylated pectin, with a basic pH optimum and an absolute requirement for Ca2+. The pelL mutant displayed a reduced virulence on potato tubers and Saintpaulia ionantha plants, demonstrating the important role of this enzyme in soft‐rot disease.
Deep Brain Stimulation of the Medial Forebrain Bundle in a Patient with Treatment-Resistant Bipolar Depression and Comorbid OCD: Acute and 12-Month Follow-Up Results

Limited but encouraging evidence exists on the efficacy of Deep Brain Stimulation (DBS) of the Medial Forebrain Bundle (MBF) in otherwise intractable patients with Major Depressive and Obsessive-Compulsive Disorder (OCD). Subject and Methods: Herein, we present acute and follow-up results (up to 12-months) of the first Italian patient, a 34 year old man with a diagnosis of treatment-resistant Bipolar Depression (BD) and comorbid OCD, successfully treated with DBS of the MFB. Periodic follow-up visits with psychometric evaluations highlighted a remarkable improvement of patient’s depressive and OC symptoms at 3 months (50-80% scores reduction), that was maintained at 6 and 12 months. In particular, suicidal ideation, which was found to be pervasive before the implant as well as patient’s overall disability, showed a rapid and significant acute response to DBS. Over the 12 months of stimulation, pre-implant pharmacological treatment could be gradually decreased, while the patient remained clinically stable. According to the limited, reported experience, we support the efficacy and tolerability of DBS of the MFB as a promising intervention in patients with treatment-resistant BD and comorbid OCD, particularly in relation to acute and post-acute outcome. Larger controlled trials are needed to confirm our findings and assess DBS therapeutic properties in the long-term.
Quality of Life in Australian Adults Aged 50 Years and Over: Data Using the Schedule for the Evaluation of Individual Quality of Life (SEIQOL-DW)

ABSTRACT Objectives: This study explored unique and personal domains associated with quality of life (QOL) in 153 mid-aged and older Australian adults over age 50, using an innovative measure of individualized QOL, the Schedule for the Evaluation of Individual Quality of Life (SEIQOL-DW). Methods: Demographic measures as well as the SEIQOL-DW were administered. The qualitative responses on this scale were analyzed by Leximancer, a text analysis program that extracts semantic meaning and relational information automatically from text. Results: For the sample as a whole, the most important QOL domain was found to be Relationships, followed by Family, Health, Activities, Community, Security, Beliefs, Independence and finally Wellbeing. When the sample was broken down into age bands for analysis, the most important domain theme was Family (50–59 year olds), Relationships (60–69 year olds), Relationships (70–79 year olds), and Health (80+ year olds). Conclusions: The wide range of concepts elicited in each domain via Leximancer underscores the argument for analyzing QOL in an individualized way, as it was clear from these concepts that different domains had unique meanings to each person. Clinical Implications: Understanding QOL at the level of which domains in an individual are important to QOL in later life is critical to providing services to both healthy aged as well as those with health and mental health needs. The SEIQOL-DW affords clinicians a unique tool with which to describe an individual’s unique and relevant quality of life areas, and affords a way to measure change in these areas as a result of interventions.
Simvastatin therapy decreases MMP‐9 levels in obese women

Statins exert cholesterol‐independent beneficial effects on multiple targets including the cardiovascular system, in addition to modulating matrix metalloproteinases (MMPs) expression. The purpose of this study was to assess the effects of simvastatin treatment in obese women without comorbidities. We recruited 33 obese women that received placebo or simvastatin at 20 mg/day for 45 days. Plasma MMP‐9, MMP‐2, TIMP‐1, and TIMP‐2 levels were measured using an enzyme‐linked immunosorbent assay (ELISA). Cardiovascular risk was assessed by the Framingham risk score and Castelli indexes I and II. Treatment with simvastatin significantly reduced MMP‐9 levels and the MMP‐9/TIMP‐1 ratio (P < .05) when compared to the placebo group (P > .05). Conversely, we found no effect on MMP‐2, TIMP‐1, and TIMP‐2 levels or on the MMP‐2/TIMP‐2 ratio (P > .05). The Framingham risk score and Castelli I and II indexes were significantly reduced in the simvastatin‐treatment group (P < .05), while we found no effect on the placebo group. These findings may have clinical importance since simvastatin therapy reduced cardiovascular risk and MMP‐9 levels in obese woman without comorbidities, indicating a potentially new therapeutic approach.
Development of the peripheral trigeminal system in the chick revealed by an isotype‐specific anti‐beta‐tubulin monoclonal antibody

Using a monoclonal antibody directed against a class III β‐tubulin isotype, cβ4, we studied the time course of the expression of this protein, the morphological differentiation of the immunoreactive cells, and the time course of peripheral axon outgrowth in the chick trigeminal (V) system. The neural crest precursors of the V ganglion neurons do not express the antigen until they begin to differentiate as neurons. The placodal precursors of the V ganglion neurons express the antigen while they still are cuboidal epithelial cells. They continue to be immunoreactive as they migrate from the placode and settle in the ganglion, prior to sprouting axons. The V motoneurons express the antigen near the time of their terminal mitotic division. Using this antibody to visualize axons, we demonstrate that both ganglionic and motoneuron axons grow out as individual fibers, much like pioneer axons. Both halt their extension for several hours once they attain the vicinity of their targets. During this pause many other axons join the nerve bundles. Finally, single pioneer axons split from the main trunk to begin local target innervation.
Automated de novo sequencing of proteins using the differential scanning technique

Despite the progress in genomic DNA sequencing de novo sequencing of peptides is still required in a biological research environment since many experiments are done in organisms whose genomes are not sequenced. A way to unambiguously retrieve a peptide sequence from a tandem mass spectrum is to assign the correct ion type to the fragments. Here we describe a method which improves the specificity in y‐ion assignment throughout the spectrum. The differential scanning technique requires that the peptides are partially 18O labelled at their C‐terminus and that two fragment spectra are acquired for each peptide, one selecting the 16O/18O isotopic cluster and a second fragmenting only the 18O labelled ions. When the spectra are acquired with a quadrupole time of flight mass spectrometer y‐ions can be very specifically filtered from the spectrum using a computer algorithm. Partial or complete peptide sequences can be assigned automatically simply by finding the most abundant series of fragments spaced by amino acid residue masses. This method was used extensively in a project investigating vesicular transport in bovine brain cells. Human or mouse homologues to the bovine proteins were found in EST databases facilitating rapid cloning of the human homologues.
Correlation of Perceived Nasality with the Acoustic Measures (One Third Octave Spectral Analysis & Voice Low Tone to High Tone Ratio)

Aim: The perceived hypernasality in speech can be evaluated using various qualitative and quantitative methods. The present study aimed to investigate, compare and correlate acoustic parameters one third octave spectra analysis and Voice Low Tone to High Tone Ratio (VLHR) with perceived nasality in children with repaired cleft lip and palate (RCLP) and in age and gender matched typically developing children (TDC). Methods: The study included 73 children (47 RCLP & 26 TDC) in the age range of four to twelve years. The spontaneous speech and sentences were recorded and analyzed for nasality using standardized perceptual four point rating scale. Based on the severity of perceived nasality children were divided into three groups namely normal, mild, and moderate to severe. The production of the vowel /a/ by participants was subjected to acoustic analysis using VLHR and One third octave spectra analysis using MATLAB software. Results: The results indicated significant differences in spectral amplitude measured using one third octave spectra analysis at high frequency region for the vowel /a/ between TDC & RCLP. The VLHR measures were not indicating statistically significant difference and relation with the perceived nasality. Conclusion: One third octave spectra analysis is an effective measure in differentiating the nasality and found to have a significant correlation with perceived nasality in children with RCLP. Hence, one third octave spectra analysis can augment the perceptual evaluation to provide additional information to arrive at a diagnosis.
In Saccharomyces cerevisiae a short amino acid sequence facilitates excretion in the growth medium of periplasmic proteins

In Saccharomyces cerevisiae the cell wall is a barrier to excretion of proteins in the growth medium. Although small proteins are more easily released than bigger ones, other factors besides molecular sieving may play a role in partitioning of periplasmic proteins. By using several complementary approaches including enzyme‐activity assays, quantitative immunoblotting on subcellular fractions and growth media, as well as a novel approach involving the use of flow cytometry and specific antibodies, we show that residues 1–8 of mature glucoamylase greatly enhance excretion of both glucoamylase and β‐galactosidase in vivo and facilitate extraction of periplasmic proteins in vitro. Immunological data obtained by flow cytometry on whole cells indicate that this amino acid sequence increases the fraction of enzyme reaching the outer cell‐wall layers. This amino acid sequence may define a novel type of topogenic sequence, facilitating the crossing of the yeast cell wall in vivo and facilitating extraction of periplasmic proteins by non‐disruptive means in vitro.
Heart rate asymmetry by Poincaré plots of RR intervals

Abstract The Poincaré plot is a widely used method for visualizing and calculating heart rate variability and for investigating the oscillatory nature of heart action. We show that the Poincaré plot produced using physiological data for RR intervals is asymmetric. This suggests that the processes of heart rate acceleration (shortening of consecutive RR intervals) and deceleration (prolongation of successive RR intervals) might be asymmetric. To investigate this phenomenon, we define descriptors quantifying the heart rate asymmetry and present the results of a study involving 5-min ECG recordings of 50 healthy subjects in which, despite of the shortness of the recordings, the asymmetry is clearly visible.
Spherical harmonic-generalized Laguerre pseudospectral method for three-dimensional exterior problems

In this paper, we develop the mixed pseudospectral method for three-dimensional exterior problems. Some basic results on the mixed spherical harmonic-generalized Laguerre interpolation are established, which play important roles in the related pseudospectral methods. As examples, we provide the mixed pseudospectral schemes for two exterior problems with convergence analysis. Numerical results demonstrate the efficiency of this approach.
Tripartite Chimeras Comprising Functional Domains Derived from the Cytosolic NADPH Oxidase Components p47phox, p67phox, and Rac1 Elicit Activator-independent Superoxide Production by Phagocyte Membranes

The superoxide-generating NADPH oxidase is converted to an active state by the assembly of a membrane-localized cytochrome b559 with three cytosolic components: p47phox, p67phox, and GTPase Rac1 or Rac2. Assembly involves two sets of protein-protein interactions: among cytosolic components and among cytosolic components and cytochrome b559 within its lipid habitat. We circumvented the need for interactions among cytosolic components by constructing a recombinant tripartite chimera (trimera) consisting of the Phox homology (PX) and Src homology 3 (SH3) domains of p47phox, the tetratricopeptide repeat and activation domains of p67phox, and full-length Rac1. Upon addition to phagocyte membrane, the trimera was capable of oxidase activation in vitro in the presence of an anionic amphiphile. The trimera had a higher affinity (lower EC50) for and formed a more stable complex (longer half-life) with cytochrome b559 compared with the combined individual components, full-length or truncated. Supplementation of membrane with anionic but not neutral phospholipids made activation by the trimera amphiphile-independent. Mutagenesis, truncations, and domain replacements revealed that oxidase activation by the trimera was dependent on the following interactions: 1) interaction with anionic membrane phospholipids via the poly-basic stretch at the C terminus of the Rac1 segment; 2) interaction with p22phox via Trp193 in the N-terminal SH3 domain of the p47phox segment, supplementing the electrostatic attraction; and 3) an intrachimeric bond among the p67phox and Rac1 segments complementary to their physical fusion. The PX domain of the p47phox segment and the insert domain of the Rac1 segment made only minor contributions to oxidase assembly.