Miracle-dz/UniFAR-FTUs huggingface dataset:
Allele-Specific Droplet Digital PCR Combined with a Next-Generation Sequencing-Based Algorithm for Diagnostic Copy Number Analysis in Genes with High Homology: Proof of Concept Using Stereocilin.

BACKGROUND Copy number variants (CNVs) can substantially contribute to the pathogenic variant spectrum in several disease genes. The detection of this type of variant is complicated in genes with high homology to other genomic sequences, yet such genomics regions are more likely to lead to CNVs, making it critical to address detection in these settings. METHODS We developed a copy number analysis approach for high homology genes/regions that consisted of next-generation sequencing (NGS)-based dosage analysis accompanied by allele-specific droplet digital PCR (ddPCR) confirmatory testing. We applied this approach to copy number analysis in STRC, a gene with 98.9% homology to a nonfunctional pseudogene, pSTRC, and characterized its accuracy in detecting different copy number states by use of known samples. RESULTS Using a cohort of 517 patients with hearing loss, we prospectively demonstrated the clinical utility of the approach, which contributed 30 of the 122 total positives (6%) to the diagnostic yield, increasing the overall yield from 17.6% to 23.6%. Positive STRC genotypes included homozygous (n = 15) or compound heterozygous (n = 8) deletions, or heterozygous deletions in trans with pathogenic sequence variants (n = 7). Finally, this approach limited ddPCR testing to cases with NGS copy number findings, thus markedly reducing the number of costly and laborious, albeit specific, ddPCR tests. CONCLUSIONS NGS-based CNV detection followed by allele-specific ddPCR confirmatory testing is a reliable and affordable approach for copy number analysis in medically relevant genes with homology issues.
Adaptation and implementation of family-based treatment enhanced with dialectical behavior therapy skills for anorexia nervosa in community-based specialist clinics

ABSTRACT Although family-based therapy (FBT) is a well-established treatment for anorexia nervosa, its implementation and effectiveness in clinical settings has been neglected. A group of seven therapists at a community-based eating disorders clinic were trained in skills-enhanced FBT and provided treatment to 11 youth with anorexia nervosa. Family-based skills training, which borrowed heavily from dialectical behavior therapy, was introduced in four additional sessions and then integrated throughout the remainder of FBT. FBT was perceived as appropriate and acceptable by all participants. Therapists reported high treatment fidelity. There was a large improvement in weight and moderate improvement in caregiver-reported eating disorder psychopathology but no clinically significant change by youth report. This study provides preliminary data on the implementation and effectiveness of FBT in the community.
Individual differences in rhesus monkeys' demand for drugs of abuse

A relatively small percentage of humans who are exposed to drugs of abuse eventually become addicted to or dependent on those drugs. These individual differences in likelihood of developing drug addiction may reflect behavioral, neurobiological or genetic correlates of drug addiction and are therefore important to model. Behavioral economic measures of demand establish functions whose overall elasticity (rate of decrease in consumption as price increases) reflects the reinforcing effectiveness of various stimuli, including drugs. Using these demand functions, we determined the reinforcing effectiveness of five drugs of abuse (cocaine, remifentanil, ketamine, methohexital and ethanol) in 10 rhesus monkeys with histories of intravenous drug‐taking. There was a continuum of reinforcing effectiveness across the five drugs, with cocaine and remifentanil showing the most reinforcing effectiveness. There was also a continuum of sensitivity of the monkeys; two of the 10 animals, in particular, showed greater demand for the drugs than did the remaining eight monkeys. In addition, monkeys that demonstrated greater demand for one drug tended to show greater demand for all drugs but did not show a similar relatively greater demand for sucrose pellets. These findings suggest that the tendency to find drugs to be reinforcing is a general one, not restricted to particular drugs and also, that a minority of animals show a substantially enhanced sensitivity to the reinforcing effects of drugs. The possibility that differences in responsiveness to the reinforcing effects of drugs may form the basis of individual differences in drug‐taking in humans should be considered.
Cost-effectiveness of a voucher-based intervention for smoking cessation

ABSTRACT Background: Contingency management (CM) has been shown to be effective in reducing smoking consumption, but has traditionally been criticized for its costs. Objectives: This study assessed the cost-effectiveness of using a voucher-based CM protocol added to a cognitive behavioral treatment (CBT) for smoking cessation among treatment-seeking patients from the general population. Methods: A total of 92 patients were randomly assigned to CBT or CBT plus CM for abstinence. Incremental cost-effectiveness ratios (ICERs) were calculated by dividing the increase in costs by the increase in effects (continuous abstinence, longest duration of abstinence at 6-month follow-up and cotinine results during the treatment). An acceptability curve illustrated the statistical uncertainty surrounding the cost-effectiveness estimate. We also determined the optimum cost per participant for predicting the smoking status at 6-month follow-up. Results: The average cost per participant in the CBT condition was €138.73 (US$ 150.23) as opposed to €411.61 (US$ 445.73) in the CBT plus CM condition (p < 0.01). The incremental cost of using voucher-based CM to increase the number of participants that maintained abstinence at 6-month follow-up by one extra participant was €68.22 (US$ 73.88), and to lengthen the longest duration of abstinence by 1 week was €53.92 (US$ 58.39). The incremental cost to obtain an extra cotinine-negative result was €181.90 (US$ 196.98). Conclusion: Compared with CBT alone, the voucher-based protocol required additional costs but achieved significantly better outcomes. These results will allow stakeholders to make policy decisions about CM implementation for smoking cessation in the broader community.
Auger-Stirring Wet and Dry Corn—Airflow Resistance and Bulk Density Effects

ABSTRACT EIGHT tests were carried out to define effects of auger stirring on the airflow resistance and bulk density of wet and dry shelled corn placed in a bin by gravity or by spreader. Stirring decreased bulk density of corn placed with a spreader, but increased or left unchanged the bulk density of gravity-placed corn.
Prognostic awareness and communication preferences among caregivers of patients with malignant glioma

Malignant glioma (MG) is a devastating neuro‐oncologic disease with almost invariably poor prognosis, yet many families facing malignant glioma have poor prognostic awareness (PA), or the awareness of the patient's incurable disease and shortened life expectancy. Accurate PA is associated with favorable medical outcomes at end‐of‐life for patients and psychosocial outcomes for informal caregivers (ICs) through bereavement. To date, however, no study has specifically examined PA among MG ICs and the information they receive that shapes their awareness.
Chapter 11 Structural Biology of Replication Initiation Factor Mcm 10

S. MacNeill (ed.), The Eukaryotic Replisome: A Guide to Protein Structure and Function, Subcellular Biochemistry 62, DOI 10.1007/978-94-007-4572-8_11, © Springer Science+Business Media Dordrecht 2012 Abstract Minichromosome maintenance protein 10 (Mcm10) is a non-enzymatic replication factor required for proper assembly of the eukaryotic replication fork. Mcm10 interacts with single-stranded and double-stranded DNA, DNA polymerase a and Mcm2-7, and is important for activation of the pre-replicative complex and recruitment of subsequent proteins to the origin at the onset of S-phase. In addition, Mcm10 has recently been implicated in coordination of helicase and polymerase activities during replication fork progression. The nature of Mcm10’s involvement in these activities, whether direct or indirect, remains unknown. However, recent biochemical and structural characterization of Mcm10 from multiple organisms has provided insights into how Mcm10 utilizes a modular architecture to act as a replisome scaffold, which helps to de fi ne possible roles in origin DNA melting, Pol a recruitment and coordination of enzymatic activities during elongation.
Autoimmune-Disease-Prone NOD Mice Help To Reveal a New Genetic Locus for Reducing Pulmonary Disease Caused by Mycoplasma pulmonis

ABSTRACT Mycoplasmas are bacterial pathogens of a range of animals, including humans, and are a common cause of respiratory disease. However, the host genetic factors that affect resistance to infection or regulate the resulting pulmonary inflammation are not well defined. We and others have previously demonstrated that nonobese diabetic (NOD) mice can be used to investigate disease loci that affect bacterial infection and autoimmune diabetes. Here we show that NOD mice are more susceptible than C57BL/6 (B6) mice to infection with Mycoplasma pulmonis, a natural model of pulmonary mycoplasmosis. The lungs of infected NOD mice had higher loads of M. pulmonis and more severe inflammatory lesions. Moreover, congenic NOD mice that harbored different B6-derived chromosomal intervals enabled identification and localization of a new mycoplasmosis locus, termed Mpr2, on chromosome 13. These congenic NOD mice demonstrated that the B6 allele for Mpr2 reduced the severity of pulmonary inflammation caused by infection with M. pulmonis and that this was associated with altered cytokine and chemokine concentrations in the infected lungs. Mpr2 also colocalizes to the same genomic interval as Listr2 and Idd14, genetic loci linked to listeriosis resistance and autoimmune diabetes susceptibility, respectively, suggesting that allelic variation within these loci may affect the development of both infectious and autoimmune disease.
Mouse model for acute Epstein–Barr virus infection

Significance Epstein–Barr Virus infects human B cells and drives them into proliferation and transformation. Although more than 90% of the human population is EBV-infected, EBV-driven pathologies including B-cell lymphomas are limited by a potent T-cell immune response. Here, we present a mouse model for acute EBV infection through conditional expression of two key EBV proteins, LMP1 and LMP2A. This model reproduces EBV-driven B-cell expansion, T-cell–mediated immune surveillance of EBV-infected B cells, and fatal lymphoproliferative disease when the T-cell response is compromised as in immunosuppressed or genetically impaired patients. It thus allows one to study EBV–host interaction functionally and from an angle that should help to develop new therapies for EBV-driven hematological diseases. Epstein–Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMP-expressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.
Microstructural Analysis of Austempered Ductile Iron Castings

Austempered ductile iron (ADI) castings have a wide range of application areas in engineering designs due to its promising mechanical properties and lower cost. ADI has very good strength and toughness values at the same time its ductility is relatively high compared to most of the other cast irons. These promising mechanical properties originate from combination of specific graphite and matrix microstructure. The size, shape and fraction of graphite as well as the matrix microstructure influences the mechanical properties. In this paper the efforts regarding to a localization project of ADI is presented. In a more detailed manner, the first locally produced ADI which cannot satisfy the mechanical properties stated in ISO 17804 is compared with the original sample which is conform with the standard. The two pieces are inspected by mechanically and microstructurally by means of which necessary actions are detected for the local production. In other words the relation between the macro mechanical properties and the microstructural conditions are tried to be clarified. Keywords: Austempered ductile iron; Mechanical properties; Microstructure; Graphite Nodularity DOI: 10.17350/HJSE19030000029 Full Text:
Co-option of bacteriophage lysozyme genes by bivalve genomes

Eukaryotes have occasionally acquired genetic material through horizontal gene transfer (HGT). However, little is known about the evolutionary and functional significance of such acquisitions. Lysozymes are ubiquitous enzymes that degrade bacterial cell walls. Here, we provide evidence that two subclasses of bivalves (Heterodonta and Palaeoheterodonta) acquired a lysozyme gene via HGT, building on earlier findings. Phylogenetic analyses place the bivalve lysozyme genes within the clade of bacteriophage lysozyme genes, indicating that the bivalves acquired the phage-type lysozyme genes from bacteriophages, either directly or through intermediate hosts. These bivalve lysozyme genes underwent dramatic structural changes after their co-option, including intron gain and fusion with other genes. Moreover, evidence suggests that recurrent gene duplication occurred in the bivalve lysozyme genes. Finally, we show the co-opted lysozymes exhibit a capacity for antibacterial action, potentially augmenting the immune function of related bivalves. This represents an intriguing evolutionary strategy in the eukaryote–microbe arms race, in which the genetic materials of bacteriophages are co-opted by eukaryotes, and then used by eukaryotes to combat bacteria, using a shared weapon against a common enemy.
Gene expression analysis: Regulation of key genes associated with mycophenolate mofetil treatment of symptomatic carotid artery stenosis

The present study analyzed gene expression arrays to identify differentially-expressed genes (DEGs) between mycophenolate mofetil (MMF)-treated and placebo-treated patients with symptomatic carotid artery stenosis (SCAS). In addition, the key genes involved in the pharmacology of MMF treatment in patients with SCAS were identified. The gene expression dataset was obtained from a Gene Expression Omnibus database, which included 9 MMF-treated and 11 placebo-treated samples. The DEGs were identified between MMF and placebo groups using R software. Furthermore, a protein-protein interaction (PPI) network of the identified DEGS was constructed. The Database for Annotation, Visualization and Integrated Discovery was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the 19 most significant DEGs. A total of 210 DEGs between the MMF and placebo groups were screened and their PPI was constructed. GO function analysis revealed that the 19 DEGs were predominantly involved in the tyrosine phosphorylation of signal transducer and activator of transcription-5 protein, which is closely associated with the activation of T cells. The KEGG pathway analysis suggested that the main metabolic pathways of the 19 DEGs were associated with the pharmacological functioning of MMF in activated T cells. In conclusion, the present study identified numerous key DEGs associated with SCAS, and the results suggested that v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog and apelin may serve important roles in the MMF treatment of SCAS.
Numerical Calculation of Rotation Effects on Hybrid Air Journal Bearings

ABSTRACT Hybrid air journal bearings are of great importance in the precision engineering. Despite much progress, the influence of the aerostatic effect and the aerodynamic effect on the bearings is still not clear. Numerical calculation is a useful technique to evaluate bearing performance. Many theoretical problems related to Reynolds equation have been figured out by numerical simulation. The present study analyzes the effects of rotational speed—that is, the bearing speed number—on the performance of hybrid bearings. The behaviors of the pure aerostatic bearing and the pure aerodynamic bearing are investigated for comparison. The second-order finite difference method (FDM) and an iterative procedure are proposed to solve the Reynolds equation and derive the air film pressure distribution. The bearing characteristics such as load capacity, stiffness, friction coefficient, attitude angle, and mass inflow rate are taken into consideration. The research reveals the very dependence of the hybrid bearing's performance on the journal rotation and eccentricity ratio. The numerical results indicate that at a small bearing speed number of 0.223 and eccentricity ratio of 0.15, about 99.8% of the load capacity and 99.7% of the stiffness are determined by the aerostatic effect, whereas at a large bearing speed number of 2.229 and eccentricity ratio of 0.55, about 63.2% of the load capacity and 83.3% of the stiffness are determined by the aerodynamic effect.
Finding the Value of Minimally Invasive Gynecologic Surgery

Minimally invasive surgery is indistinctly defined and some cases possess clinical outcomes that are similarly indistinct or excessively costly. Seeking to clarify these issues will offer organized medicine an opportunity to deliver value-based health care. Context (patient, society, and clinician) is critical to finding that clarity, although the clinician context likely offers the best insights into how the ideal of high-value care may be incorporated into minimally invasive gynecologic surgery.
Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance.

Conduction at the Purkinje-ventricular junction (PVJ) demonstrates unidirectional block under both physiological and pathophysiological conditions. Although this block is typically attributed to multidimensional electrotonic interactions, we examined possible membrane-level contributions using single, isolated rabbit Purkinje (P) and ventricular (V) myocytes coupled by an electronic circuit. When we varied the junctional resistance ( R j) between paired V myocytes, conduction block occurred at lower R j values during conduction from the smaller to larger myocyte (115 ± 59 MΩ) than from the larger to smaller myocyte (201 ± 51 MΩ). In Purkinje-ventricular myocyte pairs, however, block occurred at lower R j values during P-to-V conduction (85 ± 39 MΩ) than during V-to-P conduction (912 ± 175 MΩ), although there was little difference in the mean cell size. Companion computer simulations, performed to examine how the early plateau currents affected conduction, showed that P-to-V block occurred at lower R j values when the transient outward current was increased or the calcium current was decreased in the model P cell. These results suggest that intrinsic differences in phase 1 repolarization can contribute to unidirectional block at the PVJ.
Integrating Clipped Spherical Harmonics Expansions

Many applications in rendering rely on integrating functions over spherical polygons. We present a new numerical solution for computing the integral of spherical harmonics (SH) expansions clipped to polygonal domains. Our solution, based on zonal decompositions of spherical integrands and discrete contour integration, introduces an important numerical operating for SH expansions in rendering applications. Our method is simple, efficient, and scales linearly in the bandlimited integrand’s harmonic expansion. We apply our technique to problems in rendering, including surface and volume shading, hierarchical product importance sampling, and fast basis projection for interactive rendering. Moreover, we show how to handle general, nonpolynomial integrands in a Monte Carlo setting using control variates. Our technique computes the integral of bandlimited spherical functions with performance competitive to (or faster than) more general numerical integration methods for a broad class of problems, both in offline and interactive rendering contexts. Our implementation is simple, relying only on self-contained SH evaluation and discrete contour integration routines, and we release a full source CPU-only and shader-based implementations (<750 lines of commented code).
Bacterial gene control by DNA looping using engineered dimeric transcription activator like effector (TALE) proteins

Abstract Genetic switches must alternate between states whose probabilities are dependent on regulatory signals. Classical examples of transcriptional control in bacteria depend on repressive DNA loops anchored by proteins whose structures are sensitive to small molecule inducers or co-repressors. We are interested in exploiting these natural principles to engineer artificial switches for transcriptional control of bacterial genes. Here, we implement designed homodimeric DNA looping proteins (‘Transcription Activator-Like Effector Dimers’; TALEDs) for this purpose in living bacteria. Using well-studied FKBP dimerization domains, we build switches that mimic regulatory characteristics of classical Escherichia coli lactose, galactose and tryptophan operon promoters, including induction or co-repression by small molecules. Engineered DNA looping using TALEDs is thus a new approach to tuning gene expression in bacteria. Similar principles may also be applicable for gene control in eukaryotes.