Miracle-dz/UniFAR-FTUs huggingface dataset:
RNA editing alterations define manifestation of prion diseases

Significance Prion diseases are fatal neurodegenerative disorders characterized by rapidly progressive dementia. Sporadic Creutzfeldt–Jakob disease (sCJD) is the most prevalent. We report that, specific gene-expression alterations utilizing a reliable in vivo mouse model (tg340-PRNP129MM) with sCJD MM1 subtype, correlate with human disease manifestations in the brain cortex related to disease progression. RNA-editing functions mediated by the APOBEC and ADAR deaminases possibly affecting protein expression necessary for normal brain function, are altered in disease stages. Our data provide powerful evidence, derived from a humanized sCJD mouse model and human autopsy material, discerning the critical role of gene expression and RNA-editing signatures, introducing disease-associated targets that can be extrapolated in other neurodegenerative disorders with common clinical and molecular features. Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt–Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
Global Transcriptome and Co-Expression Network Analysis Reveal Contrasting Response of Japonica and Indica Rice Cultivar to γ Radiation

Japonica and indica are two important subspecies in cultivated Asian rice. Irradiation is a classical approach to induce mutations and create novel germplasm. However, little is known about the differential response between japonica and indica rice after γ radiation. Here, we utilized the RNA sequencing and Weighted Gene Co-expression Network Analysis (WGCNA) to compare the transcriptome differences between japonica Nipponbare (NPB) and indica Yangdao6 (YD6) in response to irradiation. Japonica subspecies are more sensitive to irradiation than the indica subspecies. Indica showed a higher seedling survival rate than japonica. Irradiation caused more extensive DNA damage in shoots than in roots, and the severity was higher in NPB than in YD6. GO and KEGG pathway analyses indicate that the core genes related to DNA repair and replication and cell proliferation are similarly regulated between the varieties, however the universal stress responsive genes show contrasting differential response patterns in japonica and indica. WGCNA identifies 37 co-expressing gene modules and ten candidate hub genes for each module. This provides novel evidence indicating that certain peripheral pathways may dominate the molecular networks in irradiation survival and suggests more potential target genes in breeding for universal stress tolerance in rice.
A 37-year Update on Mortality Patterns in an Expanded Cohort of Vermont Talc Miners and Millers.

OBJECTIVES The aim of this study was to update a cohort of Vermont talc workers to include 37 additional years of follow-up time. METHODS Standardized mortality ratios (SMR) and 95% confidence intervals (CIs) were calculated for 70+ causes of death. US population mortality rates were used as reference. RESULTS All-cause mortality was 30% higher than the US population (SMR 133.4, 95% CI, 119.7 to 148.3). Significant elevations occurred in nonmalignant respiratory disease (NMRD) (SMR 273.0, 95% CI, 210.2 to 348.6) and other nonmalignant respiratory disease (ONMRD) (SMR 413.1, 95% CI, 287.7 to 574.5). ONMRD was elevated across all length of employment categories and a test for linear trend was significant (P = 0.007). CONCLUSIONS This study provides further evidence that excess deaths among Vermont talc workers are due largely to excess mortality from NMRD; there is no evidence of increased risk of respiratory cancer.
Cuvette-Type LSPR Sensor for Highly Sensitive Detection of Melamine in Infant Formulas

The globalization of food distribution has made necessary to secure safe products to the general consumers through the rapid detection of harmful additives on the field. For this purpose, we developed a cuvette-type localized surface plasmon resonance (LSPR) sensor that can be easily used by consumers with conventional ultraviolet-visible light spectrophotometer for in-situ measurements. Gold nanoparticles were uniformly deposited on a transparent substrate via a self-assembly method to obtain a plasmonically active chip, and the chemical receptor p-nitroaniline (p-NA) was functionalized to stabilize the device sensitivity under external temperature and pH conditions. The fabricated chip was fixed onto a support and combined with a cuvette-type LSPR sensor. To evaluate the applicability of this sensor on the field, sensitivity and quantitative analysis experiments were conducted onto melamine as a model sample from harmful food additives. Under optimal reaction condition (2 mM p-NA for 20 min), we achieved an excellent detection limit (0.01 ppb) and a dynamic range allowing quantitative analysis over a wide concentration range (0.1–1000 ppb) from commercially available milk powder samples.
Metabolism of Strained Rings: Glutathione S-transferase–Catalyzed Formation of a Glutathione-Conjugated Spiro-azetidine without Prior Bioactivation

AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] is a melanin-concentrating hormone receptor 1 antagonist designed for the treatment of obesity. In this study, metabolite profiles of AZD1979 in human hepatocytes revealed a series of glutathione-related metabolites, including the glutathionyl, cysteinyl, cysteinylglycinyl, and mercapturic acid conjugates. The formation of these metabolites was not inhibited by coincubation with the cytochrome P450 (P450) inhibitor 1-aminobenzotriazole. In efforts to identify the mechanistic features of this pathway, investigations were performed to characterize the structure of the glutathionyl conjugate M12 of AZD1979 and to identify the enzyme system catalyzing its formation. Studies with various human liver subcellular fractions established that the formation of M12 was NAD(P)H-independent and proceeded in cytosol and S9 fractions but not in microsomal or mitochondrial fractions. The formation of M12 was inhibited by ethacrynic acid, an inhibitor of glutathione S-transferases (GSTs). Several human recombinant GSTs, including GSTA1, A2-2, M1a, M2-2, T1-1, and GST from human placenta, were incubated with AZD1979. All GSTs tested catalyzed the formation of M12, with GSTA2-2 being the most efficient. Metabolite M12 was purified from rat liver S9 incubations and its structure elucidated by NMR. These results establish that M12 is the product of the GST-catalyzed glutathione attack on the carbon atom α to the nitrogen atom of the strained spiro-azetidinyl moiety to give, after ring opening, the corresponding amino-thioether conjugate product, a direct conjugation pathway that occurs without the prior substrate bioactivation by P450. SIGNIFICANCE STATEMENT The investigated compound, AZD1979, contains a 6-substituted-2-oxa-6-azaspiro[3.3]heptanyl derivative that is an example of strained heterocycles, including spiro-fused ring systems, that are widely used in synthetic organic chemistry. An unusual azetidinyl ring-opening reaction involving a nucleophilic attack by glutathione, which does not involve prior cytochrome P450–catalyzed bioactivation of the substrate and which is catalyzed by glutathione transferases, is reported. We propose a mechanism involving the protonated cyclic aminyl intermediate that undergoes nucleophilic attack by glutathione thiolate anion in this reaction, catalyzed by glutathione transferases.
Nonlinear Magnetoelectric Response of Fe73.5Cu1Nb3Si13.5B9/Piezofiber Composite for a Pulsed Magnetic Field Sensor

In this paper, we report the nonlinear magnetoelectric response in a homogenous magnetostrictive/piezoelectric laminate material. The proposed magnetoelectric stack Fe73.5Cu1Nb3Si13. 5B9/piezofiber is made up of high-permeability magnetostrictive Fe73.5Cu1Nb3Si13. 5B9 foils and a piezoelectric Pb(Zr, Ti)O3 fiber composite. The time dependence of magnetoelectric interactions in the Fe73.5Cu1Nb3Si13. 5B9/piezofiber structure driven by pulsed magnetic field was investigated in detail. The experimental results show that the magnetoelectric effect is strongly dependent on the external bias magnetic and pulsed magnetic field parameters. To detect the amplitude of a pulsed magnetic field, the output sensitivity reaches 17 mV/Oe, which is excited by a 100 μs width field. In addition, to measure the pulsed width, the output sensitivity reaches 5.4 mV/μs in the range of 0–300 μs. The results show that the proposed Fe73.5Cu1Nb3Si13. 5B9/piezofiber sensor is ideally suited for pulsed magnetic field measurement.
First Comparative Study of the Effectiveness of the Use of Tranexamic Acid against ε-Aminocapróic Acid via the Oral Route for the Reduction of Postoperative Bleeding in TKA: A Clinical Trial

Abstract Total primary knee replacement results in significant postoperative bleeding. There are reports that 20 to 50% of the patients require a blood transfusion, which has been related to many complications, resulting in the search for strategies to reduce bleeding. The use of oral antifibrinolytics is becoming a low cost and safe way of achieving this goal. The hypothesis of this study was that the use of oral aminocaproic acid could provide similar results to the use of oral tranexamic acid (TXA). The purpose was to compare the effects of oral aminocaproic acid as a hemostatic agent versus the use of oral TXA administered in multiple doses pre and postsurgery in patients undergoing total primary knee replacement. We enrolled 92 patients that were randomly divided into two groups: received three doses of aminocaproic acid (2,000 mg per dose) or three doses of oral TXA (1,300 mg per dose). The drugs were administered according to the following schedule: 2 hours before surgery and 6 and 12 hours after surgery. The variables that were analyzed to compare the effectiveness of the hemostatic agents were total blood loss; hidden blood loss; external blood loss; transfusion rate; intraoperative blood loss; decreases in hemoglobin and hematocrit values; surgical drainage output; visual analogue scale; and surgical complications. There were no significant differences between any of the study variables for the group receiving oral aminocaproic acid and the group receiving oral TXA (p > 0.05), with the exception of patients who received TXA, who presented with more adverse events (p = 0.04). Our study showed that the use of oral aminocaproic acid was similar to its counterpart TXA regarding the evaluated parameters. Although patients who received TXA presented an average of 140 mL less blood loss than patients in the ε-ACA group, the difference did not appear to be clinically important, the transfusion rate was very low, and there were no between-group differences in postoperative complications.
Nasal sprayed particle deposition in a human nasal cavity under different inhalation conditions

Deposition of polydisperse particles representing nasal spray application in a human nasal cavity was performed under transient breathing profiles of sniffing, constant flow, and breath hold. The LES turbulence model was used to describe the fluid phase. Particles were introduced into the flow field with initial spray conditions, including spray cone angle, insertion angle, and initial velocity. Since nasal spray atomizer design determines the particle conditions, fifteen particle size distributions were used, each defined by a log-normal distribution with a different volume mean diameter (Dv50). Particle deposition in the anterior region was approximately 80% when Dv50 > 50μm, and this decreased to 45% as Dv50 decreased to 10μ m for constant and sniff breathing conditions. The decrease in anterior deposition was countered with increased deposition in the middle and posterior regions. The significance of increased deposition in the middle region for drug delivery shows there is potential for nasal delivered drugs to reach the highly vascularised mucosal walls in the main nasal passages. For multiple targeted deposition sites, an optimisation equation was introduced where deposition results of any two targeted sites could be combined and a weighting between 0 to 1 was applied to each targeted site, representing the relative importance of each deposition site.
RNA-Based Detection of Gene Fusions in Formalin-Fixed and Paraffin-Embedded Solid Cancer Samples

Oncogenic gene fusions are important drivers in many cancer types, including carcinomas, with diagnostic and therapeutic implications. Hence, sensitive and rapid methods for parallel profiling in formalin-fixed and paraffin-embedded (FFPE) specimens are needed. In this study we analyzed gene fusions in a cohort of 517 cases where standard treatment options were exhausted. To this end the Archer® DX Solid tumor panel (AMP; 285 cases) and the Oncomine Comprehensive Assay v3 (OCA; 232 cases) were employed. Findings were validated by Sanger sequencing, fluorescence in situ hybridization (FISH) or immunohistochemistry. Both assays demonstrated minimal dropout rates (AMP: 2.4%; n = 7/292, OCA: 2.1%; n = 5/237) with turnaround times of 6–9 working days (median, OCA and AMP, respectively). Hands-on-time for library preparation was 6 h (AMP) and 2 h (OCA). We detected n = 40 fusion-positive cases (7.7%) with TMPRSS2::ERG in prostate cancer being most prevalent (n = 9/40; 22.5%), followed by other gene fusions identified in cancers of unknown primary (n = 6/40; 15.0%), adenoid cystic carcinoma (n = 7/40; 17.5%), and pancreatic cancer (n = 7/40; 17.5%). Our results demonstrate that targeted RNA-sequencing of FFPE samples is feasible, and a well-suited approach for the detection of gene fusions in a routine clinical setting.
Effects of Differential Strategies of Emotion Regulation

Patients suffering from mental disorders, especially anxiety disorders, are often impaired by inadequate emotional reactions. Specific aspects are the insufficient perception of their own emotional states and the use of dysfunctional emotion regulation strategies. Both aspects are interdependent. Thus, Cognitive Behavioral Therapy (CBT) comprises the development and training of adequate emotion regulation strategies. Traditionally, reappraisal is the most common strategy, but strategies of acceptance are becoming more important in the course of advancing CBT. Indeed, there is evidence that emotion regulation strategies differ in self-reported effectiveness, psychophysiological reactions, and underlying neural correlates. However, comprehensive comparisons of different emotion regulation strategies are sparse. The present study, therefore, compared the effect of three common emotion regulation strategies (reappraisal, acceptance, and suppression) on self-reported effectiveness, recollection, and psychophysiological as well as electroencephalographic dimensions. Twenty-nine healthy participants were instructed to either reappraise, accept, suppress, or passively observe their upcoming emotional reactions while anxiety- and sadness-inducing pictures were presented. Results showed a compelling effect of reappraisal on emotional experience, skin conductance response, and P300 amplitude. Acceptance was almost as effective as reappraisal, but led to increased emotional experience. Combining all results, suppression was shown to be the least effective but significantly decreased emotional experience when thoughts and feelings had to be suppressed. Moreover, results show that greater propensity for rumination differentially impairs strategies of emotion regulation.
Keratinocyte Monolayers on Hyaluronic Acid Membranes as “Upside-Down” Grafts Reconstitute Full-Thickness Wounds

Background Skin replacement by means of cultured epithelial keratinocytes is a well-accepted method. However, several clinical drawbacks of sheet autografts (CEA – cultured epithelial autografts) have stimulated various efforts to optimize cell culture and cell delivery. Recent developments include use of cell monolayers instead of a fully differentiated epithelium, as well as use of various biomaterials to grow and transport the cultured cells. To optimize the transfer of human keratinocytes directly to the recipient wound bed, we used an “upside-down” technique, delivering cultured cells directly to the wound with the carrier material on top. Material/Methods Subconfluent second-passage human keratinocyte monolayers on esterified hyaluronic acid membranes (KHAMC – Keratinocyte-Hyaluronic-Acid-Membrane-Composites) were transplanted either as upside-down grafts or as upside-up grafts onto standardized full-thickness wounds in athymic nude mice versus controls with the cell-free membrane alone. Results In the upside-down group, 14 days after grafting, a multi-layered, differentiating epidermis was found, whereas the wounds in the upside-up group and in the control group were not completely closed up to day 21. Persistence of human keratinocytes was shown in the upside-down group only, from day 7 until day 35 after grafting. Conclusions This study confirms that upside-down grafting of subconfluent monolayers of serum-free cultured human keratinocytes on esterified hyaluronic acid membranes is a suitable means to transfer actively proliferative keratinocytes, and reduces wound contraction. Compared to standard grafting protocols of cultured epithelium, such as CEA sheet grafts, it is easier to apply, does not need enzymatic detachment of cells from the culture dish, and limits the number of production steps required.
Structure and Electronic Properties of InSb Nanowires Grown in Flexible Polycarbonate Membranes

A dense array of vertically aligned indium antimonide (InSb) nanowires with high aspect ratio (diameter 150 nm, length 20 μm) were grown in the pores of a track-etched polycarbonate membrane via a one-step electrochemical method. There are several reports on InSb nanowire growth in the pores of a mechanically rigid, nano-channel alumina template (NCA), where nanowire growth occurs in the pores of the NCA. This work on InSb nanowire growth in pores of track-etched polycarbonate (PC) membrane sheds light on the various factors that affect nucleation and nanowire growth. The average length and diameter of the as-grown nanowires was about 10 μm and 150 nm, respectively. Two possible mechanisms accounting for two different morphologies of the as-grown nanowires are proposed. The polycrystallinity observed in some of the nanowires is explained using the 3D ‘nucleation-coalescence’ mechanism. On the other hand, single crystal nanowires with a high density of twin defects and stacking faults grow epitaxially by a two-dimensional (2D) nucleation/growth mechanism. To assess the electrical quality of the nanowires, two- and four-terminal devices were fabricated using a single InSb nanowire contacted by two Ni electrodes. It was found that, at low bias, the ohmic current is controlled by charge diffusion from the bulk contacts. On the other hand, at high bias, the effects of space charge limited current (SCLC) are evident in the current–voltage behavior, characteristic of transport through structures with reduced electrostatic screening. A cross-over from ohmic to SCLC occurs at about 0.14 V, yielding a free carrier concentration of the order of 1014 cm−3.
Molecular and Antigenic Characterization of GI-13 and GI-16 Avian Infectious Bronchitis Virus Isolated in Chile from 2009 to 2017 Regarding 4/91 Vaccine Introduction

Simple Summary The high adaptation and recombination abilities of infectious bronchitis virus (IB) have been proven. This study aims to verify the genetic and antigenic variation of eight field IB strains regarding the 4/91 strain vaccination in Chilean chickens. Phylogenetic, serologic and challenge studies were carried out to accomplish this goal. The genetic analyses indicate that all the viruses isolated prior to the 4/91 introduction belong to the genetic group GI-16 (three isolates from 2009). On the other hand, just one of the viruses isolated after the 4/91 strain vaccine introduction in Chile (in 2015) showed relationship with GI-16 lineage. The remaining four viruses (from 2017) belong to GI-13, the group where the strain 4/91 has been previously classified. Three viruses were chosen to perform antigenic and protective studies. Antigenically, the high relationship between the 4/91 vaccine with the isolate from 2017 is remarkable and could not be observed with isolates from 2009 and 2015. The 4/91 vaccine also showed better protection against the isolate from 2017 than isolates from 2009 and 2015. These results suggest that the introduction of the 4/91 vaccine in Chile could imply a change in some viruses, showing its ability to interact with field viruses, so it is important to monitor the circulating viruses and include these results in future governmental decisions. Abstract The introduction of the 4/91 vaccine against infectious bronchitis in Chile, a lineage not described until that time in the country, led to looking for changes induced by this action. This study considers eight isolates obtained from 2009, 2015 and 2017 and uses a maximum likelihood approach to classify the field isolates. Three isolates were selected to analyze antigenic relationships through a virus neutralization test and to perform protection tests measured trough an RT-qPCR. The isolates from 2009 and 2015 showed a relationship with GI-16 while those from 2017 were related to GI-13. Though the field isolates were classified in two different phylogenetic lineages, all of them showed only minor variations in subtype. The 13885R-17 isolate from 2017 exhibited high antigenic relatedness to the 4/91 vaccine. As expected, 4/91 and Massachusetts vaccines were not antigenically related. Vaccinated birds with the 4/91 vaccine showed less tracheal virus replication for the 13885R-17 from 2017 challenge than for the 12101SP-09 from 2009 and 13347SP-15 from 2015 isolates. The results indicated genetic and antigenic diversity in the most recent infectious bronchitis virus (IBV) isolates in Chile. Moreover, the 4/91 vaccine would be involved in the generation of some current field viruses, which must be considered in vaccination programs and public policies.