Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulation of PDCD1 exon 3 splicing

ABSTRACT The PDCD1 gene encodes PD-1, an important immune checkpoint protein and key immunotherapy target to treat cancer. PDCD1 is alternatively spliced to generate an exon 3-skipped isoform PD-1Δ3 that has been suggested to play an antagonistic role to PD-1, but the mechanism underlying alternative splicing of PDCD1 has never been explored. Here using a minigene system, we analysed the splicing pattern of PDCD1 in multiple cell lines and confirmed exon 3 skipping as the main alternative splicing event. Using deletion analysis of exon 3, we mapped two splicing enhancers in the exon: ESE3a and ESE3b. Using mutagenesis, RNA-affinity chromatography, mass spectrometry as well as depletion and overexpression of MATR3, we defined MATR3 as a splicing activator during PDCD1 exon 3 splicing that operates through binding to ESE3b. MATR3’s splicing-stimulatory activity is counteracted by an RNA secondary structure around ESE3b and an RNA helicase DDX5. Furthermore, we identified ASOs that efficiently promotes PDCD1 exon 3 skipping in both minigene and endogenous-gene contexts. Our data support further study of the ASOs as potential drug candidates to treat cancer.
PARP Inhibition Suppresses GR–MYCN–CDK5–RB1–E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer

Purpose: In this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC. We further sought to determine whether PARP inhibition could suppress NEPC, and to identify molecular determinants of this therapeutic activity. Experimental Design: We used a novel prostate cancer patient–derived xenograft (PDX) treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of ENZ-induced NED, and to analyze suppression of NED and NEPC growth by PARP inhibition. Results: We identified an ENZ treatment–associated glucocorticoid receptor (GR)–MYCN–CDK5–RB1–E2F1 signaling pathway that drives NED in prostatic adenocarcinoma PDX and cell line models. Mechanistically, long-term ENZ treatment transcriptionally upregulates signaling of the GR–MYCN axis, leading to CDK5R1 and CDK5R2 upregulation, Rb1 phosphorylation, and N-Myc–mediated and E2F1-mediated NED gene expression. Importantly, olaparib (OLA) or talazoparib (TALA) suppressed these activities, and the combination of OLA and dinaciclib (DINA), an inhibitor of CDK2 and CDK5, which also inhibits Rb1 phosphorylation, suppressed NED and significantly improved therapeutic efficiency in NEPC cells in vitro and in NEPC tumors in vivo. Conclusions: The results of our study indicate an important role of GR–MYCN–CDK5R1/2–RB1–NED signaling in ENZ-induced and PARP inhibitor–suppressed NEPC. We also demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models.
Lasers in Surgery and Medicine

Background and Objectives: Erythema is one of the most common cosmetic concerns and usually responds well to pulsed dye laser (PDL) treatment. As this laser can cause significant discomfort, topical anesthesia is sometimes offered. However, it is still uncertain whether topical anesthetics can affect the outcome of the laser therapy. We performed a retrospective single site study to compare the efficacy of PDL for the treatment of erythema in patients with and without pretreatment with topical anesthetic. Study Design/Materials and Methods: A chart review was performed and patients who presented with erythema of face, neck, chest, and extremities pretreated with topical anesthesia (23% lidocaine/7% tetracaine ointment or 7% lidocaine/7% tetracaine ointment) undergoing PDL were reviewed and compared with another group without anesthesia. Two blinded dermatologists evaluated the postlaser procedure photographs and gave an assessment compared with baseline. Results: A total of 69 patient charts were reviewed. The erythema resulted from various skin conditions including telangiectasia, cherry angioma, striae, and rosacea. The mean improvement was 2.2581 in the anesthesia group and 2.2632 in the nonanesthesia group. There was no significant difference between both groups as confirmed by a noninferiority test. Conclusions: Topical anesthesia with lidocaine and tetracaine ointment do not interfere with the efficacy of the PDL. Since pain management is essential for any cosmetic procedure, the application of a local anesthetic will enhance patient comfort and satisfaction during treatment with PDL. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
Optimizing the potential bioactivity of isoflavones from soybeans via ultrasound pretreatment: Antioxidant potential and NF-κB activation.

Soybean consumption has been associated with health benefits. However, the effect of ultrasound (US) soybean pretreatment in terms of potential health benefits has not been investigated so far. Accordingly, the total phenolic content (TPC) and the total aglycone content (TAC) were optimized using the Box-Behnken design. Contrasting samples regarding isoflavones aglycones and TPCs were screened for their antioxidant and anti-inflammatory potentials using RAW 264.7 macrophages. US pretreated soybeans (55°C, 15 min, and 24 W/cm2 ) showed greater TPC and TAC compared to the control and this translated to higher antiradical activity and reduction of nuclear factor kappa B (NF-κB) activation. The concentration of genistein in treated soybeans increased by 95%. Furthermore, US pretreated soybeans rendered phenolic extracts that reduced the NF-κB activation by 86%. Therefore, this contribution demonstrates the beneficial effects of US pretreatment of soybeans, which provides a better feedstock for the functional food industry. PRACTICAL APPLICATIONS: Soybeans can be consumed as such or used as a feedstock to produce soy yogurt, fermented soymilk, tofu, and protein concentrate, among others. The greatest bioavailability of isoflavones compared to other flavonoids has recently been highlighted, and this has been explained by the relatively moderate lipophilicity of isoflavones as aglycones. The present contribution supports the use of US pretreatment of soybeans to obtain a feedstock with improved contents of isoflavones as aglycones. We have confirmed that phenolic extracts obtained from the US pretreated samples showed higher bioactivity as radical scavengers and by reducing the activation of nuclear factor kappa B (NF-κB) in a cell model, which is mediated by oxidative species. The clinical importance of NF-κB activation is derived mainly from its role in inflammatory responses. Therefore, our investigation may have a practical application in the procurement of soybean products and/or ingredients with improved functional properties related to their health benefits.
Point‐of‐care viral load monitoring: outcomes from a decentralized HIV programme in Malawi

Routinely monitoring the HIV viral load (VL) of people living with HIV (PLHIV) on anti‐retroviral therapy (ART) facilitates intensive adherence counselling and faster ART regimen switch when treatment failure is indicated. Yet standard VL‐testing in centralized laboratories can be time‐intensive and logistically difficult in low‐resource settings. This paper evaluates the outcomes of the first four years of routine VL‐monitoring using Point‐of‐Care technology, implemented by Médecins Sans Frontières (MSF) in rural clinics in Malawi.
Building an Experimental German User Interface Terminology Linked to SNOMED CT

We describe the process of creating a User Interface Terminology (UIT) with the goal to generate a maximum of German language interface terms that are mapped to the reference terminology SNOMED CT. The purpose is to offer a high coverage of medical jargon in order to optimise semantic annotations of clinical documents by text mining systems. The first step consisted in the creation of an n-gram table to which words and short phrases from the English SNOMED CT description table were automatically extracted and entered. The second step was to fill up the n-gram table with human and machine translations, manually enriched by POS tags. Top-down and bottom-up methods for manual terminology population were used. Grammar rules were formulated and embedded into a term generator, which then created one-to-many German variants per SNOMED CT description. Currently, the German user interface terminology contains 4,425,948 entries, created out of 111,605 German n-grams, assigned to 95,298 English n-grams. With 341,105 active concepts and 542,462 (non FSN) descriptions, it corresponds to an average of 13 interface terms per concept and 8.2 per description. An analysis of the current quality of this resource by blinded human assessment terminology states equivalence regarding term understandability compared to a fully automated Web-based translator, which, however does not yield any synonyms, so that there are good reasons to further develop this semi-automated terminology engineering method and recommend it for other language pairs.
Same Goals, Yet Different Outcomes: Analysing the Current State of eHealth Adoption and Policies in Austria, Germany, and Switzerland Using a Mixed Methods Approach

Despite similar policy goals, the adoption of eHealth practices took different paths in Austria (AT), Switzerland (CH), and Germany (GER). We seek to provide a rigorous analysis of the current state of hospitals by focusing on three key eHealth areas: electronic patient records (EPR), health information exchange (HIE), electronic patient communication. For validation and in order to gain better contextual insight we applied a mixed method approach by combining survey results from clinical directors with qualitative interview data from eHealth experts of all three countries. Across countries, EPR adoption rates were reported highest (AT: 52%, CH: 78%, GER: 50%), HIE-rates were partly lower (AT: 52%, CH: 14%, GER: 17%), and electronic patient communication was reported lowest overall (AT: 17%, CH: 8%, GER: 19%). Amongst others, results indicate patient awareness about eHealth to be equally weak across countries, which thus may be an important focal point of future policy initiatives.
On the conversion from dose-to-medium to dose-to-water in heterogeneous phantoms with Acuros XB and Monte Carlo calculations

The method implemented in Monte Carlo (MC) algorithm to convert dose-to-medium (Dm) to dose-to-water (Dw) is usually based on the Bragg-Gray cavity theory. Acuros XB (AXB) reports also Dm and Dw but the method to calculate Dw is based on the energy deposition cross sections for water in place of those for the local media. For both algorithms, the calculation of Dw in non-water media is similar to the dose received in a small volume of water, small enough not to disturb the fluence of charged particles. Recently, two new methods revised the Bragg-Gray cavity theory, one proposed by Andreo and the other by Reynaert et al. In this context, comparisons between AXB and MC were carried out in terms of dose-to-medium () and dose-to-water (), respectively. Multilayer slab heterogeneous phantoms made of lung, bone and polytetrafluoroethylene (PTFE) were investigated and measurements were carried out using radiochromic films. These latter were then compared to and to Dw which would be obtained according to the conversion methods proposed by Andreo and Reynaert et al agreed with for all cases (±1%). In lung, all Dw calculations and film measurements were in agreement. By contrast, and differed notably in bone (4.5%) and PTFE (3.5%), and both algorithms overestimated film measurements. These findings demonstrate that the conversion method is different between AXB and MC. Furthermore, films were not able to give dose in a small volume of water according to the definition of and . Applying either the fluence correction factor suggested by Andreo or the mass energy absorption ratios proposed by Reynaert et al, resulted in a good agreement (<1%) with film measurements. According to the method used for the conversion, different Dw could be obtained which might lead to several issues in clinical context.
SweC and SweD are essential co-factors of the FtsEX-CwlO cell wall hydrolase complex in Bacillus subtilis

The peptidoglycan (PG) sacculus is composed of long glycan strands cross-linked together by short peptides forming a covalently closed meshwork that protects the bacterial cell from osmotic lysis and specifies its shape. PG hydrolases play essential roles in remodeling this three-dimensional network during growth and division but how these autolytic enzymes are regulated remains poorly understood. The FtsEX ABC transporter-like complex has emerged as a broadly conserved regulatory module in controlling cell wall hydrolases in diverse bacterial species. In most characterized examples, this complex regulates distinct PG hydrolases involved in cell division and is intimately associated with the cytokinetic machinery called the divisome. However, in the gram-positive bacterium Bacillus subtilis the FtsEX complex is required for cell wall elongation where it regulates the PG hydrolase CwlO that acts along the lateral cell wall. To investigate whether additional factors are required for FtsEX function outside the divisome, we performed a synthetic lethal screen taking advantage of the conditional essentiality of CwlO. This screen identified two uncharacterized factors (SweD and SweC) that are required for CwlO activity. We demonstrate that these proteins reside in a membrane complex with FtsX and that amino acid substitutions in residues adjacent to the ATPase domain of FtsE partially bypass the requirement for them. Collectively our data indicate that SweD and SweC function as essential co-factors of FtsEX in controlling CwlO during cell wall elongation. We propose that factors analogous to SweDC function to support FtsEX activity outside the divisome in other bacteria.
Molecular basis for GIGYF–Me31B complex assembly in 4EHP-mediated translational repression

In this study, Peter et al. provide new insights into how GIGYF proteins function together with DDX6 in the regulation of mRNA expression. They used structural analysis, in vivo expression analysis, and biochemical assays to show that GIGYF contains a motif that is necessary and sufficient for direct interaction with Me31B/DDX6, and their findings advance our understanding of the mechanism and assembly of the 4EHP–GIGYF–DDX6 repressor complex.
Performance of seven commercial automated assays for the detection of low levels of anti-Toxoplasma IgG in French immunocompromised patients

Background: Immunocompromised patients are at high risk for the development of severe toxoplasmosis from tissue cyst reactivation, the most frequently, or from recently acquired acute infections. Knowledge of serologic status is therefore crucial. Screening for toxoplasmosis is sometimes performed while patients are already immunocompromised and have a low or even undetectable IgG titer by routine automated enzyme immunoassays. The aim of this study was to assess the sensitivity and specificity of seven reagents for the detection of low levels of IgG. Sera from 354 patients were collected and analysed. Results: Elecsys® offered the best analytic performances, superior to those of Architect® and Platelia®, which were superior to those of Access II® and TGS TA®. Vidas II® and Liaison II® reagents exhibited poor analytical performances in this cohort. For Elecsys®, Platelia® and Architect®, new thresholds for the grey zone and positive zone have been defined to improve the sensitivity of these reagents while maintaining excellent specificity. Conclusions: Commercialized assays for toxoplasmosis screening are not suitable for IgG low-level detection in patients without adapting the supplier thresholds to avoid false negative results and risk generalized toxoplasmosis.
Factors influencing erythrocyte sedimentation rate in adults

Abstract The erythrocyte sedimentation rate (ESR) is a routine test for inflammation. Few studies have investigated the potential influence of lifestyle factors and common metabolic abnormalities on the ESR. This study investigates the influence of demographic factors, alcohol consumption, smoking, physical activity, obesity, and metabolic syndrome on the ESR in adults. This cross-sectional study covered 1472 individuals (44.5% males; age range, 18–91 years) randomly selected from the population of a Spanish municipality. The ESR was measured using a standardized method. We assessed habitual alcohol consumption in standard drinking units, along with tobacco smoking, regular physical exercise (by questionnaire), body mass index, and variables defining metabolic syndrome. Multivariate analyses were performed, including mean corpuscular volume and hemoglobin concentration in the models. The ESR was higher in females than in males, and increased steadily with age. Median ESR of females was 2-fold higher than that of males, and median ESR of individuals aged >65 years was 2-fold higher than that of individuals in the youngest category (ages 18–35 years). Body mass index, presence of metabolic syndrome, and smoking were independently and positively associated with higher ESR values. Light alcohol drinkers and individuals with high regular physical activity displayed lower ESR values than did alcohol abstainers and individuals with low physical activity, respectively. ESR varies greatly with age and sex, and corresponding reference values are proposed. Lifestyle factors (physical activity, smoking, and alcohol consumption) and common metabolic abnormalities (obesity and related metabolic syndrome) may also influence ESR values.
A Wide-Range, Wireless Wearable Inertial Motion Sensing System for Capturing Fast Athletic Biomechanics in Overhead Pitching

The standard technology used to capture motion for biomechanical analysis in sports has employed marker-based optical systems. While these systems are excellent at providing positional information, they suffer from a limited ability to accurately provide fundamental quantities such as velocity and acceleration (hence forces and torques) during high-speed motion typical of many sports. Conventional optical systems require considerable setup time, can exhibit sensitivity to extraneous light, and generally sample too slowly to accurately capture extreme bursts of athletic activity. In recent years, wireless wearable sensors have begun to penetrate devices used in sports performance assessment, offering potential solutions to these limitations. This article, after determining pressing problems in sports that such sensors could solve and surveying the state-of-the-art in wearable motion capture for sports, presents a wearable dual-range inertial and magnetic sensor platform that we developed to enable an end-to-end investigation of high-level, very wide dynamic-range biomechanical parameters. We tested our system on collegiate and elite baseball pitchers, and have derived and measured metrics to glean insight into performance-relevant motion. As this was, we believe, the first ultra-wide-range wireless multipoint and multimodal inertial and magnetic sensor array to be used on elite baseball pitchers, we trace its development, present some of our results, and discuss limitations in accuracy from factors such as soft-tissue artifacts encountered with extreme motion. In addition, we discuss new metric opportunities brought by our systems that may be relevant for the assessment of micro-trauma in baseball.
Social dominance, but not parasite load, affects sperm quality and sperm redox status in house sparrows

ABSTRACT Sperm performance is an important component of male reproductive success. However, sperm production is costly and males need to optimize their investment in sperm quality versus the somatic traits involved in mating success, e.g. their social status. As oxidative stress affects both sperm performance and somatic functions, it has been hypothesized to mediate such a trade-off. According to the oxidation-based soma/germline trade-off hypothesis, dominant males should favour the antioxidant protection of their somatic tissues, and subordinate males should favour the antioxidant protection of their sperm. We tested this hypothesis by experimentally infecting wild-caught house sparrows Passer domesticus with Coccidia Isopora sp. , an internal parasite known to deplete antioxidant resources. We predicted that (i) increased parasite load affects sperm oxidative status and sperm performance and that (ii) males with experimentally high parasite load adjust the antioxidant protection of their soma versus their sperm according to their social status. Despite a 5400% increase in parasite load, sperm performance and somatic and spermatic oxidative status remained unaffected, irrespective of male social status. Nevertheless, males increased their sperm performance over time, a pattern mirrored by an increase in the antioxidant protection of their sperm. Moreover, males at the lower end of the hierarchy always produced sperm of lower velocity, suggesting that they were constrained and privileged their soma over their germline. To conclude, high parasite loads do not necessarily affect sperm performance and oxidative status. In contrast, social hierarchy and the relative investment in soma versus sperm antioxidant protection are determinants of sperm performance. Summary: Immunity does not necessarily affect sperm performance or sperm and blood oxidative balance; however, social hierarchy and the relative soma/germline oxidative balance determine sperm performance.
Preparation of isoquercitrin by biotransformation of rutin using α-L-rhamnosidase from Aspergillus niger JMU-TS528 and HSCCC purification

Abstract Isoquercitrin is a flavonoid with important applications in the pharmaceutical and nutraceutical industries. However, a low yield and high production cost hinders the industrial preparation of isoquercitrin. In the present study, isoquercitrin was prepared by biotransformation of rutin using α-L-rhamnosidase from Aspergillus niger JMU-TS528 combined with high-speed countercurrent chromatography (HSCCC) purification. As a result, the optimum transformation pH, temperature, and time were pH 4.0, 60 °C, and 60 min, respectively. The Km and Vmax were 0.36 mM and 0.460 mmol/min, respectively. For isoquercitrin production, the optimal rutin concentration and transformation time were approximately 1000 mg/L and 60 min. The rutin transformation rate reached 96.44%. The isoquercitrin was purified to a purity of 97.83% using one-step purification with HSCCC. The isoquercitrin was identified using UPLC-Q-TOF-MS. The comprehensive results indicated that the biotransformation procedure using the α-L-rhamnosidase from A. niger JMU-TS528 combined with HSCCC was a simple and effective process to prepare isoquercitrin, which might facilitate the production of isoquercitrin for industrial use.