Miracle-dz/UniFAR-FTUs huggingface dataset:
Degeneration of ipRGCs in Mouse Models of Huntington's Disease Disrupts Non-Image-Forming Behaviors Before Motor Impairment

Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are photosensitive neurons in the retina and are essential for non-image-forming functions, circadian photoentrainment, and pupillary light reflexes. Five subtypes of ipRGCs (M1–M5) have been identified in mice. Although ipRGCs are spared in several forms of inherited blindness, they are affected in Alzheimer's disease and aging, which are associated with impaired circadian rhythms. Huntington's disease (HD) is an autosomal neurodegenerative disease caused by the expansion of a CAG repeat in the huntingtin gene. In addition to motor function impairment, HD mice also show impaired circadian rhythms and loss of ipRGC. Here, we found that, in HD mouse models (R6/2 and N171-82Q male mice), the expression of melanopsin was reduced before the onset of motor deficits. The expression of retinal T-box brain 2, a transcription factor essential for ipRGCs, was associated with the survival of ipRGCs. The number of M1 ipRGCs in R6/2 male mice was reduced due to apoptosis, whereas non-M1 ipRGCs were relatively resilient to HD progression. Most importantly, the reduced innervations of M1 ipRGCs, which was assessed by X-gal staining in R6/2-OPN4Lacz/+ male mice, contributed to the diminished light-induced c-fos and vasoactive intestinal peptide in the suprachiasmatic nuclei (SCN), which may explain the impaired circadian photoentrainment in HD mice. Collectively, our results show that M1 ipRGCs were susceptible to the toxicity caused by mutant Huntingtin. The resultant impairment of M1 ipRGCs contributed to the early degeneration of the ipRGC–SCN pathway and disrupted circadian regulation during HD progression. SIGNIFICANCE STATEMENT Circadian disruption is a common nonmotor symptom of Huntington's disease (HD). In addition to the molecular defects in the suprachiasmatic nuclei (SCN), the cause of circadian disruption in HD remains to be further explored. We hypothesized that ipRGCs, by integrating light input to the SCN, participate in the circadian regulation in HD mice. We report early reductions in melanopsin in two mouse models of HD, R6/2, and N171-82Q. Suppression of retinal T-box brain 2, a transcription factor essential for ipRGCs, by mutant Huntingtin might mediate the reduced number of ipRGCs. Importantly, M1 ipRGCs showed higher susceptibility than non-M1 ipRGCs in R6/2 mice. The resultant impairment of M1 ipRGCs contributed to the early degeneration of the ipRGC–SCN pathway and the circadian abnormality during HD progression.
Inter‐ and intra‐tumoural heterogeneity in cancer‐associated fibroblasts of human pancreatic ductal adenocarcinoma

Cancer‐associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro‐ versus anti‐tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient‐derived CAF primary cultures, we demonstrated that human PDAC‐derived CAFs display a high level of inter‐ and intra‐tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC‐derived CAFs (pCAFassigner). Multiple CAF subtypes co‐existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix‐ and immune‐related signatures, vimentin and α‐smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non‐tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF‐like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter‐ and intra‐tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single‐cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Surgical Management of Discoid Meniscus

ABSTRACT The surgical management of a discoid meniscus requires an appreciation for the possible variants and an understanding of the patient's symptoms. Various surgical techniques have been used to restore knee function and anatomy in cases of discoid meniscus with mixed outcomes. This article reviews the discoid meniscus classification, incidence, and natural history. Recommendations regarding surgical indications and arthroscopic techniques for the management of discoid meniscus are presented.
Delayed Chemical Defense: Timely Expulsion of Herbivores Can Reduce Competition with Neighboring Plants

Time delays in plant responses to insect herbivory are thought to be the principal disadvantage of induced over constitutive defenses, suggesting that there should be strong selection for rapid responses. However, observed time delays between the onset of herbivory and defense induction vary considerably among plants. We postulate that strong competition with conspecifics is an important codeterminant of the cost-benefit balance for induced responses. There may be a benefit to the plant to delay mounting a full defense response until the herbivore larvae are mobile enough to leave and large enough to cause severe damage to neighboring plants. Thus, delayed responses could reduce the competitive pressure on the focal plant. To explore this idea, we developed an individual-based model using data from wild tobacco, Nicotiana attenuata, and its specialized herbivore, Manduca sexta. Chemical defense was assumed to be costly in terms of reduced plant growth. We used a genetic algorithm with the plant’s delay time as a heritable trait. A stationary distribution of delay times emerged, which under high herbivore densities peaked at higher values, which were related to the time larvae need to grow large enough to severely damage neighboring plants. Plants may thus tip the competitive balance by expelling insect herbivores to move to adjacent plants when the herbivores are most damaging. Thus, herbivores become part of a plant’s strategy for reducing competition and increasing fitness.
Managing Devices of a One-to-One Computing Educational Program Using an IoT Infrastructure

Plan Ceibal is the name coined in Uruguay for the local implementation of the One Laptop Per Child (OLPC) initiative. Plan Ceibal distributes laptops and tablets to students and teachers, and also deploys a nationwide wireless network to provide Internet access to these devices, provides video conference facilities, and develops educational applications. Given the scale of the program, management in general, and specifically device management, is a very challenging task. Device maintenance and replacement is a particularly important process; users trigger such kind of replacement processes and usually imply several days without the device. Early detection of fault conditions in the most stressed hardware parts (e.g., batteries) would permit to prompt defensive replacement, contributing to reduce downtime, and improving the user experience. Seeking for better, preventive and scalable device management, in this paper we present a prototype of a Mobile Device Management (MDM) module for Plan Ceibal, developed over an IoT infrastructure, showing the results of a controlled experiment over a sample of the devices. The prototype is deployed over a public IoT infrastructure to speed up the development process, avoiding, in this phase, the need for local infrastructure and maintenance, while enforcing scalability and security requirements. The presented data analysis was implemented off-line and represents a sample of possible metrics which could be used to implement preventive management in a real deployment.
Family Encouragement and Life Experiences: The Road to the Monastic Life

Twenty-two Cistercian monks from a suburban Atlanta, Georgia monastery participated in ninety-minute personal interviews. The monks were asked specific questions about their families, life experiences, monastic vocations, and prayer lives. They came from diverse family backgrounds and life experiences. The main research question that guided this paper was: What role did family encouragement and life experiences play in their road to the monastic life? The overwhelming majority of the monks’ parents supported their son’s monastic vocations. All but two of the monks were raised in Catholic families and most were raised in what they considered to be religious households. Prior to entering the monastery, the monks had been gainfully employed in a variety of occupations and endeavors such as the military, education, retail, construction, the diocesan priesthood, and as a member of a religious order. Keywords: monastic life, Cistercian monks, monastic vocations, Roman Catholics, family encouragement, life experiences
Designing a Performance Measurement System for Accountability, Quality Improvement, and Innovation

The purpose of this article is to detail a system for the design of performance measures that will be used to assess the achievement of a health care organization's strategic goals and its need for change. The article begins by emphasizing the importance of accountability and the need for the presence of a dynamic learning culture that is premised on a foundation of accountability, continuous improvement, learning, and innovation. This is followed by describing the importance of utilizing an interdisciplinary team with physician and patient involvement to guide the design and implementation of the performance measurement system. The goals of the system are then outlined and followed by a description of the process for the determination of the framework, scope, domains, measures, and reporting mechanisms for displaying the performance measures. Lastly, guidelines for the design of valid, reliable, and cost-effective performance measures are discussed with the aim of maximizing their utility by health care professionals, managers, and administrators.
A New Promising Treatment Strategy for Carbon Monoxide Poisoning: High Flow Nasal Cannula Oxygen Therapy

Background High-flow nasal cannula (HFNC) is an alternative to conventional normobaric oxygen therapy (NBO) for hypoxemic patients. Since nothing is known about its effect on carbon monoxide (CO) poisoning, we hypothesized that HFNC might be a useful device in the treatment of CO poisoning victims. Material/Methods We retrospectively reviewed the medical records of patients who were admitted consecutively to the emergency department with CO intoxication. Patients were divided into 2 groups: patients treated with HFNC and patients treated with conventional face mask (CFM). Demographic data, pretreatment, and control (after 1 hour) arterial blood gas analyses values of the patients were evaluated. Results Sixty-eight patients (mean age 35.8±18.7 years) were included in this study. NBO was given via HFNC to 38 patients (55.9%), and via CFM to 30 patients (44.1%). The demographic characteristics and pretreatment values of carboxy-hemoglobin (COHb) were similar in the 2 groups. The mean COHb value of the HFNC group at the first hour was found significantly lower than the CFM group: 9.5±4.7 and 12.0±5.1, respectively (P=0.041). Improvement of COHb level was significantly higher in the HFNC group compared to the CFM group: 12.5±4.5 versus 6.7±3.7, respectively (P=0.001). Conclusions HFNC was superior than CFM in alleviating COHb levels in the victims of CO poisoning. We believe that using HFNC will increase patient comfort by shortening the duration of treatment in emergency department settings, especially in patients who have mild clinical findings of CO poisoning.
LncRNA TP73-AS1 sponges miR-141-3p to promote the migration and invasion of pancreatic cancer cells through the up-regulation of BDH2

LncRNA TP73 antisense RNA 1T (TP73-AS1) plays an important role in human malignancies. However, the levels of TP73-AS1 and its functional mechanisms in pancreatic cancer metastasis remain unknown, and the clinical significance of TP73-AS1 in human pancreatic cancer is also unclear. In the present study, the levels of TP73-AS1 and its candidate target miR-141 in pancreatic cancer and adjacent normal tissue were detected using qRT-PCR. The association between TP73-AS1 levels and the clinicopathologic characteristics of pancreatic cancer patients were analyzed. The relationship between TP73-AS1 and miR-141, and miR-141 and its candidate target 3-hydroxybutyrate dehydrogenase type 2 (BDH2) was confirmed using dual-luciferase reporter assays. TP73-AS1 and/or miR-141 were knocked down using siRNA or an inhibitor in pancreatic cancer cells and cell migration and invasion then examined. The results showed that TP73-AS1 was up-regulated in pancreatic cancer tissue and cell lines. High levels of TP73-AS1 were correlated with poor clinicopathological characteristics and shorter overall survival. MiR-141 was a direct target for TP73-AS1, while BDH2 was a direct target for miR-141. The knockdown of TP73-AS1 significantly inhibited the migration and invasion of pancreatic cancer cells, while the miR-141 inhibitor significantly restored the migration and invasion. Therefore, TP73-AS1 positively regulated BDH2 expression by sponging miR-141. These findings suggest that TP73-AS1 serves as an oncogene and promotes the metastasis of pancreatic cancer. Moreover, TP73-AS1 could serve as a predictor and a potential drug biotarget for pancreatic cancer.
New approaches to cope with possible harms of low-dose environmental chemicals

Low-dose environmental chemicals including endocrine-disrupting chemicals can disturb endocrine, nervous and immune systems. Traditional chemical-focused approaches, strict regulation and avoidance of exposure sources, can help protect humans from individual or several chemicals in the high-dose range, but their value in the low-dose range is questionable. First, exposure sources to problematic environmental chemicals are omnipresent, and many common pollutants present no safe level. In this situation, the value of any effort focusing on individual chemicals is very limited. Second, critical methodological issues, including the huge number of environmental chemicals, biological complexity of mixtures and non-linearity, make it difficult for risk assessment-based regulation to provide reliable permissible levels of individual chemicals. Third, the largest exposure source is already internal; human adipose tissue contains the most complex chemical mixtures. Thus, in the low-dose range, a paradigm shift is required from a chemical-focused to a human-focused approach for health protection. Two key questions are (1) how to control toxicokinetics of chemical mixtures to decrease their burden in critical organs and (2) how to mitigate early harmful effects of chemical mixtures at cellular levels. Many lifestyles can be evaluated for these purposes. Although both the chemical-focused and human-focused approaches are needed to protect humans, the human-focused holistic approach must be the primary measure in the low-dose range of environmental chemicals.
Molecular Identification and Targeted Quantitative Analysis of Medicinal Materials from Uncaria Species by DNA Barcoding and LC-MS/MS

The genus Uncaria is an important source of traditional Chinese medicines with multiple therapeutic effects. The identification of the correct species and accurate determination of the contents of bioactive constituents are important for quality control of Uncaria medicinal materials. Here, an integrated evaluation system based on DNA barcoding for species identification and quantitative analysis by LC-MS/MS has been established. DNA barcoding based on the ITS2 barcode region showed sufficient discriminatory power to precisely identify 24 samples from seven Uncaria species. The length of the 24 ITS2 sequences of Uncaria samples is 227 bp, and 17 variation sites were detected. Additionally, the results of qualitative and quantitative chemical analyses by LC-MS/MS indicated that the chemical compositions of all Uncaria samples were similar; while their contents of targeted alkaloids in samples from different species and origin areas were different. The contents of rhynchophylline (RC) and isorhynchophylline (IRC) were 2.9–1612 mg/kg and 2.60–1299 mg/kg in all tested samples, respectively. This study concludes that DNA barcoding should be used as the first screening step for Uncaria medicinal materials. Then, integration of DNA barcoding with chemical analyses should be applied in quality control of Uncaria medicinal materials in the medicinal industry.
UK registry analysis of donor substance misuse and outcomes following pancreas transplantation

Substance abuse is unfortunately common in organ donors. Often, these organs are declined for transplant, not only because of concerns around blood‐borne virus transmission but also because of perceived poor outcomes. In kidney transplantation, previous studies have demonstrated donor smoking status significantly impacts transplant outcome, but intravenous drug use or alcohol dependence does not. This study aims to clarify these issues in pancreas transplantation. Retrospective data on all UK solid organ pancreas transplants from 1994 to 2015 were obtained from the NHSBT UK Transplant Registry. The impact of illicit drug misuse, alcohol abuse, and smoking on graft and patient survival were analyzed using Kaplan‐Meier plots and a Cox regression model. A total of 1175 of the 2317 (49.5%) donors were categorized as substance misusers. Univariate survival analysis revealed no significant impact of substance misuse on 10‐year graft or patient survival. Multivariate analysis confirmed substance misuse was not associated with impaired graft or patient survival. A history of donor substance misuse does not negatively impact 10‐year graft or patient survival following pancreas transplantation. This is a large national registry analysis with long‐term follow‐up data and should therefore provide clinicians with reassurance when considering pancreas grafts from substance misuse donors.
Theoretical solution of wave equation in an external invisibility cloak with linear transformation function

In 2009 the problem of external invisibility cloak was solved for the first time by the method of transformation optics and the properties of the external invisibility cloak was obtained with that. In this paper the material properties of an external invisibility cloak which is obtained by transformation optics, is used to solve Maxwell's wave equations theoretically inside and outside of this cloak. At the end according to the result of our theoretical solution, electric field distribution is plotted with Mathematica software and the resulting diagram is compared with the other diagram which was plotted with COMSOL software and reported in literature.
Altered expression of metabolic pathways in CLL detected by unlabelled quantitative mass spectrometry analysis

Chronic lymphocytic leukaemia (CLL) remains the most common incurable malignancy of B cells in the western world. Patient outcomes are heterogeneous and can be difficult to predict with current prognostic markers. Here, we used a quantitative label‐free proteomic technique to ascertain differences in the B‐cell proteome from healthy donors and CLL patients with either mutated (M‐CLL) or unmutated (UM‐CLL) IGHV to identify new prognostic markers. In peripheral B‐CLL cells, 349 (22%) proteins were differentially expressed between normal B cells and B‐CLL cells and 189 (12%) were differentially expressed between M‐CLL and UM‐CLL. We also examined the proteome of proliferating CLL cells in the lymph nodes, and identified 76 (~8%) differentially expressed proteins between healthy and CLL lymph nodes. B‐CLL cells show over‐expression of proteins involved in lipid and cholesterol metabolism. A comprehensive lipidomic analysis highlighted large differences in glycolipids and sphingolipids. A shift was observed from the pro‐apoptotic lipid ceramide towards the anti‐apoptotic/chemoresistant lipid, glucosylceramide, which was more evident in patients with aggressive disease (UM‐CLL). This study details a novel quantitative proteomic technique applied for the first time to primary patient samples in CLL and highlights that primary CLL lymphocytes display markers of a metabolic shift towards lipid synthesis and breakdown.
Primary Synovial Sarcoma of the Mediastinum with Long-term Follow-up

Chest radiography showed a right posterior mass on the mediastinum of an 84-year-old woman. The mass had been growing gradually for four years. Surgical excision was performed, and a pathological examination found the mass to be consistent with primary synovial sarcoma (SS) of the mediastinum. To our knowledge, this is a rare case in which follow-up imaging was able to be performed over a period of four years. This disease is aggressive, and its early diagnosis is key to achieving a cure. It is important to consider primary SS in the differential diagnosis of a primary intra-thoracic tumor, even if the tumor grows slowly.
Survival after cardiac resynchronization therapy: results from 50 084 implantations

Abstract Aims Randomized controlled trials have shown that cardiac resynchronization therapy (CRT) prolongs survival in patients with heart failure. No studies have explored survival after CRT in relation to individuals in the general population (relative survival, RS). We sought to determine observed and RS after CRT in a nationwide cohort undergoing CRT. Methods and results A national administrative database was used to quantify observed mortality for patients undergoing CRT. Relative survival (RS) was quantified using life tables. In 50 084 patients [age 72.1 ± 11.6 years (mean ± standard deviation)] undergoing CRT with (CRT-D) (n = 25 273) or without (CRT-P) defibrillation (n = 24 811) over 8.8 years (median follow-up 2.7 years, interquartile range 1.3–4.8), expected survival decreased with age. Device type, male sex, ischaemic heart disease, diabetes, and chronic kidney disease predicted excess mortality. In multivariate analyses, excess mortality (analogue of RS) was lower after CRT-D than after CRT-P in all patients [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.76–0.84] as well as in subgroups with (aHR 0.79, 95% CI 0.74–0.84) or without (aHR 0.82, 95% CI 0.74–0.91) ischaemic heart disease. A Charlson Comorbidity Index (CCI) ≥3 portended a higher excess mortality (aHR 3.04, 95% CI 2.76–3.34). Relative survival was higher in 2015–2017 than in 2009–2011 (aHR 0.64, 95% CI 0.59–0.69). Conclusion Reference RS data after CRT is presented. Sex, ischaemic heart disease, diabetes, chronic kidney disease, and CCI were major determinants of RS after CRT. CRT-D was associated with a higher RS than CRT-P in patients with or without ischaemic heart disease. Relative survival after CRT improved from 2009 to 2017.