Miracle-dz/UniFAR-FTUs huggingface dataset:
Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.
Pesticide residue survey of pollen loads collected by honeybees (Apis mellifera) in daily intervals at three agricultural sites in South Germany

In agricultural landscapes honeybees and other pollinators are exposed to pesticides, often surveyed by residue analysis of bee bread. However, bee bread is a mixture of pollen pellets of different plants collected over a longer time period. Therefore, pesticide content in the hive varies with plant species and time of pollen collection. Hence, the analysis of bee bread is an approximate approach to gain information on detailed pesticide exposure during the agronomic active season. As high-resolution data is missing, we carried out a pesticide residue survey over five years (2012–2016) of daily collected pollen pellets at three agricultural distinct sites in southern Germany. 281 single day pollen samples were selected and subjected to a multi-pesticide residue analysis. Pesticide contaminations of pollen differed between the sites. Intensive pesticide exposure can be seen by high pesticide concentrations as well as a high amount of different pesticides detected. During the five years of observation 73 different pesticides were found, of which 84% are characterized as non-harmful to honeybees. To estimate pesticide risks for honeybees, the pollen hazard quotient (PHQ) was calculated. Even though pesticides were detected in sublethal concentrations, we found substances not supposed to be exposed to honey bees, indicating the necessity for further improvement of seed treatments and increasing awareness of flowering shrubs, field margins and pesticide drift. Additionally, an in-depth analysis of nine pollen samples, divided into sub-fractions dominated by single plant species, revealed even higher concentrations in single crops for some pesticides. We give precise residue data of 1,657 single pesticide detections, which should be used for realistic laboratory and field tests.
Accuracy of colorectal cancer ICD-9-CM codes in Italian administrative healthcare databases: a cross-sectional diagnostic study

Objectives To assess the accuracy of International Classification of Diseases, Ninth Revision – Clinical Modification (ICD-9-CM) codes in identifying subjects with colorectal cancer. Design A diagnostic accuracy study comparing ICD-9-CM codes (index test) for colorectal cancers with medical chart (as a reference standard). Case ascertainment based on neoplastic lesion(s) within the colon/rectum and histological documentation from a primary or metastatic site positive for colorectal cancer. Setting Administrative databases from the Umbria region, Azienda Sanitaria Locale (ASL) Napoli 3 Sud (NA) region and Friuli Venezia Giulia (FVG) region. Participants We randomly selected 130 incident patients from each hospital discharge database, admitted between 2012 and 2014, having colorectal cancer ICD-9 codes located in primary position, and 94 non-cases, that is, patients having a diagnosis of cancer (ICD-9 140–239) other than colorectal cancer in primary position. Outcome measures Sensitivity, specificity and predictive values for 153.x code (colon cancer) and for 154.x code (rectal cancer). Results The positive predictive value (PPV) for colon cancer diagnoses was 80% for Umbria (95% CI 73% to 87%), 81% for NA (95% CI 73% to 88%) and 80% for FVG (95% CI 72% to 87%). The sensitivity ranged from 98% to 99%, while the specificity ranged from 78% to 80% in the three units. For rectal cancer, the PPV was 84% for Umbria (95% CI 77% to 90%), 80% for NA (95% CI 72% to 87%) and 81% for FVG (95% CI 73% to 87%). The sensitivities ranged from 98% to 100%, while the specificity estimates from 79% to 82%. Conclusions Administrative databases in Italy can be a valuable tool for cancer surveillance as well as monitoring geographical and temporal variation of cancer practice.
Mesenchymal Stromal Cells Stimulate the Proliferation and IL-22 Production of Group 3 Innate Lymphoid Cells

Infusion of mesenchymal stromal cells (MSCs) is a promising and increasingly applied therapy for patients who suffer from a variety of inflammatory diseases, including graft-versus-host disease (GvHD), a common and life-threatening complication after allogeneic hematopoietic stem cell transplantation. The therapeutic effect of MSCs is mainly ascribed to their ability to suppress T cells and to support tissue repair. However, clinical response rates in patients with GvHD are limited to 50%, and the determinants for MSC responsiveness are unknown. We recently reported that high frequencies of activated group 3 innate lymphoid cells (ILC3s) before and after allogeneic hematopoietic stem cell transplantation were associated with a lower risk of GvHD. This may be related to IL-22 production by ILC3s, a cytokine important for intestinal epithelial cell homeostasis. In this study, we investigated whether ILC3s may contribute to the therapeutic effect of MSCs by studying the interaction between MSCs and ILC3s in vitro. ILC3s isolated from human tonsils were cocultured with human bone marrow–derived MSCs for 5 d in the presence of IL-2. Coculture with MSCs enhanced the proliferation and IL-22 production of ILC3s. Reciprocally, ILC3s promoted ICAM-1 and VCAM-1 expression on MSCs. For both directions, the activation was mainly mediated by cell–cell contact and by MSC-derived IL-7 and likely by aryl hydrocarbon receptor ligands. Thus, in addition to inhibiting the proliferation of alloreactive T cells, MSCs also promote the expansion and IL-22 production of ILC3s, which may contribute to healthy homeostasis and wound repair in the treatment of various inflammatory conditions in the intestine, including GvHD.
Long‐term treatment costs of chronic periodontitis patients in Germany

AIM We assessed the long-term costs for treating chronic periodontitis (CP) patients. METHODS A cohort of compliant CP patients was retrospectively evaluated. Costs for active periodontal therapy (APT, including scaling and root planning, open flap debridement, root resections) and supportive periodontal therapy (SPT including periodontal, restorative, endodontic, prosthetic and surgical treatments) were estimated from a mixed payer perspective in Germany. The impact of tooth- and patient-level factors on annual costs was assessed using mixed-modelling. RESULTS Two hundred and seventy-three patients (mean ± SD age: 49.6 ± 8.8 years), with 24.3 ± 4.5 teeth, were included. Mean follow-up was 18.7 ± 5.7 years. Total treatment costs per patient and per tooth were 6,146 ± 2,236 and 222 ± 98 Euro, respectively. Costs were generated mainly by periodontal therapy and during SPT. Annualized patient- and tooth-level costs were 348 ± 159 and 12.4 ± 5.7 Euro, respectively. Annual costs increased significantly in older patients, regular attenders, those with fewer teeth (<24) at baseline and teeth with higher probing pocket depths or mobility 3 at baseline. CONCLUSIONS Annual costs for treating CP patients were lower than those found for aggressive periodontitis patients. Regular attendance and having more severe periodontitis came with higher costs per year.
Innate immune functions of avian intestinal epithelial cells: Response to bacterial stimuli and localization of responding cells in the developing avian digestive tract

Intestinal epithelial cells are multi-tasked cells that participate in digestion and absorption as well as in protection of the digestive tract. While information on the physiology and immune functions of intestinal epithelial cells in mammals is abundant, little is known of their immune function in birds and other species. Our main objectives were to study the development of anti-bacterial innate immune functions in the rapidly developing gut of the pre- and post-hatch chick and to determine the functional diversity of epithelial cells. After establishing primary intestinal epithelial cell cultures, we demonstrated their capacity to uptake and process bacteria. The response to bacterial products, LPS and LTA, induced expression of pro-inflammatory cytokine genes (IL-6, IL-18) as well as the expression of the acute phase proteins avidin, lysozyme and the secretory component derived from the polymeric immunoglobulin receptor. These proteins were then localized in gut sections, and the goblet cell was shown to store avidin, lysozyme as well as secretory component. Lysozyme staining was also located in a novel rod-shaped intestinal cell, situated at different loci along the villus, thus deviating from the classical Paneth cell in the mammal, that is restricted to crypts. Thus, in the chicken, the intestinal epithelium, and particularly goblet cells, are committed to innate immune protection. The unique role of the goblet cell in chicken intestinal immunity, as well as the unique distribution of lysozyme-positive cells highlight alternative solutions of gut protection in the bird.
Association between leukocytospermia and semen interleukin‐6 and tumor necrosis factor‐alpha in infertile men

Seminal cytokines were previously reported to adversely affect process of spermatogenesis and ultimately induce poor semen quality. However, association between both IL‐6 and TNF‐α and leukocytospermia was not yet settled. The aim of this study was to evaluate the association between leukocytospermia and levels of interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α) in semen of infertile men. This cross‐sectional study included 100 age‐matched (≥18–45 years.) men. Participants were divided into four groups with 25 patients in each group: Group (A) – infertile patients with leukocytospermia and normal other semen parameters; Group (B) – infertile patients with leukocytospermia and abnormal semen parameters; Group (C) – infertile patients with oligospermia and/or asthenospermia and/or teratospermia but with no leukocytospermia; Group (D) – fertile patients with normal semen parameters and without leukocytospermia. All patients were assessed by detailed medical, sexual, fertility history, and complete physical examination. Laboratory assessment included hormonal and semen analysis and assessment of IL‐6 and TNF‐α in semen plasma. There were significant differences among the study groups regarding total sperm count, sperm concentration, and progressive motility (p < 0.05 for each). There was significant increase in semen WBC counts in groups A and B vs. groups C and D (p = 0.003). There were significant associations between increase levels of WBCs ≥ 5/HPF and decrease levels of total sperm count (p = 0.023), sperm concentration (p = 0.001), and sperm progressive motility (p = 0.02). There were significant upregulations in mean level of IL‐6 (p = 0.001) and mean level of TNF‐α (p = 0.003) in groups A and B vs. groups C and D. Overall, leukocytospermia is associated with reduction in sperm count, progressive motility and further upregulation of seminal IL‐6 and TNF‐α. The effect of treatment of leukocytospermia on the level of seminal cytokines is important point of future research.
The Saudi Arabian 2030 vision and the nursing profession: the way forward

AIM To examine the outlook of the Saudi Arabian nursing profession in relation to the recently launched Kingdom 2030 Vision. INTRODUCTION Nursing in Saudi Arabia has advanced noticeably in education and clinical practice, but challenges remain in building and sustaining a Saudi nursing profession and workforce. BACKGROUND Health care in Saudi Arabia is currently experiencing transformation because of population and economic growth. These transformations have been influenced by the Saudi Arabian 2030 Vision. SOURCES OF EVIDENCE A literature review here examines the progress in transforming the nursing profession in Saudi Arabia. Relevant studies published between 2001 and 2017 were identified, using databases such as Medline, PubMed and PsychInfo. RESULTS Nineteen studies reporting challenges and opportunities that the nursing profession faces in Saudi Arabia were included. DISCUSSION The nursing profession in Saudi Arabia faces challenges from nursing shortages, underdeveloped nursing education and unclear scope of practice. However, the new 2030 Vision offers many opportunities for social and economic transformation. CONCLUSION Effective strategies must be implemented to accommodate the new outlook the 2030 Saudi Vision in order to advance the nursing profession and to improve healthcare delivery in Saudi Arabia. IMPLICATIONS FOR NURSING AND NURSING POLICY Nursing policymakers urgently need to improve nursing care in Saudi Arabia by addressing the nursing shortage, generating strategies to improve nursing education and establishing scope of practice guidelines. These critical issues must be addressed with the context of the 2030 Vision.
Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells

Epithelial-to-mesenchymal transition (EMT) in cancer cells facilitates tumor progression by promoting invasion and metastasis. Snail is a transcriptional factor that induces EMT, while P-glycoprotein (P-gp) is an efflux transporter involved in anticancer drug resistance, and P-gp efflux activity is stimulated in Snail-overexpressing lung cancer cells with EMT characteristics. Since the histone deacetylase (HDAC) inhibitor entinostat (Ent) reverses EMT features, our aim in this study was to determine whether Ent also suppresses P-gp activation in Snail-induced cells. First, we confirmed that Ent treatment reduced migration activity, downregulated E-cadherin and upregulated vimentin at the mRNA level in Snail-overexpressing cells, thus inhibiting EMT. Efflux and uptake assays using rhodamine123 (Rho123), a fluorescent P-gp substrate, showed that Ent also inhibited Snail-induced activation of P-gp. Moreover, P-gp activity was more strongly inhibited by Ent in Snail-overexpressing cells than in Mock cells. When we evaluated the uptakes of Rho123 by LLC-PK1 cells and P-gp-overexpressing LLC-GA5COL150 cells, Rho123 accumulation in LLC-GA5COL150 cells was significantly decreased compared with that in LLC-PK1 cells. Coincubation with Ent had no effect on Rho123 accumulation in either of the cell lines. Thus, Ent appears to be an inhibitor, but not a substrate, of P-gp at low concentration. Our results suggest that Ent treatment might suppress not only Snail-induced cancer malignant alteration, but also P-gp-mediated multidrug resistance.
Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV

Eliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery. Here we precisely characterize the functional epitopes of VRC34.01 and two vaccine-elicited murine antibodies by mapping all single amino-acid mutations to the BG505 Env that affect viral neutralization. While escape from VRC34.01 occurred via mutations in both fusion peptide and distal interacting sites of the Env trimer, escape from the vaccine-elicited antibodies was mediated predominantly by mutations in the fusion peptide. Cryo-electron microscopy of four vaccine-elicited antibodies in complex with Env trimer revealed focused recognition of the fusion peptide and provided a structural basis for development of neutralization breadth. Together, these functional and structural data suggest that the breadth of vaccine-elicited antibodies targeting the fusion peptide can be enhanced by specific interactions with additional portions of Env. Thus, our complete maps of viral escape provide a template to improve the breadth or potency of future vaccine-induced antibodies against Env’s fusion peptide. Author summary A major goal of HIV-1 vaccine design is to elicit antibodies that neutralize diverse strains of HIV-1. Recently, some of us elicited such antibodies in animal models using immunogens based on the epitope of a broad antibody (VRC34.01) isolated from an infected individual. Further improving these vaccine-elicited antibody responses will require a detailed understanding of how the resulting antibodies target HIV’s envelope protein (Env). Here, we used mutational antigenic profiling to precisely map the epitope of two vaccine-elicited antibodies and the template VRC34.01 antibody. We did this by quantifying the effect of all possible amino acid mutations to Env on antibody neutralization. Although all antibodies target a similar region of Env, we found clear differences in the functional interaction of Env with the vaccine- and infection-elicited antibodies. We combined these functional data with structural analyses to identify antibody–Env interactions that could improve the breadth of vaccine-elicited antibodies, and thereby help to refine vaccination schemes to achieve broader responses.
Mindfulness moderates the relation between trauma and anxiety symptoms in college students

Abstract Objective: To explore the relations between trauma exposure and anxiety and depression among college students, and to determine whether trait mindfulness may moderate these relations. Participants: Self-report survey data from 2,336 college sophomores were drawn from a larger university-wide study (“Spit for Science”). Methods: We constructed multiple linear regression models using past-year trauma exposure, trait mindfulness, and their multiplicative interaction to predict current anxiety and depressive symptom severity, while controlling for covariates. Results: Mindfulness was associated with lower levels of depression and anxiety symptom severity. Trauma was a significant predictor of anxiety, but not depression, and high levels of mindfulness attenuated the association between trauma exposure and higher anxiety symptom severity. Conclusions: These results have implications for the treatment and prevention of anxiety among trauma-exposed college students and provide a basis for further research into the mechanisms through which mindfulness may facilitate positive mental health.
In-Line Inspection Tool with Eddy Current Instrumentation for Fatigue Crack Detection

Eddy current transducer with sensing coils placed orthogonally and connected in differential mode was introduced to evaluate fatigue cracks in clad pipeline circumferential welds. A dedicated embedded electronic hardware was developed to drive the transducer and measure the electrical complex impedance of the coils, and was specifically designed for operation under autonomous in-line inspection tool. In the laboratory experiments, an automated inspection was performed with the goal to evaluate transducer’s detectability, and different scanning speed was tested to reproduce in service situation. The results have confirmed that the introduced eddy current transducer is a potential solution for fatigue crack detection in clad circumferential weld root, while the hardware developed presented a reasonable SNR reaching the data rate required to be incorporated in an autonomous in-line inspection tool.
The Moderating Effect of Context on the Market Reaction to IT Investments

This paper examines the moderating effects of firm and IT characteristics on the market reaction to IT investment announcements. A special emphasis has been placed on the potential interaction effects of these two types of variables, since the previous event studies have paid limited attention to the possibility that they interact and jointly alter investors' perceptions in relation to IT investment announcements. Very recently, several authors have noted the importance of interaction effects on theory development for IS research. Their assessments are particularly relevant to IT‐value event studies, since the market reaction to IT investment announcements involves a complex process shaped by the interaction of firm and IT characteristics. Based on the previous studies in IS, finance, and accounting, a firm's growth potential and uncertainty are used as proxies to represent firm characteristics, while IT strategic role and asset‐specificity of IT are chosen as the variables reflecting IT characteristics.
Imaging the Vascular Bone Marrow Niche During Inflammatory Stress

Rationale: Inflammatory stress induced by exposure to bacterial lipopolysaccharide causes hematopoietic stem cell expansion in the bone marrow niche, generating a cellular immune response. As an integral component of the hematopoietic stem cell niche, the bone marrow vasculature regulates the production and release of blood leukocytes, which protect the host against infection but also fuel inflammatory diseases. Objective: We aimed to develop imaging tools to explore vascular changes in the bone marrow niche during acute inflammation. Methods and Results: Using the TLR (Toll-like receptor) ligand lipopolysaccharide as a prototypical danger signal, we applied multiparametric, multimodality and multiscale imaging to characterize how the bone marrow vasculature adapts when hematopoiesis boosts leukocyte supply. In response to lipopolysaccharide, ex vivo flow cytometry and histology showed vascular changes to the bone marrow niche. Specifically, proliferating endothelial cells gave rise to new vasculature in the bone marrow during hypoxic conditions. We studied these vascular changes with complementary intravital microscopy and positron emission tomography/magnetic resonance imaging. Fluorescence and positron emission tomography integrin &agr;V&bgr;3 imaging signal increased during lipopolysaccharide-induced vascular remodeling. Vascular leakiness, quantified by albumin-based in vivo microscopy and magnetic resonance imaging, rose when neutrophils departed and hematopoietic stem and progenitor cells proliferated more vigorously. Conclusions: Introducing a tool set to image bone marrow either with cellular resolution or noninvasively within the entire skeleton, this work sheds light on angiogenic responses that accompany emergency hematopoiesis. Understanding and monitoring bone marrow vasculature may provide a key to unlock therapeutic targets regulating systemic inflammation.