Integrative analysis of SF-1 transcription factor dosage impact on genome-wide binding and gene expression regulation

Steroidogenic Factor-1 (SF-1) is a nuclear receptor that has a pivotal role in the development of adrenal glands and gonads and in the control of steroid hormone production, being also implicated in the pathogenesis of adrenocortical tumors. We have analyzed the mechanisms how SF-1 controls gene expression in adrenocortical cells and showed that it regulates different categories of genes according to its dosage. Significant correlations exist between the localization of SF-1-binding sites in chromatin under different dosage conditions and dosage-dependent regulation of gene expression. Our study revealed unexpected functional interactions between SF-1 and Neuron-Restrictive Silencer Factor/RE1-Silencing Transcription Factor (NRSF/REST), which was first characterized as a repressor of neuronal gene expression in non-neuronal tissues, in the regulation of gene expression in steroidogenic cells. When overexpressed, SF-1 reshapes the repertoire of NRSF/REST—regulated genes, relieving repression of key steroidogenic genes. These data show that NRSF/REST has a novel function in regulating gene expression in steroidogenic cells and suggest that it may have a broad role in regulating tissue-specific gene expression programs

Reproducibility and Accuracy of the Radiofrequency Echographic Multi-Spectrometry for Femoral Mineral Density Estimation and Discriminative Power of the Femoral Fragility Score in Patients with Primary and Disuse-Related Osteoporosis

We aimed to investigate the reproducibility and accuracy of Radiofrequency Echographic Multi-Spectrometry (REMS) for femoral BMD estimation and the reproducibility and discriminative power of the REMS-derived femoral fragility score. 175 patients with primary and disuse-related osteoporosis were recruited: one femoral Dual-energy X-ray Absorptiometry (DXA) scan and two femoral REMS scans were acquired. No significant test—retest differences were observed for all REMS-derived variables. The diagnostic concordance between DXA and REMS was 63% (Cohen’s kappa = 0.31) in patients with primary osteoporosis and 13% (Cohen’s kappa: −0.04) in patients with disuse-related osteoporosis. No significant difference was observed between REMS and DXA for either femoral neck BMD (mean difference between REMS and DXA: −0.015 g/cm(2)) or total femur BMD (mean difference: −0.004 g/cm(2)) in patients with primary osteoporosis. Significant differences between the two techniques were observed in patients with disuse-related osteoporosis (femoral neck BMD difference: 0.136 g/cm(2); total femur BMD difference: 0.236 g/cm(2)). Statistically significant differences in the fragility score were obtained between the fractured and non-fractured patients for both populations. In conclusion, REMS showed excellent test-retest reproducibility, but the diagnostic concordance between DXA and REMS was between minimal and poor. Further studies are required to improve the REMS—derived estimation of femoral BMD

Improved management of issue dependencies in issue trackers of large collaborative projects

Issue trackers, such as Jira, have become the prevalent collaborative tools in software engineering for managing issues, such as requirements, development tasks, and software bugs. However, issue trackers inherently focus on the lifecycle of single issues, although issues have and express dependencies on other issues that constitute issue dependency networks in large complex collaborative projects. The objective of this study is to develop supportive solutions for the improved management of dependent issues in an issue tracker. This study follows the Design Science methodology, consisting of eliciting drawbacks and constructing and evaluating a solution and system. The study was carried out in the context of The Qt Company's Jira, which exemplifies an actively used, almost two-decade-old issue tracker with over 100,000 issues. The drawbacks capture how users operate with issue trackers to handle issue information in large, collaborative, and long-lived projects. The basis of the solution is to keep issues and dependencies as separate objects and automatically construct an issue graph. Dependency detections complement the issue graph by proposing missing dependencies, while consistency checks and diagnoses identify conflicting issue priorities and release assignments. Jira's plugin and service-based system architecture realize the functional and quality concerns of the system implementation. We show how to adopt the intelligent supporting techniques of an issue tracker in a complex use context and a large data-set. The solution considers an integrated and holistic system view, practical applicability and utility, and the practical characteristics of issue data, such as inherent incompleteness.The work presented in this paper has been conducted within the scope of the Horizon 2020 project OpenReq, which is supported by the European Union under Grant Nr. 732463. We are grateful for the provision of the Finnish computing infrastructure to carry out the tests (persistent identifier urn:nbn:fi:research-infras-2016072533). This paper has been funded by the Spanish Ministerio de Ciencia e Innovacionúnder project / funding scheme PID2020-117191RB-I00 / AEI/10.13039/501100011033.Peer ReviewedPostprint (published version

Cancer-associated foam cells hamper protective T cell immunity and favor tumor progression in human colon carcinogenesis

Background: Colorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is not fully understood, there are evidences suggesting a link between them. In this study, we hypothesized that dysregulated lipid metabolism contributes to local accumulation of foam cells (FC) in CRC, which in turn disrupts antitumor immunosurveillance. Methods: Tumor infiltrating FC and CD8+ were quantified by digital pathology in patients affected by T2-T4 CRC with any N stage undergoing radical upfront surgery (n=65) and correlated with patients' clinical outcomes. Multiparametric high-resolution flow cytometry analysis and bulk RNAseq of CRC tissue were conducted to evaluate the phenotype and transcriptomic program of immune cell infiltrate in relation to FC accumulation. The immunosuppressive effects of FC and mechanistic studies on FC-associated transforming growth factor-beta (TGF-β) and anti-PD-L1 inhibition were explored using an in-vitro human model of lipid-engulfed macrophages. Results: FC (large CD68+ Bodipy+ macrophages) accumulated at the tumor margin in CRC samples. FChigh tumors exhibited reduced CD8+ T cells and increased regulatory T cells (Tregs). Functional transcriptional profiling depicted an immunosuppressed milieu characterized by reduced interferon gamma, memory CD8+ T cells, and activated macrophages mirrored by increased T-cell exhaustion and Treg enrichment. Furthermore, FChigh tumor phenotype was independent of standard clinical factors but correlated with high body mass index (BMI) and plasma saturated fatty acid levels. In CD8low tumors, the FChigh phenotype was associated with a 3-year disease-free survival rate of 8.6% compared with 28.7% of FClow (p=0.001). In-vitro studies demonstrated that FC significantly impact on CD8 proliferation in TFG-β dependent manner, while inhibition of TGF-β FC-related factors restored antitumor immunity. Conclusions: FC exert immunosuppressive activity through a TGF-β-related pathway, resulting in a CD8-excluded microenvironment and identifying immunosuppressed tumors with worse prognosis in patients with primary CRC. FC association with patient BMI and dyslipidemia might explain the link of CRC with obesity, and offers novel therapeutic and preventive perspectives in this specific clinical setting

Fluctuations in export productivity over the last century from sediments of a southern Chilean fjord (44°S)

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Elsevier B. V. for personal use, not for redistribution. The definitive version was published in Estuarine, Coastal and Shelf Science 65 (2005): 587-600, doi:10.1016/j.ecss.2005.07.005.Here we present the first reconstruction of changes in surface primary production during the last century from the Puyuhuapi fjord in southern Chile, using a variety of parameters (diatoms, biogenic silica, total organic carbon, chlorins, and proteins) as productivity proxies. Two sediment cores from the head and the center of the fjord were analyzed and compared to gain insights on past changes in productivity in these two different depositional environments. Higher sedimentation rates found at the head of the fjord result from the combination of a shallower water column and a restricted circulation by the occurrence of a sill. Additionally, sediment mixing depths estimated from 210Pb data suggest that suboxic conditions may dominate the bottom water and the sediment-water interface in this location. Productivity of the Puyuhuapi fjord during the last century was characterized by a constant increase from the late 19th century to the early 1980s, then decreased until the late-1990s, and then rose again to present-day values. The influence of rainfall on productivity was most noticeable during periods of low rainfall, which coincided with decreased overall productivity within the Puyuhuapi fjord. Simultaneous variations in productivity and rainfall in the study area suggest that marine productivity could respond to atmospheric-oceanic interactions at a local scale. At a regional scale, marine productivity of the area may be related to other large-scale processes such as the El Niño Southern Oscillation.We are grateful to the Ministerio de Hacienda de Chile (Chilean Ministry of Treasury) and the National Oceanographic Committee (CONA) for financial support to carry out the Cimar-7 Fiordo Program (Grant C7F 01-10 to Silvio Pantoja), the FONDAP-COPAS Center, and Grant 200.031.085-1 (UdeC) for financial support. Sepúlveda was funded by a scholarship from the Graduate School of the University of Concepción and by the FONDAP-COPAS Center. Additional support was given by Fundación Andes through the Woods Hole Oceanographic Institution/University of Concepción agreement

Development of a Nomogram Predicting the Risk of Persistence/Recurrence of Cervical Dysplasia

Background: Cervical dysplasia persistence/recurrence has a great impact on women's health and quality of life. In this study, we investigated whether a prognostic nomogram may improve risk assessment after primary conization. Methods: This is a retrospective multi-institutional study based on charts of consecutive patients undergoing conization between 1 January 2010 and 31 December 2014. A nomogram assessing the importance of different variables was built. A cohort of patients treated between 1 January 2015 and 30 June 2016 was used to validate the nomogram. Results: A total of 2966 patients undergoing primary conization were analyzed. The median (range) patient age was 40 (18-89) years. At 5-year of follow-up, 6% of patients (175/2966) had developed a persistent/recurrent cervical dysplasia. Median (range) recurrence-free survival was 18 (5-52) months. Diagnosis of CIN3, presence of HR-HPV types, positive endocervical margins, HPV persistence, and the omission of HPV vaccination after conization increased significantly and independently of the risk of developing cervical dysplasia persistence/recurrence. A nomogram weighting the impact of all variables was built with a C-Index of 0.809. A dataset of 549 patients was used to validate the nomogram, with a C-index of 0.809. Conclusions: The present nomogram represents a useful tool for counseling women about their risk of persistence/recurrence after primary conization. HPV vaccination after conization is associated with a reduced risk of CIN2+

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Rethinking place-making: aligning placeness factors with perceived urban design qualities (PUDQs) to improve the built environment in historical district

Understanding the concept of place is critically important for urban design and place-making practice, and this research attempted to investigate the pathways by which perceived urban design qualities (PUDQs) influence placeness factors in the Chinese context. Twelve hypotheses were developed and combined in a structural equation model for validation. The Tanhualin historical district in Wuhan, China was selected for the analysis. As a result, place attachment was verified as a critical bridge factor that mediated the influence of PUDQs on place satisfaction. Among the five selected PUDQs, walkability and space quality were revealed as the most influential factors associated with place attachment and place satisfaction. Accessibility was actually indirectly beneficial to place-making via the mediation of walkability. Corresponding implications and strategies were discussed to maintain the sense of place for historic districts