Miracle-dz/UniFAR-FTUs huggingface dataset:
Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase).

PURPOSE To examine the effect of free insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), independent of the effect of insulin-like growth factors, in modulating retinal vascular permeability. METHODS We assessed the ability of a form of IGFBP-3 that does not bind IGF-1 (IGFBP-3NB), to regulate the blood retinal barrier (BRB) using two distinct experimental mouse models, laser-induced retinal vessel injury and vascular endothelial growth factor (VEGF)-induced retinal vascular permeability. Additionally, in vitro studies were conducted. In the animal models, BRB permeability was quantified by intravenous injection of fluorescein labeled serum albumin followed by digital confocal image analysis of retinal flat-mounts. Claudin-5 and vascular endothelial-cadherin (VE-cadherin) localization at interendothelial junctions was studied by immunofluorescence. In vitro changes in transendothelial electrical resistance (TEER) and flux of fluorescent dextran in bovine retinal endothelial monolayers (BREC) were measured after IGFBP-3NB treatment. Acid (ASMase) and neutral (NSMase) sphingomyelinase mRNA levels and activity were measured in mouse retinas. RESULTS Four days postinjury, laser-injured mouse retinas injected with IGFBP-3NB plasmid demonstrated reduced vascular permeability compared with retinas of laser-injured mouse retinas injected with control plasmid. IGFBP-3NB administration resulted in a significant decrease in laser injury-associated increases in ASMase and NSMase mRNA and activity when compared with laser alone treated mice. In vivo, intravitreal injection of IGFBP-3NB reduced vascular leakage associated with intravitreal VEGF injection. IGFBP-3NB partially restored VEGF-induced in vivo permeability and dissociation of claudin-5 and VE-cadherin at junctional complexes. When IGFBP-3NB was applied basally to bovine retinal endothelial cells (BREC) in vitro, TEER increased and macromolecular flux decreased. CONCLUSIONS Intravitreal administration of IGFBP-3NB preserves junctional integrity in the presence of VEGF or laser injury by reducing BRB permeability in part by modulating sphingomyelinase levels.
Self -assembly on strained metallic interfaces, and, Novel collective excitations on metal surfaces

Recent interest in novel physical properties of reduced dimensional systems is spurred by the advance of investigation methods at the nanoscale. Understanding bottom-up techniques for the growth of nanomaterials with novel physical, chemical, and mechanical properties require specialized investigation tools. I am presenting a novel design and performance of an ultra high vacuum scanning tunneling microscope (STM) that allows for large scale (8 mum x 8 mum), fast scanning (3 s for a 100 A x 100 A frame), and atomically resolved studies of reduced dimensional systems on metallic surfaces. The STM proved excellent performance, allowing for variable temperature (100 K to 700 K) and high resolution (< 2 pm at 300 K) structural and dynamical studies on surfaces, as shown by the STM study of the general types of self-assembly processes on strained metallic interfaces. With this new instrument, I performed a complete experimental investigation of the misfit dislocation network of one atom thick Ag films on Ru(0001) and of the restructuring induced by molecular sulfur adsorption when S filled Ag vacancy island are formed. The experiments suggest that the mechanism through which hundreds of Ag atoms are rear-ranging themselves following S deposition is driven by a process of threading dislocation pair annihilation and glide. The experimental observations are explained via an atomistic model, which is based on first-principles interaction parameters. I have found that the self-assembly process is driven by stress relaxation in the Ag film. While the first part of my thesis is focused on the structural properties of low-dimensional metallic systems and instrumentation methods needed to access the nano-scale, in the secand part I investigated a novel lowenergy electronic excitation of a metallic surface. I am presenting the first experimental measurement of an acoustic surface plasmon on metal surfaces. The experiment was performed using electron energy loss spectroscopy on Be(0001). This new mode is a collective excitation of the surface electrons. This discovery goes against the traditional wisdom that on metal surfaces only regular (optical) surface plasmons can exist. First-principles calculations show that this mode is caused by the coexistence of a partially occupied surface state band with the underlying bulk electrons.
Adolescent Varicocele: Association with Somatometric Parameters

Introduction: The developmental changes that occur as a result of puberty have been hypothesized to be important causes of varicocele. Various somatometric parameters were known to affect the occurrence of varicocele during the growth period. We conducted this study in order to examine these relationships and to determine the incidence of varicocele in adolescent males. Patients and Methods: We evaluated 1,200 healthy males aged 0–19 years for varicocele and correlated it with the following somatometric parameters: age, height, body mass index (BMI), pubic hair distribution, penile length and testicular volume. Results: Adolescent varicocele was found in 5.6% of the participants. The 13- to 19-year age-group had the highest incidence of varicocele (10.5%). Logistic regression analysis showed that the incidence was positively correlated with age, height and penile length (odds ratio 1.61, 1.04 and 1.37, respectively) and negatively correlated with left testicular volume, BMI and pubic hair distribution (odds ratio 0.87, 0.87 and 0.47, respectively). Conclusion: Varicocele was more prevalent in tall boys with a lower BMI, who had quickly progressed through puberty. Our observations suggest that varicocele is associated with various somatometric parameters.
Proteus mirabilis fimbriae- and urease-dependent clusters assemble in an extracellular niche to initiate bladder stone formation

Significance Early events during Proteus mirabilis-mediated urinary tract infection have not been well defined. Here we demonstrate that, in contrast to uropathogenic Escherichia coli, P. mirabilis rarely forms bladder intracellular communities. Rather, in the bladder lumen it establishes large urease- and mannose-resistant Proteus-like fimbriae-dependent clusters, which draw a massive neutrophil response and are precursors to urinary stones. The catheter-associated uropathogen Proteus mirabilis frequently causes urinary stones, but little has been known about the initial stages of bladder colonization and stone formation. We found that P. mirabilis rapidly invades the bladder urothelium, but generally fails to establish an intracellular niche. Instead, it forms extracellular clusters in the bladder lumen, which form foci of mineral deposition consistent with development of urinary stones. These clusters elicit a robust neutrophil response, and we present evidence of neutrophil extracellular trap generation during experimental urinary tract infection. We identified two virulence factors required for cluster development: urease, which is required for urolithiasis, and mannose-resistant Proteus-like fimbriae. The extracellular cluster formation by P. mirabilis stands in direct contrast to uropathogenic Escherichia coli, which readily formed intracellular bacterial communities but not luminal clusters or urinary stones. We propose that extracellular clusters are a key mechanism of P. mirabilis survival and virulence in the bladder.
Uptake and Effects of the e-Vita Personal Health Record with Self-Management Support and Coaching, for Type 2 Diabetes Patients Treated in Primary Care

We studied the use, uptake, and effects of e-Vita, a personal health record, with self-management support and personalized asynchronized coaching, for type 2 diabetes patients treated in primary care. Patients were invited by their practice nurse to join the study aimed at testing use and effects of a personal health record. Patients were followed up for 6 months. Uptake and usage were monitored using log data. Outcomes were self-reported diabetes self-care, diabetes-related distress, and emotional wellbeing. Patients' health status was collected from their medical chart. 132 patients agreed to participate in the study of which less than half (46.1%) did not return to the personal health record after 1st login. Only 5 patients used the self-management support program within the personal health record, 3 of whom asked a coach for feedback. Low use of the personal health record was registered. No statistical significant differences on any of the outcome measures were found between baseline and 6 month follow-up. This study showed minimal impact of implementing a personal health record including self-management support in primary diabetes care. Successful adoption of web-based platforms, as ongoing patient centered care, is hard to achieve without additional strategies aimed at enhancing patient motivation and engaging professionals.
Dynamic Modulation of Myelination in Response to Visual Stimuli Alters Optic Nerve Conduction Velocity

Myelin controls the time required for an action potential to travel from the neuronal soma to the axon terminal, defining the temporal manner in which information is processed within the CNS. The presence of myelin, the internodal length, and the thickness of the myelin sheath are powerful structural factors that control the velocity and fidelity of action potential transmission. Emerging evidence indicates that myelination is sensitive to environmental experience and neuronal activity. Activity-dependent modulation of myelination can dynamically alter action potential conduction properties but direct functional in vivo evidence and characterization of the underlying myelin changes is lacking. We demonstrate that in mice long-term monocular deprivation increases oligodendrogenesis in the retinogeniculate pathway but shortens myelin internode lengths without affecting other structural properties of myelinated fibers. We also demonstrate that genetically attenuating synaptic glutamate neurotransmission from retinal ganglion cells phenocopies the changes observed after monocular deprivation, suggesting that glutamate may constitute a signal for myelin length regulation. Importantly, we demonstrate that visual deprivation and shortened internodes are associated with a significant reduction in nerve conduction velocity in the optic nerve. Our results reveal the importance of sensory input in the building of myelinated fibers and suggest that this activity-dependent alteration of myelination is important for modifying the conductive properties of brain circuits in response to environmental experience. SIGNIFICANCE STATEMENT Oligodendrocyte precursor cells differentiate into mature oligodendrocytes and are capable of ensheathing axons with myelin without molecular cues from neurons. However, this default myelination process can be modulated by changes in neuronal activity. Here, we show, for the first time, that experience-dependent activity modifies the length of myelin internodes along axons altering action potential conduction velocity. Such a mechanism would allow for variations in conduction velocities that provide a degree of plasticity in accordance to environmental needs. It will be important in future work to investigate how these changes in myelination and conduction velocity contribute to signal integration in postsynaptic neurons and circuit function.
Workforce Aging and Labor Productivity: The Role of Supply and Demand for Labor in the G7 Countries

It is well accepted that future economic output in most industrialized coun tries must be achieved by a smaller and older labor force. A key question is how this development might affect labor productivity as measured by output per worker.1 In the view of many economists, an aging population has nega tive consequences for growth in output per capita for two reasons. First, the support ratio changes because a decreasing ratio of the working-age popula tion to the total population increases the ratio of consumers to producers. This contributes negatively to growth in output per capita. Second, behavioral effects, that is, negative effects of an aging population, may reduce labor productivity as measured by output per worker. It is the latter effect that we investigate in this chapter. We shall study the sensitivity of projected labor productivity with re spect to assumptions concerning three key characteristics of the labor market: the projected labor force participation rates,2 the age-productivity profile of workers, and the degree of substitutability between labor of different ages. The first two characteristics determine the labor supply and the third char acteristic determines the labor demand curve.3 The assumption that workers of different ages are not perfectly substitutable and exhibit different levels of productivity implies that there is an optimal age mix of the workforce (in terms of output maximization) and that demographic change can move the actual age mix either closer to or further from the optimal mix and therefore affect labor productivity. The magnitude of this age-distribution effect de pends on the degree to which workers of different ages are substitutable. As shown by Guest (2005) for Australia and by Prskawetz and Fent (2007) for
Nanowire-Mediated Delivery Enables Functional Interrogation of Primary Immune Cells: Application to the Analysis of Chronic Lymphocytic Leukemia

A circuit level understanding of immune cells and hematological cancers has been severely impeded by a lack of techniques that enable intracellular perturbation without significantly altering cell viability and function. Here, we demonstrate that vertical silicon nanowires (NWs) enable gene-specific manipulation of diverse murine and human immune cells with negligible toxicity. To illustrate the power of the technique, we then apply NW-mediated gene silencing to investigate the role of the Wnt signaling pathway in chronic lymphocytic leukemia (CLL). Remarkably, CLL-B cells from different patients exhibit tremendous heterogeneity in their response to the knockdown of a single gene, LEF1. This functional heterogeneity defines three distinct patient groups not discernible by conventional CLL cytogenetic markers and provides a prognostic indicator for patients’ time to first therapy. Analyses of gene expression signatures associated with these functional patient subgroups reveal unique insights into the underlying molecular basis for disease heterogeneity. Overall, our findings suggest a functional classification that can potentially guide the selection of patient-specific therapies in CLL and highlight the opportunities for nanotechnology to drive biological inquiry.
cAMP/PKA-mediated Regulation of Erythropoiesis

The role of cyclic AMP (cAMP) as second messenger in erythropoiesis has been suggested in the early 1980s. However, careful analysis showed that cAMP is not generated in direct response to the main erythropoiesis-controlling cytokines such as erythropoietin (Epo). As a result, cAMP disappeared from the central stage in research of erythropoiesis. Instead, other signal transduction pathways, including the Ras/extracellular regulated kinase (ERK)-pathway, the phosphatidylinositol 3-kinase (PI3K) and the signal transducer and activator of transcription (STAT5)-pathways, have been found and explored. In concert, these signaling pathways control the transcriptional machinery of erythroid cells. Although cAMP is not directly generated in response to Epo stimulation, it has recently been demonstrated that increased cAMP-levels and in particular the cAMP-dependent protein kinase A (PKA) can modulate erythroid signal transduction pathways. In some cases, like the ERK-signaling pathway, PKA affects signal transduction by regulating the balance between specific phosphatases and kinases. In other cases, such as the STAT5 pathway, PKA enhances Epo signaling by inducing recruitment of additional co-regulators of transcription. In addition to STAT5, PKA also activates other transcription factors that are required for erythroid gene expression. This review discusses the impact of cAMP/PKA on Epo-mediated signaling pathways and summarizes the role of cAMP in malignant erythropoiesis.
Diabetes, Metabolic Syndrome, and Obesity in Relation to Serum Dioxin Concentrations: The Seveso Women’s Health Study

Background: In animal studies, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters glucose transport and increases serum lipid levels and blood pressure. Epidemiologic evidence suggests an association between TCDD and metabolic disease. Objectives: On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in the highest known residential exposure to TCDD. Using data from the Seveso Women’s Health Study (SWHS), a cohort study of the health of the women, we examined the relation of serum TCDD to diabetes, metabolic syndrome, and obesity > 30 years later. Methods: In 1996, we enrolled 981 women who were newborn to 40 years of age in 1976 and resided in the most contaminated areas. Individual TCDD concentration was measured in archived serum that had been collected soon after the explosion. In 2008, 833 women participated in a follow-up study. Diabetes was classified based on self-report or fasting serum glucose and glycated hemoglobin levels. Metabolic syndrome was defined by International Diabetes Federation criteria. Obesity was defined as body mass index ≥ 30 kg/m2. Results: A 10-fold increase in serum TCDD (log10TCDD) was not associated with diabetes (adjusted hazard ratio = 0.76; 95% CI: 0.45, 1.28) or obesity [adjusted odds ratio (OR) = 0.80; 95% CI: 0.58, 1.10]. Log10TCDD was associated with metabolic syndrome, but only among women who were ≤ 12 years of age at the time of the explosion (adjusted OR = 2.03; 95% CI: 1.25, 3.29; pinteraction = 0.01). Conclusions: We found an increased prevalence of metabolic syndrome associated with TCDD, but only among women who were the youngest at the time of the explosion. Continued follow-up of the SWHS cohort will be informative.
Multicollinearity in geographically weighted regression coefficients : Results from a new simulation experiment

Multicollinearities among the coefficients obtained from the method of geographically weighted regression have been identified in recent research. This is a serious issue that poses a critical challenge for the utility of the method as a tool to investigate multivariate relationships. The evidence regarding the ability of GWR to retrieve spatially varying processes remains mixed due to partial and inconclusive experiments. The objective of this paper is to provide stronger support to the thesis that multicollinearities are inherent to the method. This objective is accomplished by: 1) Investigating multicollinearity in situations where the underlying process is stationary and non-stationary; and 2) Using advanced visualization to report results for a range of outcomes as opposed to the average of r replications as in previous research. Extensive simulation experiments that test two different implementations of GWR provide evidence of spurious multicollinearity between local regression coefficients. This suggests that extreme caution should be exercised when drawing conclusions regarding spatial relationships retrieved using this modeling approach.
The impact of pruritus on the quality of life of patients undergoing dialysis: a single centre cohort study.

BACKGROUND Pruritus is common in dialysis patients, but no studies have addressed its impact on the patients' quality of life (QoL). OBJECTIVE We sought to measure the impact of pruritus on the QoL of patients undergoing chronic hemodialysis (HHD) or peritoneal dialysis (PPD). METHODS Pruritus intensity was measured on a 10-point visual analog scale. QoL was investigated with the 36-item Short Form of the Medical Outcomes Study questionnaire (SSF-336), the 12-item General Health Questionnaire (GHQ-12) and a dermatological questionnaire (Skindex-29). RESULTS One hundred and thirty-nine patients on HD and 30 on PD were recruited. Pruritus was found in 88/169 patients (52.1%),with no differences between HD and PD patients. Prevalence of poor sleep in patients with pruritus was higher than in those without (559% vs. 11%; p<0.001). Both physical and mental scores of SF-36 did not correlate with the presence and the intensity of pruritus. Pruritus intensity was significantly related to poor scores in all 3 subscales of Skindex-29 (symptoms, social function and emotions). In the subscales of social function and emotions, worse scores were observed in patients undergoing HD and with minor psychiatric disorders (GHQpos). CONCLUSIONS Pruritus had a high level of impact on all aspects of QoL and was a predictor of poor sleep. Type of dialysis and minor psychiatric disorders affect the emotional and social aspects of QoL.
Nature and Extent of Genetic Diversity of Dengue Viruses Determined by 454 Pyrosequencing

Dengue virus (DENV) populations are characteristically highly diverse. Regular lineage extinction and replacement is an important dynamic DENV feature, and most DENV lineage turnover events are associated with increased incidence of disease. The role of genetic diversity in DENV lineage extinctions is not understood. We investigated the nature and extent of genetic diversity in the envelope (E) gene of DENV serotype 1 representing different lineages histories. A region of the DENV genome spanning the E gene was amplified and sequenced by Roche/454 pyrosequencing. The pyrosequencing results identified distinct sub-populations (haplotypes) for each DENV-1 E gene. A phylogenetic tree was constructed with the consensus DENV-1 E gene nucleotide sequences, and the sequences of each constructed haplotype showed that the haplotypes segregated with the Sanger consensus sequence of the population from which they were drawn. Haplotypes determined through pyrosequencing identified a recombinant DENV genome that could not be identified through Sanger sequencing. Nucleotide level sequence diversities of DENV-1 populations determined from SNP analysis were very low, estimated from 0.009–0.01. There were also no stop codon, frameshift or non-frameshift mutations observed in the E genes of any lineage. No significant correlations between the accumulation of deleterious mutations or increasing genetic diversity and lineage extinction were observed (p>0.5). Although our hypothesis that accumulation of deleterious mutations over time led to the extinction and replacement of DENV lineages was ultimately not supported by the data, our data does highlight the significant technical issues that must be resolved in the way in which population diversity is measured for DENV and other viruses. The results provide an insight into the within-population genetic structure and diversity of DENV-1 populations.