Miracle-dz/UniFAR-FTUs huggingface dataset:
Contribution of resident and recruited macrophages in vascular physiology and pathology

Purpose of review Macrophages are generally believed to originate entirely from the bone marrow; however, this paradigm is challenged by the discovery of yolk-sac-derived resident macrophages. Here, we provide an overview of recent advances in the ontogeny and function of resident macrophages. Recent findings Macrophage precursors from three distinct embryonic sources (yolk sac, fetal liver and bone marrow) are found to colonize various tissues via the blood circulation early during embryogenesis until shortly after birth. They differentiate into distinct long-lived resident macrophages in response to the expression of tissue-specific transcription factors. Resident macrophages are proficient at taking up tissue-specific cellular debris and consequently acquire tissue-specific imprints. They are primarily involved in homeostasis but can also support the functionality of various tissues. Under pathological settings, dysregulation of resident macrophages can promote disease progression. Summary Resident macrophages maintain themselves via in-situ proliferation under steady state. Following injury, bone marrow monocytes can contribute to the resident macrophage pool in adult animal. Embryonically and postnatally derived resident macrophages are similar but not identical: the former are more efficient at efferocytosis, whereas the latter are more competent at host defense. Thus, specific targeting of these two different resident macrophage populations may lead to better therapeutic strategies.
Damage tolerance of nanolayer grained ceramics and quantitative estimation

Abstract In order to meet increasing requirement for the evaluation and design of damage tolerance of brittle materials, a simple expression was proposed to estimate the damage tolerance quantitatively using basic material parameters, based on the features of damage tolerance and fracture mechanics. The calculated results from this equation indicated that the damage tolerance of nanolayer grained ceramics was over 10 times higher than that of some brittle ceramics, while glass has the lowest damage tolerance. Therefore, the damage tolerance of various ceramics can be estimated directly using their basic properties data without the necessity of additional tests. SEM examination and finite element simulation showed that the high damage tolerance of the layer grained ceramics was attributed to delamination in grains, interlocking microstructures and crack deflection.
Could Local Dynamic Stability Serve as an Early Predictor of Falls in Patients with Moderate Neurological Gait Disorders? A Reliability and Comparison Study in Healthy Individuals and in Patients with Paresis of the Lower Extremities

Falls while walking are frequent in patients with muscular dysfunction resulting from neurological disorders. Falls induce injuries that may lead to deconditioning and disabilities, which further increase the risk of falling. Therefore, an early gait stability index would be useful to evaluate patients in order to prevent the occurrence of future falls. Derived from chaos theory, local dynamic stability (LDS), defined by the maximal Lyapunov exponent, assesses the sensitivity of a dynamic system to small perturbations. LDS has already been used for fall risk prediction in elderly people. The aim of the present study was to provide information to facilitate future researches regarding gait stability in patients with neurological gait disorders. The main objectives were 1) to evaluate the intra-session repeatability of LDS in patients and 2) to assess the discriminative power of LDS to differentiate between healthy individuals and neurological patients. Eighty-three patients with mild to moderate neurological disorders associated with paresis of the lower extremities and 40 healthy controls participated in the study. The participants performed 2×30 s walking wearing a 3D accelerometer attached to the lower back, from which 2×35 steps were extracted. LDS was defined as the average exponential rate of divergence among trajectories in a reconstructed state-space that reflected the gait dynamics. LDS assessed along the medio-lateral axis offered the highest repeatability and discriminative power. Intra-session repeatability (intraclass correlation coefficient between the two repetitions) in the patients was 0.89 and the smallest detectable difference was 16%. LDS was substantially lower in the patients than in the controls (33% relative difference, standardized effect size 2.3). LDS measured in short over-ground walking tests seems sufficiently reliable. LDS exhibits good discriminative power to differentiate fall-prone individuals and opens up the possibility of future clinical applications for better prediction of fall risk in neurological patients.
Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action

Understanding the mechanism of action of PARP inhibitors is key to optimizing their clinical use and effectiveness. Poly(ADP-ribose) polymerase (PARP) inhibitors are the first DNA damage response targeted agents approved for cancer therapy. Here, we focus on their molecular mechanism of action by PARP “trapping” and what this means for both clinical monotherapy and combination with chemotherapeutic agents.
Diagnostic Accuracy of Qualitative and Quantitative Computed Tomography Analysis for Diagnosis of Pathological Grade and Stage in Upper Tract Urothelial Cell Carcinoma

Objective The aim of this study was to compare grade and stage of upper tract urothelial cell carcinoma (UCC) using computed tomography. Materials and Methods With institutional review board approval, 48 patients with 49 UCC (44 high grade and 5 low grade, 26 ⩽ T1 and 23 ≥ T2) underwent nephroureterectomy and preoperative computed tomography between 2013 and 2015. Two blinded radiologists assessed for tumor appearance (filling defect/mass or wall thickening/stricture), margin (smooth or spiculated/irregular), texture (homogeneous, heterogeneous), hydronephrosis, and calcification. A third blinded radiologist established consensus. A fourth blinded radiologist measured size and first-order histogram texture features. Comparisons were performed using &khgr;2 test, multivariable logistic regression, and receiver operator characteristic analysis. Results There was no difference in size of tumors compared by grade or stage (P = 0.80 and 0.13, respectively). Among subjective variables, only tumor texture was significantly different between low- and high-grade UCC (P = 0.03; &kgr; = 0.45). Tumors characterized as spiculated/irregular margin (P = 0.003; 0.30) and heterogeneous (P < 0.001; &kgr; = 0.45) were associated with T2 disease or higher. Entropy was greater in higher grade (6.23 ± 0.46 vs 5.72 ± 0.28) and T2 disease or higher (6.40 ± 0.33 vs 5.95 ± 0.48), (P = 0.03 and 0.02, respectively) with no differences in Kurtosis or Skewness (P > 0.05). Area under the receiver operator characteristic curve for entropy to diagnose high-grade and T2 tumors or higher was 0.83 (confidence interval, 0.64–1.0) and 0.79 (confidence interval 0.59–0.98), respectively. Conclusions Heterogeneity, assessed qualitatively and quantitatively, is accurate for diagnosis of higher grade and stage of disease in upper tract UCC. Spiculated/irregular margins are also associated with T2 disease or higher.
Everyday ethics: ethical issues and stress in nursing practice.

AIM This paper is a report of a study of the type, frequency, and level of stress of ethical issues encountered by nurses in their everyday practice. BACKGROUND Everyday ethical issues in nursing practice attract little attention but can create stress for nurses. Nurses often feel uncomfortable in addressing the ethical issues they encounter in patient care. METHODS A self-administered survey was sent in 2004 to 1000 nurses in four states in four different census regions of the United States of America. The adjusted response rate was 52%. Data were analysed using descriptive statistics, cross-tabulations and Pearson correlations. RESULTS A total of 422 questionnaires were used in the analysis. The five most frequently occurring and most stressful ethical and patient care issues were protecting patients' rights; autonomy and informed consent to treatment; staffing patterns; advanced care planning; and surrogate decision-making. Other common occurrences were unethical practices of healthcare professionals; breaches of patient confidentiality or right to privacy; and end-of-life decision-making. Younger nurses and those with fewer years of experience encountered ethical issues more frequently and reported higher levels of stress. Nurses from different regions also experienced specific types of ethical problems more commonly. CONCLUSION Nurses face daily ethical challenges in the provision of quality care. To retain nurses, targeted ethics-related interventions that address caring for an increasingly complex patient population are needed.
Pulmonary Rehabilitation and Exercise Training in Chronic Obstructive Pulmonary Disease.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a common condition that is becoming increasingly prevalent. It affects 13.2% of the population over age 40 in Germany. In 2020, it will be the third most common cause of morbidity and mortality around the world. It markedly impairs the quality of life of those who suffer from it and presents a major economic challenge to the health-care system. METHODS This review is based on pertinent publications retrieved by a selective literature search and on the authors' clinical experience. RESULTS Pulmonary rehabilitation (PR) for patients with COPD is supported by evidence on the highest level. It is associated with statistically significant (p <0.001) and clinically relevant improvement in physical performance (6-minute walk distance: + 44 m; 95% confidence interval [33; 55]), shortness of breath (Chronic Respiratory Disease Questionnaire: +0.79 points [0.56; 1.03]), and the quality of life (Saint George´s Respiratory Questionnaire: -6.9 points [-9.3; -4.5]). The benefits of PR are especially evident after an acute exacerbation of COPD: it significantly lowers the rate of readmission to the hospital (odds ratio 0.22 [0.08; 0.58], p = 0.002) and improves physical performance ability (6-minute walk distance: + 62 m [38; 86] and the quality of life (Saint George´s Respiratory Questionnaire: -7.8 points [-12.1; -3.5]; p <0.001 for both). CONCLUSION PR is an effective and cost-effective therapeutic intervention that improves physical performance ability, shortness of breath, and the quality of life in patients with COPD, but it has not yet been fully implemented as recommended in the relevant guidelines. There is a need for targeted, problem-oriented referral to a range of PR programs with problem-specific content. The necessary outpatient PR structures still need to be established in Germany.
Facial affect processing in social anxiety disorder with early onset: evidence of an intensity amplification bias

ABSTRACT The present event-related potential (ERP) study investigated for the first time whether children with early-onset social anxiety disorder (SAD) process affective facial expressions of varying intensities differently than non-anxious controls. Participants were 15 SAD patients and 15 non-anxious controls (mean age of 9 years). They were presented with schematic faces displaying anger and happiness at four intensity levels (25%, 50%, 75%, and 100%), as well as with neutral faces. ERPs in early and later time windows (P100, N170, late positivity [LP]), as well as affective ratings (valence and arousal) for the faces, were recorded. SAD patients rated the faces as generally more arousing, regardless of the type of emotion and intensity. Moreover, they displayed enhanced right-parietal LP (350–650 ms). Both arousal ratings and LP reflect stimulus intensity. Therefore, this study provides first evidence of an intensity amplification bias in pediatric SAD during facial affect processing.
Thresholds of Auditory-Motor Coupling Measured with a Simple Task in Musicians and Non-Musicians: Was the Sound Simultaneous to the Key Press?

The human brain is able to predict the sensory effects of its actions. But how precise are these predictions? The present research proposes a tool to measure thresholds between a simple action (keystroke) and a resulting sound. On each trial, participants were required to press a key. Upon each keystroke, a woodblock sound was presented. In some trials, the sound came immediately with the downward keystroke; at other times, it was delayed by a varying amount of time. Participants were asked to verbally report whether the sound came immediately or was delayed. Participants' delay detection thresholds (in msec) were measured with a staircase-like procedure. We hypothesised that musicians would have a lower threshold than non-musicians. Comparing pianists and brass players, we furthermore hypothesised that, as a result of a sharper attack of the timbre of their instrument, pianists might have lower thresholds than brass players. Our results show that non-musicians exhibited higher thresholds for delay detection (180±104 ms) than the two groups of musicians (102±65 ms), but there were no differences between pianists and brass players. The variance in delay detection thresholds could be explained by variance in sensorimotor synchronisation capacities as well as variance in a purely auditory temporal irregularity detection measure. This suggests that the brain's capacity to generate temporal predictions of sensory consequences can be decomposed into general temporal prediction capacities together with auditory-motor coupling. These findings indicate that the brain has a relatively large window of integration within which an action and its resulting effect are judged as simultaneous. Furthermore, musical expertise may narrow this window down, potentially due to a more refined temporal prediction. This novel paradigm provides a simple test to estimate the temporal precision of auditory-motor action-effect coupling, and the paradigm can readily be incorporated in studies investigating both healthy and patient populations.
A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors

Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8+ T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday–Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. Clin Cancer Res; 24(7); 1525–35. ©2017 AACR.
Dual-pH Sensitive Charge-reversal Nanocomplex for Tumor-targeted Drug Delivery with Enhanced Anticancer Activity

Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity.
Mechanisms of carbon dioxide acquisition and CO2 sensing in marine diatoms: a gateway to carbon metabolism

Diatoms are one of the most successful marine eukaryotic algal groups, responsible for up to 20% of the annual global CO2 fixation. The evolution of a CO2-concentrating mechanism (CCM) allowed diatoms to overcome a number of serious constraints on photosynthesis in the marine environment, particularly low [CO2]aq in seawater relative to concentrations required by the CO2 fixing enzyme, ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO), which is partly due to the slow diffusion rate of CO2 in water and a limited CO2 formation rate from in seawater. Diatoms use two alternative strategies to take up dissolved inorganic carbon (DIC) from the environment: one primarily relies on the direct uptake of through plasma-membrane type solute carrier (SLC) 4 family transporters and the other is more reliant on passive diffusion of CO2 formed by an external carbonic anhydrase (CA). Bicarbonate taken up into the cytoplasm is most likely then actively transported into the chloroplast stroma by SLC4-type transporters on the chloroplast membrane system. Bicarbonate in the stroma is converted into CO2 only in close proximity to RubisCO preventing unnecessary CO2 leakage. CAs play significant roles in mobilizing DIC as it is progressively moved towards the site of fixation. However, the evolutionary types and subcellular locations of CAs are not conserved between different diatoms, strongly suggesting that this DIC mobilization strategy likely evolved multiple times with different origins. By contrast, the recent discovery of the thylakoid luminal θ-CA indicates that the strategy to supply CO2 to RubisCO in the pyrenoid may be very similar to that of green algae, and strongly suggests convergent coevolution in CCM function of the thylakoid lumen not only among diatoms but among eukaryotic algae in general. In this review, both experimental and corresponding theoretical models of the diatom CCMs are discussed. This article is part of the themed issue ‘The peculiar carbon metabolism in diatoms’.
Relationship between Impulsivity, Snack Consumption and Children's Weight

Background Childhood overweight is a public health problem associated with psychosocial and physical problems. Personality traits, such as impulsivity, may contribute to the development of overweight. Objective This study examines 1) the association between general impulsivity traits (reward sensitivity and disinhibition) and children's weight, 2) the association between impulsivity traits and unhealthy snack consumption, and 3) the potential mediating role of unhealthy snack consumption in the relationship between impulsivity traits and children's weight. Methods Included were 1,377 parent-child dyads participating in the IVO Nutrition and Physical Activity Child cohorT (INPACT). Children had a mean age of 10 years. Parents completed a questionnaire to measure children's unhealthy snack consumption. Children completed a door-opening task to assess reward sensitivity and completed a questionnaire to measure disinhibition. Children's height and weight were measured to calculate their BMI z-scores. Cross-sectional linear regression analyses were performed to test the associations. Results Disinhibition was positively associated with unhealthy snack consumption but not with BMI z-scores. Reward sensitivity was not related to unhealthy snack consumption or to BMI z-scores. Conclusions No evidence was found for a mediating effect of unhealthy snack consumption in the relation between impulsivity traits and children's weight. However, disinhibition appears to have a negative influence on children's unhealthy snack consumption. Future research focusing on food-related impulsivity in addition to general impulsivity will provide additional insight into factors that influence children's unhealthy snack consumption and weight.
Potential of compressed sensing in quantitative MR imaging of cancer

Abstract Classic signal processing theory dictates that, in order to faithfully reconstruct a band-limited signal (e.g., an image), the sampling rate must be at least twice the maximum frequency contained within the signal, i.e., the Nyquist frequency. Recent developments in applied mathematics, however, have shown that it is often possible to reconstruct signals sampled below the Nyquist rate. This new method of compressed sensing (CS) requires that the signal have a concise and extremely dense representation in some mathematical basis. Magnetic resonance imaging (MRI) is particularly well suited for CS approaches, owing to the flexibility of data collection in the spatial frequency (Fourier) domain available in most MRI protocols. With custom CS acquisition and reconstruction strategies, one can quickly obtain a small subset of the full data and then iteratively reconstruct images that are consistent with the acquired data and sparse by some measure. Successful use of CS results in a substantial decrease in the time required to collect an individual image. This extra time can then be harnessed to increase spatial resolution, temporal resolution, signal-to-noise, or any combination of the three. In this article, we first review the salient features of CS theory and then discuss the specific barriers confronting CS before it can be readily incorporated into clinical quantitative MRI studies of cancer. We finally illustrate applications of the technique by describing examples of CS in dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI.