Miracle-dz/UniFAR-FTUs huggingface dataset:
Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

The translation of new therapies for spinal cord injury to clinical trials can be facilitated with large animal models close in morpho-physiological scale to humans. Here, we report functional restoration and morphological reorganization after spinal contusion in pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Preliminary results obtained on a small sample of pigs 2 months after spinal contusion revealed the difference in post-traumatic spinal cord outcomes in control and treated animals. In treated pigs, motor performance was enabled by EES and the corresponding morpho-functional changes in hind limb skeletal muscles were accompanied by the reorganization of the glial cell, the reaction of stress cell, and synaptic proteins. Our data demonstrate effects of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further animal studies and clinical translation.
Expression of Main Toll-Like Receptors in Patients with Different Types of Colorectal Polyps and Their Relationship with Gut Microbiota

Abnormal activation of Toll-like receptor (TLRs) signaling can result in colon cancer development. The aim of this study was to investigate the expression of important TLRs in different histological types of colorectal polyps and evaluate their relationship with intestinal microbiota. The expression levels of TLR2, 3, 4, and 5 were analyzed in intestinal biopsy specimens of 21 hyperplastic polyp (HP), 16 sessile serrated adenoma (SSA), 29 tubular adenoma (TA), 21 villous/tubulovillous (VP/TVP) cases, and 31 normal controls. In addition, selected gut bacteria including Streptococcus bovis, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Fusobacterium nucleatum, Porphyromonas spp. , Lactobacillus spp. , Roseburia spp. , and Bifidobacterium spp. were quantified in fecal samples using absolute qRT PCR, and, finally, the association between TLRs and these gut microbiota- was evaluated by Spearman’s correlation coefficient. Higher expression of TLR2 and TLR4 in VP/TVP and TA, and lower expression levels of TLR3 and TLR5 in all type of polyps were observed. The differences in TLR expression patterns was not only dependent on the histology, location, size, and dysplasia grade of polyps but also related to the intestinal microbiota patterns. TLR2 and TLR4 expression was directly associated with the F. nucleatum, E. faecalis, S. bovis, Porphyromonas, and inversely to Bifidobacterium, Lactobacillus, and Roseburia quantity. Furthermore, TLR3 and TLR5 expression was directly associated with Bifidobacterium, Roseburia, and Lactobacillus quantity. Our results suggest a possible critical role of TLRs during colorectal polyp progression. An abnormal regulation of TLRs in relation to gut microbial quantity may contribute to carcinogenesis.
Functionally Relevant Differences in Plasma Fatty Acid Composition and Expression of Cytotoxic and Inhibitory NK Cell Receptors between Healthy Young and Healthy Elder Adults

(1) Background: In the healthy ageing, NK cell number is not modified; however, their spontaneous cytotoxicity decreases. We postulated that the age-dependent decline in metabolic activities might be responsible for this effect. (2) Methods: The fatty acid profile of 30 healthy young males (23 ± 4 years old, BMI 22.1 ± 1.3) and 30 older males (63 ± 5 years old, BMI 22.9 ± 2.5) donors were evaluated along with the expression of killing (KR) and inhibitory NK receptors (KIR) at basal level and after cultivation with fatty acids for 24 h. (3) Results: Significantly higher levels of oleic (p < 0.01), arachidonic (p < 0.001), lignoceric (p < 0.001), and nervonic acids (p < 0.0001) and significantly lower levels of docosapentaenoic and docosahexaenoic acids (p < 0.01) were found in elders as compared to young adults. At basal levels, significant (p < 0.005) differences in KR and KIR expression were encountered; 12/16 antigens. Treatment of cells with saturated fatty acids or arachidonic acid (AA) significantly enhanced KR expressions (p < 0.001). AA treatment decreased inhibitory KIR expression while docosahexaenoic, and eicosapentaenoic acid increased them. (4) Conclusions: Changes in fatty acids blood levels, and KR and KIR expression in NK cell, are age-dependent. Supplementation of NK cells with eicosapentaenoic or docosahexaenoic acid enhanced inhibitory KIR receptors’ expression which may improve their cell function.
Development and Validation of a Mixture Toxicity Implementation in the Dynamic Energy Budget–Individual‐Based Model: Effects of Copper and Zinc on Daphnia magna Populations

Mechanistic population models are gaining considerable interest in ecological risk assessment. The dynamic energy budget approach for toxicity (DEBtox) and the general unified threshold model for survival (GUTS) are well‐established theoretical frameworks that describe sublethal and lethal effects of a chemical stressor, respectively. However, there have been limited applications of these models for mixtures of chemicals, especially to predict long‐term effects on populations. We used DEBtox and GUTS in an individual‐based model (IBM) framework to predict both single and combined effects of copper and zinc on Daphnia magna populations. The model was calibrated based on standard chronic toxicity test results with the single substances. A mixture toxicity implementation based on the general independent action model for mixtures was developed and validated with data from a population experiment with copper and zinc mixtures. Population‐level effects of exposure to individual metals were accurately predicted by DEB‐IBM. The DEB‐IBM framework also allowed us to identify the potential mechanisms underlying these observations. Under independent action the DEB–IBM was able to predict the population dynamics observed in populations exposed to the single metals and their mixtures (R2 > 65% in all treatments). Our modeling shows that it is possible to extrapolate from single‐substance effects at the individual level to mixture toxicity effects at the population level, without the need for mixture toxicity data at the individual level from standard mixture toxicity tests. The application of such modeling techniques can increase the ecological realism in risk assessment. Environ Toxicol Chem 2021;40:513–527. © 2020 SETAC
Multi-Sensor Extrinsic Calibration Using an Extended Set of Pairwise Geometric Transformations

Systems composed of multiple sensors for exteroceptive perception are becoming increasingly common, such as mobile robots or highly monitored spaces. However, to combine and fuse those sensors to create a larger and more robust representation of the perceived scene, the sensors need to be properly registered among them, that is, all relative geometric transformations must be known. This calibration procedure is challenging as, traditionally, human intervention is required in variate extents. This paper proposes a nearly automatic method where the best set of geometric transformations among any number of sensors is obtained by processing and combining the individual pairwise transformations obtained from an experimental method. Besides eliminating some experimental outliers with a standard criterion, the method exploits the possibility of obtaining better geometric transformations between all pairs of sensors by combining them within some restrictions to obtain a more precise transformation, and thus a better calibration. Although other data sources are possible, in this approach, 3D point clouds are obtained by each sensor, which correspond to the successive centers of a moving ball its field of view. The method can be applied to any sensors able to detect the ball and the 3D position of its center, namely, LIDARs, mono cameras (visual or infrared), stereo cameras, and TOF cameras. Results demonstrate that calibration is improved when compared to methods in previous works that do not address the outliers problem and, depending on the context, as explained in the results section, the multi-pairwise technique can be used in two different methodologies to reduce uncertainty in the calibration process.
Interrogating Host Antiviral Environments Driven by Nuclear DNA Sensing: A Multiomic Perspective

Nuclear DNA sensors are critical components of the mammalian innate immune system, recognizing the presence of pathogens and initiating immune signaling. These proteins act in the nuclei of infected cells by binding to foreign DNA, such as the viral genomes of nuclear-replicating DNA viruses herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). Upon binding to pathogenic DNA, the nuclear DNA sensors were shown to initiate antiviral cytokines, as well as to suppress viral gene expression. These host defense responses involve complex signaling processes that, through protein–protein interactions (PPIs) and post-translational modifications (PTMs), drive extensive remodeling of the cellular transcriptome, proteome, and secretome to generate an antiviral environment. As such, a holistic understanding of these changes is required to understand the mechanisms through which nuclear DNA sensors act. The advent of omics techniques has revolutionized the speed and scale at which biological research is conducted and has been used to make great strides in uncovering the molecular underpinnings of DNA sensing. Here, we review the contribution of proteomics approaches to characterizing nuclear DNA sensors via the discovery of functional PPIs and PTMs, as well as proteome and secretome changes that define a host antiviral environment. We also highlight the value of and future need for integrative multiomic efforts to gain a systems-level understanding of DNA sensors and their influence on epigenetic and transcriptomic alterations during infection.
Increased Stopover Duration and Low Body Condition of the Pied Flycatcher (Ficedula hypoleuca) at an Autumn Stopover Site

Simple Summary Many bird species that migrate long distances are in decline partly because of environmental changes, such as climate change or land-use changes. Although much is already known on the effects of environmental change on birds that are on their spring migration or on their breeding grounds, little is known with regard to possible negative effects on birds that are on their autumn migration and visiting so-called stopover sites on their way to their wintering grounds. These stopover sites are vital for birds to refuel, and a potential deteriorating quality of the stopover sites may lead to individuals dying during migration. We investigated the impacts of local environmental conditions on the migration strategy and body condition of the Pied Flycatcher at an autumn migration stopover site using long-term ringing data and local environmental conditions. We found that although birds arrived and departed the stopover site around the same time over the years, the body condition of the individuals caught decreased, and the length of their stay at the stopover site increased. This suggests that conditions at the stopover site during the autumn migration period have deteriorated over time which may lead to the death of more birds during autumn migration. Abstract Many long-distance migratory bird species are in decline, of which environmental changes, such as climate change and land-use changes, are thought to be important drivers. The effects of environmental change on the migration of these birds have often been studied during spring migration. Fewer studies have explored the impacts of environmental change on autumn migration, especially at stopover sites. However, stopover sites are important, as the quality of these sites is expected to change over time. We investigated impacts of local environmental conditions on the migration strategy and body condition of the Pied Flycatcher (Ficedula hypoleuca) at an autumn migration stopover site using long-term ringing data (1996–2018) and local environmental conditions. We found that although the arrival and departure dates of birds at the stopover site remained unchanged, the body condition (fat score) of the individuals caught decreased, and the stopover duration increased. This suggests that conditions at the stopover site during the autumn migration period have deteriorated over time. This study emphasizes the importance of suitable stopover sites for migratory birds and stresses that changes in environmental conditions during the autumn migration period may be contributing to the current decline in long-distance migratory passerines.
Pseudomonas aeruginosa Polynucleotide Phosphorylase Controls Tolerance to Aminoglycoside Antibiotics by Regulating the MexXY Multidrug Efflux Pump

Pseudomonas aeruginosa is an opportunistic pathogen that shows high intrinsic resistance to a variety of antibiotics. The MexX-MexY-OprM efflux pump plays an important role in bacterial resistance to aminoglycoside antibiotics. ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that shows high intrinsic resistance to a variety of antibiotics. The MexX-MexY-OprM efflux pump plays an important role in bacterial resistance to aminoglycoside antibiotics. Polynucleotide phosphorylase (PNPase) is a highly conserved exonuclease that plays important roles in RNA processing and the bacterial response to environmental stresses. Previously, we demonstrated that PNPase controls the tolerance to fluoroquinolone antibiotics by influencing the production of pyocin in P. aeruginosa. In this study, we found that mutation of the PNPase-encoding gene (pnp) in P. aeruginosa increases bacterial tolerance to aminoglycoside antibiotics. We further demonstrate that the upregulation of the mexXY genes is responsible for the increased tolerance of the pnp mutant. Furthermore, our experimental results revealed that PNPase controls the translation of the armZ mRNA through its 5′ untranslated region (UTR). ArmZ had previously been shown to positively regulate the expression of mexXY. Therefore, our results revealed a novel role of PNPase in the regulation of armZ and subsequently the MexXY efflux pump.
In Silico Design of a Peptide Receptor for Dopamine Recognition

Dopamine (DA) is an important neurotransmitter with a fundamental role in regulatory functions related to the central, peripheral, renal, and hormonal nervous systems. Dopaminergic neurotransmission dysfunctions are commonly associated with several diseases; thus, in situ quantification of DA is a major challenge. To achieve this goal, enzyme-based biosensors have been employed for substrate recognition in the past. However, due to their sensitivity to changes in temperature and pH levels, new peptide bioreceptors have been developed. Therefore, in this study, four bioreceptors were designed in silico to exhibit a higher affinity for DA than the DA transporters (DATs). The design was based on the hot spots of the active sites of crystallized enzyme structures that are physiologically related to DA. The affinities between the chosen targets and designed bioreceptors were calculated using AutoDock Vina. Additionally, the binding free energy, ∆G, of the dopamine-4xp1 complex was calculated by molecular dynamics (MD). This value presented a direct relationship with the E_refine value obtained from molecular docking based on the ∆G functions obtained from MOE of the promising bioreceptors. The control variables in the design were amino acids, bond type, steric volume, stereochemistry, affinity, and interaction distances. As part of the results, three out of the four bioreceptor candidates presented promising values in terms of DA affinity and distance.
The Roles of Work-Life Conflict and Gender in the Relationship between Workplace Bullying and Personal Burnout. A Study on Italian School Principals

The present study sought to investigate the associations between workplace bullying and personal burnout both directly and indirectly via work-life conflict. Furthermore, the moderating role of gender in these relations was examined. Traditional research on stress at work focuses on the role of dimensions related to job tasks, demands, and organizational support in influencing the risks for stress-related problems in employees. At the same time, other experiences at work may reduce employees’ well-being, such as workplace bullying and family life. Specifically, considering the detrimental role of work-life conflict, it is possible to hypothesize that it would exacerbate workplace bullying’s harmful effects on employees’ health. Moreover, since previous studies have reported mixed or inconsistent results when considering gender differences with the above-mentioned dimensions, it seems worth investigating the role of employee gender in representing (and response to) the bullying experiences. Building on these considerations, this work verifies whether: (1) work-life conflict mediates the relationship between workplace bullying and burnout; (2) gender moderates all the possible relationships among the constructs. Such hypotheses are verified on a sample of school principals, in light of their peculiar job role. Overall, our findings showed that: (1) Workplace bullying and burnout are associated, both with and without the perception of a concurring work-life conflict; (2) Gender does not moderate all the possible relationships among workplace bullying, work-life conflict and burnout. Overall, being female heightens the risk to perceive work-life conflict in general, as well as to be burnt out, when bullied, with and without the presence of work-life conflict; being male heightens the risk to perceive work-life conflict when bullied. Furthermore, the current findings suggest that family demands may influence school principals’ feelings of exhaustion regardless of gender. These findings confirm and expand previous literature, especially concerning a less studied occupation, namely school principals, shedding a new light on their work experiences. Furthermore, the present study offers interesting implications for trainings on principal’s skills and professional identity.
Early Adaptation of Colorectal Cancer Cells to the Peritoneal Cavity Is Associated with Activation of “Stemness” Programs and Local Inflammation

Purpose: At diagnosis, colorectal cancer presents with synchronous peritoneal metastasis in up to 10% of patients. The peritoneum is poorly characterized with respect to its superspecialized microenvironment. Our aim was to describe the differences between peritoneal metastases and their matched primary tumors excised simultaneously at the time of surgery. Also, we tested the hypothesis of these differences being present in primary colorectal tumors and having prognostic capacity. Experimental Design: We report a comprehensive analysis of 30 samples from peritoneal metastasis with their matched colorectal cancer primaries obtained during cytoreductive surgery. We tested and validated the prognostic value of our findings in a pooled series of 660 colorectal cancer primary samples with overall survival (OS) information and 743 samples with disease-free survival (DFS) information from publicly available databases. Results: We identified 20 genes dysregulated in peritoneal metastasis that promote an early increasing role of “stemness” in conjunction with tumor-favorable inflammatory changes. When adjusted for age, gender, and stage, the 20-gene peritoneal signature proved to have prognostic value for both OS [adjusted HR for the high-risk group (vs. low-risk) 2.32 (95% confidence interval, CI, 1.69–3.19; P < 0.0001)] and for DFS [adjusted HR 2.08 (95% CI, 1.50–2.91; P < 0.0001)]. Conclusions: Our findings indicated that the activation of “stemness” pathways and adaptation to the peritoneal-specific environment are key to early stages of peritoneal carcinomatosis. The in silico analysis suggested that this 20-gene peritoneal signature may hold prognostic information with potential for development of new precision medicine strategies in this setting.
Cerebrospinal Fluid and Serum d-Serine Levels in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Objective: Alzheimer’s disease (AD) is a complex and severe neurodegenerative disease and still lacks effective methods of diagnosis. Dysfunction of the N-methyl-D-aspartate receptor (NMDAR) has been found to be involved in synapse dysfunction and neurotoxicity of AD mechanisms. d-Serine, an NMDAR receptor coagonist, is reported as a potential new biomarker for AD. However, the results of serum and cerebrospinal fluid (CSF) d-serine levels are conflicting. We conducted a meta-analysis to investigate the serum and CSF d-serine levels in patients with AD. Methods: We searched PubMed, the Cochrane central register of controlled trials, and the Cochrane database of systematic reviews for trials that measured d-serine levels both in patients with AD and in controls. We included controlled trials that analyzed d-serine levels in human samples (e.g., serum and CSF). Studies were pooled using a random-effect model for comparisons between AD and control group. We used effect size (ES; expressed as d-serine levels) in each selected meta-analysis to calculate standardized mean difference (SMD). Positive values indicated increased d-serine levels in AD group. We presented results with 95% confidence intervals (CIs). The heterogeneity of the included trials was evaluated through visually inspecting funnel plots and using the I2 statistic. Moderators of effects were explored using metaregression. Results: Seven trials with more than 1186 participants were included in this meta-analysis. d-serine levels in patients with AD were significantly higher than those in controls (SMD = 0.679, 95% CI = 0.335 to 1.022, p < 0.001). Subgroup analyses showed that the AD group had significantly higher d-serine levels in serum and CSF compared with the control group (SMD = 0.566 (serum) and 1.008 (CSF); 95% CI = 0.183 to 0.948 (serum) and 0.168 to 1.849 (CSF)). Moreover, a metaregression revealed a significant negative association between ES and mean mini-mental state examination score in AD group (slope = −0.1203, p = 0.0004). Conclusions: Our results revealed higher d-serine levels in the serum and CSF of patients with AD relative to the controls. Further studies with a larger sample size and longer follow-up are recommended to clarify this association.