Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Regulation of Microglial Activation in Response to Different Degree of Ischemia

Microglia are primary immune cells within the brain and are rapidly activated after cerebral ischemia. The degree of microglial activation is closely associated with the severity of ischemia. However, it remains largely unclear how microglial activation is differentially regulated in response to a different degree of ischemia. In this study, we used a bilateral common carotid artery ligation (BCAL) model and induced different degrees of ischemia by varying the duration of ligation to investigate the microglial response in CX3CR1GFP/+ mice. Confocal microscopy, immunofluorescence staining, RNA sequencing, and qRT-PCR were used to evaluate the de-ramification, proliferation, and differential gene expression associated with microglial activation. Our results showed that 30 min of ischemia induced rapid de-ramification of microglia but did not have significant influence on the microglial density. In contrast, 60 min of ischemia led to a significant decrease in microglial density and more pronounced de-ramification of microglial processes. Importantly, 30 min of ischemia did not induce proliferation of microglia, but 60 min of ischemia led to a marked increase in the density of proliferative microglia. Further analysis utilized transcriptome sequencing showed that microglial activation is differentially regulated in response to different degrees of ischemia. A total of 1,097 genes were differentially regulated after 60 min of ischemia, but only 68 genes were differentially regulated after 30 min of ischemia. Pathway enrichment analysis showed that apoptosis, cell mitosis, immune receptor activity and inflammatory-related pathways were highly regulated after 60 min of ischemia compared to 30 min of ischemia. Multiple microglia-related genes such as Cxcl10, Tlr7, Cd86, Tnfrsf1a, Nfkbia, Tgfb1, Ccl2 and Il-6, were upregulated with prolonged ischemia. Pharmacological inhibition of CSF1 receptor demonstrated that CSF1R signaling pathway contributed to microglial proliferation. Together, these results suggest that the proliferation of microglia is gated by the duration of ischemia and microglia were differentially activated in responding to different degrees of ischemia.
Cyclooxygenase 2 Effector Genes as Potential Inflammation-Related Biomarkers for Colorectal Cancer Circulating Tumor Cells Detection by Liquid Biopsy

Cyclooxygenase 2 (COX2) has been implicated in cancer development and metastasis. We have identified several COX2-regulated inflammation-related genes in human colorectal cancer cells and shown that some of them play important roles in tumor progression. In this work, we have studied the COX2-regulated genes in the mouse colorectal cancer cell line CT26, to find that many are also regulated by COX2 over-expression. On the other hand, we generated a CT26 cell line expressing Gfp and Luciferase, to study tumor growth and metastasis in immunocompetent Balb/c mice. We then collected solid tissue, and blood samples, from healthy and tumor-bearing mice. Using the Parsortix® cell separation system and taking advantage of the fact that the tumor cells expressed Gfp, we were able to identify circulating tumor cells (CTCs) in some of the mice. We compared the mRNA expression levels of Ptgs2 and effector genes in the samples obtained from tumor-bearing or healthy mice, namely, tumor or healthy colon, Ficoll purified buffy coat, and Parsortix-isolated cells to find different patterns between healthy, tumor-bearing mice with or without CTCs. Although for genes like Il15 we did not observe any difference between healthy and tumor-bearing mice in Ficoll or Parsortix samples; others, such as Egr1, Zc3h12a, Klf4, or Nfat5, allowed distinguishing for cancer or CTC presence. Gene expression analysis in Ficoll or Parsortix processed samples, after liquid biopsy, may offer valuable diagnostic and prognostic information and thus should be further studied.
Functional and Structural Architectures of Allocentric and Egocentric Spatial Coding in Aging: A Combined DTI and fMRI Study

Background Aging disrupts the optimal balance between neural nodes underlying orienting and attention control functions. Previous studies have suggested that age-related changes in cognitive process are associated to the changes in the myelinated fiber bundles, which affected the speed and actions of the signal propagation across different neural networks. However, whether the age-related difference in allocentric and egocentric spatial coding is accounted by the difference in white-matter integrity is unclear. In this study, using diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI), we sought to elucidate whether age-related differences in white matter integrity accounts for the difference in nodes to the distributed spatial coding-relevant brain networks. Material and Method Older (n = 24) and younger (n = 27) participants completed the structural DTI and fMRI scans during which they engaged in a cue-to-target task to elicit allocentric or egocentric processes. Results and Conclusion Efficient modulation of both allocentric and egocentric spatial coding in fronto-parietal attention network (FPAN) requires structure–function interaction. Allocentric task-modulated connectivity of the fronto-parietal network (FPN) and dorsal attention network (DAN) with the temporal lobe was influenced by the aging differences of the white-matter tracts of the posterior and superior corona radiata (PCR and SCR), respectively. On the other hand, aging difference of the superior longitudinal fasciculus mainly influenced the egocentric-task-modulated connections of the DAN and FPN with frontal regions and posterior cingulate cortex. This study suggested that functional connections of the FPAN with near and far task-relevant nodes vary significantly with age and conditions.
Dermal Fibroblast Migration and Proliferation Upon Wounding or Lipopolysaccharide Exposure is Mediated by Stathmin

The dermal fibroblast is a crucial executor involved in wound healing, and lipopolysaccharide is a key factor in initiating the migration and proliferation of the dermal fibroblasts, followed by wound healing. However, the underlying molecular mechanism is still unknown. In this study, we demonstrated that stathmin increased concomitantly with p38/MAPK pathway activation by lipopolysaccharide stimulation of the human dermal fibroblast (HDF), which induced microtubule (MT) depolymerization followed by increased HDF migration and proliferation. In contrast, the application of taxol, the small interfering RNA transfection of stathmin, or the application of the p38/MAPK inhibitor SB203580 suppressed MT depolymerization and HDF migration and proliferation. Additionally, the overexpression of a MKK6(Glu) mutant, which constitutively activated p38/MAPK, resulted in MT depolymerization and, subsequently, promoted HDF migration and proliferation. Our data reveal a crucial role of stathmin in HDF migration and proliferation. These findings will provide new targets and strategies for clinical interventions in wound healing.
Enzymatic Oxidation of Ca-Lignosulfonate and Kraft Lignin in Different Lignin-Laccase-Mediator-Systems and MDF Production

Laccase-mediator-oxidized lignin offers replacement for conventional chemical binders to produce fiberboards. Compared to the previously reported laccase–mediator system (LMS), a lignin-laccase-mediator-system (LLMS) has an advantage in that it requires much shorter fiber-enzyme incubation time due to significantly increased redox reactions. However, the cost of regularly applying laccase on an industrial scale is currently too high. We have employed CcLcc5 from cultures of the basidiomycete Coprinopsis cinerea as a novel basi-laccase (a CAZy subfamily AA1_1 laccase) in medium-density fiberboard (MDF) production, in comparison to the commercial formulation Novozym 51003 with recombinantly produced asco-laccase MtL (a CAZy subfamily AA1_3 laccase-like multicopper oxidase from the ascomycete Myceliophthora thermophila). With the best-performing natural mediator 2,6-dimethoxyphenol (DMP), unpurified CcLcc5 was almost as good as formulated Novozym 51003 in increasing the molecular weight (MW) of the technical lignins tested, the hydrophilic high-MW Ca-lignosulfonate and the hydrophobic low-MW kraft lignin (Indulin AT). Oxygen consumption rates of the two distantly related, poorly conserved enzymes (31% sequence identity) with different mediators and lignosulfonate were also comparable, but Indulin AT significantly reduced the oxidative activity of Novozym 51003 unlike CcLcc5, regardless of the mediator used, either DMP or guaiacol. Oxygen uptake by both laccases was much faster with both technical lignins with DMP than with guaiacol. In case of lignosulfonate and DMP, 20–30 min of incubation was sufficient for full oxygen consumption, which fits in well in time with the usual binder application steps in industrial MDF production processes. LLMS-bonded MDF was thus produced on a pilot-plant scale with either crude CcLcc5 or Novozym 51003 at reduced enzyme levels of 5 kU/kg absolutely dry wood fiber with lignosulfonate and mediator DMP. Boards produced with CcLcc5 were comparably good as those made with Novozym 51003. Boards reached nearly standard specifications in internal bond strength (IB) and modulus of rupture (MOR), while thickness swelling (TS) was less good based on the hydrophilic character of lignosulfonate. LLMS-bonded MDF with Indulin AT and DMP performed better in TS but showed reduced IB and MOR values.
Toll-Like Receptor- and Protein Kinase R-Induced Type I Interferon Sustains Infection of Leishmania donovani in Macrophages

Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis, provoking liver and spleen tissue destruction that is lethal unless treated. The parasite replicates in macrophages and modulates host microbicidal responses. We have previously reported that neutrophil elastase (NE) is required to sustain L. donovani intracellular growth in macrophages through the induction of interferon beta (IFN-β). Here, we show that the gene expression of IFN-β by infected macrophages was reduced by half when TLR4 was blocked by pre-treatment with neutralizing antibodies or in macrophages from tlr2 -/- mice, while the levels in macrophages from myd88-/- mice were comparable to those from wild-type C57BL/6 mice. The neutralization of TLR4 in tlr2 -/- macrophages completely abolished induction of IFN-β gene expression upon parasite infection, indicating an additive role for both TLRs. Induction of type I interferon (IFN-I), OASL2, SOD1, and IL10 gene expression by L. donovani was completely abolished in macrophages from NE knock-out mice (ela2 -/-) or from protein kinase R (PKR) knock-out mice (pkr -/-), and in C57BL/6 macrophages infected with transgenic L. donovani expressing the inhibitor of serine peptidase 2 (ISP2). Parasite intracellular growth was impaired in pkr -/- macrophages but was fully restored by the addition of exogenous IFN-β, and parasite burdens were reduced in the spleen of pkr -/- mice at 7 days, as compared to the 129Sv/Ev background mice. Furthermore, parasites were unable to grow in macrophages lacking TLR3, which correlated with lack of IFN-I gene expression. Thus, L. donovani engages innate responses in infected macrophages via TLR2, TLR4, and TLR3, via downstream PKR, to induce the expression of pro-survival genes in the host cell, and guarantee parasite intracellular development.
The Correlation Between Wall Shear Stress and Plaque Composition in Advanced Human Carotid Atherosclerosis

The role of wall shear stress (WSS) in atherosclerotic plaque development is evident, but the relation between WSS and plaque composition in advanced atherosclerosis, potentially resulting in plaque destabilization, is a topic of discussion. Using our previously developed image registration pipeline, we investigated the relation between two WSS metrics, time-averaged WSS (TAWSS) and the oscillatory shear index (OSI), and the local histologically determined plaque composition in a set of advanced human carotid plaques. Our dataset of 11 carotid endarterectomy samples yielded 87 histological cross-sections, which yielded 511 radial bins for analysis. Both TAWSS and OSI values were subdivided into patient-specific low, mid, and high tertiles. This cross-sectional study shows that necrotic core (NC) size and macrophage area are significantly larger in areas exposed to high TAWSS or low OSI. Local TAWSS and OSI tertile values were generally inversely related, as described in the literature, but other combinations were also found. Investigating the relation between plaque vulnerability features and different combinations of TAWSS and OSI tertile values revealed a significantly larger cap thickness in areas exposed to both low TAWSS and low OSI. In conclusion, our study confirmed previous findings, correlating high TAWSS to larger macrophage areas and necrotic core sizes. In addition, our study demonstrated new relations, correlating low OSI to larger macrophage areas, and a combination of low TAWSS and low OSI to larger cap thickness.
Wave Reflection and Ventriculo-Arterial Coupling in Bicuspid Aortic Valve Patients With Repaired Aortic Coarctation

Background Ventriculo-arterial (VA) coupling in bicuspid aortic valve (BAV) patients can be affected by the global aortopathy characterizing BAV disease and the presence of concomitant congenital lesions such as aortic coarctation (COA). This study aimed to isolate the COA variable and use cardiovascular magnetic resonance (CMR) imaging to perform wave intensity analysis non-invasively to shed light on VA coupling changes in BAV. The primary hypothesis was that BAV patients with COA exhibit unfavorable VA coupling, and the secondary hypothesis was that BAV patients with COA exhibit increased wave speed as a marker of reduced aortic distensibility despite successful surgical correction. Methods Patients were retrospectively identified from a CMR database and divided into two groups: isolated BAV and BAV associated with repaired COA. Aortic and ventricular dimensions, global longitudinal strain (GLS), and ascending aortic flow data and area were collected and used to derive wave intensity from CMR data. The main variables for the analysis included all wave magnitudes (forward compression/expansion waves, FCW and FEW, respectively, and reflected backward compression wave, BCW) and wave speed. Results In the comparison of patients with isolated BAV and those with BAV associated with repaired COA (n = 25 in each group), no differences were observed in left ventricular ejection fraction, GLS, or ventricular volumes, whilst significant increases in FCW and FEW magnitude were noted in the BAV and repaired COA group. The FCW inversely correlated with age and aortic size. Whilst the BCW was not significantly different compared with that in patients with/without COA, its magnitude tends to increase with a lower COA index. Patients with repaired COA exhibited higher wave speed velocity. Aortic wave speed (inversely related to distensibility) was not significantly different between the two groups. Conclusion In the absence of a significant restenosis, VA coupling in patients with BAV and COA is not negatively affected compared to patients with isolated BAV. A reduction in the magnitude of the early systolic FCW was observed in patients who were older and with larger aortic diameters.
Genomic Insights Into Cadmium Resistance of a Newly Isolated, Plasmid-Free Cellulomonas sp. Strain Y8

Our current knowledge on bacterial cadmium (Cd) resistance is mainly based on the functional exploration of specific Cd-resistance genes. In this study, we carried out a genomic study on Cd resistance of a newly isolated Cellulomonas strain with a MIC of 5 mM Cd. Full genome of the strain, with a genome size of 4.47 M bp and GC-content of 75.35%, was obtained through high-quality sequencing. Genome-wide annotations identified 54 heavy metal-related genes. Four potential Cd-resistance genes, namely zntAY8, copAY8, HMTY8, and czcDY8, were subjected to functional exploration. Quantitative PCR determination of in vivo expression showed that zntAY8, copAY8, and HMTY8 were strongly Cd-inducible. Expression of the three inducible genes against time and Cd concentrations were further quantified. It is found that zntAY8 responded more strongly to higher Cd concentrations, while expression of copAY8 and HMTY8 increased over time at lower Cd concentrations. Heterologous expression of the four genes in Cd-sensitive Escherichia coli led to different impacts on hosts’ Cd sorption, with an 87% reduction by zntAY8 and a 3.7-fold increase by HMTY8. In conclusion, a Cd-resistant Cellulomonas sp. strain was isolated, whose genome harbors a diverse panel of metal-resistance genes. Cd resistance in the strain is not controlled by a dedicated gene alone, but by several gene systems collectively whose roles are probably time- and dose-dependent. The plasmid-free, high-GC strain Y8 may provide a platform for exploring heavy metal genomics of the Cellulomonas genus.
Plant-Derived Polysaccharides Regulated Immune Status, Gut Health and Microbiota of Broilers: A Review

In modern intensive breeding system, broilers are exposed to various challenges, such as diet changes and pathological environment, which may cause the increase in the incidence rate and even death. It is necessary to take measures to prevent diseases and maintain optimal health and productivity of broilers. With the forbidden use of antibiotics in animal feed, polysaccharides from plants have attracted much attention owing to their lower toxicity, lower drug resistance, fewer side effects, and broad-spectrum antibacterial activity. It had been demonstrated that polysaccharides derived from plant exerted various functions, such as growth promotion, anti-inflammation, maintaining the integrity of intestinal mucosa, and regulation of intestinal microbiota. Therefore, the current review aimed to provide an overview of the recent advances in the impacts of plant-derived polysaccharides on anti-inflammation, gut health, and intestinal microbiota community of broilers in order to provide a reference for further study on maintaining the integrity of intestinal structure and function, and the related mechanism involved in the polysaccharide administration intervention.
Large-Scale Sheep Losses to Wolves (Canis lupus) in Germany Are Related to the Expansion of the Wolf Population but Not to Increasing Wolf Numbers

Recovery of predator populations triggers conflicts due to livestock depredation losses, particularly in Germany where the wolf (Canis lupus) population grows exponentially and livestock (especially sheep) losses raise public concerns and motivate the authorities to control wolf numbers. Yet, the effects of wolf numbers and alternative factors, such as abundance of prey and livestock, on livestock losses in this country are not investigated. In this study, we collected and analyzed data on the numbers of reproductive units of wolves (packs and pairs together) as a surrogate of adult wolf numbers, sheep killed by wolves, living sheep, red deer (Cervus elaphus), roe deer (Capreolus capreolus), and wild boar (Sus scrofa) in every German state and year from 2002 to 2019. We applied a negative binomial Generalized Linear Mixed Model (GLMM) to estimate the effects of these predictors on the numbers of sheep killed by wolves. We also examined the relationships between the percentages of killed/living sheep and the numbers of living sheep. Ranking of 63 models based on the Akaike information criterion revealed that sheep losses were determined by state, year, and number of living sheep, not by wolf numbers, at high precision and accuracy. The number of sheep killed by wolves increased consistently by 41% per year and by 30% for every additional 10,000 sheep, mainly in the north where most wolf territories are concentrated. This means that sheep are protected insufficiently and/or ineffectively. The percentages of killed/living sheep consistently increased by 0.02–0.05% per state and year, with the maximum percentage of 0.7%, on a backdrop of decreasing numbers of living sheep. In conclusion, we demonstrate that sheep losses in Germany have been driven by the expansion of the wolf population, not by wolf numbers, and by the number of sheep available. We suggest that Germany’s wolf conservation policy should focus on alternative non-lethal interventions, enforcement and standardization of intervention monitoring, and promotion of wolf tolerance rather than on lethal control of wolf population size.
Changes in Serum Cystatin C Levels and the Associations With Cognitive Function in Alzheimer's Disease Patients

Background and Objective Cystatin C is indicated to be involved in the pathogenesis of Alzheimer's disease (AD) and cognitive impairment. Our objective is to examine the serum Cystatin C levels, and to clarify the correlations between serum Cystatin C and cognitive performance in Chinese AD patients. Methods The serum Cystatin C concentrations in AD patients and age, sex, and body mass index (BMI) matched-healthy controls were measured. The cognitive functions of the AD patients were evaluated by using the Mini-mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The severity of dementia was determined with clinical dementia rating (CDR). Results A total of 463 AD patients and 1,389 matched healthy subjects were included. AD patients had higher serum Cystatin C than healthy controls. Serum cystatin C levels were correlated with MoCA scores in AD patients. In an ordinal logistic regression model, AD patients with higher serum cystatin C levels had increased odds of severe cognitive dysfunction. Conclusion Our study suggested that AD patients had higher levels of serum cystatin C than age/sex/BMI-matched normal control subjects. Higher serum cystatin C may be associated with worse cognitive performance, but more studies are required to verify such association.
Predictive Values of Pathological and Clinical Risk Factors for Positivity of Sentinel Lymph Node Biopsy in Thin Melanoma: A Systematic Review and Meta-Analysis

Background The indications for sentinel lymph node biopsy (SLNB) for thin melanoma are still unclear. This meta-analysis aims to determine the positive rate of SLNB in thin melanoma and to summarize the predictive value of different high-risk features for positive results of SLNB. Methods Four databases were searched for literature on SLNB performed in patients with thin melanoma published between January 2000 and December 2020. The overall positive rate and positive rate of each high-risk feature were calculated and obtained with 95% confidence intervals (CIs). Both unadjusted odds ratios (ORs) and adjusted ORs (AORs) of high-risk features were analyzed. Pooled effects were estimated using random-effects model meta-analyses. Results Sixty-six studies reporting 38,844 patients with thin melanoma who underwent SLNB met the inclusion criteria. The pooled positive rate of SLNB was 5.1% [95% confidence interval (CI) 4.9%-5.3%]. Features significantly predicted a positive result of SLNB were thickness≥0.8 mm [AOR 1.94 (95%CI 1.28-2.95); positive rate 7.0% (95%CI 6.0-8.0%)]; ulceration [AOR 3.09 (95%CI 1.75-5.44); positive rate 4.2% (95%CI 1.8-7.2%)]; mitosis rate >0/mm2 [AOR 1.63 (95%CI 1.13-2.36); positive rate 7.7% (95%CI 6.3-9.1%)]; microsatellites [OR 3.8 (95%CI 1.38-10.47); positive rate 16.6% (95%CI 2.4-36.6%)]; and vertical growth phase [OR 2.76 (95%CI 1.72-4.43); positive rate 8.1% (95%CI 6.3-10.1%)]. Conclusions The overall positive rate of SLNB in thin melanoma was 5.1%. The strongest predictor for SLN positivity identified was microsatellites on unadjusted analysis and ulceration on adjusted analysis. Breslow thickness ≥0.8 mm and mitosis rate >0/mm2 both predict SLN positivity in adjusted analysis and increase the positive rate to 7.0% and 7.7%. We suggest patients with thin melanoma with the above high-risk features should be considered for giving an SLNB.