Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessing mucociliary transport of single particles in vivo shows variable speed and preference for the ventral trachea in newborn pigs

Significance Mucociliary transport (MCT) defends lungs by removing particulates, and defective MCT is hypothesized to contribute to the onset of lung diseases such as asthma, chronic bronchitis, and cystic fibrosis. However, testing those hypotheses has been limited by current MCT assays and mouse models of human disease. We developed an in vivo MCT assay in newborn pigs, which share physiological and anatomical features with humans. The X-ray–computed tomographic-based method provided high spatial and temporal resolution. We discovered that particles preferentially travel up the ventral airway surface. We also discovered substantial heterogeneity in rates of individual particle movement, indicating that MCT does not likely involve homogeneous mucus blankets. The granularity of the data may aid understanding of MCT and disease pathogenesis. Mucociliary transport (MCT) is an innate defense mechanism that removes particulates, noxious material, and microorganisms from the lung. Several airway diseases exhibit abnormal MCT, including asthma, chronic bronchitis, and cystic fibrosis. However, it remains uncertain whether MCT abnormalities contribute to the genesis of disease or whether they are secondary manifestations that may fuel disease progression. Limitations of current MCT assays and of current animal models of human disease have hindered progress in addressing these questions. Therefore, we developed an in vivo assay of MCT, and here we describe its use in newborn wild-type pigs. We studied pigs because they share many physiological, biochemical, and anatomical features with humans and can model several human diseases. We used X-ray multidetector-row–computed tomography to track movement of individual particles in the large airways of newborn pigs. Multidetector-row–computed tomography imaging provided high spatial and temporal resolution and registration of particle position to airway anatomy. We discovered that cilia orientation directs particles to the ventral tracheal surface. We also observed substantial heterogeneity in the rate of individual particle movement, and we speculate that variations in mucus properties may be responsible. The increased granularity of MCT data provided by this assay may provide an opportunity to better understand host defense mechanisms and the pathogenesis of airway disease.
Effect of P-glycoprotein on the ocular disposition of a model substrate, quinidine

Purpose. The objective of this study was to determine the effect of the multi-drug efflux transport protein, P-glycoprotein (P-gp), on the ocular distribution of a model substrate, quinidine. Methods. Male New Zealand albino rabbits (2–2.5 kg) were employed in these studies. Animals were kept under anesthesia and a concentric microdialysis probe was implanted in the vitreous humor and a linear probe in the anterior chamber. Isotonic phosphate buffered saline was perfused through the probes, and samples were collected every 20 minutes over a period of 10 hours. Quinidine was administered both systemically (5mg/kg bodyweight) and intravitreally (5.68µg and 0.568µg). Inhibition experiments were performed in vivo in the presence of verapamil, which is a known P-gp inhibitor. Results. Vitreal pharmacokinetic parameters of quinidine in the presence of verapamil, i.e., Area under the curve (AUC) (39.27 ± 6.47 min.µg/ml), maximum concentration achieved (C max) (0.095 ± 0.011µg/ml), vitreal elimination half-life (231.96 ± 10.77 min), vitreal permeation half-life (16.57 ± 6.96 min) were significantly different from the control values (19.21 ± 3.73 min.µg/ml, 0.05 ± 0.008µg/ml, 165.08 ± 31.5 min, 43.29 ± 12.5 min respectively). A significant elevation in anterior chamber C max and AUC was also observed in the presence of verapamil. Verapamil had no significant effect on vitreal kinetics of quinidine following intravitreal dose of 5. 68µg, but a significant difference was observed at a lower dose of quinidine (0.568µg). A decrease in vitreal elimination half-life and AUC was observed in the presence of verapamil relative to control. Ocular kinetics of fluorescein was studied to ascertain ocular barrier integrity in the presence of verapamil. Western-blot analysis of retina-choroid sections indicates expression of P-gp on rabbit retina-choroid. Conclusion. Results suggest the involvement of a multi drug efflux transporter on the retinal pigment epithelium and neural retina affecting the intraocular kinetics of its substrates following systemic and intravitreal administrations.
Comparison of elbow flexor isokinetic peak torque and fatigue index between men and women of different training level

The purpose of the study was to compare elbow flexion peak torque (PT) and fatigue index (FI) during isokinetic concentric contractions in men and women with different training levels. Sixty-eight young men and women were divided into four groups: resistance trained men (RTM), non-resistance trained men (NRTM), resistance trained women (RTW) and non- resistance trained women (NRTW). Participants performed two tests on an isokinetic dynamometer, one to evaluate PT and one to evaluate FI. Significant interactions were found for sex and resistance training status with both PT and FI. In general, resistance-trained subjects had higher PT, and women showed lower PT than men. PT values were 67.12 ± 9.93 N·m for RTM, 49.9 ± 8.5 N·m for NRTM, 41.84 ± 7.52 N·m for RTW, and 26.05 ± 3.34 N·m for NRTW. Separate analysis revealed that RTM had higher PT than all other groups. However, FI was higher for NRTM than for RTM and NRTW and no difference was found between RTM and NRTW. FI was 37.86 ± 10.89 % for RTW, 45.74 ± 13.17 % for NTRW, 45.89 ± 8.24 % for RTM, and 51.92 ± 4.5 % for NRTM. Women produce lower PT, and have a higher fatigue tolerance than men of similar training status. Considering that women showed to be more resistant to fatigue than men, women can manipulate training variables differently from men, such as, including more repetitions at the same relative load or using higher relative loads at the same number of repetitions.
Cytotoxicity of multi-walled carbon nanotubes in three skin cellular models: Effects of sonication, dispersive agents and corneous layer of reconstructed epidermis

Abstract The effects of multi-walled carbon nanotubes were investigated in SZ95 sebocytes, IHK keratinocytes and reconstructed human epidermises. Carbon nanotubes were subjected to dispersion protocols leading to different agglomeration states. Toxicological methods were chosen and adapted in order to ensure compatibility with nanotubes. Results show that: (i) Water-suspended nanotubes, as micrometric agglomerates, were not harmful to skin cells, except minor effects in keratinocytes, (ii) mild sonication slightly decreased nanotube agglomeration but increased cytotoxicity on keratinocytes, (iii) addition of hydroxypropylcellulose or Pluronic F108, which improved nanotube dispersion, masked the harmful effects of sonicated nanotubes. Altogether, these results indicate that carbon nanotubes induced cytotoxicity in human keratinocytes after a short exposure (24–48 h), particularly when they were sonicated before cell incubations. However, the cytotoxic effects of raw and sonicated nanotubes could be prevented in presence of dispersive agents. No cytotoxic effects were observed in SZ95 sebocytes or in stratified epidermises reconstructed in vitro.
Use of serum biomarkers to predict the development and severity of osteochondrosis lesions in the distal portion of the femur in pigs.

OBJECTIVE To evaluate the use of serum biomarkers of cartilage and bone metabolism to predict the occurrence and severity of osteochondrosis (OC) lesions in the distal portion of the femur in growing swine. ANIMALS 71 gilts. PROCEDURES At an abattoir, serum samples for analysis of 10 biomarkers indicative of cartilage and bone metabolism were obtained prior to processing of the pigs. The distal portion of each pig's left femur was directly examined and cut into longitudinal sections to evaluate the number and severity of abnormalities on the external surface, articular cartilage, and growth plate. Each specimen was categorized as with (n = 56) or without (15) OC, and an overall OC severity score was assigned to affected pigs. Logistic and linear regression analyses were performed to predict odds of OC on the basis of biomarker concentrations and predict the severity of OC values in affected pigs, respectively. RESULTS Compared with values in unaffected pigs, serum concentrations of C-propeptide of type II collagen (CPII) and cartilage oligomeric matrix protein were significantly increased and concentrations of carboxy-terminal telopeptide of type II collagen 3/4-length fragment (C2C) and pyridinoline cross-links were significantly decreased in affected pigs. A 2-fold increase in CPII concentration increased the odds of pigs having OC by a factor of 97 (95% confidence interval, 6 to infinity). Changes in serum C2C concentration accounted for 49% of the variation in overall OC severity score. CONCLUSIONS AND CLINICAL RELEVANCE Assessment of serum biomarker concentrations may be useful in the diagnosis of OC and aid in reduction of lameness in swine herds.
New Models and Methods for Formation and Analysis of Social Networks

This doctoral work focuses on three main problems related to social networks: (1) Orchestrating Network Formation: We consider the problem of orchestrating formation of a social network having a certain given topology that may be desirable for the intended usecases. Assuming the social network nodes to be strategic in forming relationships, we derive conditions under which a given topology can be uniquely obtained. We also study the efficiency and robustness of the derived conditions. (2) Multi-phase Influence Maximization: We propose that information diffusion be carried out in multiple phases rather than in a single instalment. With the objective of achieving better diffusion, we discover optimal ways of splitting the available budget among the phases, determining the time delay between consecutive phases, and also finding the individuals to be targeted for initiating the diffusion process. (3) Scalable Preference Aggregation: It is extremely useful to determine a small number of representatives of a social network such that the individual preferences of these nodes, when aggregated, reflect the aggregate preference of the entire network. Using real-world data collected from Facebook with human subjects, we discover a model that faithfully captures the spread of preferences in a social network. We hence propose fast and reliable ways of computing a truly representative aggregate preference of the entire network. In particular, we develop models and methods for solving the above problems, which primarily deal with formation and analysis of social networks.
EPIYA Motif Is a Membrane-targeting Signal of Helicobacter pylori Virulence Factor CagA in Mammalian Cells*

Helicobacter pylori contributes to the development of peptic ulcers and atrophic gastritis. Furthermore, H. pylori strains carrying the cagA gene are more virulent than cagA-negative strains and are associated with the development of gastric adenocarcinoma. The cagA gene product, CagA, is translocated into gastric epithelial cells and localizes to the inner surface of the plasma membrane, in which it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. Tyrosine-phosphorylated CagA specifically binds to and activates Src homology 2-containing protein-tyrosine phosphatase-2 (SHP-2) at the membrane, thereby inducing an elongated cell shape termed the hummingbird phenotype. Accordingly, membrane tethering of CagA is an essential prerequisite for the pathogenic activity of CagA. We show here that membrane association of CagA requires the EPIYA-containing region but is independent of EPIYA tyrosine phosphorylation. We further show that specific deletion of the EPIYA motif abolishes the ability of CagA to associate with the membrane. Conversely, reintroduction of an EPIYA sequence into a CagA mutant that lacks the EPIYA-containing region restores membrane association of CagA. Thus, the presence of a single EPIYA motif is necessary for the membrane localization of CagA. Our results indicate that the EPIYA motif has a dual function in membrane association and tyrosine phosphorylation, both of which are critically involved in the activity of CagA to deregulate intracellular signaling, and suggest that the EPIYA motif is a crucial therapeutic target of cagA-positive H. pylori infection.
Reclassification and emended description of Caulobacter leidyi as Sphingomonas leidyi comb. nov., and emendation of the genus Sphingomonas.

'Caulobacter leidyi' DSM 4733(T) has been shown to be affiliated with the family Sphingomonadaceae instead of the Caulobacteraceae, and due to its poor characterization has been omitted from the current edition of Bergey's Manual of Systematic Bacteriology and removed to limbo. We isolated a novel sphingoglycolipid-containing dimorphic prosthecate bacterium, designated strain 247, from a pre-alpine freshwater lake. Strain 247 and 'Caulobacter leidyi' DSM 4733(T) were characterized in detail. The rod-shaped cells were Gram-stain-negative, aerobic, catalase- and oxidase-positive, and formed a stalk or polar flagellum. Both strains grew optimally at 28-30 °C, and pH 6.0-8.0. The major fatty acids were C(18 : 1)ω7c, C(16 : 0) and 11-methyl C(18 : 1)ω7c. C(14 : 0) 2-OH represents the major 2-hydroxy fatty acid. Q-10 was the major respiratory quinone and the major polar lipids were diphosphatidylglycerol, phosphatidyldimethylethanolamine, phosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylcholine, three glycolipids, two phosphoaminolipids and two unidentified sphingoglycolipids. The major polyamine was sym-homospermidine. The G+C content of genomic DNA of strains 247 and DSM 4733(T) was 67.6 mol% and 67.0 mol%, respectively. According to 16S rRNA gene sequence analysis and DNA-DNA hybridization, strains DSM 4733(T) and 247 were phylogenetically closely related (99.6 % 16S rRNA gene sequence similarity, 82.9 % DNA-DNA hybridization value) and affiliated to the genus Sphingomonas. The closest recognized species was Sphingomonas aquatilis DSM 15581(T) (98.1 % sequence similarity). In addition, the presence of cystine arylamidase, absence of β-galactosidase, and the inability to utilize l-arabinose, galactose and sucrose distinguished strains DSM 4733(T) and 247 from most other members of the family Sphingomonadaceae. So far, the dimorphic life cycle that involves a prosthecate and a flagellated stage is unique for strains DSM 4733(T) and 247 among all members of the family Sphingomonadaceae. Therefore, Caulobacter leidyi is reclassified as Sphingomonas leidyi, with the type strain DSM 4733(T) ( = ATCC 15260(T) = CIP 106443(T) = VKM B-1368(T)) and strain 247 (DSM 25078 = LMG 26658) as an additional strain of this species.
Perineal Group A Streptococcal Disease in a Pediatric Practice

Objective. This study was designed to document the frequency and define the clinical, epidemiologic, and microbiologic characteristics of perineal disease caused by group A β-hemolytic streptococci (GAS) in a pediatric practice in which increased numbers of cases had been observed. Methods. Clinical, epidemiologic, and microbiologic data were collected on all culture-confirmed cases of perineal GAS disease during the calendar year 1997. GAS isolates from clinical cases and a comparison group of children with GAS pharyngitis were analyzed by T typing, emm gene analysis, and pulsed-field gel electrophoresis (PFGE). Results. Twenty-three cases of GAS perineal disease were diagnosed during 4530 office visits in 1997. Thirteen cases had perianal disease, 8 had vulvovaginal infection, and 2 were infected at both sites. No cases of penile disease were identified. Infections peaked in late winter and early spring and affected children with an average age of 5 years with a range of perineal, gastrointestinal, and genitourinary symptoms. Analysis of T and emm types showed the majority (82%) of perineal isolates to be T 28emm 28, showing 2 closely related PFGE patterns. In contrast, the pharyngeal isolates were distributed among 6 different T and emm types. Conclusion. Perineal infection caused by GAS may be a relatively common diagnosis in a pediatric or family practice setting. There may be specific GAS types that have a tropism for perineal tissues but the mechanism of infection is yet to be established.
A Role for Stefin B (Cystatin B) in Inflammation and Endotoxemia*

Background: The lack of cysteine cathepsin inhibitor, stefin B (cystatin B), results in progressive myoclonus epilepsy, type 1. Results: Stefin B deficiency in macrophages resulted in increased inflammasome activation. Conclusion: Stefin B-deficient mice are significantly more sensitive to e LPS-induced sepsis due to increased caspase-11 expression and mitochondrial damage. Significance: Stefin B has an important role in limiting the inflammatory response during LPS-induced sepsis. Stefin B (cystatin B) is an endogenous cysteine cathepsin inhibitor, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht-Lundborg disease (EPM1). In this study we demonstrated that stefin B-deficient (StB KO) mice were significantly more sensitive to the lethal LPS-induced sepsis and secreted higher amounts of pro-inflammatory cytokines IL-1β and IL-18 in the serum. We further showed that increased caspase-11 gene expression and better pro-inflammatory caspase-1 and -11 activation determined in StB KO bone marrow-derived macrophages resulted in enhanced IL-1β processing. Pretreatment of macrophages with the cathepsin inhibitor E-64d did not affect secretion of IL-1β, suggesting that the increased cathepsin activity determined in StB KO bone marrow-derived macrophages is not essential for inflammasome activation. Upon LPS stimulation, stefin B was targeted into the mitochondria, and the lack of stefin B resulted in the increased destabilization of mitochondrial membrane potential and mitochondrial superoxide generation. Collectively, our study demonstrates that the LPS-induced sepsis in StB KO mice is dependent on caspase-11 and mitochondrial reactive oxygen species but is not associated with the lysosomal destabilization and increased cathepsin activity in the cytosol.
Choroidopathy of systemic lupus erythematosus

Purpose: To describe the ocular and systemic manifestations associated with systemic lupus erythematosus (SLE) choroidopathy. Methods: Three new cases of choroidopathy in patients with active SLE were described. Twentyfive published cases of lupus choroidopathy were summarized. Results: There have been 28 cases of lupus choroidopathy (47 involved eyes) that have been reported in the English literature since 1968, including the three current cases. Only two of the patients were male. The choroidopathy was bilateral in 19 patients (68%). All 28 patients (100%) had active systemic vascular disease at the onset of their choroidopathy; 18 (64%) had nephropathy and 10 (36%) had central nervous system (CNS) lupus vasculitis. All but one of the patients had a known diagnosis of SLE at the onset of choroidopathy. 30 of the 47 involved eyes had presenting visual acuity of 20=40 or better; 14 eyes showed improvement in visual acuity with therapy. 23 patients (82%) had resolution of their choroidopathy when their systemic disease was brought under control. Despite treatment, 4 of the 28 patients (14%) died from complications of SLE. Conclusions: Although less known than retinopathy, lupus choroidopathy may be more common than generally appreciated. It usually serves as a sensitive indicator of lupus activity. The presence of SLE choroidopathy is generally indicative of coexistent (although sometimes occult) nephropathy, CNS vasculitis, and other SLE visceral lesions. Immunomodulation of the systemic disease can lead to improvement and resolution of the systemic vasculitis as well as the choroidopathy.
Generation of Reactive Oxygen Species by Endothelial and Smooth Muscle Cells: Influence of Hyperglycemia and Metformin

There is evidence that reactive oxygen intermediates (ROI) play an important role in the pathogenesis of vascular complications in diabetes. On the other hand, metformin, one of the most often used antidiabetic compounds has not only been shown to reduce the risk for vascular complications, but in addition these protective effects are largely independent of its well-known antihyperglycemic action. Therefore, to explain the vasculoprotective effects of metformin, a direct antioxidative action of this compound has been suggested. We show here that human endothelial cells (HUVEC) generate ROI not only in response to high glucose (30 mmol/l glucose), but also in response to palmitic acid, and advanced glycation end-products (carboxymethyllysine and S100 proteins). Metformin inhibited the production of ROI in response to all these stimuli. By double staining-dichlorofluorescein as marker of ROI and Mitotracker CMH-Ros for mitochondria-the mechanism of ROI generation was analyzed in more detail in smooth muscle cells. Our data suggest that ROI are generated by uncoupling of the mitochondrial respiratory chain as well as by activation of the cytosolic NADPH-oxidase. A complete inhibition of ROI generation is only achieved by simultaneous inhibition of the mitochondrial electron flux (theonyltrifluoroacetone) and NADPH-oxidase (apocynin). Our data suggest that the various processes contributing to generation of ROI are closely linked. Activation of AMP kinase may represent an important mechanism to understand the antioxidative effects of metformin on the mitochondrial and cytosolic generation of ROI.
Effects of Adipose Tissue Stem Cell Concurrent with Greater Omentum on Experimental Long-Bone Healing in Dog

Repair of large bone defects resulting from trauma, tumors, and osteitis is a current challenge to surgeons. Adipose-derived adult stem cells (ASCs) are multipotent cells that are able to differentiate into osteoblasts in the presence of certain factors. In this study, the role of greater omentum as a scaffold incorporation of ASCs was evaluated in long-bone defect healing in dog model. Sixteen 3–4-year-old, male adult mongrel dogs, weighing 25.2 ± 3.5 kg, were used in this study. In the control group (n = 4), the defect was left empty. In the omental group (n = 4), the defect was filled with harvested omentum. In the omental-ASCs group (n = 4), the defect was filled with omentum and 1 mL of ASCs was injected into the grafted omentum. In the omental-culture medium group (n = 4), 1 mL of culture medium was injected into the grafted omentum. Finally, the injured radial bones were fixed with plate and screw. Radiographs of each forelimb was taken postoperatively on the first day and at the second, fourth, sixth, and eighth weeks postinjury to evaluate bone formation, union, and remodeling of the defect. The operated radii were removed on the 56th postoperative day and were histopathologically evaluated. In this study, both omental-culture medium and omental-ASCs groups demonstrated superior osteogenic potential in healing the radial bone defect. Compared to those of the omental and control groups, more advanced bone healing criteria were present in the omental-culture medium and omental-ASCs groups at radiological and histopathological levels at 8 weeks postsurgery.