Miracle-dz/UniFAR-FTUs huggingface dataset:
Feed-Forward Regulation of Phagocytosis by Entamoeba histolytica

ABSTRACT The parasitic protozoan Entamoeba histolytica is aptly named for its capacity to destroy host tissue. When E. histolytica trophozoites invade the lamina propria of a host colon, extracellular matrices are degraded while host cells are killed and phagocytosed. The ability of E. histolytica to phagocytose host cells correlates with virulence in vivo. In order to better understand the mechanism of phagocytosis, we used an E. histolytica Affymetrix microarray chip to measure the total gene expression of phagocytic and nonphagocytic subpopulations. Using paramagnetic beads coated with a known host ligand that stimulates phagocytosis, phagocytic and nonphagocytic amoebae from a single culture were purified. Microarray analysis of the subpopulations identified 121 genes with >2-fold higher expression in phagocytic than in nonphagocytic amoebae. Functional annotation identified genes encoding proteins involved in actin binding and cytoskeletal organization as highly enriched gene clusters. Post hoc analyses of selected genes showed that the gene expression profile identified in the microarray experiment did not exist prior to cell sorting but rather was stimulated through phagocytosis. Further, these expression profiles correlated with an increase in phagocytic ability, as E. histolytica cultures exposed to an initial stimulus of phagocytosis showed increased phagocytic ability upon a second stimulus. To our knowledge, this is the first description of such feed-forward regulation of gene expression and phagocytic ability in a phagocyte.
Limited Role of Nuclear Receptor Nur77 in Escherichia coli-Induced Peritonitis

ABSTRACT Nuclear receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to play an anti-inflammatory role in macrophages, which have a crucial function in defense against peritonitis. The function of Nur77 in Escherichia coli-induced peritoneal sepsis has not yet been investigated. Wild-type and Nur77-knockout mice were inoculated with E. coli, and bacterial outgrowth, cell recruitment, cytokine profiles, and tissue damage were investigated. We found only a minor transient decrease in bacterial loads in lung and liver of Nur77-knockout compared to wild-type mice at 14 h postinfection, yet no changes were found in the peritoneal lavage fluid or blood. No differences in inflammatory cytokine levels or neutrophil/macrophage numbers were observed, and bacterial loads were equal in wild-type and Nur77-knockout mice at 20 h postinfection in all body compartments tested. Also, isolated peritoneal macrophages did not show any differences in cytokine expression patterns in response to E. coli. In endothelial cells, Nur77 strongly downregulated both protein and mRNA expression of claudin-5, VE-cadherin, occludin, ZO-1, and β-catenin, and accordingly, these genes were upregulated in lungs of Nur77-deficient mice. Functional permeability tests pointed toward a strong role for Nur77 in endothelial barrier function. Indeed, tissue damage in E. coli-induced peritonitis was notably modulated by Nur77; liver necrosis and plasma aspartate aminotransferase (ASAT)/alanine aminotransferase (ALAT) levels were lower in Nur77-knockout mice. These data suggest that Nur77 does not play a role in the host response to E. coli in the peritoneal and blood compartments. However, Nur77 does modulate bacterial influx into the organs via increased vascular permeability, thereby aggravating distant organ damage.
Mining Protein Kinases Regulation Using Graphical Models

Abnormal kinase activity is a frequent cause of diseases, which makes kinases a promising pharmacological target. Thus, it is critical to identify the characteristics of protein kinases regulation by studying the activation and inhibition of kinase subunits in response to varied stimuli. Bayesian network (BN) is a formalism for probabilistic reasoning that has been widely used for learning dependency models. However, for high-dimensional discrete random vectors the set of plausible models becomes large and a full comparison of all the posterior probabilities related to the competing models becomes infeasible. A solution to this problem is based on the Markov Chain Monte Carlo (MCMC) method. This paper proposes a BN-based framework to discover the dependency correlations of kinase regulation. Our approach is to apply the MCMC method to generate a sequence of samples from a probability distribution, by which to approximate the distribution. The frequent connections (edges) are identified from the obtained sampling graphical models. Our results point to a number of novel candidate regulation patterns that are interesting in biology and include inferred associations that were unknown.
Evaluation of the Single Yeast Cell's Adhesion to ITO Substrates With Various Surface Energies via ESEM Nanorobotic Manipulation System

Cell-surface adhesion force is important for cell activities and the development of biomaterials. In this paper, a method for in situ single cell (W303) adhesion force measurement was proposed based on nanorobotic manipulation system inside an environment scanning electron microscope (ESEM). An end effector was fabricated from a commercial atomic force microscope (AFM) cantilever by focused ion beam (FIB) etching. The spring constant of it was calibrated by nanomanipulation approach. Three kinds of hydrophilic and hydrophobic ITO plates were prepared by using VUV-irradiation and OTS coating techniques. The shear adhesion strength of the single yeast cell to each substrate was measured based on the deflection of the end effector. The results demonstrated that the cell adhesion force was larger under the wet condition in the ESEM environment than in the aqueous condition. It also showed that the cell adhesion force to hydrophilic surface was larger than that to the hydrophobic surface. Studies of single cell's adhesion on various plate surfaces and environments could give new insights into the tissue engineering and biological field.
Adhesion and Proliferation of Osteoblast-Like Cells on Anodic Porous Alumina Substrates With Different Morphology

We have fabricated nanoporous alumina surfaces by means of anodization in oxalic acid in different conditions and used them as the substrates for the growth of cells from a human osteoblast-like cell line. The rough nanoporous alumina substrates have been compared both with smooth standard Petri dishes used as the control and with commercial substrates of similar material. The viability of the cells has been assessed at different culture times of 4, 11, 18, and 25 days in vitro. It turned out that the porous side of the galvanostatically fabricated alumina performed similar to the control and better than the commercial porous alumina, whereas the potentiostatically fabricated porous alumina performed better than all the other substrates at all times, and in particular at the two shortest time periods of 4 and 11 days in vitro. The best performance of the substrates is associated with intermediate surface roughness and feature spacing.
Ceratodermia mutilante de Vohwinkel: relato de três casos em uma família

Keratoderma hereditarium mutilans, or Vohwinkel´s syndrome, is a rare cutaneous disease characterized by thickening of the palms, soles and dorsa of the hands and feet, and by ainhum-like constriction of the fingers. This paper reports a case of three family members, over a span of two generations, who were affected by this disorder. Sensorineural deafness was also observed in each patient. We discuss differential diagnosis and retinoid treatment of this condition. This is the first case report on this disease to come from Brazil.
In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials

Current strategies to delineate the risk of serious drug-induced liver injury associated with drugs rely on assessment of serum biomarkers that have been utilized for many decades. In particular, serum alanine aminotransferase and total bilirubin levels are typically used to assess hepatic integrity and function, respectively. Parallel measurement of these biomarkers is utilized to identify patients with drug-induced hepatocellular jaundice (“Hy’s Law” cases) which carries at least a 10% risk of death or liver transplant. However, current guidelines regarding use of these biomarkers in clinical trials can put study subjects at risk for life-threatening drug-induced liver injury, or result in over estimation of risk that may halt development of safe drugs. In addition, pharmaceutical companies are increasingly being required to conduct large and expensive clinical trials to “defend” the safety of their new drug when results from smaller trials are inconclusive. Innovative approaches and some novel biomarkers are now being employed to maximize the value of traditional biochemical tests. DILIsym®, a product of the DILIsim Initiative, utilizes serial serum alanine aminotransferase values, along with serum biomarkers of apoptosis vs necrosis, to estimate percent hepatocyte loss and total bilirubin elevations resulting from loss of global liver function. The results from analyses conducted with DILIsym have been reported to the FDA to support the safety of entolimod and cimaglermin alfa after elevations in serum alanine aminotransferase and/or bilirubin halted clinical development. DILIsym can also be utilized to determine whether rises in serum conjugated and unconjugated bilirubin are consistent with mechanisms unrelated to toxicity (i.e. inhibition of bilirubin transport or metabolism). In silico modeling of traditional and novel drug-induced liver injury biomarker data obtained in clinical trials may be the most efficient and accurate way to define the liver safety profile of new drug candidates. Impact statement Blood tests used in clinical trials to detect and monitor drug-induced liver injury (DILI) have not changed in half a century. These tests have several shortcomings: their use has not completely prevented clinical trial participants from risk of life-threatening DILI, they can give false positive results that halt the development of safe drug candidates, and they can create liver safety “concerns” that require large additional clinical trials to accurately define DILI risk. This review highlights the use of in silico modeling to improve interpretation of the blood tests currently available to detect DILI risk in new drug candidates. This approach is increasingly being applied in clinical trials to more precisely assess the degree of hepatocellular injury and its functional impact. This new approach holds the promise of more accurately defining DILI risk in smaller clinical trials.
Primary Activation of Antigen-Specific Naive CD4+ and CD8+ T Cells following Intranasal Vaccination with Recombinant Bacteria

ABSTRACT The primary activation of T-helper and T-cytotoxic cells following mucosal immunization with recombinant Streptococcus gordonii was studied in vivo by adoptive transfer of ovalbumin (OVA)-specific transgenic CD8+ (OT-I) and CD4+ (OT-II) T cells. A recombinant strain, expressing on the surface the vaccine antigen Ag85B-ESAT-6 from Mycobacterium tuberculosis fused to OVA T-helper and T-cytotoxic epitopes (peptides 323 to 339 and 257 to 264), was constructed and used to immunize C57BL/6 mice by the intranasal route. Recombinant, but not wild-type, bacteria induced OVA-specific CD4+ and CD8+ T-cell clonal expansion in cervical lymph nodes, lung, and spleen. OVA-specific CD4+ and CD8+ T-cell proliferation appeared first in cervical lymph nodes and later in the spleen, suggesting a possible migration of activated cells from the inductive site to the systemic district. A significant correlation between the percentages of CD4+ and CD8+ proliferating T cells was observed for each animal. The expression of CD69, CD44, and CD45RB on proliferating T lymphocytes changed as a function of the cell division number, confirming T-cell activation following the antigen encounter. These data indicate that intranasal immunization with recombinant S. gordonii is capable of inducing primary activation of naive antigen-specific CD4+ and CD8+ T cells, both locally and systemically.
Memory T-Cell Responses to Vibrio cholerae O1 Infection

ABSTRACT Vibrio cholerae O1 can cause diarrheal disease that may be life-threatening without treatment. Natural infection results in long-lasting protective immunity, but the role of T cells in this immune response has not been well characterized. In contrast, robust B-cell responses to V. cholerae infection have been observed. In particular, memory B-cell responses to T-cell-dependent antigens persist for at least 1 year, whereas responses to lipopolysaccharide, a T-cell-independent antigen, wane more rapidly after infection. We hypothesize that protective immunity is mediated by anamnestic responses of memory B cells in the gut-associated lymphoid tissue, and T-cell responses may be required to generate and maintain durable memory B-cell responses. In this study, we examined B- and T-cell responses in patients with severe V. cholerae infection. Using the flow cytometric assay of the specific cell-mediated immune response in activated whole blood, we measured antigen-specific T-cell responses using V. cholerae antigens, including the toxin-coregulated pilus (TcpA), a V. cholerae membrane preparation, and the V. cholerae cytolysin/hemolysin (VCC) protein. Our results show that memory T-cell responses develop by day 7 after infection, a time prior to and concurrent with the development of B-cell responses. This suggests that T-cell responses to V. cholerae antigens may be important for the generation and stability of memory B-cell responses. The T-cell proliferative response to VCC was of a higher magnitude than responses observed to other V. cholerae antigens.
Deletion of BBA64, BBA65, and BBA66 Loci Does Not Alter the Infectivity of Borrelia burgdorferi in the Murine Model of Lyme Disease

ABSTRACT Borrelia burgdorferi, the causative agent of Lyme disease, alters its gene expression in response to highly disparate environmental signals encountered in its tick vector versus vertebrate hosts. Whole-genome transcriptional profile analysis of B. burgdorferi, propagated in vitro under mammalian-host-specific conditions, revealed significant upregulation of several linear plasmid 54 (lp54)-encoded open reading frames (ORFs). Among these ORFs, BBA64, BBA65, and BBA66 have been shown to be upregulated in response to multiple mammalian-host-specific signals. Recently, we determined that there was no significant difference in the ability of BBA64− mutant to infect C3H/HeN mice compared to its isogenic control strains, suggesting that B. burgdorferi might utilize multiple, functionally related determinants to establish infection. We further generated BBA65− and BBA66− single mutants in a noninfectious, lp25− clonal isolate of B. burgdorferi strain B31 (ML23) and complemented them with the minimal region of lp25 (BBE22) required for restoring the infectivity. In addition, we generated a BBA64− BBA65− BBA66− triple mutant using an infectious, clonal isolate of B. burgdorferi strain B31 (5A11) that has all of the infection-associated plasmids. There were no significant differences in the ability to isolate viable spirochetes from different tissues of C3H/HeN mice infected via intradermal needle inoculation with either the individual single mutants or the triple mutant compared to their respective isogenic parental strains at days 21 and 62 postinfection. These observations suggest that B. burgdorferi can establish infection in the absence of expression of BBA64, BBA65, and BBA66 in the murine model of Lyme disease.
Analysis of Selected Clinical and Laboratory Parameters in Patients with Splenectomy Complications Due to Hematological Disorders

The aim of the study was to investigate the role of certain clinical characteristics and laboratory examination results as prognostic factors for complications after splenectomy in patients with hematological disorders. Material and methods. Ninety-eight adult patients with hematological disorders who underwent splenectomy in our department between years of 1994 and 2004. A retrospective analysis of the medical records from patients who underwent splenectomy was conducted; we divided the patients into 6 groups with various postoperative complications; patients without complications after splenectomy were the control group (the seventh group). Then, we compared patients from groups 1 – 6 with patients from the control group (group 7) before and after splenectomy with regard to various parameters including age, sex, presence of splenomegaly or accessory spleen, the operation’s duration, hemoglobin level, number of erythrocytes, leukocytes and plateletes, levels of protein and fibrinogen, activity of prothrombin, INR, APTT, TT, proteinogram and levels of IgG, IgM and IgA. Results. We found that postoperative complications, especially early complications, were more common in groups with malignant hematological complications and in older patients. Infection complications appear more often in men than in women with benign hematological disorders. The sustained platelet level elevation after splenectomy is positively associated with a higher number of thrombotic complications. Also, a lower level of gamma globulin, IgG and IgM after splenectomy correlated with a higher number of infection complications. Conclusions. Splenectomy in patients with hematological disorders is burdened with small risks of postoperative complications. Some clinical and laboratory parameters can be used to select the group of patients with higher risks of complications, but there remains a lack of objective prognostic factors which are sure in every clinical situation.
Predicting residual disease after excision of cervical dysplasia

Dysplastic epithelium at the resection margin after a cervical cone is known to predict persisting disease. We followed 702 women for 30 months after cervical excision to see which resection margin was predictive. The risk of persisting cytological abnormalities was doubled when CIN extended to the endocervical resection margin and was doubled when there was evidence of HPV. In contrast, disease at the ectocervical resection margin and the grade of CIN were not associated with a higher risk of residual disease.
Endovascular Repair of a Ruptured Internal Iliac Arterial Aneurysm With a Novel Application of the Aorto-uni-iliac Converter Device

Internal iliac artery aneurysms are rarely discovered by examination and may consequently present with rupture in a patient without an established diagnosis. Ruptured internal iliac aneurysms harbor a high risk of morbidity and mortality. Although open repair is possible, endovascular repair may be an option in some patients. We present a case of a ruptured internal iliac artery aneurysm with an adjoining ipsilateral common iliac artery aneurysm repaired with a novel use of an aorto-uni-iliac device.
Helicobacter pylori Stores Nickel To Aid Its Host Colonization

ABSTRACT The transition metal nickel (Ni) is critical for the pathogenicity of Helicobacter pylori. Indeed the element is a required component of two enzymes, hydrogenase and urease, that have been shown to be important for in vivo colonization of the host gastric mucosa. Urease accounts for up to 10% of the total cellular H. pylori protein content, and therefore the bacterial Ni demand is very high. H. pylori possess two small and abundant histidine-rich, Ni-binding proteins, Hpn and Hpn-like, whose physiological role in the host have not been investigated. In this study, special husbandry conditions were used to control Ni levels in the host (mouse), including the use of Ni-free versus Ni-supplemented food. The efficacy of each diet was confirmed by measuring the Ni concentrations in sera of mice fed with either diet. Colonization levels (based on rank tests) of the Δhpn Δhpn-like double mutants isolated from the mice provided Ni-deficient chow were statistically lower than those for mice given Ni in their diet. In contrast, H. pylori wild-type colonization levels were similar in both host groups (e.g., regardless of Ni levels). Our results indicate that the gastric pathogen H. pylori can utilize stored Ni via defined histidine-rich proteins to aid colonization of the host.
AAA Repair: Sociodemographic Disparities in Management and Outcomes

Objective: To evaluate sociodemographic influences on utilization and outcomes of endovascular abdominal aortic repair (EVAR) for the treatment of abdominal aortic aneurysm (AAA). Methods: Secondary data analysis of the State Inpatient Databases for New Jersey. Results: Between 2001 and 2006, a total of 6227 adult subjects (mean [SD] age, 73.3 [8.3] years; 77.6% male) underwent AAA repair (3167 EVAR and 3060 open surgery [OS]). Patients receiving EVAR were older than those undergoing OS (mean [SD] age, 74.2 [8.0] vs 72.4 [8.6] years) (P < .001). Men were 1.60 (95% confidence interval [CI], 1.39-1.77) times more likely to receive EVAR than women. White subjects had the same odds of undergoing EVAR as black subjects, and white subjects had 1.60 (95% CI, 1.29-2.06) times higher odds of receiving EVAR than Hispanics. Subjects with Medicare coverage were 3.90 (96% CI, 2.28-6.59) times more likely to receive EVAR than uninsured subjects. Logistic regression analysis demonstrated that older age, male sex, and Medicare coverage were significantly associated with increased utilization of EVAR and that uninsured subjects and Hispanics are less likely to receive EVAR. Octogenarians and black subjects (odds ratios: 3.69 CI: 2.31-5.91, and 2.59 CI: 1.47-4.54 respectively) had significantly greater likelihood of death after elective AAA repair. Conclusions: For AAA repair, significant sociodemographic disparities exist in the use of endovascular technology and in mortality. The risk of death after elective AAA repair was significantly greater for black subjects. Further analysis is warranted to delineate inequalities of vascular care for AAA and to assist in formulating policy to address these disparities.
Major T Cell Response to a Mycolyl Glycolipid Is Mediated by CD1c Molecules in Rhesus Macaques

ABSTRACT Human CD1b molecules contain a maze of hydrophobic pockets and a tunnel capable of accommodating the unusually long, branched acyl chain of mycolic acids, an essential fatty acid component of the cell wall of mycobacteria. It has been accepted that CD1b-bound mycolic acids constitute a scaffold for mycolate-containing (glyco)lipids stimulating CD1b-restricted T cells. Remarkable homology in amino acid sequence is observed between human and monkey CD1b molecules, and indeed, monkey CD1b molecules are able to bind glucose monomycolate (GMM), a glucosylated species of mycolic acids, and present it to specific human T cells in vitro. Nevertheless, we found, unexpectedly, that Mycobacterium bovis bacillus Calmette-Guerin (BCG)-vaccinated monkeys exhibited GMM-specific T cell responses that were restricted by CD1c rather than CD1b molecules. GMM-specific, CD1c-restricted T cells were detected in the circulation of all 4 rhesus macaque monkeys tested after but not before vaccination with BCG. The circulating GMM-specific T cells were detected broadly in both CD4+ and CD8+ cell populations, and upon antigenic stimulation, a majority of the GMM-specific T cells produced both gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), two major host protective cytokines functioning against infection with mycobacteria. Furthermore, the GMM-specific T cells were able to extravasate and approach the site of infection where CD1c+ cells accumulated. These observations indicate a previously inconceivable role for primate CD1c molecules in eliciting T cell responses to mycolate-containing antigens.