Miracle-dz/UniFAR-FTUs huggingface dataset:
Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans.

BACKGROUND Bronchiolitis obliterans is the most significant complication adversely affecting prolonged survival of lung allograft recipients. The evolution from the initial insult to the final pathologic entity is largely unknown. The aim of this study was to characterize the evolution of transplant-induced fibrous airway obliteration in a rat tracheal transplant model of bronchiolitis obliterans. METHODS Tracheal segments were transplanted from Brown Norway rats to Brown Norway rats (isografts) or to Lewis rats (allografts). Grafts were implanted into a subcutaneous pouch and an abdominal omental wrap. They were harvested at 14 different time points (from 1 day to 1 year after transplantation) and assessed histologically. RESULTS The fibrous airway obliteration developed only in allografts showing a triphasic time course: an initial ischemic phase (observed in both isografts and allografts) was followed by a marked lymphocytic infiltrative phase with complete epithelial loss (observed only in allografts, P<0.01), and finally by an obliterative phase with fibrous obliteration of the allograft airway lumen (P<0.01). CONCLUSIONS This animal model shows a distinct and reproducible triphasic time course in the development of obliterative airway lesions in allografts. It confirms that the mechanism leading to airway obliteration is immune mediated as only allografts showed this lesion and that lymphocytic infiltration is a precursor of the lesion in this model. The insights into the different phases demonstrated may lead to novel approaches regarding the type and timing of therapeutic interventions.
An algorithm to aid in the investigation of thalassemia trait in multicultural populations.

CONTEXT The differentiation between iron deficiency and a thalassemia syndrome is an important consideration in the investigation of microcytic anemia. OBJECTIVE An established statistical method was used to demonstrate the importance of considering ethnic background in combination with mean cell volume (MCV) in the investigation of beta-thalassemia trait in a multicultural urban population. DESIGN Posttest probabilities for beta-thalassemia trait were calculated using likelihood ratios for various microcytic MCV ranges in conjunction with published pretest probabilities for beta-thalassemia trait based on ethnic background. SETTING Regional hemoglobinopathy laboratory, St Joseph's Hospital, Hamilton, Ontario, Canada. PATIENTS Patient data were derived from a previously published study. The original study cohort consisted of 789 patients aged 18 years or older who had an MCV less than 80 fL and were referred for routine complete blood count during a 6-month period. MAIN OUTCOME MEASURES Posttest probabilities. RESULTS Simplified tables for the determination of posttest probabilities for beta-thalassemia trait in individual patients based on ethnic background and MCV are provided. An algorithm to assist in determining when thalassemia investigations are indicated is presented. CONCLUSIONS A high index of suspicion based on ethnic background and low MCV can provide increased sensitivity and specificity for the detection of thalassemia trait in centers with multicultural populations similar to the study population.
A phylogenetic reconstruction and emendation of Agaricus section Duploannulatae

Agaricus section Duploannulatae comprises the group of species allied with A. bisporus and A. bitorquis. Disagreement exists in the literature regarding the composition of this group. We used DNA sequence data from the ITS segments of the nuclear ribosomal DNA region, in a sample of European and North American isolates, to identify characters shared by this group, to further delimit species-level taxa within the section, and to develop a phylogenetic hypothesis. Shared polymorphisms that suggest a natural limit for section Duploannulatae were found. ITS1 data were assessed using parsimony, distance and maximum likelihood methods of phylogeny. The section Duploannulatae comprised six robust clades. Five clades corresponded to well characterized species from the temperate Northern Hemisphere (A. bisporus, A. subfloccosus, A. bitorquis, A. vaporarius, A. cupressicola). The sixth clade encompassed an A. devoniensis complex. Species concepts, nomenclature, and relationships are discussed and compared with prior reports.
Tuberculosis treatment outcomes in State Hospital, Osogbo, southwestern Nigeria: a four year review.

BACKGROUND A retrospective review of all cases of tuberculosis (TB) enrolled in the directly observed treatment-short course chemotherapy (DOT-SCC) between June 2000 and June 2004 at a General Hospital in Southwestern Nigeria was undertaken. The aim is to determine treatment outcomes and ascertain the effectiveness of the programme for TB control. METHODOLOGY Case registers of all TB patients enrolled were reviewed and data obtained analyzed by statistical methods. RESULTS A total of 879 TB patients (467 males, 412 females; M: F ratio 1.13:1) aged 1 to 80 years (mean age 33.0 +/- 14.0 years) were enrolled. The disease was pulmonary in 98.4% and extrapulmonary in 1.6%. Seven hundred and thirty four (83.6%) patients complied with the DOTS-SCC regimen, 127 (14.4%) defaulted while 18 (2%) transferred out. The overall treatment success rate was 76.3% while 3.8% had treatment failures. Outcome was not significantly affected by types of TB lesion (P = 0.1103), patient category (P = 0.4968), age (P = 0.7198), gender (P = 0.1726) or smear positivity (P = 0.5497). CONCLUSION Although the currently advocated DOT-SCC regimen achieved a high success rate in this locality, it fell below the 85% recommended target. There is need to step up health education campaign on compliance with therapy and aggressively follow up defaulters to forestall the emergence of multidrug resistant M. tuberculosis.
Deducing polymeric structure from aqueous molecular dynamics simulations of oligosaccharides: predictions from simulations of hyaluronan tetrasaccharides compared with hydrodynamic and X-ray fibre diffraction data.

Molecular dynamics simulations of the two hyaluronan tetrasaccharides in water predict that over a period of 500 ps, their central linkages populate a single primary minima. Over the same period the peripheral linkages explore this minima, but also a secondary minima. Structures constructed using the primary minima were found to be extended left-handed helices of axial rise per disaccharide (h) 0.8 to 1.0 nm and 2.8 to 4.5 disaccharides per turn (n), in good agreement with n=3 and n=4 helices found by X-ray fibre diffraction studies. We have used the predicted average conformation from molecular dynamics to calculate the translational diffusion coefficients of the oligosaccharide series up to decasaccharide, and compared these with experimental measurements obtained using the method of capillary dispersion. Our calculated values are found to be in good agreement with experiment beyond the size of a tetrasaccharide. A partial digest of hyaluronan in the molecular mass range 10 to 100 kDa was fractionated by gel chromatography. Molecular weights were determined by in-line laser light-scattering measurements, and the translational diffusion coefficients of selected fractions were determined by dynamic laser light-scattering. A similar experiment was performed on hyaluronan with a molecular mass greater than 1MDa. The data suggest a change from rod-like to stiff coil behaviour beyond a molecular weight of 10 kDa. We have also examined the conformations available using the secondary minima, found at the peripheral linkages. In contrast to the extended structures previously described we have found left and right-handed helices with high values of n (5-10) and low values of h. Although there is no experimental evidence for these structures, they are of interest as, over short stretches, they would introduce folds, loops, and turns into the hyaluronan molecule. Such shapes may play an important role in the hydrodynamics of hyaluronan and its interaction with lipids and proteins.
Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood‐Derived Mesenchymal Stem Cells

Therapeutic applications of mesenchymal stem cells (MSCs) for treating various diseases have increased in recent years. To ensure that treatment is effective, an adequate MSC dosage should be determined before these cells are used for therapeutic purposes. To obtain a sufficient number of cells for therapeutic applications, MSCs must be expanded in long‐term cell culture, which inevitably triggers cellular senescence. In this study, we investigated the surface markers of human umbilical cord blood‐derived MSCs (hUCB‐MSCs) associated with cellular senescence using fluorescence‐activated cell sorting analysis and 242 cell surface‐marker antibodies. Among these surface proteins, we selected the melanoma cell adhesion molecule (MCAM/CD146) for further study with the aim of validating observed expression differences and investigating the associated implications in hUCB‐MSCs during cellular senescence. We observed that CD146 expression markedly decreased in hUCB‐MSCs following prolonged in vitro expansion. Using preparative sorting, we found that hUCB‐MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence‐associated β‐galactosidase, compared with that observed in hUCB‐MSCs with low‐level CD146 expression. In contrast, CD146 downregulation with small interfering RNAs enhanced the senescence phenotype. In addition, CD146 suppression in hUCB‐MSCs caused downregulation of other cellular senescence regulators, including Bmi‐1, Id1, and Twist1. Collectively, our results suggest that CD146 regulates cellular senescence; thus, it could be used as a therapeutic marker to identify senescent hUCB‐MSCs.
Crucial Role of Bysl in Mammalian Preimplantation Development as an Integral Factor for 40S Ribosome Biogenesis

ABSTRACT Blastocyst formation during mammalian preimplantation development is a unique developmental process that involves lineage segregation between the inner cell mass and the trophectoderm. To elucidate the molecular mechanisms underlying blastocyst formation, we have functionally screened a subset of preimplantation embryo-associated transcripts by using small interfering RNA (siRNA) and identified Bysl (bystin-like) as an essential gene for this process. The development of embryos injected with Bysl siRNA was arrested just prior to blastocyst formation, resulting in a defect in trophectoderm differentiation. Silencing of Bysl by using an episomal short hairpin RNA expression vector inhibited proliferation of embryonic stem cells. Exogenously expressed Bysl tagged with a fluorescent protein was concentrated in the nucleolus with a diffuse nucleoplasmic distribution. Furthermore, the loss of Bysl function by using RNA interference or dominant negative mutants caused defects in 40S ribosomal subunit biogenesis. These findings provide evidence for a crucial role of Bysl as an integral factor for ribosome biogenesis and suggest a critical dependence of blastocyst formation on active translation machinery.
Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes–Prone Mice

Autoreactive B lymphocytes that commonly arise in the developing repertoire can be salvaged by receptor editing, a central tolerance mechanism that alters BCR specificity through continued L chain rearrangement. It is unknown whether autoantigens with weak cross-linking potential, such as insulin, elicit receptor editing, or whether this process is dysregulated in related autoimmunity. To resolve these issues, we developed an editing-competent model in which anti-insulin Vκ125 was targeted to the Igκ locus and paired with anti-insulin VH125Tg. Physiologic, circulating insulin increased RAG-2 expression and was associated with BCR replacement that eliminated autoantigen recognition in a proportion of developing anti-insulin B lymphocytes. The proportion of anti-insulin B cells that underwent receptor editing was reduced in the type 1 diabetes–prone NOD strain relative to a nonautoimmune strain. Resistance to editing was associated with increased surface IgM expression on immature (but not transitional or mature) anti-insulin B cells in the NOD strain. The actions of mAb123 on central tolerance were also investigated, because selective targeting of insulin-occupied BCR by mAb123 eliminates anti-insulin B lymphocytes and prevents type 1 diabetes. Autoantigen targeting by mAb123 increased RAG-2 expression and dramatically enhanced BCR replacement in newly developed B lymphocytes. Administering F(ab′)2123 induced IgM downregulation and reduced the frequency of anti-insulin B lymphocytes within the polyclonal repertoire of VH125Tg/NOD mice, suggesting enhanced central tolerance by direct BCR interaction. These findings indicate that weak or faulty checkpoints for central tolerance can be overcome by autoantigen-specific immunomodulatory therapy.
The lag time between onset of symptoms and diagnosis of rheumatoid arthritis.

OBJECTIVE Rheumatoid arthritis (RA) may be biologically reversible if treated in the first several months, yet it is unknown whether patients are diagnosed that early. We investigated the lag time between symptom onset and diagnosis of RA in a population with excellent access to rheumatology care. METHODS Using review of medical records, we evaluated all patients newly diagnosed as having RA from 1987 through 1990, at a health maintenance organization in central Massachusetts. Total lag time from symptom onset to first definite diagnosis was divided into medical encounter lag time (from symptom onset to first medical encounter) and diagnosis lag time (from first medical encounter to diagnosis). RESULTS The median total lag time was 36 weeks (range 4 weeks to > 10 years). The median medical encounter lag time was 4 weeks (not all patients included in the analysis). The median diagnosis lag time was 18 weeks. Diagnosis lag time was shorter for patients with progressive disease and positive rheumatoid factor on the initial test. Of 25 patients with symmetric arthritis and positive rheumatoid factor, only 5 (20%) were diagnosed within 2 months, and 10 (40%) were diagnosed more than 6 months after symptom onset. CONCLUSION RA diagnosis is usually delayed for several months after symptoms begin, in large part because of delay in diagnosis by the physician. Thus, the goal of initiating treatment extremely early may be unrealistic for most patients.
In Silico Identification of Candidate Genes for Fertility Restoration in Cytoplasmic Male Sterile Perennial Ryegrass (Lolium perenne L.)

Perennial ryegrass (Lolium perenne L.) is widely used for forage production in both permanent and temporary grassland systems. To increase yields in perennial ryegrass, recent breeding efforts have been focused on strategies to more efficiently exploit heterosis by hybrid breeding. Cytoplasmic male sterility (CMS) is a widely applied mechanism to control pollination for commercial hybrid seed production and although CMS systems have been identified in perennial ryegrass, they are yet to be fully characterized. Here, we present a bioinformatics pipeline for efficient identification of candidate restorer of fertility (Rf) genes for CMS. From a high-quality draft of the perennial ryegrass genome, 373 pentatricopeptide repeat (PPR) genes were identified and classified, further identifying 25 restorer of fertility-like PPR (RFL) genes through a combination of DNA sequence clustering and comparison to known Rf genes. This extensive gene family was targeted as the majority of Rf genes in higher plants are RFL genes. These RFL genes were further investigated by phylogenetic analyses, identifying three groups of perennial ryegrass RFLs. These three groups likely represent genomic regions of active RFL generation and identify the probable location of perennial ryegrass PPR-Rf genes. This pipeline allows for the identification of candidate PPR-Rf genes from genomic sequence data and can be used in any plant species. Functional markers for PPR-Rf genes will facilitate map-based cloning of Rf genes and enable the use of CMS as an efficient tool to control pollination for hybrid crop production.
Control and variability of gastric pH in critically ill children

To determine the effect of illness severity and acute central nervous system injury on the control and variability of gastric pH in pediatric intensive care unit (ICU) patients receiving ranitidine. Design:Prospective, descriptive study. Setting:Pediatric ICU of a children's hospital. Patients:Fourteen pediatric ICU patients. Interventions:Ranitidine (4 mg/kg/day) was administered to all patients. Measurements and Main Results:Patients enrolled in the study were divided into two groups based on illness type and severity. Illness severity was measured by the Pediatric Risk of Mortality (PRISM) score, with a PRISM score of >20 defining severe illness. Illness type was designated as central nervous system or noncentral nervous system. Gastric pH was continuously monitored in all patients using an intragastric, pH-sensitive electrode. Poor control of gastric pH was defined as a pH of <4.0 for >20% of the time monitored. The statistical significance of the differences between groups was measured using the Wilcoxon two-sample test or Fisher's exact test. Patients with severe illness or acute central nervous system injury had a lower mean gastric pH than all other patients (4.6 vs. 6.4;p = .008) and spent more time with a gastric pH of <4.0 than other patients (47.5% of time monitored vs. 12.5% of time monitored; p = .003). Poor control of gastric pH occurred in 100% of patients with severe illness or acute central nervous system injury, while only 20% of the remaining patients had poor control of gastric pH (p = .01). Using power-spectrum analysis to evaluate gastric pH variability, gastric pH in patients receiving bolus ranitidine was more variable than gastric pH in patients receiving ranitidine continuously (p = .045). Illness severity or type had no effect on gastric pH variability (p = .78). Conclusions:a) Continuous infusion of ranitidine decreases variability of gastric pH in pediatric ICU patients; b) gastric pH variability may make intermittent monitoring of gastric pH inaccurate; c) children with acute central nervous system injury or PRISM scores of ≥20 have poor control of gastric pH; d) type of injury and PRISM scores predict response to ranitidine therapy. (Crit Care Med 1993; 21:1850–1855)
Information Acquisition and Welfare in Network Games

This paper studies information acquisition and use in network games. The network structure incorporates both strategic complements (positive links) and substitutes (negative links). An information-use game played on a correlation-adjusted network is derived. Equilibrium inefficiencies in both acquisition and use of information are characterized. Inefficient bunching obtains in information acquisition, where the spread in equilibrium signal precisions is below that prescribed by the planner. The welfare analysis offers a policy intervention publicizing players' information investments. The more linked a player is, positively or negatively, the more strongly they respond to the policy to influence others' information acquisition and use.
NF‐κB‐regulated suppression of T‐bet in T cells represses Th1 immune responses in pregnancy

The molecular mechanisms that suppress Th1 immune responses in pregnancy are unknown. We assessed the expression of the Th1 cytokine transcription factor T‐bet. We isolated PBMC and T cells from non‐pregnant and pregnant women and demonstrated that T‐bet is specifically down‐regulated in pregnancy under basal and stimulated conditions. Low levels of T‐bet protein were detected in the nuclear fraction of unstimulated PBMC from non‐pregnant, but not pregnant women. Nuclear levels of T‐bet increased in response to PMA/ionomycin in PBMC from non‐pregnant, but not pregnant women. T‐bet expression was greater in whole cell lysates of stimulated CD3+ T cells from non‐pregnant relative to pregnant women. NF‐κB is specifically down‐regulated in T cells in pregnant women, resulting in suppressed expression of Th1 cytokines IL‐2, IFN‐γ and TNF‐α. In this study, down‐regulation of NF‐κB also resulted in diminished expression of T‐bet. PMA induces NF‐κB translocation, T‐bet expression and IL‐2, IFN‐γ and TNF‐α production. Conversely, pre‐incubation with SN50, and NF‐κB oligodeoxyribonucleotide decoys suppressed PMA‐induced NF‐κB translocation and gene transcription, respectively, resulting in diminished T‐bet expression and Th1 cytokine production. Therefore, maintenance of the cytokine environment for pregnancy success is mediated via strict regulation of Th1 immune responses, more specifically through control of NF‐κB and T‐bet transcription.
Immunogenicity, safety, and immune persistence of a novel inactivated human enterovirus 71 vaccine: a phase II, Randomized, double-blind, placebo-controlled Trial.

BACKGROUND Vaccination is considered a top priority for the control of human enterovirus 71 (EV71) infection outbreaks. METHODS On the basis of phase I trial results, we conducted a double-blind, randomized, controlled trial to evaluate the optimal dose, immunogenicity, safety and immune persistence of the vaccine. A total of 480 healthy infants were randomly assigned to receive 2 injections of 100 U of vaccine, 200 U of vaccine, 400 U of vaccine, or placebo. Solicited adverse events (AEs) within 7 days and unsolicited AEs within 28 days after each vaccination were collected for safety evaluation. Blood samples were collected for neutralizing antibody assay. RESULTS EV71 vaccine was well tolerated, and no dose-related safety concerns were observed. Two doses of the vaccine yielded seropositivity frequencies of 92.3%, 95.9%, and 99.0% (with titers ≥1:8) in the 100 U, 200 U, and 400 U groups, respectively. Geometric mean titers measured by neutralizing antibody assay increased to 60.2 (95% confidence interval [CI], 41.9-86.4), 72.8 (95% CI, 50.8-104.3), and 252.1 (95% CI, 180.8-351.6) for the 100 U, 200 U, and 400 U groups, respectively. The dose-response relationship, with the 400 U dose showing higher immunogenicity than the 100 U and 200 U doses, remained until 13 months after the second vaccination, despite waning antibody levels. CONCLUSIONS The 400 U dose was recommended as the optimal dose for the phase III trial because of its good safety profile and higher immunogenicity.