Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

ABSTRACT Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (106 CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3−/−). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3−/− mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3−/− mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3−/− mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility.
Thymic Selection Generates T Cells Expressing Self-Reactive TCRs in the Absence of CD451

The CD45 protein tyrosine phosphatase regulates Ag receptor signaling in T and B cells. In the absence of CD45, TCR coupling to downstream signaling cascades is profoundly reduced. Moreover, in CD45-null mice, the maturation of CD4+CD8+ thymocytes into CD4+CD8− or CD4−CD8+ thymocytes is severely impaired. These findings suggest that thymic selection may not proceed normally in CD45-null mice, and may be biased in favor of thymocytes expressing TCRs with strong reactivity toward self-MHC-peptide ligands to compensate for debilitated TCR signaling. To test this possibility, we purified peripheral T cells from CD45-null mice and fused them with the BWα−β− thymoma to generate hybridomas expressing normal levels of TCR and CD45. The reactivity of these hybridomas to self or foreign MHC-peptide complexes was assessed by measuring the amount of IL-2 secreted upon stimulation with syngeneic or allogeneic splenocytes. A very high proportion (55%) of the hybridomas tested reacted against syngeneic APCs, indicating that the majority of T cells in CD45-null mice express TCRs with high avidity for self-MHC-peptide ligands, and are thus potentially autoreactive. Furthermore, a large proportion of TCRs selected in CD45-null mice (H-2b) were also shown to display reactivity toward closely related MHC-peptide complexes, such as H-2bm12. These results support the notion that modulating the strength of TCR-mediated signals can alter the outcome of thymic selection, and demonstrate that CD45, by molding the window of affinity/avidity for positive and negative selection, directly participates in the shaping of the T cell repertoire.
Ormetoprim-sulfadimethoxine in cattle: pharmacokinetics, bioavailability, distribution to the tears, and in vitro activity against Moraxella bovis.

The pharmacokinetics, bioavailability, and distribution to the tears of ormetoprim (OMP; 5.5 mg/kg of body weight) and sulfadimethoxine (SDM; 27.5 mg/kg of body weight) were determined following IV or oral administration to 6 Holstein steers. After IV administration, the disposition kinetics of both drugs were best described by a 2-compartment open model. Sulfadimethoxine had a moderately rapid distribution phase, followed by a slower elimination phase, with a mean half-life (t 1/2) of 7.91 hours. The mean volume of distribution of SDM was 185 ml/kg, and the mean body clearance was 0.28 ml/min X kg. The concentration of SDM in tears was lower than the corresponding plasma concentration, and the elimination of SDM from tears (t 1/2 = 3.02 hours) was significantly faster than its elimination from plasma (t 1/2 = 7.91 hours). The disposition of OMP administered IV was characterized by a rapid distribution phase, followed by a rapid elimination phase (t 1/2 = 1.37 hours). The high values of the mean volume of distribution (1,450 ml/kg) and mean rate of body clearance (13.71 ml/min X kg) indicated that OMP was widely distributed in the body and was rapidly cleared from the body. Ormetoprim concentrations in tears exceeded corresponding plasma concentrations, and the elimination of OMP from tears was significantly slower (t 1/2 = 1.91 hours) than from plasma (t 1/2 = 1.37 hours). After oral administration of an OMP-SDM combination in bolus form, the absorption of SDM was slow (absorption t 1/2 = 3.32 hours), but complete. (ABSTRACT TRUNCATED AT 250 WORDS)
Brain-Derived Neurotrophic Factor Induces Matrix Metalloproteinase 9 Expression in Neurons via the Serum Response Factor/c-Fos Pathway

ABSTRACT Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the regulation of the transcription of genes that encode proplasticity proteins. In the present study, we provide evidence that stimulation of rat primary cortical neurons with BDNF upregulates matrix metalloproteinase 9 (MMP-9) mRNA and protein levels and increases enzymatic activity. The BDNF-induced MMP-9 transcription was dependent on extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and c-Fos expression. Overexpression of AP-1 dimers in neurons led to MMP-9 promoter activation, with the most potent being those that contained c-Fos, whereas knockdown of endogenous c-Fos by small hairpin RNA (shRNA) reduced BDNF-mediated MMP-9 transcription. Additionally, mutation of the proximal AP-1 binding site in the MMP-9 promoter inhibited the activation of MMP-9 transcription. BDNF stimulation of neurons induced binding of endogenous c-Fos to the proximal MMP-9 promoter region. Furthermore, as the c-Fos gene is a known target of serum response factor (SRF), we investigated whether SRF contributes to MMP-9 transcription. Inhibition of SRF and its cofactors by either overexpression of dominant negative mutants or shRNA decreased MMP-9 promoter activation. In contrast, MMP-9 transcription was not dependent on CREB activity. Finally, we showed that neuronal activity stimulates MMP-9 transcription in a tyrosine kinase receptor B (TrkB)-dependent manner.
What is considered important for life balance? Similarities and differences among some working adults

Abstract Life balance seems subjective, health related, and multidimensional. However, the concept is complex. Exploring what people themselves consider more or less important for their life balance and whether this differs between people would develop new knowledge. Q methodology was chosen for the present study, in which 32 working men and women without recent long-term sick leave participated. They sorted 42 statements regarding life balance according to their importance for each participant's life balance. The analysis resulted in four different viewpoints concerning life balance. All four viewpoints considered good relationships with those closest to them, as well as knowing that these people were doing well, as important. Each viewpoint also showed a unique orientation towards what was considered important for life balance: occupational balance (viewpoint 1), self-actualization (viewpoint 2), self-awareness (viewpoint 3), and reciprocal relationships (viewpoint 4). The results. showed support for life balance as being a subjective, multidimensional, and health-related phenomenon. The results demonstrated the importance of relationships for life balance and heterogeneity in what people considered important for their own life balance.
Minimizing the Severity of rhBMP-2–Induced Inflammation and Heterotopic Ossification With a Polyelectrolyte Carrier Incorporating Heparin on Microbead Templates

Study Design. A rodent model of posterior spinal fusion. Objective. The aim of this study was to evaluate the efficacy of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered with a heparin based polylectrolyte complex (PEC) carrier in facilitating posterior spinal fusion while concurrently minimizing seroma and heterotopic ossification. Summary of Background Data. rhBMP-2 is being used to augment spinal fusion. However, complications such as heterotopic ossification and local soft tissue swellings have been reported. These are attributed to supraphysiological amount of rhBMP-2 and the poor modulation capacity of absorbable collagen sponge. Methods. Forty rats were randomized into 6 groups as follows. Group I: absorbable collagen sponge without rhBMP-2 (n = 4); group II: positive control, absorbable collagen sponge + 10 &mgr;g rhBMP-2 (n = 4); group III: alginate-(poly-L-lysine)-heparin (PEC) without rhBMP-2 (n = 8); group IV: PEC + 4.5 &mgr;g rhBMP-2 (n = 8); group V: PEC + 1.5 &mgr;g rhBMP-2 (n = 8); group VI: PEC + 0.5 &mgr;g rhBMP-2 (n = 8). Results. Between postoperative days 5 and 7, seroma was observed in all rhBMP-2 implanted groups irrespective of carrier and dose. However, the rate and size of seroma differed considerably. Although all animals (100%) in positive control group showed seroma, only one animal (12.5%) in group VI developed seroma at the implant site. The size of seroma in group VI was significantly smaller than that in positive control group. Micro-computed tomography evaluation revealed comparable mean fusion scores in all rhBMP-2 implanted groups. More importantly, although new bone was well contained within the cage in group VI, heterotopic ossification beyond the cage was observed in positive control group. Conclusion. A new carrier has demonstrated capacity to minimize seroma formation as well as heterotopic ossification associated with rhBMP-2 by reducing the efficacious dose needed for consistent fusion. The results of this study indicate that PEC alginate microbeads may represent a new opportunity to define an efficient rhBMP-2 carrier.
Indicated labor induction with vaginal prostaglandin E2 increases the risk of cesarean section even in multiparous women with no previous cesarean section

Abstract Aims: To evaluate the impact of induction of labor with vaginal tablets of prostaglandin E2 on the rate of cesarean section (CS), and to identify possible predictors of successful vaginal delivery. Methods: 1541 consecutive women admitted for induction of labor with vaginal tablets of PGE2 were retrospectively compared with 574 consecutive women with spontaneous onset of labor. Results: Maternal age, nulliparity, previous CS, gestational age, and birth weight were similar in the study and control groups. The CS rate was twofold higher in the study group (20.7% vs 10.6%). CS rates in the study and control groups were 26.9% and 12.8% for the nulliparous women, and 11.2% and 5.1% for the multiparous women with no previous CS. Neither group had major maternal or fetal complications. A logistic regression model and stepwise analysis showed that nulliparity, previous CS, maternal age, number of PGE2 applications, birth weight, and the induction of labor by itself were independent significant risk factors for increased CS rate. Conclusions: Induction of labor with vaginal PGE2 tablets results in a vaginal delivery rate of 79.3%, with apparently no serious maternal or fetal complications. Nulliparity, and previous CS are the most significant risk factors for increased CS rate. However, even after these risk factors are excluded and controlling for possible predictors for CS, PGE2 induction is independently associated with a twofold increase in CS rate, most often because of labor dystocia.
RID1, encoding a Cys2/His2-type zinc finger transcription factor, acts as a master switch from vegetative to floral development in rice

Transition from the vegetative phase to reproductive phase is a crucial process in the life cycle of higher plants. Although the molecular mechanisms of flowering regulation have been extensively characterized in a number of plant species, little is known regarding how the transition process initiates. Here, we show that the Rice Indeterminate 1 (RID1) gene acts as the master switch for the transition from the vegetative to reproductive phase. RID1 encodes a Cys-2/His-2-type zinc finger transcription factor that does not have an ortholog in Arabidopsis spp. A RID1 knockout (rid1), mutated by T-DNA insertion, never headed after growing for >500 days under a range of growth conditions and is thus referred to as a never-flowering phenotype. This mutation-suppressed expression of the genes is known to be involved in flowering regulation, especially in the Ehd1/Hd3a pathway and a series of RFT homologs. RID1 seems to be independent of the circadian clock. A model was proposed to place RID1 in the molecular pathways of flowering regulation in rice, for which there are two indispensable elements. In the first, RID1 is controlling the phase transition and initiation of floral induction. In the other, the Hd3a/RFL1/FTL complex acts as the immediate inducer of flowering. Loss of function in either element would cause never-flowering. Once the phase transition is induced with the activation of RID1, flowering signal is transduced and regulated through the various pathways and eventually integrated with FT-like proteins to induce flowering.
A patient-oriented approach to treatment of myelodysplastic syndromes.

BACKGROUND AND OBJECTIVE There are several therapeutic options for patients with myeiodysplastic syndrome (MDS) but most of them are poorly effective and the potentially curative ones are available only for a minority of individuals. The aim of this article is to define a rational basis for a patient-oriented approach to treatment of MDS. EVIDENCE AND INFORMATION SOURCES All four authors have done clinical studies of treatment of MDS, including stem cell transplantation, intensive and low-dose chemotherapy, and use of hematopoietic growth factors. They also participated in the Fourth international Symposium on MDS (Barcelona, 24-27 April 1997). In addition, the present review critically examines relevant articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART AND PERSPECTIVES At present, the only two treatments that can prolong survival are allogeneic stem cell transplantation (SCT) and intensive chemotherapy, but only a minority of MDS patients can really benefit from them. The heterogeneity of MDS patients, the wide variety of patient inclusion criteria and transplant procedures used, and relatively small numbers of patients in the individual reports of allogeneic SCT make it difficult to draw many definitive conclusions. However, approximately 40% of patients with MDS who are eligible for allogeneic SCT are likely to be cured by this treatment. Intensive chemotherapy with a combination of cytosine arabinoside and an anthracycline should be offered to all patients with an increase in bone marrow blasts who are not eligible for allogeneic SCT, especially those patients up to 65 years of age. Complete remission rates are similar to those obtained in patients with acute myelogenous leukemia, but probability of long-term survival is low. The remaining treatments validated in clinical trials (erythropoietin and/or granulocyte colony-stimulating factor, low-dose cytosine arabinoside) can improve the efficiency of hematopoiesis in subsets of patients. Responsive individuals might experience an improvement in quality of life but very few studies have addressed this question so far. The majority of MDS patients still rely upon supportive therapy. A clinical decision path based on findings of clinical trials and the patient's expectations can help physicians in decision making. Because of the inadequacies of all current treatment modalities, participation in clinical trials should always be encouraged.
Heidelberg's first experiences in establishing a living-donation liver transplantation programme.

BACKGROUND Since indications for liver transplantation (LTx) have increased and the shortage of brain dead transplant organs continues, an increase in deaths related to extended waiting periods can be documented. Living-related LTx (LRLTx) is a good alternative that can help compensate the shortness of organs for transplantation and can reduce waiting periods and deaths related to a long waiting list. We started a LRLTx programme at the transplantation centre, Department of Surgery at the University of Heidelberg to increase our transplantation activities. In this article we present our primary experiences and protocol. METHODS From September 2002 to June 2003, three LRLTx were performed. Indications in recipients were hepatocellular carcinoma in two cases and liver cirrhoses due to hepatitis B in one patient. Two patients received the right liver (segments V-VIII) of their donors. One patient received the complete liver collected as a Domino LTx. All liver transplants were performed without the use of a venous bypass. RESULTS The peri- and post-operative courses of our donors were without complications, except for an infected intraabdominal bilioma, which was drained interventionally. The donors were fully able to work after the operation. The coordinative and logistical work should not be underestimated. CONCLUSIONS This therapy should only be offered and performed in centres with excellent expert knowledge in liver and transplantation surgery.
Growth Phase-Coupled Changes of the Ribosome Profile in Natural Isolates and Laboratory Strains of Escherichia coli

ABSTRACT The growth phase-dependent change in sucrose density gradient centrifugation patterns of ribosomes was analyzed for both laboratory strains of Escherichia coli and natural isolates from the ECOR collection. All of the natural isolates examined formed 100S ribosome dimers in the stationary phase, and ribosome modulation factor (RMF) was associated with the ribosome dimers in the ECOR strains as in the laboratory strain W3110. The ribosome profile (70S monomers versus 100S dimers) follows a defined pattern over time during lengthy culture in both the laboratory strains and natural isolates. There are four discrete stages: (i) formation of 100S dimers in the early stationary phase; (ii) transient decrease in the dimer level; (iii) return of dimers to the maximum level; and (iv) dissociation of 100S dimers into 70S ribosomes, which are quickly degraded into subassemblies. The total time for this cycle of ribosome profile change, however, varied from strain to strain, resulting in apparent differences in the ribosome profiles when observed at a fixed time point. A correlation was noted in all strains between the decay of 100S ribosomes and the subsequent loss of cell viability. Two types of E. coli mutants defective in ribosome dimerization were identified, both of which were unable to survive for a prolonged period in stationary phase. The W3110 mutant, with a disrupted rmf gene, has a defect in ribosome dimerization because of lack of RMF, while strain Q13 is unable to form ribosome dimers due to a ribosomal defect in binding RMF.
Child-, adolescent- and young adult-onset depressions: differential risk factors in development?

Background Previous research reported that childhood adversity predicts juvenile- onset but not adult-onset depression, but studies confounded potentially genuine differences in adversity with differences in the recency with which adversity was experienced. The current study paper took into account the recency of risk when testing for differences among child-, adolescent- and young adult-onset depressions. Method Up to nine waves of data were used per subject from two cohorts of the Great Smoky Mountains Study (GSMS; n=1004), covering children in the community aged 9–16, 19 and 21 years. Youth and one of their parents were interviewed using the Child and Adolescent Psychiatric Assessment (CAPA) between ages 9 and 16; these same youth were interviewed using the Young Adult Psychiatric Assessment (YAPA) at ages 19 and 21. The most common psychosocial risk factors for depression were assessed: poverty, life events, parental psychopathology, maltreatment, and family dysfunction. Results Consistent with previous research, most childhood psychosocial risk factors were more strongly associated with child-onset than with adolescent-/adult-onset depression. When potentially genuine risk differences among the depression-onset groups were disentangled from differences due to the recency of risk, child- and young adult-onset depression were no longer different from one another. Adolescent-onset depression was associated with few psychosocial risk factors. Conclusions There were no differences in putative risk factors between child- and young adult-onset depression when the recency of risk was taken into account. Adolescent-onset depression was associated with few psychosocial risk factors. It is possible that some adolescent-onset depression cases differ in terms of risk from child- and young adult-onset depression.
Critical mass of islets that function after implantation in a large mammalian.

A major problem that limits clinical islet transplantation is insufficient information on the critical quantity of islets needed to reverse insulin dependence. To address this problem, we have previously identified the critical number of purified islets of known size that consistently induced normoglycemia in a large mammal model of type I diabetes. In the present studies, we found that the dose-response relationship between the volume of islets transplanted and consistent normoglycemia in dogs corresponded to greater than 4.1 microliters islet tissue per kilogram body weight. The functional outcome of similar quantities of purified islets was then examined after autoimplantation into splenic or hepatic sites and after splenic implantation by venous reflux or pulp injection. During prolonged follow-up, four of five initially normoglycemic recipients of intrahepatic islets became hyperglycemic within 1 year and the other failed at 26 months. In contrast, function of intrasplenic islets was more durable with delayed onset of hyperglycemia observed in only two of six grafts at 13 and 18 months. Sustained normoglycemia was induced by splenic venous reflux of islets in six of seven dogs, but intrapulp injection succeeded in only two of six. Islet allografts implanted to the spleen (n = 10) or to the kidney capsule (n = 6) of Cyclosporine-treated recipients induced normoglycemia in all, but sustained function ensued in only the intrasplenic group when the islet mass was augmented by 40%. These data define the critical islet volume needed to induce normoglycemia in a large mammal. Islets implanted by venous reflux to spleen provide more durable long-term function than the liver. (ABSTRACT TRUNCATED AT 250 WORDS)