Miracle-dz/UniFAR-FTUs huggingface dataset:
ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms.

The rat ROMK gene encodes inwardly rectifying, ATP-regulated K+ channels [K. Ho, C. G. Nichols, W. J. Lederer, J. Lytton, P. M. Vassilev, M. V. Kanazirska, and S. C. Hebert. Nature Lond. 362: 31-38, 1993; H. Zhou, S. S. Tate, and L. G. Palmer. Am. J. Physiol. 266 (Cell Physiol. 35): C809-C824, 1994], and mRNA encoding these channels is widely expressed in distal cortical and outer medullary nephron segments [see companion study; W. -S. Lee and S. C. Hebert. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F1124-F1131, 1995]. Using approaches based on homology to ROMK1, we have identified two additional ROMK isoforms, ROMK2b and ROMK3. Analysis of the nucleotide sequences of the ROMK isoforms indicates that molecular diversity of ROMK transcripts is due to alternative splicing at both the 5'-coding and 3'-noncoding regions. The splicing at the 5' end of ROMK gives rise to channel proteins with variable-length NH2 termini containing different initial amino acid sequences. Functional expression of these isoforms in Xenopus oocytes showed that they form functional Ba(2+)-sensitive K+ channels. The nephron distribution of mRNAs encoding alternatively spliced isoforms of ROMK (ROMK1-ROMK3) was investigated by reverse transcription-polymerase chain reaction (RT-PCR) of nephron segments dissected from rat kidney. Nondegenerate PCR primer pairs were designed to span at least one intron and to amplify specific alternatively spliced forms of ROMK. (ABSTRACT TRUNCATED AT 250 WORDS)
Complexity complicates lean: lessons from seven emergency services.

PURPOSE The purpose of this paper is to explain how different emergency services adopt and adapt the same hospital-wide lean-inspired intervention and how this is reflected in hospital process performance data. DESIGN/METHODOLOGY/APPROACH A multiple case study based on a realistic evaluation approach to identify mechanisms for how lean impacts process performance and services' capability to learn and continually improve. Four years of process performance data were collected from seven emergency services at a Swedish University Hospital: ear, nose and throat (ENT) (two), pediatrics (two), gynecology, internal medicine, and surgery. Performance patterns were linked with qualitative data collected through realist interviews. FINDINGS The complexity of the care process influenced how improvement in access to care was achieved. For less complex care processes (ENT and gynecology), large and sustained improvement was mainly the result of a better match between capacity and demand. For medicine, surgery, and pediatrics, which exhibit greater care process complexity, sustainable, or continual improvement were constrained because the changes implemented were insufficient in addressing the higher degree of complexity. ORIGINALITY/VALUE The variation in process performance and sustainability of results indicate that lean efforts should be carefully adapted to the complexity of the care process and to the educational commitment of healthcare organizations. Ultimately, the ability to adapt lean to a particular context of application depends on the development of routines that effectively support learning from daily practices.
Chapitre 11. Le new public management ou la gestion malade de la société

En 2005 Vincent de Gaulejac publiait « La société malade de la gestion ». Le sous-titre, « Idéologie gestionnaire, pouvoir managérial et harcèlement social », était très explicite sur la thèse défendue dans l’ouvrage : l’idéologie gestionnaire, qui colonise toutes les sphères de la société, installe une culture de la performance et un climat de compétition qui mettent le monde sous pression. Un tel harcèlement se traduit notamment par l’épuisement professionnel, le stress et la souffrance au travail. Dès sa parution, cet opus d’un sociologue qui, dès les années 1990, nous alertait sur le « coût de l’excellence » (Aubert et Gaulejac, 1991), suscita de nombreuses controverses et de vives critiques au sein des milieux académiques gestionnaires. Il ne s’agit pas ici de reprendre à notre compte ces critiques ; spécialiste en sciences de gestion, et en contrôle de gestion tout particulièrement, nous savons bien qu’une pratique gestionnaire sans conscience peut conduire à de nombreux excès sur le plan humain et social : « Science sans conscience n’est que ruine de l’âme » écrivait au 16e siècle un ancien élève de l’École de Médecine de Montpellier. Appliquée aux sciences de gestion, la célèbre maxime de François Rabelais pourrait s’énoncer ainsi : « efficience sans conscience, n’est que perte de sens ». Dit autrement, sans conscience éthique, la puissance de la doxa managériale et de la violence symbolique dont elle est porteuse, peuvent entraîner des gestionnaires à sombrer corps et âme dans le « côté obscur de la force » du management. La société serait dès lors malade de la gestion. Mais si l’on renverse la sentence, le problème ne doit-il pas plutôt être recherché dans une société qui se rend malade en se consumant au feu incandescent d’une quête éperdue de performance et la gestion ne serait-elle pas atteinte par le virus d’une société dont elle est à la fois le reflet et le médium ?
Nanotechnology and Drug Delivery Part 2: Nanostructures for Drug Delivery

This is the second part of a review on nanotechnology in general and particularly as it pertains to drug deliver. In the earlier paper (Part 1), nanotechnology in nature, its history as well as design and methods were discussed. Its applications, benefits and risks were also outlined. In this paper (Part 2), various nanostructures employed in drug delivery, their methods of fabrication and challenges of nano drug delivery are reviewed. Nanotechnology is one approach to overcome challenges of conventional drug delivery systems based on the development and fabrication of nanostructures. Some challenges associated with the technology as it relates to drug effectiveness, toxicity, stability, pharmacokinetics and drug regulatory control are discussed in this review. Clearly, nanotechnology is a welcome development that is set to transform drug delivery and drug supply chain management, if optimally developed .
European Union governance in the shadow of contradicting ideas: the decoupling of policy ideas and policy instruments

The institutional architecture of the European Union is based on two fundamentally competing ideas: supranational rule and national sovereignty. These two underlying ideas are not reconcilable and work at different levels in the background of the policy debate. While on the normative level public sentiments remain strongly linked to the idea of state autonomy, on the cognitive level the paradigm of a functional necessity to cooperate is decisive for actual policy making. Only in some policy domains, such as the single market program, have policy-makers attempted to re-couple normative and cognitive ideas. In contrast to this, the central argument is that policy-makers mostly adhere to an alternative strategy: the systematic decoupling of normative and cognitive ideas. Focusing on public administration, it is shown how deft policy instrumentation allows actors to realize program ideas that satisfy demands for increased supranational governance. At the same time, however, these instruments are in dissonance with how policies are framed against the background of public sentiments that assume domestic bureaucratic independence.
A Role of IgM Antibodies in Monosodium Urate Crystal Formation and Associated Adjuvanticity1

Uric acid is released from injured cells and can act as an adjuvant signal to the immune system. Uric acid crystals invoke strong inflammatory responses in tissues. Although their biological effects are evident and the associated signaling mechanisms are becoming clear, it remains unexplained as to why uric acid precipitates rapidly in vivo, in sharp contrast to the minimal crystallization in vitro. We report in this study that a group of IgM Abs is able to bind to these crystals, which is interesting in light that B cell-deficient mice do not sense the proinflammatory adjuvant effect of uric acid. The titers of these Abs increase upon immunization with uric acid crystals. We have produced large quantities of such mAbs. The purified IgM Abs can significantly facilitate uric acid precipitation to form the inflammatory crystals in vitro. Infusion of these Abs into B cell-deficient mice significantly increases the basal level of inflammation in these recipients and restores the host’s ability to sense uric acid’s adjuvanticity. Therefore, we have identified a factor in determining uric acid precipitation and possibly its ability to function as an endogenous adjuvant. This finding suggests a new mechanism of the pathogenesis of gouty arthritis and uric acid-induced immune activation.
Clinical outcome of Turkish metastatic breast cancer patients with currently available treatment modalities--single center experience.

BACKGROUND Breast cancer is the most common malignancy and the second leading cause of cancer-related death among women in the developed countries. Despite advances in screening, improved local therapies and adjuvant systemic treatments, median survival of metastatic breast cancer patients (MBC) is in the range of 2-3 years at most. We aimed to investigate whether the prognostic factors and therapeutic responses of our Turkish patients are similar to those in the literature. MATERIALS AND METHODS We reviewed the medical records of MBC patients who had been treated in our institution between 1999-2009 and analyzed their clinicopathological features and survival outcomes retrospectively. RESULTS A hundred and sixty patients were included. Median age was 47 (23-82), median follow up was 24 (2-186) months. At the time of diagnosis 59% of patients were under the age of 50 and 46% were postmenopausal. The majority (37%) had multiple sites of metastases. Forty percent received endocrine therapy and 40% chemotherapy as first line metastatic treatment. Thirty (20%) patients were treated with molecular targeting agents like trastuzumab, lapatinib and sunitinib, frequently combined with a chemotherapy agent. Five-year overall survival (OS) was 32% and median OS was 38 months for the whole group. Five year progression free survival (PFS) was 10% and median PFS was 10 months. Menopausal status, hormone receptor expression and disease free status had a significant impact on overall survival in the multivariate analysis (p 0.018, p 0.018 and p:0.003, respectively). CONCLUSIONS All our patients were treated with the modern oncologic therapies recommended by the international guidelines. From our data, MBC patients live up to 3-4 years, indicating that further improvement beyond that requires development of new treatment modalities. The survival outcomes of our patients were consistent with the data reported in the literature.
Multimodular Penicillin-Binding Proteins: An Enigmatic Family of Orthologs and Paralogs

SUMMARY The monofunctional penicillin-binding dd-peptidases and penicillin-hydrolyzing serine β-lactamases diverged from a common ancestor by the acquisition of structural changes in the polypeptide chain while retaining the same folding, three-motif amino acid sequence signature, serine-assisted catalytic mechanism, and active-site topology. Fusion events gave rise to multimodular penicillin-binding proteins (PBPs). The acyl serine transferase penicillin-binding (PB) module possesses the three active-site defining motifs of the superfamily; it is linked to the carboxy end of a non-penicillin-binding (n-PB) module through a conserved fusion site; the two modules form a single polypeptide chain which folds on the exterior of the plasma membrane and is anchored by a transmembrane spanner; and the full-size PBPs cluster into two classes, A and B. In the class A PBPs, the n-PB modules are a continuum of diverging sequences; they possess a five-motif amino acid sequence signature, and conserved dicarboxylic amino acid residues are probably elements of the glycosyl transferase catalytic center. The PB modules fall into five subclasses: A1 and A2 in gram-negative bacteria and A3, A4, and A5 in gram-positive bacteria. The full-size class A PBPs combine the required enzymatic activities for peptidoglycan assembly from lipid-transported disaccharide-peptide units and almost certainly prescribe different, PB-module specific traits in peptidoglycan cross-linking. In the class B PBPs, the PB and n-PB modules cluster in a concerted manner. A PB module of subclass B2 or B3 is linked to an n-PB module of subclass B2 or B3 in gram-negative bacteria, and a PB module of subclass B1, B4, or B5 is linked to an n-PB module of subclass B1, B4, or B5 in gram-positive bacteria. Class B PBPs are involved in cell morphogenesis. The three motifs borne by the n-PB modules are probably sites for module-module interaction and the polypeptide stretches which extend between motifs 1 and 2 are sites for protein-protein interaction. The full-size class B PBPs are an assortment of orthologs and paralogs, which prescribe traits as complex as wall expansion and septum formation. PBPs of subclass B1 are unique to gram-positive bacteria. They are not essential, but they represent an important mechanism of resistance to penicillin among the enterococci and staphylococci. Natural evolution and PBP- and β-lactamase-mediated resistance show that the ability of the catalytic centers to adapt their properties to new situations is limitless. Studies of the reaction pathways by using the methods of quantum chemistry suggest that resistance to penicillin is a road of no return.
The amino terminus of the F1-ATPase beta-subunit precursor functions as an intramolecular chaperone to facilitate mitochondrial protein import

Mitochondrial import signals have been shown to function in many steps of mitochondrial protein import. Previous studies have shown that the F1-ATPase beta-subunit precursor (pre-F1beta) of the yeast Saccharomyces cerevisiae contains an extended, functionally redundant mitochondrial import signal at its amino terminus. However, the full significance of this functionally redundant targeting sequence has not been determined. We now report that the extended pre-F1beta signal acts to maintain the precursor in an import-competent conformation prior to import, in addition to its previously characterized roles in mitochondrial targeting and translocation. We found that this extended signal is required for the efficient posttranslational mitochondrial import of pre-F1beta both in vivo and in vitro. To determine whether the pre-F1beta signal directly influences precursor conformation, fusion proteins that contain wild-type and mutant forms of the pre-F1beta import signal attached to the model passenger protein dihydrofolate reductase (DHFR) were constructed. Deletions that reduced the import signal to a minimal functional unit decreased both the half-time of precursor folding and the efficiency of mitochondrial import. To confirm that the reduced mitochondrial import associated with this truncated signal was due to a defect in its ability to maintain DHFR in a loosely folded conformation, we introduced structurally destabilizing missense mutations into the DHFR passenger to block precursor folding independently of the import signal. We found that the truncated signal imported this destabilized form of DHFR as efficiently as the intact targeting signal, indicating that the primary defect associated with the minimal signal is an inability to maintain the precursor in a loosely folded conformation. Our results suggest that the loss of this intramolecular chaperone function leads to defects in the early stages of the import process.
Monoclonal Antibodies Directed against Conserved Epitopes on the Nucleocapsid Protein and the Major Envelope Glycoprotein of Equine Arteritis Virus

ABSTRACT We recently developed a highly effective immunization procedure for the generation of monoclonal antibodies (MAbs) directed against the porcine reproductive and respiratory syndrome virus (E. Weiland, M. Wieczorek-Krohmer, D. Kohl, K. K. Conzelmann, and F. Weiland, Vet. Microbiol. 66:171–186, 1999). The same method was used to produce a panel of 16 MAbs specific for the equine arteritis virus (EAV). Ten MAbs were directed against the EAV nucleocapsid (N) protein, and five MAbs recognized the major viral envelope glycoprotein (GL). Two of the EAV GL-specific MAbs and one antibody of unknown specificity neutralized virus infectivity. A comparison of the reactivities of the MAbs with 1 U.S. and 22 newly obtained European field isolates of EAV demonstrated that all N-specific MAbs, the three nonneutralizing anti-GL MAbs, and the weakest neutralizing MAb (MAb E7/d15-c9) recognized conserved epitopes. In contrast, the two MAbs with the highest neutralization titers bound to 17 of 23 (MAb E6/A3) and 10 of 23 (MAb E7/d15-c1) of the field isolates. Ten of the virus isolates reacted with only one of these two MAbs, indicating that they recognized different epitopes. The GL-specific MAbs and the strongly neutralizing MAb of unknown specificity (MAb E6/A3) were used for the selection of neutralization-resistant (NR) virus variants. The observation that the E6/A3-specific NR virus variants were neutralized by MAb E7/d15-c1 and that MAb E6/A3 blocked the infectivity of the E7/d15-c1-specific NR escape mutant confirmed that these antibodies reacted with distinct antigenic sites. Immunoelectron microscopy revealed for the first time that the antigenic determinants recognized by the anti-GL MAbs were localized on the virion surface. Surprisingly, although the immunofluorescence signal obtained with the neutralizing antibodies was relatively weak, they mediated binding of about three times as much gold granules to the viral envelope than the nonneutralizing anti-GL MAbs.
Construction of Urbanization Motivation Mechanism of the N-B-Q-F City Cluster

Cities vary in their process of evolution in urbanization motive mechanism.In Guangxi,as a underdeveloped region,top-down urbanization model has always been occupying the ruling position.So,what is the driving force of N-BQ-F City Cluster urbanization? According to the development of N-B-Q-F city cluster urbanization progress and present condition,this paper puts forward a frame for the urbanization motive system in N-B-Q-F region,and proposes to divide the urbanization motive system into main motivation system and non-nuclear motive system.This research will be beneficial for the reasonable construction of the motivation mechanism of N-B-Q-F city cluster,and will lay a solid foundation for accelerating urbanization progress of the cities involved,and realizing the goal of integrating city with country as a whole.
Protective Effect of an Oral Adsorbent on Renal Function in Chronic Renal Failure: Determinants of its Efficacy in Diabetic Nephropathy

Abstract: Large‐scale clinical trials have shown that the oral adsorbent AST‐120 improves renal function and delays the initiation of dialysis in chronic renal failure (CRF) secondary to chronic glomerulonephritis. If renal failure progresses via common mechanisms, then the same effects can be expected in diabetic nephropathy. However, no study on diabetic nephropathy has been reported. Thus, we enrolled patients with statistically significant progression of CRF secondary to diabetic nephropathy, and analyzed the changes in renal function after AST‐120 therapy, and the clinical factors associated with response to therapy. We enrolled 276 patients with diabetic nephropathy, whose serum creatinine (Scr) had increased from 3.4 to 4.5 mg/dL during the 4.5 ± 3.7 months prior to the study. These patients took AST‐120 at a dose of 5.0 ± 1.4 g/day for 6 months. The clinical data were analyzed by dividing the patients into three groups based on the changes in Scr after AST‐120 therapy, with responders showing a decrease (N = 82), partial responders showing <1.5‐fold increase (N = 144), and non‐responders showing ≥1.5‐fold increase (N = 50). AST‐120 significantly lowered the slope of 1/Scr–time line, suggesting that AST‐120 suppressed the progression of renal impairment. No responders required dialysis, whereas 24.3% of the partial responders and 36.0% of the non‐responders started dialysis therapy. In responders, the 1/Scr–time slope showed a negative‐to‐positive shift and serum urea nitrogen decreased significantly, whereas the improvement was moderate in partial responders and minimal in non‐responders. Among responders, AST‐120 therapy significantly improved renal function despite the presence of hypoproteinemia, hyperlipidemia, anemia or hypertension in many patients. The beneficial effect of AST‐120 was significantly more marked in patients with blood pressure controlled within the normal ranges and hematocrit maintained at 30% or above. AST‐120 reversed renal dysfunction or delayed the initiation of dialysis therapy in patients with progressive aggravation of CRF secondary to diabetic nephropathy, independent of hypoproteinemia, hyperlipidemia, anemia and hypertension. Active use of AST‐120 may be recommended in patients with good control of blood pressure and hematocrit above 30%.
Verbal working memory and inhibition‐concentration in adults with cochlear implants

Neurocognitive functions contribute to speech recognition in postlingual adults with cochlear implants (CIs). In particular, better verbal working memory (WM) on modality‐specific (auditory) WM tasks predicts better speech recognition. It remains unclear, however, whether this association can be attributed to basic underlying modality‐general neurocognitive functions, or whether it is solely a result of the degraded nature of auditory signals delivered by the CI. Three hypotheses were tested: 1) Both modality‐specific and modality‐general tasks of verbal WM would predict scores of sentence recognition in speech‐shaped noise; 2) Basic modality‐general neurocognitive functions of controlled fluency and inhibition‐concentration would predict both modality‐specific and modality‐general verbal WM; and 3) Scores on both tasks of verbal WM would mediate the effects of more basic neurocognitive functions on sentence recognition.
Characterization and physiological roles of membrane-bound hydrogenase isoenzymes from Salmonella typhimurium

We found that Salmonella typhimurium strain LT2 (Z) possessed two immunologically distinct, membrane-bound hydrogenase isoenzymes, which were similar in electrophoretic mobilities and apoprotein contents to hydrogenase isoenzymes 1 and 2 of Escherichia coli. The S. typhimurium enzymes cross-reacted with antibodies raised to the respective hydrogenase isoenzymes of E. coli. As for E. coli, an additional membrane-bound hydrogenase activity (termed hydrogenase 3), which did not cross-react with antibodies raised against either hydrogenase 1 or 2, was also present in detergent-dispersed membrane preparations. The physiological role of each of the three isoenzymes in E. coli has remained unclear owing to the lack of mutants specifically defective for individual isoenzymes. However, analysis of two additional wild-type isolates of S. typhimurium revealed specific defects in their hydrogenase isoenzyme contents. S. typhimurium LT2 (A) lacked isoenzyme 2 but possessed normal levels of hydrogenases 1 and 3. S. typhimurium LT7 lacked both isoenzymes 1 and 2 but retained normal hydrogenase 3 activity. Characterization of hydrogen metabolism by these hydrogenase-defective isolates allowed us to identify the physiological role of each of the three isoenzymes. Hydrogenase 3 activity correlated closely with formate hydrogenlyase-dependent hydrogen evolution, whereas isoenzyme 2 catalyzed hydrogen uptake (oxidation) during anaerobic, respiration-dependent growth. Isoenzyme 1 also functioned as an uptake hydrogenase but only during fermentative growth. We postulate that this enzyme functions in a hydrogen-recycling reaction which operates during fermentative growth.