Miracle-dz/UniFAR-FTUs huggingface dataset:
Small RNA binding to the lateral surface of Hfq hexamers and structural rearrangements upon mRNA target recognition

The bacterial Sm-like protein Hfq is a central player in the control of bacterial gene expression. Hfq forms complexes with small regulatory RNAs (sRNAs) that use complementary “seed” sequences to target specific mRNAs. Hfq forms hexameric rings, which preferably bind uridine-rich RNA 3′ ends on their proximal surface and adenine-rich sequences on their distal surface. However, many reported properties of Hfq/sRNA complexes could not be explained by these RNA binding modes. Here, we use the RybB sRNA to identify the lateral surface of Hfq as a third, independent RNA binding surface. A systematic mutational analysis and competition experiments demonstrate that the lateral sites have a preference for and are sufficient to bind the sRNA “body,” including the seed sequence. Furthermore, we detect significant structural rearrangements of the Hfq/sRNA complex upon mRNA target recognition that lead to a release of the seed sequence, or of the entire sRNA molecule in case of an unfavorable 3′ end. Consequently, we propose a molecular model for the Hfq/sRNA complex, where the sRNA 3′ end is anchored in the proximal site of Hfq, whereas the sRNA body, including the seed sequence, is bound by up to six of the lateral sites. In contrast to previously proposed arrangements, the presented model explains how Hfq can protect large parts of the sRNA body while still allowing a rapid recycling of sRNAs. Furthermore, our model suggests molecular mechanisms for the function of Hfq as an RNA chaperone and for the molecular events that are initiated upon mRNA target recognition.
Dyskinesia in Parkinson's disease: mechanisms and current non‐pharmacological interventions

Dopamine replacement therapy in Parkinson's disease is associated with several unwanted effects, of which dyskinesia is the most disabling. The development of new therapeutic interventions to reduce the impact of dyskinesia in Parkinson's disease is therefore a priority need. This review summarizes the key molecular mechanisms that underlie dyskinesia. The role of dopamine receptors and their associated signaling mechanisms including dopamine‐cAMP‐regulated neuronal phosphoprotein, extracellular signal‐regulated kinase, mammalian target of rapamycin, mitogen and stress‐activated kinase‐1 and Histone H3 are summarized, along with an evaluation of the role of cannabinoid and nicotinic acetylcholine receptors. The role of synaptic plasticity and animal behavioral results on dyskinesia are also evaluated. The most recent therapeutic advances to treat Parkinson's disease are discussed, with emphasis on the possibilities and limitations of non‐pharmacological interventions such as physical activity, deep brain stimulation, transcranial magnetic field stimulation and cell replacement therapy. The review suggests new prospects for the management of Parkinson's disease‐associated motor symptoms, especially the development of dyskinesia.
Effect of Acidic pH on Expression of Surface-Associated Proteins of Streptococcus oralis

ABSTRACT Streptococcus oralis, a member of the mitis group of oral streptococci, is implicated in the pathogenesis of infective endocarditis and is the predominant aciduric non-mutans-group streptococcus in dental plaque. We undertook to identify the most abundant surface-associated proteins of S. oralis and to investigate changes in protein expression when the organism was grown under acidic culture conditions. Surface-associated proteins were extracted from cells grown in batch culture, separated by two-dimensional gel electrophoresis, excised, digested with trypsin, and analyzed by matrix-assisted laser desorption ionization-time of flight mass spectrometry and liquid chromatography-tandem mass spectrometry. Putative functions were assigned by homology to a translated genomic database of Streptococcus pneumoniae. A total of 27 proteins were identified; these included a lipoprotein, a ribosome recycling factor, and the glycolytic enzymes phosphoglycerate kinase, fructose bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, and enolase. The most abundant protein, phosphocarrier protein HPr, was present as three isoforms. Neither lactate dehydrogenase nor pyruvate oxidase, dominant intracellular proteins, were present among the proteins on the gels, demonstrating that proteins in the surface-associated pool did not arise as a result of cell lysis. Eleven of the proteins identified were differentially expressed when cells were grown at pH 5.2 versus pH 7.0, and these included superoxide dismutase, a homologue of dipeptidase V from Lactococcus lactis, and the protein translation elongation factors G, Tu, and Ts. This study has extended the range of streptococcal proteins known to be expressed at the cell surface. Further investigations are required to ascertain their functions at this extracellular location and determine how their expression is influenced by other environmental conditions.
Notice of RetractionA new solution method for non-probabilistic reliability model of linear structural system

Considering that the excessive sample data points are needed in the probabilistic method, non-probabilistic method can be a viable alternative of the uncertainty analysis. However, how to calculate non-probabilistic reliability precisely and quickly is always a difficult problem. In this paper, a new non-probabilistic reliability measurement for linear structural system is proposed and a common, ultimate expression of structure's non-probabilistic reliability is obtained by the new measurement through the way of mathematical induction. The amount of the computation is highly reduced and the compatibility between the presented non-probabilistic safety measure and probability reliability is also demonstrated. Researches of comparisons between the new method and the existed non-probabilistic method are performed by a cantilever beam and a ten-bar planar truss structure. The results show the feasibility and validity of the proposed method.
Quality of life in the Canadian Implantable Defibrillator Study (CIDS).

BACKGROUND The primary aim of this study was to compare quality-of-life outcome between patients randomized to implantable cardioverter defibrillator (ICD) therapy and patients randomized to amiodarone treatment in the Canadian Implantable Defibrillator Study (CIDS). A secondary aim was to evaluate the effects on quality-of-life outcomes of receiving shocks from the device. METHODS Quality of life was assessed in 317 English-speaking participants by use of the Rand Corporation's 38-item Mental Health Inventory (MHI) and the Nottingham Health Profile (NHP). Assessments were done in the hospital at baseline and with mailed questionnaires after 2, 6, and 12 months of follow-up. Sixty-two percent of patients completed the follow-up assessments at 6 and 12 months. RESULTS Repeated measures analysis of variance revealed significant time by treatment group interaction effect on total MHI and the psychological distress and psychological well-being sub-scales, and on 5 of the 7 NHP scales (energy, physical mobility, emotional reactions, sleep disturbance, and lifestyle impairment) (P <.05). Emotional and physical health scores were shown to improve significantly in the ICD group and were either unchanged (emotional health) or deteriorated (energy and physical mobility) in the amiodarone-treated group by means of post-hoc comparisons. Quality of life did not improve in the subgroup of patients in the ICD-treated group who received > or =5 shocks from their device. CONCLUSION Quality of life is better with ICD therapy than with amiodarone therapy. The beneficial quality-of-life effects from an ICD are not evident in patients who receive numerous shocks from their device.
Effect of hypercortisolism on bone mineral density and bone metabolism: A potential protective effect of adrenocorticotropic hormone in patients with Cushing’s disease

Objective To investigate the effects of Cushing’s disease (CD) and adrenal-dependent Cushing’s syndrome (ACS) on bone mineral density (BMD) and bone metabolism. Methods Data were retrospectively collected for 55 patients with hypercortisolism (CD, n = 34; ACS n = 21) from January 1997 to June 2014. BMD was examined in all patients, and bone turnover markers were tested in some patients. Healthy controls (n = 18) were also recruited. Results The lumbar spine and femoral neck BMD were significantly lower in the ACS and CD groups than in the control group. Lumbar BMD was significantly lower in the ACS than CD group. The collagen breakdown product (CTX) concentrations were significantly higher while the osteocalcin and procollagen type I N-terminal propeptide (PINP) concentrations were significantly lower in the ACS and CD groups than in the control group. The PINP concentration was significantly lower while the CTX concentration was significantly higher in the ACS than CD group. In the CD group only, lumbar BMD and serum adrenocorticotropic hormone had a significant positive correlation. Conclusions Bone turnover markers indicated suppressed osteoblast and enhanced osteoclast activities. PINP and CTX changes might indicate bone mass deterioration. Adrenocorticotropic hormone might be protective for lumbar BMD in patients with CD.
Local drug and gene delivery through microbubbles.

Ultrasound contrast agents (microbubbles) lower the threshold for cavitation by ultrasound energy. Ultrasound microbubbles may be used as cavitation nuclei for drug and gene delivery. By tailoring the physical properties of microbubbles and coating materials, drugs and genetic drugs can be incorporated into ultrasound contrast agents. As the microbubbles enter the region of insonation, the microbubbles cavitate, locally releasing the therapeutic agents. Cavitation also causes a local shockwave that improves cellular uptake of the therapeutic agent. As a result of the human genome project and continuing advances in molecular biology, many therapeutic genes have been discovered. In the cardiovascular system, gene therapy has the potential to improve myocardial vascularization and ameliorate congestive heart failure. For successful development of clinical gene therapy, however, effective gene delivery vectors are needed. Ultrasound contrast agents can be used to develop new, more effective vectors for gene delivery. Transthoracic ultrasound can be focused on the heart so that an intravenous injection of gene-bearing microbubbles will deliver genes relatively selectively to the myocardium. Using this technique, we have produced high levels of transgene expression in the insonated region of the myocardium. This new technology, using microbubbles and ultrasound for drug and gene delivery, merits further study and development.
Histologic grade remains a prognostic factor for breast cancer regardless of the number of positive lymph nodes and tumor size: a study of 161 708 cases of breast cancer from the SEER Program.

CONTEXT The appropriate staging of breast cancers includes an evaluation of tumor size and nodal status. Histologic grade in breast cancer, though important and assessed for all tumors, is not integrated within tumor staging. OBJECTIVE To determine whether the histologic grade remains a prognostic factor for breast cancer regardless of tumor size and the number of involved axillary lymph nodes. DESIGN By using a new clustering algorithm, the 10-year survival for every combination of T, N, and the histologic grade was determined for cases of breast cancer obtained from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. There were 36 combinations of TN, defined according to the American Joint Committee on Cancer, and grade. RESULTS For each combination of T and N, a categorical increase in the histologic grade was associated with a progressive decrease in 10-year survival regardless of the number of involved axillary lymph nodes or size of the primary tumor. Absolute survival differences between high and low grade persisted despite larger tumor sizes and greater nodal involvement, though trends were apparent with increasing breast cancer stage. Statistical significance depended on the number of cases for each combination. CONCLUSIONS Histologic grade continues to be of prognostic importance for overall survival despite tumor size and nodal status. Furthermore, these results seem to indicate that the assignment of the histologic grade has been consistent among pathologists when evaluated in a large data set of patients with breast cancer. The incorporation of histologic grade in TNM staging for breast cancer provides important prognostic information.
Toll‐like receptor 4 functions intracellularly in human coronary artery endothelial cells: roles of LBP and sCD14 in mediating LPS‐responses

Endothelial cells are activated by microbial agonists through Toll‐like receptors (TLRs) to express inflammatory mediators; this is of significance in acute as well as chronic inflammatory states such as septic shock and atherosclerosis, respectively. We investigated mechanisms of lipopolysaccharide (LPS)‐induced cell activation in human coronary artery endothelial cells (HCAEC) using a combination of FACS, confocal microscopy, RT‐PCR, and functional assays. We found that TLR4, in contrast to TLR2, is not only located intracellularly but also functions intracellularly. That being the case, internalization of LPS is required for activation. We further characterized the HCAEC LPS uptake system and found that HCAEC exhibit an effective LPS uptake only in the presence of LPS binding protein (LBP). In addition to its function as a catalyst for LPS‐CD14 complex formation, LBP enables HCAEC activation at low LPS concentrations by facilitating the uptake, and therefore delivery, of LPS‐CD14 complexes to intracellular TLR4‐MD‐2. LBP‐dependent uptake involves a scavenger receptor pathway. Our findings may be of pathophysiological relevance in the initial response of the organism to infection. Results further suggest that LBP levels, which vary as LBP is an acute phase reactant, could be relevant to initiating inflammatory responses in the vasculature in response to chronic or recurring low LPS.
Identification of the proton pathway in bacterial reaction centers: decrease of proton transfer rate by mutation of surface histidines at H126 and H128 and chemical rescue by imidazole identifies the initial proton donors.

The pathway for proton transfer to Q(B) was studied in the reaction center (RC) from Rhodobacter sphaeroides. The binding of Zn(2+) or Cd(2+) to the RC surface at His-H126, His-H128, and Asp-H124 inhibits the rate of proton transfer to Q(B), suggesting that the His may be important for proton transfer [Paddock, M. L. , Graige, M. S. , Feher, G. and Okamura, M. Y. (1999) Proc. Natl. Acad. Sci. U.S.A. 96, 6183-6188]. To assess directly the role of the histidines, mutant RCs were constructed in which either one or both His were replaced with Ala. In the single His mutant RCs, no significant effects were observed. In contrast, in the double mutant RC at pH 8.5, the observed rates of proton uptake associated with both the first and the second proton-coupled electron-transfer reactions k(AB)(()(1)()) [Q(A)(-)(*)Q(B)-Glu(-) + H(+) --> Q(A)(-)(*)Q(B)-GluH --> Q(A)Q(B)(-)(*)-GluH] and k(AB)(()(2)()) [Q(A)(-)(*)Q(B)(-)(*) + H(+) --> Q(A)(-)(*)(Q(B)H)(*) --> Q(A)(Q(B)H)(-)], were found to be slowed by factors of approximately 10 and approximately 4, respectively. Evidence that the observed changes in the double mutant RC are due to a reduction in the proton-transfer rate constants are provided by the observations: (i) k(AB)(1) at pH approximately pK(a) of GluH became biphasic, indicating that proton transfer is slower than electron transfer and (ii) k(AB)(2) became independent of the driving force for electron transfer, indicating that proton transfer is the rate-limiting step. These changes were overcome by the addition of exogenous imidazole which acts as a proton donor in place of the imidazole groups of His that were removed in the double mutant RC. Thus, we conclude that His-H126 and His-H128 facilitate proton transfer into the RC, acting as RC-bound proton donors at the entrance of the proton-transfer pathways.
Mucous membrane pemphigoid with generalized blisters: IgA and IgG autoantibodies target both laminin‐332 and type XVII collagen

Mucous membrane pemphigoid (MMP) is a mucous membrane‐dominated, subepidermal autoimmune blistering disease in which autoantibodies usually react with the C‐terminal domain of type XVII collagen (COL17) or with laminin‐332. Only a few cases of MMP with widespread blisters have been reported. Serologically, IgA and IgG class autoantibodies directed against COL17 or IgG autoantibodies directed against laminin‐332 in patients with MMP have been well documented. MMP cases in which IgA reacts with laminin‐332, however, are extremely rare. We report a case of MMP in a 67‐year‐old man. Clinical examination revealed extensive mucosal lesions as well as generalized blisters and erosions that healed with scar formation. The disease was intractable to treatment with systemic steroids. Interestingly, in addition to IgG directed against laminin‐332 and the noncollagenous 16A (NC16A) and C‐terminal domains of COL17, circulating IgA reacting with laminin‐332 and with the NC16A domain of COL17 was also detected. This is the first MMP case with circulating IgA and IgG autoantibodies against both laminin‐332 and COL17.
Breastfeeding Initiation and Continuation by Employment Status among Korean Women.

PURPOSE The objective of this study was to examine the factors associated with initiation and continuation of breastfeeding among Korean women in relation to their employment status. METHODS Data were collected using a web-based self-administered questionnaire from 1,031 Korean mothers living in Seoul with babies younger than 24 months. Demographic characteristics, education on breastfeeding, rooming in, breastfeeding during hospital stay, and breastfeeding knowledge were examined. Multivariate logistic regression analyses were performed to identify factors associated with initiation and continuation at 1, 6 and 12 months according to mothers' employment status. RESULTS Breastfeeding initiation rates were similar regardless of mothers' employment status. Continuation rates decreased for both groups of mothers, but were significantly lower among employed mothers at all duration points. Unemployed mothers who were able to keep their babies in the same room during the hospital stay were more likely to initiate breastfeeding. The factor that was consistently associated with breastfeeding continuation for all duration points among unemployed mothers was whether the mother breastfed during the hospital stay. Higher knowledge scores and having an infant with atopic dermatitis were also associated with breastfeeding continuation at 6 months and 12 months, respectively for unemployed mothers, and receiving education on breastfeeding was associated with 12-month continuation for employed mothers. CONCLUSION These results emphasize the significant roles of hospitals for breastfeeding initiation and continuation, with rooming-in, initial breastfeeding practice and education during hospital stay as important practices. In addition, for working mothers to continue their breastfeeding, significant support from the workplace is crucial.
Assay of von Willebrand Factor (vWF)-cleaving Protease Based on Decreased Collagen Binding Affinity of Degraded vWF

Summary Patients with thrombotic thrombocytopenic purpura (TTP) have a deficiency of von Willebrand factor (vWF)-cleaving protease, whereas patients with hemolytic-uremic syndrome (HUS) show normal activity of this protease. Present methods for assaying vWF-cleaving protease by immunoblotting are time-intensive and cumbersome. We therefore developed a new functional assay based on the preferential binding of high-molecular-weight forms of vWF to collagen. In this assay, the diluted plasma sample to be tested is added to normal human plasma in which protease activity had been abolished. The vWF present in the protease-depleted plasma is digested by the vWF-cleaving protease in the test plasma. The proteolytic degradation leads to low-molecular-weight forms of vWF, which show impaired binding to microtiter plates coated with human collagen type III. The collagen-bound vWF is quantified using a peroxidase-conjugated rabbit antibody against human vWF. The values of vWF-cleaving protease activity in tested plasma samples are read from a calibration curve achieved by incubating the vWF-substrate with dilutions of a normal human plasma pool (NHP). Testing of plasma from patients with TTP and HUS showed that the assay can be used to distinguish between these two syndromes. The presence of an inhibitor can be detected by carrying out the test after incubation of NHP with the patient plasma sample, thus enabling differentiation of patients with familial TTP from those with non-familial TTP.
Prostate cancer stem/progenitor cells: Identification, characterization, and implications

Several solid tumors have now been shown to contain stem cell‐like cells called cancer stem cells (CSC). These cells, although generally rare, appear to be highly tumorigenic and may be the cells that drive tumor formation, maintain tumor homeostasis, and mediate tumor metastasis. In this Perspective, we first provide our insight on how a CSC should be defined. We then summarize our current knowledge of stem/progenitor cells in the normal human prostate (NHP), an organ highly susceptible to hyperproliferative diseases such as benign prostate hyperplasia (BPH) and prostate cancer (PCa). We further review the evidence that cultured PCa cells, xenograft prostate tumors, and patient tumors may contain stem/progenitor cells. Along with our discussion, we present several methodologies that can be potentially used to identify putative tumor‐reinitiating CSC. Finally, we present a hypothetical model for the hierarchical organization of human PCa cells and discuss the implications of this model in helping understand prostate carcinogenesis and design novel diagnostic, prognostic, and therapeutic approaches. © 2006 Wiley‐Liss, Inc.