Miracle-dz/UniFAR-FTUs huggingface dataset:
PvdQ Quorum Quenching Acylase Attenuates Pseudomonas aeruginosa Virulence in a Mouse Model of Pulmonary Infection

Pseudomonas aeruginosa is the predominant pathogen in pulmonary infections associated with cystic fibrosis. Quorum sensing (QS) systems regulate the production of virulence factors and play an important role in the establishment of successful P. aeruginosa infections. Inhibition of the QS system (termed quorum quenching) renders the bacteria avirulent thus serving as an alternative approach in the development of novel antibiotics. Quorum quenching in Gram negative bacteria can be achieved by preventing the accumulation of N-acyl homoserine lactone (AHL) signaling molecule via enzymatic degradation. Previous work by us has shown that PvdQ acylase hydrolyzes AHL signaling molecules irreversibly, thereby inhibiting QS in P. aeruginosa in vitro and in a Caenorhabditis elegans model of P. aeruginosa infection. The aim of the present study is to assess the therapeutic efficacy of intranasally instilled PvdQ acylase in a mouse model of pulmonary P. aeruginosa infection. First, we evaluated the deposition pattern of intranasally administered fluorochrome-tagged PvdQ (PvdQ-VT) in mice at different stages of pulmonary infection by in vivo imaging studies. Following intranasal instillation, PvdQ-VT could be traced in all lung lobes with 42 ± 7.5% of the delivered dose being deposited at 0 h post-bacterial-infection, and 34 ± 5.2% at 72 h post bacterial-infection. We then treated mice with PvdQ during lethal P. aeruginosa pulmonary infection and that resulted in a 5-fold reduction of lung bacterial load and a prolonged survival of the infected animals with the median survival time of 57 hin comparison to 42 h for the PBS-treated group. In a sublethal P. aeruginosa pulmonary infection, PvdQ treatment resulted in less lung inflammation as well as decrease of CXCL2 and TNF-α levels at 24 h post-bacterial-infection by 15 and 20%, respectively. In conclusion, our study has shown therapeutic efficacy of PvdQ acylase as a quorum quenching agent during P. aeruginosa infection.
Acute myeloid leukaemia in childhood: clinical features and prognosis

Clinical and laboratory features at presentation were correlated with morphological (FAB) subclass of AML in a group of 112 children diagnosed between 1972 and 1982. Patients with a monocytic component of AML (M4, M5) had higher initial leucocyte counts, a higher incidence of extramedullary infiltration and of CNS involvement. In M4 AML CNS relapse occurred in patients with a high initial leucocyte count whereas in M5 AML CNS involvement tended to occur at presentation in children with low initial counts. Two‐thirds of patients treated achieved remission and most failures were due to inadequate chemotherapy, although haemorrhage, leucostasis or metabolic complications caused early death in patients with M4 and M5 AML. With a minimum follow up of 3 years only 12% of patients are alive; these figures have not improved in consecutive series despite increasing intensity of induction and more recent availability of bone marrow transplantation. No features predictive of long‐term survival were identified, but patients with myeloid differentiation (M1, M2, M3) did better than those with a monocytic or erythroid component (M4, M5, M6).
Cyclin D3 is down-regulated by rapamycin in HER-2-overexpressing breast cancer cells

Rapamycin and its analogues are being tested as new antitumor agents. Rapamycin binds to FKBP-12 and this complex inhibits the activity of FRAP/mammalian target of rapamycin, which leads to dephosphorylation of 4EBP1 and p70 S6 kinase, resulting in blockade of translation initiation. We have found that RAP inhibits the growth of HER-2-overexpressing breast cancer cells. The phosphorylation of mammalian target of rapamycin, p70 S6 kinase, and 4EBP1 is inhibited by rapamycin and cells are arrested in the G1 phase, as determined by growth assays, fluorescence-activated cell sorting analysis, and bromodeoxyuridine incorporation studies. Rapamycin causes down-regulation of cyclin D3 protein, retinoblastoma hypophosphorylation, loss of cyclin-dependent kinase (cdk) 4, cdk6, and cdk2 activity. The half-life of cyclin D3 protein decreases after rapamycin treatment, but not its synthesis, whereas the synthesis or half-life of cyclin D1 protein is not affected by the drug. Additionally, rapamycin caused accumulation of ubiquitinated forms of cyclin D3 protein, proteasome inhibitors blocked the effect of rapamycin on cyclin D3, and rapamycin stimulated the activity of the proteasome, showing that the effect of rapamycin on cyclin D3 is proteasome proteolysis dependent. This effect depends on the activity of HER-2 because Herceptin, a neutralizing antibody against HER-2, is able to block both the induction of proteasome activity and the cyclin D3 down-regulation due to rapamycin. Furthermore, inhibition of HER-2 gene expression by using small interfering RNA blocked the rapamycin effects on cyclin D3. These data indicate that rapamycin causes a G1 arrest in HER-2-overexpressing breast cancer cells that is associated with a differential destabilization and subsequent down-regulation of cyclin D3 protein. [Mol Cancer Ther 2006;5(9):2172–81]
Evolutionary Paths Underlying Flower Color Variation in Antirrhinum

To understand evolutionary paths connecting diverse biological forms, we defined a three-dimensional genotypic space separating two flower color morphs of Antirrhinum. A hybrid zone between morphs showed a steep cline specifically at genes controlling flower color differences, indicating that these loci are under selection. Antirrhinum species with diverse floral phenotypes formed a U-shaped cloud within the genotypic space. We propose that this cloud defines an evolutionary path that allows flower color to evolve while circumventing less-adaptive regions. Hybridization between morphs located in different arms of the U-shaped path yields low-fitness genotypes, accounting for the observed steep clines at hybrid zones.
FtsI and FtsW Are Localized to the Septum inEscherichia coli

ABSTRACT The localization of FtsI (PBP3), a penicillin-binding protein specifically required for cell division in Escherichia coli, was investigated by immunofluorescence microscopy and found to localize to the septum. The localization of FtsI was not observed inftsZ or ftsA mutants, indicating that it was dependent on the prior localization of these proteins. Addition of furazlocillin, a specific inhibitor of FtsI, prevented localization of FtsI even though FtsZ and FtsA localization occurred. Interestingly, the localization of FtsN was also prevented by furazlocillin. FtsZ displayed limited localization in furazlocillin-treated cells, whereas it was efficiently localized in FtsI-depleted cells. FtsW, another essential cell division protein, was also localized to the septum.
Insulin Access and Affordability Working Group: Conclusions and Recommendations

There are more than 30 million Americans with diabetes, a disease that costs the U.S. more than $327 billion per year (1,2). Achieving glycemic control and controlling cardiovascular risk factors have been conclusively shown to reduce diabetes complications, comorbidities, and mortality. To achieve these desired outcomes, the medical community now has available many classes of medications and many formulations of insulin to effectively manage the metabolic abnormalities for people with diabetes. However, the affordability of medications in general, and for insulin specifically, is currently of great concern to people with diabetes, their families, health care providers, insurers, and employers. For millions of people living with diabetes, including all individuals with type 1 diabetes, access to insulin is literally a matter of life and death. The average list price of insulin has skyrocketed in recent years, nearly tripling between 2002 and 2013 (3). The reasons for this increase are not entirely clear but are due in part to the complexity of drug pricing in general and of insulin pricing in particular. As the price of insulin continues to rise, individuals with diabetes are often forced to choose between purchasing their medications or paying for other necessities, exposing them to serious short- and long-term health consequences (4–9). To find solutions to the issue of insulin affordability, there must be a better understanding of the transactions throughout the insulin supply chain, the impact each stakeholder has on what people with diabetes pay for insulin, and the relative efficacy of therapeutic options. Thus, as the nation’s leading voluntary health organization whose mission is “to prevent and cure diabetes and to improve the lives of all people affected by diabetes,” the American Diabetes Association (ADA) is committed to finding ways to provide relief for individuals and families who lack affordable access …
Lysosomal storage disorder gene variants in multiple system atrophy.

1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK 2. National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 3. Oslo University Hospital, Oslo, Norway. 4. French Reference Center for MSA, Department of Neurology, University Hospital Bordeaux, 33000 Bordeaux and Institute of Neurodegenerative Diseases, CNRS UMR 5293, University Bordeaux, 33000 Bordeaux, France. 5. Laboratory of Neurogenetics, NIH/NIA, Bethesda, USA. * h.houlden@ucl.ac. uk
An optimal packet scheduling and load balancing algorithm for LEO/MEO satellite networks

LEO/MEO constellations of communication satellites have recently been proposed as a powerful tool for improving internet performance and for extending it beyond the earth (InterPlanetary Internet). Several aspects of such usage must still be investigated. Among them, proper routing and MAC protocols play a prominent role. In this paper,we assume that the MAC protocol is an MF/TDMA one (as usual in satellite communication), and we consider the problem of assigning packets to a set of shortest paths in a satellite constellation, with the goal of minimizing the overall packet scheduling problem. We present an optimal polynomial time algorithm which works offline and balances the load over all possible shortest paths, allowing a minimum schedule length for the entire constellation to be found in polynomial time.
Effect of magnesium supplementation on blood pressure and vascular reactivity in nitric oxide synthase inhibition-induced hypertension model

Abstract The aim of this study was to assess the effect of oral magnesium supplementation (Mg-supp) on blood pressure (BP) and possible mechanism in nitric oxide synthase (NOS) inhibition-induced hypertension model. Hypertension and/or Mg-supp were created by N-nitro-l-arginine methyl ester (25 mg/kg/day by drinking water) and magnesium-oxide (0.8% by diet) for 6 weeks. Systolic BP was measured weekly by tail-cuff method. The effects of hypertension and/or Mg-supp in thoracic aorta and third branch of mesenteric artery constriction and relaxation responses were evaluated. NOS-inhibition produced a gradually developing hypertension and the magnitude of the BP was significantly attenuated after five weeks of Mg-supp. The increased phenylephrine-induced contractile and decreased acetylcholine (ACh)-induced dilation responses were found in both artery segments of hypertensive groups. Mg-supp was restored ACh-relaxation response in both arterial segments and also Phe-constriction response in thoracic aorta but not in mesenteric arteries. The contributions of NO, prostaglandins and K+ channels to the dilator response of ACh were similar in the aorta of all the groups. The contribution of the NO to the ACh-mediated relaxation response of mesenteric arteries was suppressed in hypertensive rats, whereas this was corrected by Mg-supp. The flow-mediated dilation response of mesenteric arteries in hypertensive rats failed and could not be corrected by Mg-supp. Whereas, vascular eNOS protein and magnesium levels were not changed and plasma nitrite levels were reduced in hypertensive rats. The results of this study showed that Mg-supp lowered the arterial BP in NOS-inhibition induced hypertension model by restoring the agonist-induced relaxation response of the arteries.
Novel directions for psychiatric diagnosis: from psychopathology to motor function to monitoring technology

In the light of the recent publication of the DSM-5, there is renewed debate about the relative merit of categorical diagnosis, as laid down in Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD) diagnostic manuals. Issues such as validity, usefulness and acceptability of the diagnoses in this manual are increasingly debated. Several alternative possibilities have been suggested including: (i) the introduction of truly cross-cutting dimensional measures, that would facilitate dynamic multidimensional formulations of psychopathology, (ii) the Research Domain Criteria, that may facilitate biological research but move away from clinical symptoms, (iii) a system of personalized diagnosis based on psychopathology as a network of symptoms and contexts, and (iv) enhanced focus on motor alterations, other than catatonia, as a possible additional informative dimension of diagnosis in psychiatry, particularly as a possible marker of underlying neurodevelopmental alterations. We suggest that novel systems of diagnosis are likely to rely more on continuous monitoring of diagnostically relevant information in daily life, complementing retrospective symptom criteria in DSM and ICD. Patients and their families are likely to benefit from these projects, as novel models of diagnosis based on daily life information may be linked more strongly to treatment needs and prognosis.
Caprine blastocyst formation following intracytoplasmic sperm injection and defined culture

Summary Experiments were undertaken to develop intracytoplasmic sperm injection (ICSI) to produce caprine embryos out of the normal breeding season. Oocytes were obtained from 2–6 mm ovarian follicles at slaughter. Selected oocytes with two to four layers of cumulus cells were incubated in 1 ml of H-TCM 199 supplemented with 10 μg each of oFSH and bLH (NHPP, NIDDK, NICHD, USDA) and 20% fetal bovine serum (FBS) in a thermos (38.5°C) for 4.5 h during transportation. Then, oocytes were transferred into 75 μl of freshly prepared maturation medium under paraffin oil and a mixture of 5% O2, 5% CO2 and 90% N2. Approximately 26 h after recovery oocytes were denuded by incubation with hyaluronidase (100 IU/ml) and pipetting and held at 38.5°C for 90 min. Spermatozoa frozen in egg yolk extender were thawed in a 37°C water bath for 15s. Motile fractions were selected by swim-up, then incubated for 90 mm in TALP with 10 μg heparin/ml. Each oocyte was positioned with its first polar body at 6 or 12 o'clock by a holding pipette. Sperm (1 μl) were added to 10 μl medium containing 10% polyvinylpyrrolidone. A sperm cell was aspirated into a pipette, and then injected head-first into the cytoplasm of an oocyte maintained in H-TCM 199 + 20% FBS at 37°C. Injected oocytes were transferred to HM and, after 90 min, cultured in 50 μl of BSA-free synthetic oviduct fluid plus polyvinyl alcohol, citrate and non-essential amino acids. Results demonstrate that caprine blastocysts can be produced outside the breeding season by the use of frozen-thawed semen and injection of sperm cells with broken tails into ova followed by culture in defined medium.
Filamin and Phospholipase C-ε are required for calcium signaling in the Caenorhabditis elegans Spermatheca

Mechanical properties of the microenvironment are fundamental in orchestrating normal tissue function, disease progression, and organismal development. Studies of mechanotransduction in cultured cells on artificial substrates have revealed underlying principles, but the in vivo roles of mechanotransduction remain unclear. We recently reported that the Caenorhabditis elegans spermatheca—a myoepithelial tube composed of a cell monolayer—may be mechanosensitive. Live imaging with the genetically encoded calcium indicator GCaMP revealed that oocyte-induced stretching of the spermatheca resulted in calcium oscillations and constriction of the tube. FLN-1/filamin, a mechanosensitive cytoskeletal scaffolding protein, is required to correctly trigger the calcium transients. PLC-1/phospholipase C-epsilon and ITR-1/IP3 receptor are required to produce the calcium transients, and may function downstream of filamin. In addition to providing important insights into the biology of C. elegans, our studies offer a novel and genetically tractable model for studying mechanotransduction in a myoepithelial tissue.
Systematic review of peer education intervention programmes among individuals with type 2 diabetes

AIMS AND OBJECTIVES To systematically review published randomised controlled trials of peer education interventions among adults with type 2 diabetes. BACKGROUND Systematic reviews have shown mixed results for peer support interventions to improve diabetes self-management. Given the effectiveness of diabetes education by healthcare professionals, peer education interventions may be a useful alternative approach. This review addressed that gap. DESIGN Systematic review. METHOD A systematic search of published randomised controlled trials between 2006-2016 was conducted using the keywords diabetes, type 2 diabetes, randomised controlled trials, self-management, peer education and peer support. The methodological quality of each study was assessed using the Jadad scale. RESULTS Seven studies were included in the final review, and the Jadad scores ranged from 8-10 of a possible 13 points. There was no consistent design, setting, or outcome measurement among the studies. There were two types of peer education interventions compared to traditional diabetes education: face-to-face or a combination of face-to-face and telephone/texting. The most common clinical outcome measure was HbA1c. Two of six studies showed statistically significant improvement in HbA1c between intervention and control groups. An increase in diabetes knowledge was also statistically significant in two of five studies. CONCLUSION Peer education could be successful in improving clinical outcomes. No evidence was found indicating that healthcare provider education was superior in regard to clinical knowledge or behavioural or psychological outcome measures than peer education. HbA1c was statistically significantly lower in some peer education groups compared to control groups. RELEVANCE TO CLINICAL PRACTICE There is evidence that peer education can be useful in achieving positive clinical outcomes such as decreasing HbA1c levels and increasing diabetes knowledge. A certified diabetes educator or a trained healthcare professional should not be overlooked though when using peer educators.
Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity

The identification and characterization of the cellular and molecular pathways involved in the differentiation and morphogenesis of specific cell types of the developing heart are crucial to understanding the process of cardiac development and the pathology associated with human congenital heart disease. Here, we show that the cardiac transcription factor CASTOR (CASZ1) directly interacts with congenital heart disease 5 protein (CHD5), which is also known as tryptophan-rich basic protein (WRB), a gene located on chromosome 21 in the proposed region responsible for congenital heart disease in individuals with Down's syndrome. We demonstrate that loss of CHD5 in Xenopus leads to compromised myocardial integrity, improper deposition of basement membrane, and a resultant failure of hearts to undergo cell movements associated with cardiac formation. We further report that CHD5 is essential for CASZ1 function and that the CHD5-CASZ1 interaction is necessary for cardiac morphogenesis. Collectively, these results establish a role for CHD5 and CASZ1 in the early stages of vertebrate cardiac development.
Severe Acute Kidney Injury Following Stage 1 Norwood Palliation: Effect on Outcomes and Risk of Severe Acute Kidney Injury at Subsequent Surgical Stages*

Objectives: To identify associations of severe acute kidney injury early after stage 1 (Norwood) operation with risk of severe acute kidney injury and comorbidities at subsequent palliative stages in patients with hypoplastic left heart syndrome and other single ventricle lesions with left-sided obstruction. Design: Retrospective cohort study. Severe acute kidney injury defined as Kidney Disease Improving Global Outcomes stage 3. Setting: Single pediatric cardiac center. Patients: Infants less than or equal to 28 days old with single ventricle physiology and left-sided obstruction undergoing stage 1 operation between September 2007 and November 2012 (n = 136). Interventions: None. Measurements and Main Results: The occurrence rate of severe acute kidney injury was 21% (28/136) following stage 1, 12% (12/98) following stage 2 palliation (superior cavo-pulmonary anastomosis), and 10% (7/73) following stage 3 palliation (total cavo-pulmonary anastomosis). Severe acute kidney injury early after stage 1 operation was significantly associated with continuous intravenous loop diuretic infusion, need for extracorporeal membrane oxygenation, and in-hospital death (all p < 0.05). Gestational age at birth was associated with severe acute kidney injury at stage 2 (p = 0.04) and stage 3 (p = 0.01). Severe acute kidney injury at stage 1 was an independent risk factor for severe acute kidney injury at stage 2 (adjusted odds ratio, 4.3; 95% CI, 1.1–16.9; p = 0.04). Development of severe acute kidney injury after stage 1 was associated with longer mechanical ventilation time after stage 3 (p = 0.047). Conclusions: Severe acute kidney injury after stage 1 palliation was an independent risk factor for developing severe acute kidney injury at stage 2, and was associated with prolonged duration of mechanical ventilation following stage 3. Information on the incidence and associated risk factors for postoperative acute kidney injury in hypoplastic left heart syndrome patients from multiple congenital heart centers is a necessary next step to further understand the long-term burden of severe acute kidney injury after staged palliation.
A transfectant RK13 cell line permissive to classical caprine scrapie prion propagation

ABSTRACT To assess scrapie infectivity associated with caprine-origin tissues, bioassay can be performed using kids, lambs or transgenic mice expressing caprine or ovine prion (PRNP) alleles, but the incubation periods are fairly long. Although several classical ovine scrapie prion permissive cell lines with the ability to detect brain-derived scrapie prion have been available, no classical caprine scrapie permissive cell line is currently available. Therefore, the aims of this study were to generate a rabbit kidney epithelial cell line (RK13) stably expressing caprine wild-type PRNP (cpRK13) and then to assess permissiveness of cpRK13 cells to classical caprine scrapie prion propagation. The cpRK13 and plasmid control RK13 (pcRK13) cells were incubated with brain-derived classical caprine scrapie inocula prepared from goats or ovinized transgenic mice (Tg338, express ovine VRQ allele) infected with caprine scrapie. Significant PrPSc accumulation, which is indicative of scrapie prion propagation, was detected by TSE ELISA and immunohistochemistry in cpRK13 cells inoculated with classical caprine scrapie inocula. Western blot analysis revealed the typical proteinase K-resistant 3 PrPres isoforms in the caprine scrapie prion inoculated cpRK13 cell lysate. Importantly, PrPSc accumulation was not detected in similarly inoculated pcRK13 cells, whether by TSE ELISA, immunohistochemistry, or western blot. These findings suggest that caprine scrapie prions can be propagated in cpRK13 cells, thus this cell line may be a useful tool for the assessment of classical caprine prions in the brain tissues of goats.