Miracle-dz/UniFAR-FTUs huggingface dataset:
Fungal prion HET-s as a model for structural complexity and self-propagation in prions

Significance Prions are self-propagating infectious proteins that have been implicated in a number of invariably fatal diseases. Increasing evidence suggests that this self-propagating activity is present in most or all amyloid diseases. To understand the pathology of these diseases, it is imperative to understand the mechanisms involved in self-propagation. To this end, we have used the fungal prion-forming domain HET-s(218–289) as a model system for studying sequence determinants required for structural propagation. We have determined the requirements for folding into the biologically active β-solenoid conformation and characterized the roles of different interactions in the assembly and overall stability of HET-s(218–289) prions. Our results provide insights into the fundamental mechanisms of prion assembly and propagation. The highly ordered and reproducible structure of the fungal prion HET-s makes it an excellent model system for studying the inherent properties of prions, self-propagating infectious proteins that have been implicated in a number of fatal diseases. In particular, the HET-s prion-forming domain readily folds into a relatively complex two-rung β-solenoid amyloid. The faithful self-propagation of this fold involves a diverse array of inter- and intramolecular structural features. These features include a long flexible loop connecting the two rungs, buried polar residues, salt bridges, and asparagine ladders. We have used site-directed mutagenesis and X-ray fiber diffraction to probe the relative importance of these features for the formation of β-solenoid structure, as well as the cumulative effects of multiple mutations. Using fibrillization kinetics and chemical stability assays, we have determined the biophysical effects of our mutations on the assembly and stability of the prion-forming domain. We have found that a diversity of structural features provides a level of redundancy that allows robust folding and stability even in the face of significant sequence alterations and suboptimal environmental conditions. Our findings provide fundamental insights into the structural interactions necessary for self-propagation. Propagation of prion structure seems to require an obligatory level of complexity that may not be reproducible in short peptide models.
Typical Versus Atypical Anorexia Nervosa Among Adolescents: Clinical Characteristics and Implications for ICD-11.

There is scant research on the clinical utility of differentiating International Classification of Diseases (ICD) 10 diagnoses F50.0 anorexia nervosa (typical AN) and F50.1 atypical anorexia. We reviewed systematically records of 47 adolescents who fulfilled criteria for ICD-10 F50.0 (n = 34) or F50.1 (n = 13), assessing the impact of diagnostic subtype, comorbidity, background factors and treatment choices on recovery. Atypical AN patients were significantly older (p = 0.03), heavier (minimum body mass index 16.7 vs 15.1 kg/m(2) , p = 0.003) and less prone to comorbidities (38% vs 71%, p = 0.04) and had shorter, less intensive and less costly treatments than typical AN patients. The diagnosis of typical versus atypical AN was the sole significant predictor of treatment success: recovery from atypical AN was 4.3 times (95% confidence interval [1.1, 17.5]) as likely as recovery from typical AN. Overall, our findings indicate that a broader definition of AN may dilute the prognostic value of the diagnosis, and therefore, ICD-11 should retain its distinction between typical and atypical AN.
Pulmonary Hypertension in Lambs Transfused with Stored Blood Is Prevented by Breathing Nitric Oxide

Background: During extended storage, erythrocytes undergo functional changes. These changes reduce the viability of erythrocytes leading to release of oxyhemoglobin, a potent scavenger of nitric oxide. We hypothesized that transfusion of ovine packed erythrocytes (PRBC) stored for prolonged periods would induce pulmonary vasoconstriction in lambs, and that reduced vascular nitric oxide concentrations would increase this vasoconstrictor effect. Methods: We developed a model of autologous stored blood transfusion in lambs (n = 36). Leukoreduced blood was stored for either 2 days (fresh PRBC) or 40 days (stored PRBC). Fresh or stored PRBC were transfused into donors instrumented for awake hemodynamic measurements. Hemodynamic effects of PRBC transfusion were also studied after infusion of NG-nitro-L-arginine methyl-ester (25 mg/kg) or during inhalation of nitric oxide (80 ppm). Results: Cell-free hemoglobin levels were higher in the supernatant of stored PRBC than in supernatant of fresh PRBC (Mean ± SD, 148 ± 20 vs. 41 ± 13 mg/dl, respectively, P < 0.001). Pulmonary artery pressure during transfusion of stored PRBC transiently increased from 13 ± 1 to 18 ± 1 mmHg (P < 0.001) and was associated with increased plasma hemoglobin concentrations. NG-nitro-L-arginine methyl-ester potentiated the increase in pulmonary arterial pressure induced by transfusing stored PRBC, whereas inhalation of nitric oxide prevented the vasoconstrictor response. Conclusions: Our results suggest that patients with reduced vascular nitric oxide levels because of endothelial dysfunction may be more susceptible to adverse effects of transfusing blood stored for prolonged periods. These patients might benefit from transfusion of fresh PRBC, when available, or inhaled nitric oxide supplementation to prevent the pulmonary hypertension associated with transfusion of stored PRBC.
Juvenile hormone regulation of longevity in the migratory monarch butterfly

Monarch butterflies (Danaus plexippus) of eastern North America are well known for their long–range migration to overwintering roosts in south–central Mexico. An essential feature of this migration involves the exceptional longevity of the migrant adults; individuals persist from August/September to March while their summer counterparts are likely to live less than two months as adults. Migrant adults persist during a state of reproductive diapause in which both male and female reproductive development is arrested as a consequence of suppressed synthesis of juvenile hormone. Here, we describe survival in monarch butterflies as a function of the migrant syndrome. We show that migrant adults are longer lived than summer adults when each are maintained under standard laboratory conditions, that the longevity of migrant adults is curtailed by treatment with juvenile hormone and that the longevity of summer adults is increased by 100% when juvenile hormone synthesis is prevented by surgical removal of its source, the corpora allatum. Thus, monarch butterfly persistence through a long winter season is ensured in part by reduced ageing that is under endocrine regulation, as well as by the unique environmental properties of their winter roost sites. Phenotypic plasticity for ageing is an integral component of the monarch butterflies' migration–diapause syndrome.
A Novel Group of Moraxella catarrhalis UspA Proteins Mediates Cellular Adhesion via CEACAMs and Vitronectin

Moraxella catarrhalis (Mx) is a common cause of otitis media and exacerbation of chronic obstructive pulmonary disease, an increasing worldwide problem. Surface proteins UspA1 and UspA2 of Mx bind to a number of human receptors and may function in pathogenesis. Genetic recombination events in the pathogen can generate hybrid proteins termed UspA2H. However, whether certain key functions (e.g. UspA1-specific CEACAM binding) can be exchanged between these adhesin families remains unknown. In this study, we have shown that Mx can incorporate the UspA1 CEACAM1-binding region not only into rare UspA1 proteins devoid of CEACAM-binding ability, but also into UspA2 which normally lack this capacity. Further, a screen of Mx isolates revealed the presence of novel UspA2 Variant proteins (UspA2V) in ∼14% of the CEACAM-binding population. We demonstrate that the expression of UspA2/2V with the CEACAM-binding domain enable Mx to bind both to cell surface CEACAMs and to integrins, the latter via vitronectin. Such properties of UspA2/2V have not been reported to date. The studies demonstrate that the UspA family is much more heterogeneous than previously believed and illustrate the in vivo potential for exchange of functional regions between UspA proteins which could convey novel adhesive functions whilst enhancing immune evasion.
CD10, Actin, and Vimentin Expression in Breast Phyllodes Tumors Correlates with Tumor Grades of the WHO Grading System

The discrimination of borderline from malignant primary breast phyllodes (PT) tumor is still unclear. We studied 22 PT cases to investigate the immunohistochemical expression (staining of stromal CD10, SMA [smooth muscle actin], and vimentin) as well as the features of focal glandular atypia to determine whether these correlated with the histopathologic grading system. In our results, the stromal staining of CD10 was positive in 4 of 6 malignant and 2 of 5 borderline PT cases, but negative in all benign PT cases. Stromal actin and intraglandular vimentin-expressive tumor cells were found in 5 of 6 malignant PT cases but not in borderline and benign PT cases. There is a significant difference in the panel of stromal CD10, actin, and vimentin expression between borderline and malignant PT (p<0.05). Besides, the progression of malignant potential breast phyllodes tumor may cause glandular epithelium atypia with loss of polarity.
Naturally Occurring Deletional Mutation in the C-Terminal Cytoplasmic Tail of CCR5 Affects Surface Trafficking of CCR5

ABSTRACT CCR5 is an essential coreceptor for the cellular entry of R5 strains of human immunodeficiency virus type 1 (HIV-1). CCR5-893(−) is a single-nucleotide deletion mutation which is observed exclusively in Asians (M. A. Ansari-Lari, et al., Nat. Genet. 16:221–222, 1997). This mutant gene produces a CCR5 which lacks the entire C-terminal cytoplasmic tail. To assess the effect of CCR5-893(−) on HIV-1 infection, we generated a recombinant Sendai virus expressing the mutant CCR5 and compared its HIV-1 coreceptor activity with that of wild-type CCR5. Although the mutant CCR5 has intact extracellular domains, its coreceptor activity was much less than that of wild-type CCR5. Flow cytometric analyses and confocal microscopic observation of cells expressing the mutant CCR5 revealed that surface CCR5 levels were greatly reduced in these cells, while cytoplasmic CCR5 levels of the mutant CCR5 were comparable to that of the wild type. Peripheral blood CD4+ T cells obtained from individuals heterozygous for this allele expressed very low levels of CCR5. These data suggest that the CCR5-893(−) mutation affects intracellular transport of CCR5 and raise the possibility that this mutation also affects HIV-1 transmission and disease progression.
Factors affecting patients' rights practice: the lived experiences of Iranian nurses and physicians.

BACKGROUND The Iranian Ministry of Health and Medical Education published a 'Patient's Bill of Rights' in 2001. AIM To gain insight into the perception and practice of patients' rights in Iran. This paper reports on Iranian nurses' and physicians' perceptions and lived experiences of respecting patients' rights. METHODS A purposeful sample of eight nurses and five physicians working in a central teaching hospital in Tehran were interviewed during 2005-2006 for a qualitative study. Data were analysed using thematic analysis. FINDINGS The emerging themes were categorized as 'barriers to patients' rights practice' and 'facilitators of patients' rights practice'. Under these themes three subgroups were discussed: awareness, resources and accountability. CONCLUSION Healthcare professionals' lived experiences are an important source of data if managers and policy makers are to make changes and legislate for protecting and promoting patients' rights.
[Effect of hormone therapy with estrogens on oxidative stress and quality of life in postmenopausal women].

BACKGROUND Estrogen therapy has an antioxidant effect and improves quality of life. There is no report on estrogen therapy and quality of life in relation to oxidative stress. OBJECTIVE To determine the effect of estrogen hormonal therapy on quality of life and oxidative stress in postmenopausal women. PATIENTS AND METHODS We carried out a controlled clinical trial including 111 perimenopausal women (40 to 60 years old) living in Mexico City. Women were assigned into three groups: (1) control group, 39 premenopausal women; (2) 33 postmenopausal women receiving oral conjugated estrogens and medroxyprogesterone (0.625 mg/d plus medroxyprogesterone 5 mg/d for 10 days); (3) 33 postmenopausal women taking placebo pills. We measured at baseline and at six months biochemical markers of oxidative stress: lipoperoxides by TBARS assay, erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx) and total antioxidant status (TAS) with Randox Laboratories, Ltd. kits. We also applied the World Health Organization Quality of Life, Brief (WHOQoL-Brief). RESULTS Levels of lipoperoxides were higher in postmenopausal women with low quality of life vs. premenopausal women with high quality of life (0.357 +/- 0.06 vs0.315 +/- 0.04 micromol/L, p <0.05). Plasma lipoperoxides diminished in women taking hormonal therapy with low quality of life after six months of treatment (0.357 +/- 0.06 vs. 0.293 +/- 0.08 micromol/L, p < 0.01); also, the proportion of women in therapy with basal high lipoperoxides and quality of life average-low diminished (p < 0.05). There were no differences in the other groups. CONCLUSION Estrogen therapy improves quality of life and reduces lipoperoxides as oxidative stress biomarker in postmenopausal women.
Five phase multi-layer drive with fault tolerant neuro-fuzzy features for safety critical applications

This article presents a method for control of a multiphase motor drive based on the use of a cognitive network that is capable of modelling nonlinearities of the system in fault conditions. To obtain a faithful model of the drive, a neural network (trained with the results of simulated faults) is used in the control algorithm in order to predict the system performance and adapt the control. A new multiphase motor with variable characteristics, particularly suited to applications in which a very wide variability of the speed range is required, will be described and presented in its structure. The technique to remedy failure adopted for this drive will be presented and described in its characteristics. The effectiveness of the control technique lastly will be highlighted by simulations that put it in comparison with classical solutions that employ PID controllers.
Phase I trial of intraperitoneal taxol: a Gynecoloic Oncology Group study.

PURPOSE To evaluate the safety and pharmacology of the intraperitoneal (IP) administration of the antineoplastic agent taxol. PATIENTS AND METHODS Twenty-five pretreated patients who were entered onto a phase I clinical trial; 24 had advanced ovarian cancer. Patients were treated with taxol administered IP in 2 L of normal saline every 3 to 4 weeks. The starting dose was 25 mg/m2. There were no intrapatient dose escalations. RESULTS The dose-limiting toxicity was the development of severe abdominal pain at taxol doses more than 175 mg/m2. Moderate leukopenia (WBC count less than 2,000/mm3) was observed at IP doses of greater than or equal to 175 mg/m2. The exposure of the peritoneal cavity (peak levels and area under the time-versus-concentration curve [AUC]) to taxol after IP delivery exceeded that of the plasma by approximately 1,000-fold. However, concentrations of the agent previously shown to produce cytotoxicity in experimental systems were demonstrated in the systemic compartment after regional delivery, which was considered important. Significant concentrations of taxol persisted within the peritoneal cavity for more than 24 to 48 hours after a single IP installation. Several antitumor responses, which included control of platinum-refractory ascites, were documented. CONCLUSION Taxol can be delivered by the IP route with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure.
Adjuvant Treatment With a Mammalian Target of Rapamycin Inhibitor, Sirolimus, and Steroids Improves Outcomes in Patients With Severe H1N1 Pneumonia and Acute Respiratory Failure*

Objectives:Severe H1N1 pneumonia with acute respiratory failure results in infiltration of lungs due to the presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells. Design:Open-label prospective randomized controlled trial. Setting:A tertiary medical center, Chang Gung Memorial Hospital, located in Taiwan. Patients:Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure were enrolled. Measurements and Main Results:Thirty-eight patients with confirmed H1N1 pneumonia and on mechanical ventilatory support were randomized to receive adjuvant treatment of corticosteroids with an mTOR inhibitor, either with sirolimus (Rapamune 2 mg/d) (sirolimus group, n = 19) for 14 days or without sirolimus (nonsirolimus group, n = 19). The clinical values measured included PaO2/FIO2, Sequential Organ Failure Assessment score, duration of ventilatory support, and mortality. The baseline demography was similar between the two groups. After treatment, the PaO2/FIO2 values on day 3 (167.5 [95% CI, 86.7–209.2 mm Hg], n = 19 vs 106.8 [95% CI, 73.0–140.7 mm Hg], n = 19; p = 0.025] and day 7 (241.6 [95% CI, 185.2–297.9 mm Hg], n = 19 vs 147.0 [95% CI, 100.7–193.7 mm Hg], n = 17; p = 0.008) in the sirolimus group were significantly better over the nonsirolimus group. Similarly, the Sequential Organ Failure Assessment score on day 3 (4.3 [95% CI, 3.1–5.5]; p = 0.029) and day 7 (5.9 [95% CI, 4.8–6.9], n = 19 and 6.2 [95% CI, 4.7–7.8], n = 17, respectively) significantly improved in the sirolimus group. The liberation from a mechanical ventilator at 3 months was also better in the sirolimus combined with corticosteroids treatment. Similarly, the duration of ventilator use was significantly shorter in the sirolimus group (median, 7 vs 15 d; p = 0.03 by log-rank test). In the sirolimus combined with corticosteroids treatment group, a rapid clearance of virus also occurred after 7 days of treatment. Conclusions:In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroids and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days.
Mimicking the haematopoietic niche microenvironment provides a novel strategy for expansion of haematopoietic and megakaryocyte‐progenitor cells from cord blood

Severe neutropenia and protracted thrombocytopenia remain serious clinical problems following cord blood transplantation (CBT) due to the paucity of stem and progenitor cells in the grafts. Administration of ex‐vivo expanded megakaryocyte progenitor cells may facilitate platelet production. We propose a novel strategy to expand these rare cells ex‐vivo, from a small portion of the cord blood (CB) unit, using fibronectin (FN), a major component of hematopoietic niches, combined with cytokines, including thrombopoietin and the hematopoietic stress‐associated acetylcholinesterase readthrough peptide (ARP). Application of multiple gates and high definition flow cytometry enabled clear resolution of expanded hematopoietic stem/precursor cells (HSPC) and megakaryocyte progenitors (Mk‐p) and their early subsets while eliminating positively stained non‐relevant cells. FN increased viability, expansion of all CD34+ HSPC populations and Mk‐p. The combination of FN + thrombopoietin + ARP maintained and expanded very early myeloid and thrombopoietic precursors, increased the proliferation of megakaryocyte, granulocyte‐macrophage and multilineage colony‐forming progenitors and supported Mk maturation as measured by ploidy and glycoprotein IIb/IIIa expression by quantiative reverse transcription polymerase chain reaction. This approach, which involves expanding HSPC and Mk precursors from a small portion of the CB unit, without sacrificing the coveted stem cells, may lead to improved cell therapy modalities to facilitate earlier myelopoiesis and platelet production post‐CBT.
Cellular and Network MIMO architectures: MU-MIMO spectral efficiency and costs of channel state information

Cooperative Multi-User MIMO signaling across cells, also known as Network MIMO, has recently received a great deal of attention as a potential physical layer technique for future high-throughput wireless systems. Indeed, cooperative signaling is able to reduce inter-cell interference within groups of coordinated cells thereby improving system throughput. Such benefits, however, are often assessed ignoring inherent overheads such as those required to obtain channel state information (CSI) to enable downlink signaling by MU-MIMO. In fact CSI estimation does take physical layer resources from data and thus should be accounted for in assessing the net benefits of any cooperative signalling strategy. The paper characterizes some elements of this overhead and its effect on CSI estimation error and MU-MIMO efficiency. The results show that, when CSI overheads are taken into account, conventional cellular architectures, with no coordination across cells, can be quite attractive relative to Network MIMO.
Validity of a 12-item version of the CES-D used in the National Longitudinal Study of Children and Youth.

This validation study assessed the degree of confidence that can be placed on inferences from depressive symptoms among adolescents, based on a 12-item version of the Centre for Epidemiological Studies Depression scale (CES-D). This short version of the scale had been developed for application in the National Longitudinal Study of Children and Youth and we refer to it as the CES-D-12-NLSCY. The major data source for the present validation study was a 2002/2003 survey of 12,990 students in junior and senior high school in the Atlantic provinces of Canada. Receiver operating characteristic curve analyses for two different proxy gold standards yielded adequate areas under the curve (AUCs) of . 84 and . 80, allowing us to establish cut points for three categories of depressive symptoms in the general adolescent population: Minimal (CES-D-12-NLSCY total score 0 to 11), Somewhat Elevated (total score 12 to 20) and Very Elevated (total score 21 to 36). The CES-D-12-NLSCY was found to have acceptable internal consistency (Cronbach=s alpha .85). All but one of the 12 items of the CES-D-12-NLSCY were found to have acceptable discrimination ability. The prevalence of Minimal, Somewhat and Very Elevated depressive symptoms in the adolescent student population of the Atlantic provinces was estimated to be 72.3, 19.5 and 5.5 percent, respectively. A further 2.6 percent of students who responded to fewer than 11 items of the scale were classified as Indeterminate with regards to depressive symptom category. The major threat to the accuracy of the CES-D-12-NLSCY is its lack of inquiry about irritability, which is a key symptom of depression in youth.